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Background
Melanoma can be a simple cancer for the pathologist to diagnose under the microscope or it can be one of the most difficult. It is often a mimic of other cancers and the pathologist may rely upon specialized studies such as special stains or immunoperoxidase studies to confirm the diagnosis.
OUTLINE
HISTOLOGICAL TYPES CHARACTERIZATION BIOPSY SAMPLING
- Impact of thorough block sampling in the histologic evaluation of melanomas.
Dyson SW, Bass J, Pomeranz J, Jaworsky C, Sigel J, Somach S.
Department of Dermatology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
Arch Dermatol. 2005 Jun;141(6):734-6. Abstract quote
OBJECTIVE: To determine if changes in histologic parameters obtained from intermittent sampling of the entire block correlated with differences in prognosis and management.
DESIGN: Prospective analysis of skin biopsy specimens.
SETTING: Skin pathology laboratory.Patients One hundred consecutive patients with an unequivocal diagnosis of melanoma.Interventions Two initial slides were prepared from serial sections of 5-mum thickness. When evaluation of the initial slide revealed melanoma, 5 additional slides were obtained by sectioning at levels through the entire block. Breslow depth, Clark level, ulceration, tumor infiltrating lymphocytes, vascular invasion, regression, presence of a precursor lesion, and histologic type of melanoma for the first slide and the additional 6 slides were analyzed and compared.
RESULTS: Review of the additional 6 slides from level sectioning revealed a greater maximum tumor thickness than was evident from the original slide in 43% of the cases. In 10 of these cases, the new maximum tumor thickness measurements changed the surgical management of the patients. Ulceration was observed in 6% of cases on the initial slides, and an additional 3% of lesions were found to have ulceration on levels. The level of invasion was deeper than originally found in 10% of the cases.
CONCLUSIONS: Level sectioning through an entire block of a melanoma specimen provides additional information in the classification and management of melanomas. Extensive block sampling will result in more accurate information regarding histologic parameters of melanoma, but the yield must be balanced with the extra cost of materials, time, labor, and the potential disadvantage of not retaining tissue for future use.
- Microstaging accuracy after subtotal incisional biopsy of cutaneous melanoma.
Karimipour DJ, Schwartz JL, Wang TS, Bichakjian CK, Orringer JS, King AL, Huang CC, Johnson TM.
Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
J Am Acad Dermatol. 2005 May;52(5):798-802. Abstract quote
BACKGROUND: A significant portion of cutaneous melanoma may remain after subtotal incisional biopsy. The accuracy of microstaging and impact on clinical practice in this scenario are unknown.
OBJECTIVE: Our purpose was to examine microstaging accuracy of an initial incisional biopsy with a significant portion of the clinical lesion remaining (> or =50%).
METHODS: Patients with cutaneous melanoma, diagnosed by incisional biopsy with > or =50% of the lesion remaining, were prospectively evaluated for microstaging accuracy, comparing initial Breslow depth (BD1) to final depth (BD2) after excision of the residual lesion. Impact on prognosis and treatment was also evaluated.
RESULTS: Two hundred fifty of 1783 patients (14%) presented with > or =50% residual clinical lesion after incisional biopsy. The mean BD1 was 0.66 mm; the mean BD2, 1.07 mm (P = .001). After complete excision of the residual lesion, upstaging occurred in 21% and 10% became candidates for sentinel node biopsy.
CONCLUSION: An incisional biopsy with > or =50% clinical lesion remaining afterward may be inadequate for accurate microstaging of melanoma. This scenario is relatively uncommon but clinically significant.FROZEN SECTIONS Are En Face Frozen Sections Accurate for Diagnosing Margin Status in Melanocytic Lesions?
Victor G. Prieto, MD, PhD,
Zsolt B. Argenyi, MD, Raymond L. Barnhill, MD, etal.Am J Clin Pathol 2003;120:203-208 Abstract quote To assess the diagnostic accuracy of margin evaluation of melanocytic lesions using en face frozen sections compared with standard paraffin-embedded sections, we studied 2 sets of lesions in which en face frozen sections were used for analysis of surgical margins (13 from malignant melanomas [MMs] and 10 from nonmelanocytic lesions [NMLs]). Routine permanent sections were cut after routine processing. The slides were mixed and coded randomly.
Fifteen dermatopathologists examined the cases separately. Margin status was categorized as positive, negative, or indeterminate. Kappa statistics were calculated per dermatopathologist and per case.
One case from each group was excluded because epidermis was not available in the routine sections. Of 330 evaluations (22 cases, 15 dermatopathologists), there were 132 diagnostic discrepancies (40.0%): 66 each for MM and NML (mean per case for both diagnoses, 6). In 9 instances (6.8%), the change was from positive (frozen) to negative (permanent) and in 43 (32.6%), from negative (frozen) to positive (permanent). There was poor agreement between frozen and permanent sections (k range per dermatopathologist, –0.1282 to 0.6615).
If permanent histology is considered the "gold standard" for histologic evaluation, en face frozen sections are not suitable for accurate surgical margin assessment of melanocytic lesions.SECOND OPINION
Pitfalls in the diagnosis of malignant melanoma: findings of a risk management panel study.
Troxel DB.
Department of Pathology, Mt. Diablo Medical Center, Concord, CA, USA.
Am J Surg Pathol. 2003 Sep;27(9):1278-83. Abstract quote
The misdiagnosis of melanoma is a major cause of malpractice claims involving pathologists and dermatologists.
A detailed analysis of individual surgical pathology and cytology claims (excluding Pap smears) reported to The Doctors Company from 1995 through 2001 revealed that 46 of 362 claims (13%) involved the misdiagnosis of melanoma; 70% of these claims were for false-negative diagnoses. Melanoma claims were second only to claims involving breast biopsy. A Melanoma Risk Management Panel of expert dermatopathologists was convened to discuss recurrent "problem areas" identified by the author in claims reviewed from 1998 through 2001.
The purpose was to devise useful strategies that pathologists and dermatologists could use in their practices to reduce the risk of diagnostic error and/or patient mismanagement when dealing with melanocytic lesions. The panel's findings and recommendations are the subject of this review.
Interobserver reproducibility of histopathologic prognostic variables in primary cutaneous melanomas.
Scolyer RA, Shaw HM, Thompson JF, Li LX, Colman MH, Lo SK, McCarthy SW, Palmer AA, Nicoll KD, Dutta B, Slobedman E, Watson GF, Stretch JR.
Department of Anatomical Pathology, and Sydney Melanoma Unit, and the Melanoma and Skin Cancer Research Institute, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
Am J Surg Pathol. 2003 Dec;27(12):1571-6. Abstract quote
BACKGROUND: The prognosis for patients with localized primary cutaneous melanoma is known to depend principally on tumor thickness, and to a lesser extent on ulcerative state and Clark level. We have recently found in an analysis of 3661 patients that tumor mitotic rate (TMR) is also an important prognostic parameter, ranking second only to tumor thickness. However, few studies have assessed the accuracy and reproducibility with which these features of a melanoma are recorded by histopathologists. AIM: To assess interobserver reproducibility of major pathologic prognostic parameters in cutaneous melanoma.
METHODS: Single hematoxylin and eosin-stained slides of 69 dermally invasive primary cutaneous melanomas were circulated among six pathologists with differing experience in the assessment of melanocytic tumors. The observers independently determined the tumor thickness, Clark level of invasion, ulcerative state, and TMR for each lesion. Intraclass correlation coefficients and kappa scores for multiple ratings per subject were calculated.
RESULTS: The intraclass correlation coefficients were 0.96 for tumor thickness and 0.76 for TMR. The kappa scores were 0.83 for ulcerative state and 0.60 for Clark level. These results indicated excellent agreement among the pathologists for measurements of tumor thickness, ulcerative state, and TMR and fair to good agreement for Clark level.
CONCLUSIONS: Appropriately trained and experienced histopathologists can assess prognostically important features of melanomas accurately and reproducibly. Given our recent finding of the significance of TMR in determining prognosis, it is important that this feature be assessed by a standardized method and documented for all primary cutaneous melanomas.Quality assessment by expert opinion in melanoma pathology: experience of the pathology panel of the Dutch Melanoma Working Party.
Veenhuizen KC, De Wit PE, Mooi WJ, Scheffer E, Verbeek AL, Ruiter DJ.
Institute of Pathology, University Hospital Nijmegen St. Radboud, The Netherlands.
J Pathol 1997 Jul;182(3):266-72 Abstract quote
Some cutaneous melanocytic lesions are notoriously difficult to diagnose by histopathology. For that reason, the Pathology Panel of the Dutch Melanoma Working Party was instituted and is regularly approached to provide an expert opinion on problem cases.
In order to identify the most common diagnostic problems, 1069 consecutive referral cases of submitted lesions (1992 to 1994 inclusive) were analysed. About 60 per cent of the requests came from small laboratories, with up to three consultant pathologists. Two-thirds of the lesions reviewed concerned women and nearly 50 per cent of the patients were 30 years of age or younger. In 8 per cent of the cases, the referring pathologists felt unable to make a confident diagnosis; in 14 per cent, melanoma was suspected; and in 12 per cent, a differential diagnosis only had been formulated. The panel felt able to provide an unequivocal diagnosis in 93 per cent of the requests. Of the 158 lesions classified as 'invasive melanoma' by the referring pathologists, 22 were considered to be benign by the panel. Conversely, 108 invasive melanomas (panel diagnosis) had originally been considered as benign lesions, dysplastic naevi or melanoma in situ. These high numbers of discordancies reflect the intrinsic difficulty of the differential diagnoses in this selected material submitted to the panel.
Diagnostic difficulties were most often encountered with Spitz naevi and dysplastic naevi. Although the rate of overdiagnosis and underdiagnosis is quite high, in the majority of cases the diagnosis of the referring pathologist matched the diagnosis of the panel. This may reflect a proper awareness of difficult melanocytic lesions in pathology practice. The activities of the Pathology Panel of the Dutch Melanoma Working Party contribute to the improvement of the quality of diagnosis in cutaneous melanocytic lesions, as they increase the number of unequivocal diagnoses and reduce the number of incorrect diagnoses. On the basis of the systematic comparison of the diagnosis by the referring pathologist and the panel, postgraduate teaching and quality control can be more focused on specific diagnostic problems.
Pathology Review of Cases Presenting to a Multidisciplinary Pigmented Lesion Clinic.McGinnis KS, Lessin SR, Elder DE, Guerry D IV, Schuchter L, Ming M, Elenitsas R.
Department of Dermatology, 2 Maloney Bldg, 3600 Spruce St, Philadelphia, PA 19104.
Arch Dermatol 2002 May;138(5):617-621 Abstract quote OBJECTIVES: To determine if pathology review, within the context of a multidisciplinary pigmented lesion clinic, results in changes in diagnosis of melanocytic lesions and to ascertain if the change in diagnosis altered clinical management and outcome.
METHODS: Retrospective review of pathology reports, progress notes, and diagnoses entered in the University of Pennsylvania (Philadelphia) Pigmented Lesion Clinic database.
RESULTS: A total of 5136 primary melanocytic lesions from patients referred to the pigmented lesion clinic between 1991 and 1999 were reviewed by a single pathologist. Of these, 559 (11%) had diagnoses that were changed significantly from the submitting diagnosis, with 120 (2.3%) undergoing a "critical" revision, 63 (1.2%) defined as a change from malignant to benign, and 57 (1.1%) from benign to malignant; 171 (3.3%) remained within the same category (benign or malignant) but had a downgrade in diagnosis (less severe) that would have a significant impact on treatment, prognosis, and research. Likewise, 268 (5.2%) remained within the same category but had an upgrade in diagnosis (more severe) that would have a significant impact on the same parameters. In addition, 257 reexcisions of melanocytic lesions were reviewed, of which 15 (5.8%) were changed from clear to involved margins, while another 16 (6.2%) were changed from involved to clear margins, for a total of 12%. Of the lesions with a critical revision, follow-up was obtained in 98 (83%). The patients in the malignant-to-benign category were followed up for an average of 2.6 years while those in the benign-to-malignant category were followed up for an average of 4.2 years. The change of diagnosis from malignant to benign resulted in 9 patients (17%) being spared a reexcision while 12 patients (23%) were downgraded from a radical to moderate reexcision. The change in diagnosis from benign to malignant resulted in 45 patients (98%) requiring a reexcision after review. Twenty-five of these patients were found to have residual disease in their reexcision specimens or had already had recurrence at the excision site. Furthermore, 7 patients (15%) underwent lymph node dissection or sentinel lymph node biopsy after review. However, none of the nodes were positive for metastatic disease. During this time, 8 patients (17%) in the benign-to-malignant category, and 1 patient (1.9%) in the malignant-to-benign category (who had previously had 4 primary melanomas) developed metastatic disease.
CONCLUSIONS: Pathology review of primary melanocytic lesions, within the context of a multidisciplinary pigmented lesion clinic, results in changes in diagnosis in a significant proportion of cases. These changes have important implications for clinical decision making, patient outcome, and research data collection.
VERTICAL GROWTH PHASE
Relevance of Vertical Growth Pattern in Thin Level II Cutaneous Superficial Spreading Melanomas.Lefevre M, Vergier B, Balme B, Thiebault R, Delaunay M, Thomas L, Beylot-Barry M, Machet L, De Muret A, Bioulac-Sage P, Bailly C.
Am J Surg Pathol. 2003 Jun;27(6):717-24. Abstract quote Thin (</=0.76 mm) level II cutaneous superficial spreading melanomas (SSMs) are known to be of excellent prognosis and very few recur, metastasize, or are lethal. Although many prognostic features at this stage have been studied, none appears to be statistically significant.
The concept of tumor growth phase is correlated with Clark's level except for level II. SSM level II show either an invasive vertical growth phase or an invasive radial growth phase. The aim of our study (retrospective, multicenter, and case-control type) was to investigate the prognostic impact of vertical growth phase in thin level II cutaneous SSM. We identified 12 patients of poor outcome with complete initial excision. Each case was matched with three controls for gender, age, location, tumor thickness, and follow-up period since diagnosis. Independent pathologists studied all cases and controls. Univariate analyses were performed with a conditional logistic regression method. A kappa test was used to assess reproducibility between pathologists. Our study is the first and largest that shows that vertical growth phase is the only statistically significant prognostic factor for thin level II cutaneous SSM.
We propose that growth phase evaluation (a minimum of eight serial sections being mandatory not to underdiagnose vertical growth phase) should be added to the recommendations for melanoma histologic report, at least for level II SSM.
Problems in the interpretation of apparent 'radial growth phase' malignant melanomas that metastasize.Abramova L, L Slingluff C, Patterson JW.
Departments of Pathology and Dermatology, University of Virginia Health Sciences Center, Charlottesville, Virginia, USA Division of Surgical Oncology, University of Virginia Health Sciences Center, Charlottesville, Virginia, USA.
J Cutan Pathol 2002 Aug;29(7):407-14 Abstract quote BACKGROUND: The delineation of radial and vertical growth phases in primary cutaneous malignant melanomas has contributed to our understanding of melanoma progression and has enhanced the ability of pathologists to provide clinicians with meaningful prognostic information. Vertical growth phase (VGP) lesions have the potential to metastasize, but radial growth phase (RGP) melanomas are believed to lack competence for metastasis.
METHODS: We have identified three cases in which metastasis occurred in association with lesions initially interpreted as RGP melanomas. To determine whether these cases truly represented exceptional metastasizing RGP melanomas or VGP lesions incorrectly identified as RGP lesions, careful microscopic re-review of these cases was performed.
RESULTS: In one case, additional microscopic sectioning revealed a focus of vertical growth that was not evident on the original sections. In the other two cases, only radial growth was found. In one of these cases there was melanoma in situ with regressive changes, but no evidence for invasive melanoma. In the other, a RGP lesion was associated with an adjacent compound nevus with periadnexal involvement.
CONCLUSIONS: These cases suggest that, while true RGP melanomas have an excellent prognosis, caution must be exercised in defining a lesion as having no metastatic potential when multiple sections of the primary lesion are unavailable, when the lesion is accompanied by regressive changes, or when there is an associated melanocytic nevus. It is possible that strictly defined RGP melanomas may metastasize in very rare cases. Our observations also suggest that metastatic potential is a function of numerous factors, and may not be evaluable on morphological grounds alone.
CYTOLOGY
Cytopathology of malignant melanoma in conventional and liquid-based smears.Morrison C, Young DC, Wakely PE Jr.
Department of Pathology, Ohio State University College of Medicine, Columbus 43210, USA.
Am J Clin Pathol 2002 Sep;118(3):435-41 Abstract quote We evaluated 62fine-needle aspiration (FNA) biopsy specimens of metastatic malignant melanoma (MM) from 62 patients and compared 84 smears with the corresponding tissue sections.
Melanin is found more often in FNA smears than in corresponding tissue sections of metastatic MM but is significantly less abundant in smears. Melanin is present more often in liquid-based than in conventional smears. Pseudoinclusions were almost twice as frequent in tissue sections as in corresponding aspirates, regardless of the preparation method.
There was no statistical difference for cell type or cytoplasmic features in the tissue sections and aspirates or between the type of preparation and/or stain used. With the exception of melanin, direct comparison of liquid-based and conventional smears showed higher cellularity in the former as the only difference.
MAIN HISTOLOGIC VARIANTS MELANOMA IN SITU
LENTIGO MALIGNA INVASIVE MELANOMAS
5-15%
Usually occurs on sun-exposed surfaces of elderly people, usually the face and upper extremities
Lentigo maligna (melanoma in situ) is the precursor lesion and presents as an irregular darkly pigmented macule
About 5% of lentigo malignas become invasive lentigo maligna melanomasEpidermal atrophy occurring on sun-damaged skin
Pleomorphic melanocytes are usually confined to the basal epidermal layer with little tendency for upward intraepithelial pagetoid spread
Usually considerable downward extension along adnexal epithelium.
50-75%
Occur anywhere on the body but particularly on the trunk in males and lower extremities in females
Proliferation of melanocytes through all layers of the epidermis (pagetoid spread)
If the melanoma is invasive into the underlying dermis, it may be present as solid masses
NODULAR MELANOMA
15-35%
Nodules or polypoid in appearance and are characterized by having no antecedent radial growth phase.
Expansile nodule of malignant melanocytes fills the dermis
By definition, a nodular melanoma is a level III melanoma and acks an adjacent intraepidermal component or radial growth phase
Usually epidermal involvement as the underlying melanoma may secondarily invade the epidermis
- Early detection of thick melanomas in the United States: beware of the nodular subtype.
Demierre MF, Chung C, Miller DR, Geller AC.
Department of Dermatology, Boston University School of Medicine, Boston, MA 02118, USA.
Arch Dermatol. 2005 Jun;141(6):745-50. Abstract quote
BACKGROUND: Incidence and mortality of melanoma in the United States have risen steeply. Part of this mortality increase may be related to late detection of biologically aggressive nodular melanomas. We determined trends in distribution of thin and thick melanoma, with emphasis on the histopathologic subtype nodular melanoma.
METHODS: Surveillance, Epidemiology, and End Results melanoma incidence data for whites were obtained for 1988 through 1999 and stratified according to histologic subtype: lentigo maligna melanoma, superficial spreading melanoma, nodular melanoma, other, and not otherwise specified (NOS); thickness: 0-0.99 mm, 1.00 mm-1.99 mm, and > or =2.0 mm; patient age (0-49, 50+); gender; and year (1988-1991, 1992-1995, 1996-1999). Comparison of tumor thickness between strata was defined by year of diagnosis, sex, age, and histologic subtype.
RESULTS: The number of new melanoma cases in a 3-year period increased 60% from 1988-1991 (n = 9132) to 1996-1999 (n = 14 575). The proportion of thick melanomas (> or =2 mm) remained relatively stable during the 12 study years. Nodular melanoma comprised 9% of all recorded cases but 34% of melanomas 2 mm or larger, including melanoma not otherwise specified (NOS), and nearly 50% of all melanomas 2 mm or larger when NOS cases were excluded. In contrast, superficial spreading melanoma was almost uniformly diagnosed as an early tumor, mostly (77%) presenting as thin melanoma (<1 mm) and with only 7% presenting as thick melanoma (> or =2 mm).
CONCLUSIONS: A substantial number of thick melanomas in the United States are of the nodular subtype, and median thickness of nodular melanoma has not changed during the 12 years of study. New strategies are needed to decrease the incidence of thick melanoma in the United States.
Nodular melanoma: Patients' perceptions of presenting features and implications for earlier detection.Chamberlain AJ, Fritschi L, Kelly JW.
Victorian Melanoma Service, Alfred Hospital, and the Department of Public Health, University of Western Australia.
J Am Acad Dermatol 2003 May;48(5):694-701 Abstract quote BACKGROUND: The incidence of thick melanoma and related mortality is largely static despite advances in early detection during the last 20 years. Nodular melanoma (NM) accounts for the majority of thick lesions and is difficult to recognize in the early stages of its evolution.
OBJECTIVE: The purpose of this study was to identify historic or clinical features that may facilitate earlier detection of NM.
METHODS: A questionnaire was administered to 125 patients attending the Victorian Melanoma Service between 1998 and 2000 with superficial spreading melanoma or NM. Parameters were compared by tumor type and thickness.
RESULTS: NMs are more often symmetric, elevated, uniform in color, and nonpigmented. Color change is uncommon.
CONCLUSION: NM often fails to fulfill the ABCD diagnostic criteria. Biopsy after a set period of observation should aid differentiation from inflammatory lesions and enable earlier detection of this subtype.ACRAL LENTIGINOUS MELANOMA 5-10%
Occur on the palms, feet, and the nailbeds
Lentiginous growth pattern with considerable upward intraepithelial scatter and nuclear pleomorphism
More common in Japanese and blacks
*Department of Anatomical Pathology ‡Sydney Melanoma Unit, Sydney Cancer Centre ¶Sydney Melanoma Diagnostic Centre, Royal Prince Alfred Hospital §Melanoma and Skin Cancer Research Institute ∥Discipline of Surgery, Faculty of Medicine **Discipline of Pathology, Faculty of Medicine, The University of Sydney ♯Skin and Cancer Foundation, Australia, Sydney, Australia †Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, National University Hospital, Singapore.
Subungual melanoma (SUM) is an uncommon variant of melanoma that is often difficult to diagnose, both clinically and pathologically. In an attempt to provide pathologic clues to diagnosis, especially in early lesions or small biopsies, and to provide practical advice to pathologists in reporting, the clinicopathologic features of 124 cases of SUM were reviewed, the largest series reported to date.
The features of 28 cases of subungual melanoma in situ (MIS), comprising 4 cases of MIS and 24 cases where areas of MIS were present adjacent to dermal-invasive SUMs, were compared with those of a similar number of acral nevi to identify useful distinguishing features. The median age of the patients was 59 years and the most common site was the great toe (24%). Nine percent of cases were AJCC stage 0, 14% were stage I, 41% were stage II, 32% were stage III, and 4% were stage IV at initial diagnosis. The commonest histogenetic subtype was acral lentiginous (66%), followed by nodular (25%) and desmoplastic (7%). The majority of tumors were locally advanced at presentation with 79% being Clark level IV or V. The median Breslow thickness was 3.2 mm. The median mitotic rate was 3 per mm and 33% of cases demonstrated primary tumor ulceration. Seven of 29 patients (24%) who underwent a sentinel lymph node biopsy had nodal disease. Multivariate Cox-regression analysis showed higher disease stage to be the only significant predictor of shortened survival. In comparison to acral nevi, MIS more frequently showed lack of circumscription, a prominent lentiginous growth pattern, predominance of single cells over nests, moderate-to-severe cytologic atypia, a dense and haphazard pagetoid intraepidermal spread of melanocytes, and the presence of junctional/subjunctional lymphocytes ("tumor infiltrating lymphocytes"). Tumor infiltrating lymphocytes have not been highlighted previously as a feature of subungual MIS and represent a useful diagnostic clue.
Guidelines for the reporting of SUMs are also presented. Knowledge and recognition of the pathologic features of SUMs and the important features that distinguish them from nevi should reduce the frequency of misdiagnosis.
Acral lentiginous melanoma mimicking benign disease: The Emory experience.Soon SL, Solomon AR Jr, Papadopoulos D, Murray DR, McAlpine B, Washington CV.
Departments of Dermatology and Surgery-Surgical Oncology, Emory University School of Medicine, and the Bethesda Dermatopathology Laboratory.
J Am Acad Dermatol 2003 Feb;48(2):183-8 Abstract quote BACKGROUND: Plantar and subungual melanoma exhibits a higher misdiagnosis rate relative to other anatomic sites. Misdiagnosis and delay in diagnosis are statistically associated with poorer patient outcome. Awareness of atypical presentations of acral melanoma may, thus, be important to decrease misdiagnosis rates and improve patient outcome.
METHODS: We conducted a retrospective case review of plantar or lower-extremity subungual melanoma performed at Winship Cancer Center, a tertiary care, referral center affiliated with Emory University, between 1985 and 2001.
RESULTS: A total of 53 cases of plantar or lower-extremity subungual melanoma were identified. Of 53 cases with a final diagnosis of melanoma, 18 were initially misdiagnosed. Misdiagnoses included wart, callous, fungal disorder, foreign body, crusty lesion, sweat gland condition, blister, nonhealing wound, mole, keratoacanthoma, subungual hematoma, onychomycosis, ingrown toenail, and defective/infected toenail. Of the 18 misdiagnosed cases, 9 were clinically amelanotic.
CONCLUSION: Awareness that amelanotic variants of acral melanoma may assume the morphology of benign hyperkeratotic dermatoses may increase the rate of correct diagnosis and improve patient outcome.
Arch Otolaryngol Head Neck Surg 1989;115:374-9.
J Am Acad Dermatol 1995;32:717-25.
Cancer 1998;83:1128-35.Rare
Clinical presentation is that of a slow-growing (months to years), painless, innocuous, rarely ulcerating, frequently amelanotic nodule on sun-exposed areas on the head and neck and upper part of the trunk for male patients and the extremities for female patients.
Older men with a 2:1 male predilection
Melanoma cells usually have a bland spindled cell appearance and deceptively infiltrate deeply into the dermis
Usually a lentigo maligna junctional component which may provide a clue to the origin of the spindled cells
Usally amelanotic-immunoperoxidase stains are often needed to confirm the diagnosis. However, unlike most melanomas, 80% of these melanomas may be S-100 negative. In addition, HMB-45, a usually reliable melanoma specific marker is positive in only 0-20% of cases.
Occasionally, electron microscopy must be used in an attempt to identify premelanosomes, the diagnostic hallmark of melanocytes
Variant of desmoplastic melanomas known as neurotropic melanomas. These melanomas also have a spindled appearance with a propensity to form a circumferential arrangement around preexisting nerves. Both types of melanomas are prone to local recurrence.
Department of Pathology, University of Washington, Seattle, WA, USA.
BACKGROUND: There is disagreement about the behavior and optimal management of desmoplastic melanoma (DM), particularly regarding the incidence of lymph node (LN) involvement. Recently, investigators have noted the frequently heterogeneous histologic composition of DM and have found significant differences between pure desmoplastic melanoma (PDM) (>or=90% comprised of histologically typical DM) and mixed desmoplastic melanoma (MDM) [>or=10% DM and >10% conventional melanoma (CM)].
METHOD: We reviewed 87 cases of DM comparing the histologic and clinical features of PDM (n = 44) to MDM (n = 43).
RESULTS: At surgical staging, there were LN metastases in 5 of 23 (22%) MDM patients, whereas all 17 PDM patients had negative LN biopsies (0%) (p = 0.04). PDM was less often clinically pigmented (36% vs. 67%) and had a lower mean mitotic index (1.3 vs. 3.0).
CONCLUSIONS: There are differences between PDM and MDM, the most important of which is the incidence of LN involvement. Our findings support the clinical utility of classifying DM into pure and mixed subtypes because the negligible rate of nodal involvement in PDM does not support the routine performance of sentinel LN biopsy in this subgroup of melanoma patients. In contrast, the incidence of LN involvement in MDM is comparable to that of CM.
Department of Dermatology, Hospital de Santa Maria, Universidade de Lisboa, Lisboa, Portugal.
Desmoplastic melanoma (DM) is a rare variant of spindle cell melanoma, which usually develops in sun-damaged skin of elderly patients. Often the lesion is nonpigmented and frequently mistaken for a nonmelanocytic proliferation, which delays diagnosis and treatment and therefore worsens the prognosis. The spindle shape of neoplastic melanocytes, the prominent desmoplasia, and the frequent neurotropism of neoplastic melanocytes are its most characteristic histopathological features.
We have studied the clinicopathologic features of 113 cases of DM. The mean age of the patients was 71.1 years; 48% of the patients were males and 52% were females. The neoplasm was located on the head in 72% of the cases. Malignant melanoma was the initial clinical diagnosis in only 27% of the cases.
Histopathologically, all lesions appeared as poorly demarcated neoplasms that involved the entire dermis and often extended into the subcutaneous tissue. The neoplasms were composed of ill-defined fascicles of spindle cells. Desmoplasia was defined as the presence of spindle cells associated with a fibrotic stroma. Fifty-one cases (45%) were classified as "pure DM" when the lesion was entirely desmoplastic, and 62 cases (55%) were considered as "combined DM" when a recognizable desmoplastic component was seen in an otherwise conventional malignant melanoma. In 81% of the cases, an atypical intraepidermal melanocytic component (in situ malignant melanoma) was identified, whereas in the remaining 19% of the cases the intraepidermal component was lacking. Seventy-one percent of the cases were histologically amelanotic, 23% showed a small amount of pigment, and only 6% were heavily pigmented. Neural involvement was identified in 40/113 cases (35%), predominantly in the thickest tumors. Lymphoid nodules, found in 42/113 cases (37%), were significantly more frequent in pure DM than in combined DM (53% vs 24%). The null hypothesis of homogeneity of the "pure" and "combined" subgroups should be rejected (P < 0.002). Solar elastosis, with variable intensity, was seen in 82% of the cases. Mean Breslow thickness was 4.1 mm (4.6/3.7 mm, in the pure/combined subgroups, respectively), median was 4.0 mm (4.0/3.0 mm); Breslow thickness ranged from 0.3 to 11.0 mm, with half of the cases thicker than 4 mm. Only 4% of the cases showed Clark level below IV. The predominant neoplastic cells consisted of spindle-shaped melanocytes in 85% of the cases, whereas the remaining 15% of the cases demonstrated round neoplastic cells forming the main mass of the neoplasm. The mitotic rate of the neoplastic cells was low in 72% of the cases, 23% had an intermediate mitotic rate, and 5% showed a high mitotic rate.
On follow-up, 55/113 patients (49%) (with an average of 55 months) demonstrated persistence of the disease. About 4% had local recurrences, 2% of lymph node invasion, 9% systemic metastases, and 12% died from the disease (2 cases of pure DM and 5 cases of combined DM).
Although a better prognosis has been postulated for DM when compared with conventional cutaneous malignant melanomas of the same thickness, in most cases, a DM is diagnosed only in established long-standing and thick melanomas. Therefore, dermatologists and dermatopathologists should be more aware of this clinicopathologic variant of cutaneous malignant melanoma.
- Expression of Melan-A and Ki-67 in desmoplastic melanoma and desmoplastic nevi.
Kucher C, Zhang PJ, Pasha T, Elenitsas R, Wu H, Ming ME, Elder DE, Xu X.
Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Am J Dermatopathol. 2004 Dec;26(6):452-7. Abstract quote
BACKGROUND: Desmoplastic melanoma (DMM) is an uncommon melanoma variant with a distinct morphology, including a prominent spindle cell component with fibrosis, as well as a distinct immunohistochemical profile. Histologically, the spindle cell component of DMM can be confused with sclerotic/desmoplastic nevi, nonpigmented blue nevi, scar, and neural tumors. The histological distinction between sclerotic/desmoplastic/blue nevi and DMM using standard light microscopic techniques can be exceedingly subtle. Therefore, we investigated whether immunohistochemical staining for Melan-A and Ki-67 expression can be used to discriminate these lesions, distinguishing between epithelioid and spindle cell compartments of the lesions.
DESIGN: Fifty cases of DMM and 13 cases of sclerotic/desmoplastic/blue nevi were identified. Standard immunohistochemical techniques were used with antibodies towards HMB-45, Melan-A (A103), and Ki-67; 43 of 50 DMM cases were available for staining with Melan-A, 42 of 50 for HMB-45, and 31 of 50 cases were stained with Ki-67. All 13 nevi were stained for Melan-A and 8 for Ki-67. Immunoreactivity to Ki-67 antibody was scored as 0 to 5%, 6 to 10%, 11 to 30%, or greater than 30% positive tumor cells.
RESULTS: Only 3 of 43 and 3 of 42 of spindle cell compartments of DMMs were positive for Melan-A and HMB-45, respectively. Focal staining of epithelioid cells in the junctional component or superficial dermis was observed in 33% (14/43). In contrast, 100% of the 13 nevi were strongly positive for Melan-A (P < 0.001). Seventeen melanomas (55%) were 0 to 5% positive for Ki-67, five (16%) fell into the 6 to 10% category, three (10%) were between 11 and 30%, and six (19%) were at least focally greater than 30% positive. All 8 nevi (100%) had less than 5% positive cells for Ki-67 (P = 0.02), with only 2 cases having more than 2% positive cells.
CONCLUSION: The sclerotic/desmoplastic and hypopigmented blue nevi were uniformly positive for Melan-A, while the vast majority of DMM were negative in their spindle cell compartments. Melan-A is very useful in distinguishing between DMM and sclerotic nevi. Ki-67 appears to be an inconsistent marker for DMM. However, a high labeling index (over 5%) may be used as a clue in diagnosing DMM.
- Cutaneous Desmoplastic Melanoma: Reappraisal of Morphologic Heterogeneity and Prognostic Factors.
Busam KJ, Mujumdar U, Hummer AJ, Nobrega J, Hawkins WG, Coit DG, Brady MS.
From the Departments of *Pathology, daggerEpidemiology and Biostatistics, and double daggerSurgery, Memorial Sloan-Kettering Cancer Center, New York, NY.
Am J Surg Pathol. 2004 Nov;28(11):1518-1525. Abstract quote
Desmoplastic melanoma (DM) is a variant of melanoma, which may be confused with nonmelanocytic benign or malignant spindle cell proliferations. The histologic hallmark of DM is the presence of fusiform melanocytes dispersed in a prominent collagenous stroma. Phenotypic heterogeneity of DM is underrecognized. Desmoplasia may be prominent throughout the entire tumor ("pure" DM) or represent a portion of an otherwise nondesmoplastic melanoma ("combined" DM).
We reviewed melanomas with desmoplasia from 92 patients seen at a single institution between 1980 and 2002. Fifty-five of the tumors were pure DM. Thirty-seven were classified as combined. Mean follow-up of patients was 46 months for those alive at the last follow-up. Univariate analysis of clinical and pathologic parameters revealed four significant variables for disease-free survival: Clark level (IV vs. V; P = 0.005), DM subtype (pure vs. combined; P = 0.01), tumor mitotic rate (<1, 1-4, >4 mitoses/mm; P = 0.01), and tumor thickness (<1 mm, 1-4 mm, >4 mm; P = 0.02). Only histologic subtype (P = 0.02) and Clark level (P = 0.05) were independently significant by Cox regression analysis.
Our results indicate that distinguishing pure from combined forms of DM is clinically relevant for prognosis (pure forms being associated with longer disease-specific survival). Failure to make this distinction may account for conflicting reports in the literature on the biologic behavior and prognosis of DM.Desmoplastic malignant melanoma: diagnosis of early clinical lesions.
Wharton JM, Carlson JA, Mihm MC Jr. Division of Dermatopathology and Dermatology, Albany Medical College, NY 12208, USA.
Hum Pathol 1999 May;30(5):537-42 Abstract quote
Desmoplastic malignant melanoma (DMM) is an uncommon but potentially devastating malignancy that can be cured with early recognition and surgery. DMM has clinical as well as histological features that may be subtle and overlooked, or misdiagnosed as other benign or malignant lesions that would require less aggressive therapy for cure.
We have reviewed the preliminary clinical diagnoses and histological features of 18 cases of desmoplastic malignant melanoma, defined as either an inapparent lesion clinically, or a papule or small nodule less than 0.7 cm, which proved histologically to be DMM. Nine of 18 cases (50%) were clinically pigmented. Histologically, early lesions were characterized by superficial tumor fascicles, and random diffuse hypercellularity in the upper dermis identified as elongated hyperchromatic pleomorphic spindle cells with stromal myxoid change. Neuroidal melanocytic structures, invasion of adventitial dermis, islands of inflammation, and epidermal lentiginous melanocytic hyperplasia were often present.
The most reliable and characteristic features of an early lesion of DMM are aggregates of lymphocytes, tumor cell cytological atypia, stromal myxoid change, and poor circumscription of the dermal infiltrate. DMM is a disease best treated by complete excision at the time of initial surgery, but is also a lesion easily missed or misdiagnosed in the early stages. Features of early DMM are identified and illustrated to enable early diagnosis and cure of these lesions.
Desmoplastic and spindle cell melanomas express protein markers of the neural crest but not of later committed stages of Schwann cell differentiation.Huttenbach Y, Prieto VG, Reed JA.
Section of Dermatopathology, Departments of Pathology and Dermatology, Baylor College of Medicine, and Department of Pathology, UT-M.D. Anderson Cancer Center, Houston, TX, USA.
J Cutan Pathol 2002 Oct;29(9):562-8 Abstract quote BACKGROUND: The rare desmoplastic and spindle cell variants of malignant melanoma exhibit histological and biochemical features suggestive of early Schwann cell differentiation. These features include a spindle-shaped morphology, neurotropism, and the expression of the low affinity nerve growth factor receptor (p75NGFR).
METHODS: We evaluated by immunohistochemistry (using formalin-fixed, paraffin-embedded tissues) nine desmoplastic and three spindle cell melanomas for the expression of peripherin, p75NGFR, neural cell adhesion molecule (CD56/N-CAM), and growth-associated phosphoprotein-43 (GAP-43). Peripherin is expressed in the neural crest and in neurons, but not in cells committed to the Schwann cell lineage. p75NGFR and CD56/N-CAM also are expressed in early neural crest cells, but persist in unmyelinated and early premyelinating Schwann cells. GAP-43 is expressed in unmyelinated Schwann cells, but is downregulated in the later premyelinating to promyelinating stages of cells committed to the Schwann cell lineage.
RESULTS: Peripherin was expressed in 7/12 (58%), p75NGFR in 4/12 (33%), and CD56/N-CAM in 6/12 (50%) of the desmoplastic and spindle cell melanomas. GAP-43 was not expressed (0%) in any of the 12 melanomas (chi2, p = 0.05).
CONCLUSIONS: Desmoplastic and spindle cell melanomas express protein markers common to cells of the neural crest and to neurons similar to the immunophenotype previously reported for epithelioid cell melanomas. The expression of peripherin and the lack of expression of GAP-43 further define that these rare subtypes of melanoma do not recapitulate the later committed stages of Schwann cell differentiation.
Desmoplastic malignant melanoma of the lip: A report of 6 cases and review of the literature.Hui JI, Linden KG, Barr RJ.
Dermatopathology Laboratory, Department of Dermatology, University of California, Irvine.
J Am Acad Dermatol 2002 Dec;47(6):863-8 Abstract quote Desmoplastic malignant melanoma is a rare neoplasm consisting primarily of spindle-shaped melanoma cells embedded in a fibrous stroma, with approximately 6% of cases occurring in the lip. A literature search revealed that most reported cases occur in sun-exposed areas in older men. Few cases of desmoplastic malignant melanoma of the lip in young people (in their mid-twenties) have been described.
We report 6 previously undocumented cases of labial desmoplastic malignant melanoma occurring in young individuals and review 20 cases from the literature. Physicians should consider the possibility of desmoplastic malignant melanoma in young people who present with atypical lip lesions, which on histopathologic analysis demonstrate spindle-cell hyperplasia.
Although this diagnosis is rare and there have not been reports of such patients in the literature thus far, our findings should alert clinicians to the possibility of desmoplastic malignant melanoma as a diagnosis for lip lesions in young people.
ADDITIONAL VARIANTS-ALPHABETICAL
- Unusual histological variants of cutaneous malignant melanoma with some clinical and possible prognostic correlations.
Rongioletti F, Smoller BR.
Section of Dermatology, DISEM, University of Genoa, Italy.
J Cutan Pathol. 2005 Oct;32(9):589-603. Abstract quote
Malignant melanoma is known for the wide range of histological patterns it can assume mimicking other malignant tumors.
We present a review of most of the unusual histological variants of cutaneous melanoma and describe their immunohistochemical features, associate clinical findings, and possible behavior related to the histological subtype. In addition, we propose their classification into four groups corresponding to the (1) architectural patterns; (2) cytologic features; (3) stromal changes; and (4) the possible association of these findings (i.e. architectural + cytologic features).
Although most of these unusual variants have the same prognosis as conventional melanomas, with Breslow thickness and ulceration, being the most important predictor of survival in clinical stage I, some of them have a peculiar biologic behavior that the clinicians and the dermatopathologists should know in order to give melanoma patients all educational information available.ANIMAL TYPE MELANOMA
- Melanoma with prominent pigment synthesis (animal-type melanoma): a case report with ultrastructural studies.
Kazakov DV, Rutten A, Kempf W, Michal M.
Sikl's Department of Pathology, Charles University, Medical Faculty Hospital, Pilsen, Czech Republic.
Am J Dermatopathol. 2004 Aug;26(4):290-7. Abstract quote
Melanoma with prominent pigment synthesis or animal-type melanoma (ATM) is a very rare type of melanoma. Its histogenesis has not been elucidated and ultrastructural features have not been described in human beings.
We present an additional case of ATM in a 28-year-old woman with positive sentinel node biopsy and provide the results of electron microscopic studies. Histopathologically, the skin lesion was composed of heavily pigmented neoplastic cells mostly arranged as large sheets, focally also in a nodular growth pattern. After bleaching, the neoplastic cells demonstrated round nuclei with 1 or rarely 2 conspicuous nucleoli and a prominent nuclear membrane and abundant, gray, slate-like cytoplasm. Some cells demonstrated round cytoplasmic inclusions. There was no nuclear pleomorphism, and only a few mitotic figures could be found after extensive search. Multiple areas of necrosis en masse of tumor cells were seen.
The lymph node biopsy revealed a complete effacement of the lymph node architecture by the extensive proliferation of hyperpigmented cells in the parenchyma. Immunohistochemically, the same pattern of staining was seen on the bleached and unbleached slides both in the skin and in the lymph node. The neoplastic cells stained positively with MiTF (nuclei), NSE, NKI/C3, tyrosinase (weak), p53, and CD68. S-100 protein, HMB45, Melan A, Mac367, and lysozyme reacted negatively. Occasional cells (<1%) reacted with MIB-1.
Ultra-structural studies revealed that the neoplastic cells possessed a large, indented nucleus with a prominent nuclear membrane, a single (para) centrally located nucleolus, and peripherally marginated chromatin. The cytoplasm was abundant and contained numerous single melanosomes and rare compound melanosomes. The melanosomes were in stages II to IV of maturation, with a marked predominance of stage II and stage III melanosomes. There was a high number of aberrant melanosomes with a wide variety of configurations. Melanophages were a minor component of the lesion.
Our ultrastructural studies provide unequivocal evidence that ATM is a neoplasm of melanosome-producing cells. We also review the literature on ATM.Malignant melanoma with prominent pigment synthesis: "animal type" melanoma--a clinical and histological study of six cases with a consideration of other melanocytic neoplasms with prominent pigment synthesis.
Crowson AN, Magro CM, Mihm MC Jr.
Department of Laboratories, Misericordia General Hospital, Winnipeg, Manitoba, Canada.
Hum Pathol 1999 May;30(5):543-50 Abstract quote
Rare skin neoplasms in humans, comprising nodules of heavily melanized cells, mimic melanocytic neoplasms seen in horses and laboratory animals and thus are termed animal type melanomas. In part because of their rarity, behavior is unpredictable; many cases manifest a long indolent phase, and metastases are reportable.
Over 6 years, the authors encountered nine skin and one lymph node biopsy specimens from six patients in whom light microscopy of formalin-fixed, paraffin-embedded tissue sections stained with hematoxylin and eosin showed melanocytic neoplasms with prominent pigment synthesis. Clinical follow-up was obtained by telephone contact with clinicians. There were three women, two men, and one boy, aged 9 to 85 years, whose lesions were described as blue-black nodules with irregular borders from 1.0 to 4.0 cm in size, located on the scalp, lower extremities, back, and sacrum.
The dermatopathology comprised confluent dermal sheets of heavily melanized cells whose nuclei, where discernible, were large with irregularly thickened membranes, coarse chromatin, prominent, often spiculated nucleoli, and irregular parachromatinic clearing. Mitoses were infrequent. Four lesions had an epidermal component. One patient suffered metastases to regional lymph nodes, liver, and lungs with lethal effect, one experienced regional lymph node metastases but is still alive, one had local cutaneous metastases but was lost to follow-up, and one has a chest wall mass that has not yet been investigated.
This rare dermal-based melanocytic neoplasm with prominent pigment synthesis, the animal type melanoma, has a biological behavior difficult to predict on morphological grounds. We advise complete excision with a 1.0- to 2.0-cm margin of normal skin and clinical investigation for regional or distant metastases.
Animal Type Melanoma A Report of a Case with Balloon-cell Change and Sentinel Lymph Node Metastasis
Luis Requena, M.D.; Alberto de la Cruz, M.D.; Carmen Moreno, M.D.; Omar Sangüeza, M.D.; Celia Requena, M.D.
From Departments of Dermatology (L.R.) and Pathology (C.M.), Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain; Pathology (A. de la C.), Centro Oncológico de Galicia, La Coruña, Spain; Dermatopathology (O.S.), Wake Forest University, Winston Salem, NC, U.S.A. and Dermatology (C.R.), Hospital General, Valencia, Spain.
Am J Dermatopathol 2001;23:341-346 Abstract quote
Animal type melanoma is a rare histopathologic variant of melanoma characterized by sheets and nodules of heavily pigmented epithelioid melanocytes that involve the entire thickness of the dermis. This human neoplasm mimics melanocytic neoplasms seen in gray horses and laboratory animals; thus, is termed animal type melanoma. It is quite rare and, with only a few reported cases, its biological behavior is not well understood.
We report an example of animal type melanoma on the back of a 27-year-old man. The lesion showed areas of melanoma in situ, which ruled out the possibility of metastatic melanoma. Features of regression were also seen at dermo-epidermal junction and papillary dermis. In some areas, neoplastic melanocytes exhibited a balloon-cell appearance; in others the neoplasm was composed of sheets and fascicles of heavily pigmented epithelioid melanocytes that permeated the entire dermis and extended into the dermal-subcutaneous interface, mimicking a cellular blue nevus. Epithelioid melanocytes in deeper areas showed abundant, heavily pigmented cytoplasm and pleomorphic nuclei with prominent eosinophilic nucleoli and some mitotic figures. The neoplastic cells did not show evidence of maturation in deeper areas of the lesion. In some sections, a nodule of heavily pigmented epithelioid melanocytes was seen far from the main bulk of the lesion, at the dermal-subcutaneous interface, raising the possibility of a satellite lesion. A lymphoscintigraphy showed a sentinel lymph node in the right axilla and a subsequent axillary lymphadenectomy demonstrated that the architecture of the sentinel lymph node was effaced by metastatic melanoma. The patient received adjuvant chemotherapy with inteferon alfa-2b and four months after this treatment the patient is alive and well, without evidence of recurrences or additional metastases.
ANGIOMATOID MELANOMA Angiomatoid melanoma: a novel pattern of differentiation in invasive periocular desmoplastic malignant melanoma.
Baron JA, Monzon F, Galaria N, Murphy GF.
Jefferson Medical College and Thomas Jefferson University, Philadelphia, PA, USA.
Hum Pathol 2000 Dec;31(12):1520-2 Abstract quote
A case of locally invasive, long-standing desmoplastic and amelanotic malignant melanoma is described in an 84-year-old man.
Histologic examination of the involved periorbital tissue showed neoplastic foci exhibiting a novel pattern reminiscent of microvascular proliferation. These regions were characterized by malignant, S-100-positive tumor cells lining vessel-like spaces in transverse sections and forming tubuler-like structures in longitudinal sections.
Recent data indicate that melanoma cells may express genes and patterns of differentiation in vitro akin to endothelial cells. Because angiosarcoma often involves facial and scalp skin of elderly individuals, awareness of angiomatoid differentiation in melanoma has important diagnostic implications.
ANGIOTROPIC MELANOMA Angiotropic malignant melanoma: A rare pattern of local metastases
Anita Saluja, etal.
J Am Acad Dermatol 2001;44:829-32 Abstract quote
We report a case of angiotropic malignant melanoma and review previously reported cases. Vessel walls should be scanned for tumor cells in biopsy and re-excision specimens of melanoma.
BALLOON CELL MELANOMA Balloon cell malignant melanoma of the skin. A clinicopathologic study of 34 cases with histochemical, immunohistochemical, and ultrastructural observations.
Kao GF, Helwig EB, Graham JH.
Department of Pathology, Georgetown University Medical School, Washington, DC.
Cancer 1992 Jun 15;69(12):2942-52 Abstract quote Balloon cell malignant melanoma (BCMM) is a rare histologic variant of malignant melanoma (MM).
Thirty-four patients with BCMM from the files of the Armed Forces Institute of Pathology (AFIP) were studied by means of clinicopathologic correlation and histochemical, immunohistochemical, and ultrastructural methods to better define this entity.
The cytoplasmic features of the balloon cells observed in BCMM resemble those noticed in balloon cell nevus (BCN), but the presence of nuclear pleomorphism, atypia, and mitoses and the absence of intervening stroma help distinguish BCMM. The cells also show many histochemical, immunochemical, and ultrastructural features of conventional melanoma cells. Although it is generally believed that balloon melanoma cells represent a degenerative change, the immunohistochemical and electron microscopic findings suggest that the balloon tumor cells are most likely metabolically active melanocytic cells. Microscopically, BCMM also must be differentiated from other clear cell tumors such as clear cell sarcoma (MM of soft parts), hibernoma, xanthoma, sebaceous neoplasms, metastatic renal cell carcinoma, (malignant) clear cell acrospiroma, (malignant) granular cell tumor, granular (clear) cell basal cell carcinoma, clear cell syringoma, and atypical fibroxanthoma.
The prognosis of BCMM usually correlates with the tumor thickness similar to that in other histologic types of cutaneous MM. Nineteen (57.5%) of 33 patients with adequate follow-up information died of disseminated tumors from 2 months to 12 years after the initial treatment. Six (18.2%) patients developed local recurrences: four of these patients died of metastasis and two were alive with metastatic tumor at last contact.
Five (15.2%) patients were alive with metastatic tumors, and seven (21.2%) were alive without evidence of disease at last contact. Recognition of BCMM is important because of its malignant biologic behavior.
Glycogen-rich malignant melanomas and glycogen-rich balloon cell malignant melanomas: frequency and pattern of PAS positivity in primary and metastatic melanomas.
Nowak MA, Fatteh SM, Campbell TE.
Department of Pathology, Western Reserve Care System, Youngstown, Ohio 44501, USA.
Arch Pathol Lab Med 1998 Apr;122(4):353-60 Abstract quote
OBJECTIVE: After identifying a metastatic glycogen-rich balloon cell malignant melanoma, originally thought to be a benign clear cell tumor of the lung, we investigated the extent of positive reactions, or "positivity," of malignant melanoma to periodic acid-Schiff (PAS) staining.
METHODS: Frequency, intensity, and distribution of PAS positivity was studied in 61 excisional biopsy specimens from 58 patients with malignant melanoma. For comparison, 17 benign nevi from 10 patients were examined.
RESULTS: Positivity for PAS was seen in all cases. All malignant melanomas and benign nevi were characterized by weak, diffuse, diastase-resistant PAS positivity. Additionally, focal or diffuse, strong diastase-sensitive PAS positivity was observed in 9 of 61 melanomas (15%); 7 were metastatic and 2 were primary invasive melanomas. Strong diastase-sensitive PAS positivity was seen in all lesions with 30% or more balloon cell features and only in advanced primary or metastatic lesions. The presence of glycogen was confirmed by transmission electron microscopy.
CONCLUSIONS: Cutaneous malignant melanomas have weak, diastase-resistant PAS positivity. Strong diastase-sensitive PAS positivity, consistent with the presence of intracytoplasmic glycogen, is seen in many primary and metastatic melanomas with balloon cell features. Depending on the content of the balloon cells, these melanomas are best categorized as either glycogen-rich malignant melanomas or glycogen-rich balloon cell malignant melanomas. Because many tumors with clear cell features contain glycogen, such content often is an unreliable differential feature.
CHONDROID MELANOMA Primary chondroid melanoma
Christopher D. Ackley1, Victor G. Prieto1,2, Rex C. Bentley1, Marcelo G. Horenstein1, Hilliard F. Seigler3 and Christopher R. Shea1,2 1
Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA, 2 Department of Medicine, Division of Dermatology, Duke University Medical Center, Durham, North Carolina, USA, 3 Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
Journal of Cutaneous Pathology 2001;28 (9), 482-485 Abstract quote
Background: Malignant melanoma is notorious for the wide range of histologic patterns it can assume, among the least frequent of which is chondroid melamona.
Methods: Two cases of primary chondroid melanoma of the distal lower extremity were studied. Tissue for light microscopy was fixed in formalin, embedded in paraffin, and processed routinely. In one case, transmission electron microscopy and immunohistochemical evaluation were performed.
Results: Both cases exhibited melanoma in-situ, a conventional (non-chondroid) invasive component, and areas of chondroid differentiation, as confirmed by strongly positive staining with Alcian blue at pH 2.5 and Safranin O. Immunohistochemically, one case expressed S-100 protein and vimentin, and did not express gp100 (HMB-45), tyrosinase, MART-1, the Mel-5 antigen, the NKI/C3 antigen, CD45Ro, cytokeratin, or desmin. Electron microscopy of the chondroid component revealed occasional tumor cells with rare, membrane-bound, electron-dense organelles; the extracellular compartment showed amorphous ground substance consistent with cartilaginous differentiation.
Conclusions: Chondroid change in the absence of osteogenic differentiation is extremely rare in malignant melanoma. Melanoma should be considered in the differential diagnosis of primary cutaneous neoplasms exhibiting cartilaginous differentiation.
DERMAL MELANOMA Primary Dermal Melanoma Distinct Immunohistochemical Findings and Clinical Outcome Compared With Nodular and Metastatic Melanoma
David S. Cassarino, MD, PhD; Erik S. Cabral, BS; Reena V. Kartha, PhD; Susan M. Swetter, MD
Arch Dermatol. 2008;144(1):49-56. Abstract quote Objective To provide an updated and expanded analysis of clinical outcome and immunohistochemical (IHC) findings unique to primary dermal melanoma (PDM) that may be used to differentiate this entity from primary nodular melanoma (PNM) and cutaneous metastatic melanoma (MM).
Design Cohort analysis and extensive IHC panel comparing PDM with PNM and cutaneous MM.
Setting Melanoma clinics and pathology departments of academic and VA medical centers.
Patients Thirteen patients with a solitary dermal or subcutaneous nodule of histologically proven melanoma, prospectively followed through April 30, 2007.
Interventions Clinical, pathologic, and IHC assessment of patients diagnosed as having PDM.
Main Outcome Measures Long-term clinical outcome and determination of unique clinical and IHC features in the study cohort compared with other melanoma subtypes.
Results Histologically, there was no evidence of an overlying in situ component, ulceration, or regression, and there was no associated nevus in any cases. Clinical history and findings from workup, including imaging studies, skin examination, and sentinel lymph node biopsy, were negative for evidence of melanoma elsewhere. The mean Breslow depth was 9.6 mm. Two patients developed satellite or in-transit recurrences, 1 developed pulmonary metastasis, and another died of liver metastases. Overall, the cohort showed a 92% melanoma-specific survival rate at a mean duration of follow-up of 44 months. The IHC findings showed that PDM exhibited lower levels of staining for the antigens p53 (P = .02), Ki-67 (Mib-1) (P = .002), cyclin D1 (P = .001), and podoplanin (recognized by D2-40 antibody) lymphovascular staining (P <.001) compared with MM and PNM. All other markers were comparable.
Conclusions Patients with PDM have remarkably prolonged survival compared with patients with MM or PNM of similar thickness. Preliminary results suggest that PDM may be characterized by lower levels of p53, Ki-67, cyclin D1, and D2-40 compared with histologically similar MM and PNM.
Primary dermal melanoma: a distinct subtype of melanoma.
Swetter SM, Ecker PM, Johnson DL, Harvell JD.
Dermatology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif., USA.
Arch Dermatol. 2004 Jan;140(1):99-103. Abstract quote
BACKGROUND: The term primary dermal melanoma has been used to describe a subtype of melanoma confined to the dermis and/or subcutaneous fat that histologically simulates metastasis but is associated with an unexpectedly prolonged survival. We report 7 cases of primary dermal melanoma diagnosed from 1998 to 2002 with no identifiable junctional or epidermal component or nevoid precursor. Histopathologic and immunohistochemical features were compared with known cases of cutaneous metastasis and nodular melanoma in an attempt to differentiate this entity from clinical and pathologic mimics.
OBSERVATIONS: Seven patients had a single dermal and/or subcutaneous focus of melanoma. Metastatic staging workup findings were negative, including results from sentinel node and imaging studies. Mean Breslow depth was 7.0 mm, and mean maximum tumor diameter was 6.2 mm. The study cohort showed 100% survival at mean follow-up of 41 months (range, 10-64 months). Immunohistochemical analysis with S100, HMB-45, Ki-67, CD34, and p75 antibodies showed no significant staining patterns compared with metastatic and nodular melanomas.
CONCLUSIONS: Primary dermal melanoma appears to be a distinct subtype of melanoma based on the excellent prognosis associated with this case series and others. Additional research focusing on cause, appropriate staging, and outcome of previously identified solitary dermal metastasis is warranted to further delineate this entity.EXTRAVASCULAR MELANOMA
- Angiotropism of Human Melanoma: Studies Involving In Transit and Other Cutaneous Metastases and the Chicken Chorioallantoic Membrane: Implications for Extravascular Melanoma Invasion and Metastasis.
Lugassy C, Vernon SE, Busam K, Engbring JA, Welch DR, Poulos EG, Kleinman HK, Barnhill RL.
Departments of *Pathology paragraph signDermatology, University of Miami School of Medicine/Jackson Memorial Hospital, Miami, FL daggerDepartment of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021 double daggerNational Institute of Dental and Craniofacial Research (HKK, JAE), National Institutes of Health, Bethesda, MD section signDepartment of Pathology and Comprehensive Cancer Center (DRW), University of Alabama, Birmingham, AL.
Am J Dermatopathol. 2006 Jun;28(3):187-193. Abstract quote
Melanoma cell migration along the outside of vessels has been termed "extravascular migratory metastasis" (EVMM), as distinct from intravascular dissemination. Previous studies in both human and experimental melanoma models have shown angiotropism of melanoma cells, suggesting EVMM.
Our objectives are to study the mechanism of dissemination of human melanoma cells in the chick chorioallantoic membrane (CAM) and to compare the histopathology in the CAM with that of patients with in transit and other cutaneous melanoma metastases.Human and murine melanoma cells were inoculated onto the CAM and observed over a 10-day period for tumor dissemination. Both human melanoma specimens from 26 patients and melanoma cells growing on the CAM showed the presence of tumor cell angiotropism at the invasive front of the tumor and at some distance from the tumor mass. In addition, a clear progression of melanoma cells spreading on the CAM was observed along the abluminal surface of vessels, where they occupied a perivascular location. By day 10 after injection, small micrometastases had developed along vessels, in a pattern similar to that in transit and other cutaneous melanoma metastases. In addition, the results suggested that the number of micrometastases directly correlated with increasing tumor volume.
Taken together, these data suggest that the CAM is a relevant model for studying tumor cell dissemination, and that EVMM may be a mechanism by which some melanoma cells spread to nearby and even distant sites.
FOLLICULAR
BACKGROUND: Seborrheic keratosislike melanoma could be one of the most problematic melanoma simulators, and it may be incorrectly treated by electrocautery or cryotherapy. Dermoscopic examination of pigmented tumors improves the diagnostic accuracy in these challenging lesions. In these tumors, numerous comedolike openings are present.
OBSERVATIONS: A 34-year-old man was seen for a conspicuous pigmented lesion on his back that clinically resembled a seborrheic keratosis because of the presence of multiple comedolike openings. Findings from dermoscopic examination showed distinct melanoma criteria (atypical pigmented network, asymmetric globules and dots, and a blue-whitish veil), in addition to multiple comedolike openings. Histopathological examination confirmed a peculiar melanoma variant characterized by prominent folliculotropism and minimal radial spreading. This tumor was not associated with chronic sun-damaged skin.
CONCLUSION: Dermoscopy was useful in identifying a particular case of seborrheic keratosislike melanoma with folliculotropism, thus avoiding incorrect treatment.
- Follicular Malignant Melanoma: A Variant of Melanoma to be Distinguished from Lentigo Maligna Melanoma.
Hantschke M, Mentzel T, Kutzner H.
Dermatopathologische Gemeinschaftspraxis, Friedrichshafen, Germany.
Am J Dermatopathol. 2004 Oct;26(5):359-363. Abstract quote
Follicular malignant melanoma can be regarded as a rare and unique presentation of melanoma. It is characterized by a deep-seated follicular structure in which atypical melanocytes extend downward along the follicular epithelium and permeate parts of the follicle as well as the adjacent dermis. The clinical diagnosis of follicular malignant melanoma may be difficult because the tumor mostly resembles a comedo or a pigmented cyst.
We studied five cases of follicular malignant melanoma in which the patients were between 61 and 82 years old. Three lesions were localized on the nose, one on the cheek, and one on the back of the neck. Clinically, all five cases measured distinctly less than 0.5 cm in size. While lentigo maligna is traditionally known as a pigmented macule in actinically damaged skin that gradually evolves in a slow process before invasive growth, three follicular malignant melanomas had developed in relatively short timeframes of 9 months to 1 ½ years. In all five cases the inconspicuous clinical appearance did not herald a malignant melanoma with invasive growth.
Follicular malignant melanoma underlines the importance of a correct excision technique with subsequent histologic workup and diagnosis. Superficial shave excision or even laser treatment in these specific cases may lead to a fatal prognosis for the patient.GANGLIO-
NEUROBLASTIC DIFFERENTIATION
Ganglioneuroblastic differentiation in a primary cutaneous malignant melanoma.Grayson W, Mare LR.
Am J Dermatopathol 2003 Feb;25(1):40-4 Abstract quote Ganglioneuroblastic differentiation in malignant melanomas is an exceedingly rare event. Although there has been a single report of this occurrence in a metastatic melanoma, divergent ganglioneuroblastic differentiation has not been documented previously in a primary cutaneous lesion of melanoma.
The present report describes an unusual case of invasive melanoma arising on the lower leg of a 61-year-old woman. The 16.9-mm thick tumor showed extensive ganglioneuroblastic differentiation, which was confirmed both immunohistochemically and ultrastructurally.
Although the prognostic significance of this observation remains uncertain, the unique case reaffirms the potential morphologic diversity of melanomas and suggests a shared histogenetic origin from a common neural crest derivative.
GIANT CELLS
- Malignant melanoma with osteoclast-like giant cells: an unusual host response: immunohistochemical and ultrastructural study of three cases and literature review.
Al-Brahim N, Salama S.
From St. Joseph's Hospital and McMaster University, Hamilton, Ontario, Canada.
Am J Dermatopathol. 2005 Apr;27(2):126-9. Abstract quote
Melanomas with unusual histologic features are very rarely reported in the literature and demonstrate the diversity of melanocytic expression. Three cases of malignant melanoma with osteoclast-like giant cells are reported. Two cases showed undifferentiated malignant cells without melanin pigment and one showed spindled cell morphology.
Immunohistochemistry showed that the osteoclast- like giant cells expressed CD68, but not melanocytic markers (HMB45, Melan-A, and S100). Ultrastructural analysis further supports that these cells are reactive histiocytes rather than transformed malignant cells. This suggests they represent an unusual host response, similar to those rarely observed in other neoplasms. Awareness of this entity is important to avoid misdiagnosis of melanoma as a histiocytic tumor.
Since only few cases have been reported, greater recognition and documentation may help to evaluate the prognosis of such cases with unusual morphology.LIPOBLAST-LIKE CELLS Primary cutaneous malignant melanoma with lipoblast-like cells.
Cruz J, Reis-Filho JS, Lopes JM.
Department of Pathology, Sao Joao Hospital, and Medical Faculty, University of Porto, Porto, Portugal.
Arch Pathol Lab Med 2003 Mar;127(3):370-1 MINIMAL DEVIATION MELANOMA Clin Lab Med 2000;20:745-758
Controversial term coined by Richard Reed, M.D., a noted dermatopathologist at Tulane Medical School. He has described several histologic variants:
Spitz nevus-like variant
Pigmented Spindle Cell Variants
Halo Nevus-like variant
Dermal-type minimal deviation melanomas
Nevus cell variant
Ki-67 and p53 expression in minimal deviation melanomas as compared with other nevomelanocytic lesions.Chorny JA, Barr RJ, Kyshtoobayeva A, Jakowatz J, Reed RJ.
Dermatopathology Laboratory, University of California Irvine Medical Center, Orange, California 92868-3201, USA.
Mod Pathol. 2003 Jun;16(6):525-9. Abstract quote Minimal deviation melanoma is a controversial entity encompassing a heterogeneous group of lesions cytologically in the spectrum between recognized subtypes of nevi and conventional "primary configuration" melanomas and reported to have a better prognosis than the latter.
To evaluate the distinctiveness of minimal deviation melanoma, Ki-67 proliferation rates and p53 expression in minimal deviation melanomas were compared with those in compound nevi, Spitz nevi, and vertical growth phase superficial spreading malignant melanoma. Twelve examples of each lesion were immunostained with antibodies to the Ki-67 and p53 proteins and evaluated by a pathologist who was blind to the diagnoses.
The mean Ki-67 (MIB-1) proliferation rates for the compound nevi, Spitz nevi, minimal deviation melanomas, and superficial spreading malignant melanomas were 0, 3%, 13%, and 25%, respectively. The mean Ki-67 proliferation rate was statistically greater in the minimal deviation melanomas than in the compound nevi or the Spitz nevi (P <.05), but the proliferation rates in the two melanoma subtypes were not statistically significant (P =.08). The mean p53 values for these lesions were 0, 9%, 9%, and 26%, respectively; the latter two were statistically different (P <.01).
Based on these Ki-67 and p53 immunophenotypes, minimal deviation melanoma may represent a distinct entity.MONSTER CELLS
- Monster Cells in Malignant Melanoma.
Boyd AS, Wu H, Shyr Y.
From the Departments of *Medicine (Dermatology), daggerPathology, and double daggerPreventive Medicine, Vanderbilt University, Nashville, Tennessee.
Am J Dermatopathol. 2005 Jun;27(3):208-210. Abstract quote
Cells with significantly enlarged nuclei have been described in basal cell carcinomas, dermatofibromas, and pleomorphic fibromas, to name a few. These cells are typically visible using low power microscopy and have been termed "pleomorphic" or "monster cells." They have not been previously described in cutaneous melanomas.
We sought to determine the prevalence of monster cells in otherwise conventional biopsies of primary cutaneous melanomas and its association with other histopathologic features of this malignancy. Ninety-nine superficial spreading melanomas, nodular melanomas, and acral lentiginous melanomas/lentigo malignas were retrospectively evaluated for the presence of monster cells, multinucleated giant cells, ulceration, inflammation, and depth of invasion (Breslow level).Thirteen cases of melanoma containing monster cells were found.
A statistically significant association was noted between the presence of these cells, the histologic subtype of nodular melanoma (P = 0.0125), ulceration (P = 0.0127), the depth of invasion (P = 0.0103), and the presence of multinucleated giant cells (P = 0.0016). The finding of monster cells is not an uncommon occurrence and is seen more often in nodular melanomas.MYXOID MELANOMA
- Cutaneous melanoma with pseudomyxoid features.
Urso C.
Dermatopathology Section - Pigmented Skin Lesions, S. M. Annunziata Hospital - ASL 10 Florence, Florence, Italy.
J Cutan Pathol. 2006 Apr;33(4):312-4. Abstract quote
A 96-year-old man presented with a polypoid melanoma, which showed a prominent clear stroma, similar to that of myxoid melanoma, but stained negative for Alcian blue at pH 2.5 and for colloidal iron. It is not clear whether melanoma displaying pseudomyxoid features (pseudomyxoid melanoma) may represent a distinct histological variant of melanoma.
However, it must be differentiated from true myxoid melanomas, in which Alcian blue-positive acid mucopolysaccharides are present.Cutaneous melanoma with myxoid features: twelve cases with differential diagnosis.
Hitchcock MG, McCalmont TH, White WL.
Department of Pathology, TheWake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Am J Surg Pathol 1999 Dec;23(12):1506-13 Abstract quote
Substantial myxoid change can occur in malignant melanoma, but its importance in primary disease has not been systematically evaluated.
This report describes the clinical, microscopic, histochemical, and immunohistochemical findings in 12 patients with primary cutaneous malignant melanoma with myxoid features.
The tumors presented as solitary lesions situated on the limbs (six lesions), trunk (four lesions), and head and neck (two lesions). The patients included six women and six men, whose ages ranged from 26 to 95 years, with a mean of 63 years. Breslow thickness varied from 0.48 mm to more than 12 mm, with a mean of more than 3.2 mm. Clinical follow-up for an average of 22 months showed one local recurrence, but no evidence of metastases yet. In all cases, there was a combination of myxoid and nonmyxoid areas. A minimum of 15% myxoid cross-sectional area was required for inclusion in the study, and up to 80% was observed. The pale blue mucin identified on hematoxylin and eosin staining was sensitive to hyaluronidase and positive for alcian blue in the 10 cases stained. Immunohistochemical staining was positive for S-100 in all 9 cases stained, positive for HMB-45 in 9 (90%) of 10, and negative for cytokeratin in all 9 cases in which myxoid melanoma remained in the block after previous sections.
The presence of myxoid stroma did not define a biologically significant subgroup of melanoma. Only in cases with extensive (>50%) myxoid stromal effacement of the melanoma was there a major diagnostic hurdle. The diagnosis of primary cutaneous melanoma with myxoid features was seldom as problematic as metastatic myxoid melanoma. Positive S-100 stains, negative cytokeratin immunohistochemical stains, and hyaluronidase-sensitive alcian blue staining assisted in the diagnosis of this entity.
Myxoid melanoma: Immunohistochemical studies and a review of the literature
Purvisha Patel, BA
Kimberly Levin, MD
Karen Waltz, MD
Klaus F. Helm, MD
Hershey, PennsylvaniaJ Am Acad Dermatol 2002;46:264-70 Abstract quote
Malignant myxoid melanoma (MMM) is a rarely reported variant of malignant melanoma, which can often be confused with other mucin-containing neoplasms.
A retrospective study of 3 cases of MMM and a review of the English-language literature was performed. MMM affects an older population and is frequently misdiagnosed. The major pathologic features are atypical spindle cells embedded in a myxoid stroma. Immunohistochemistry analysis of the tumor shows uniform staining of the spindle cells with S-100. In our 3 cases, there were noticeably more mast cells that could be detected with Giemsa stain and with antibody against transforming growth factor. The prognosis appears to be equivalent to other primary melanomas. Diagnosing MMM requires a high index of suspicion.
We hypothesize that mast cells and secretion of transforming growth factor stimulates fibroblast secretion of mucin, which contributes to the tumor's invasive potential.
NEVOID MELANOMA Metastatic nevoid melanoma in a 41/2-year-old child
David S. Cassarino, Douglas R. Fullen, Vernon K. Sondak and Paul H. Duray
J Cutan Pathol 2003;30:647-651 Abstract quote
Background: Childhood melanoma is a rare and controversial diagnosis.Methods: We present the case of a 4-year-old child found to have an expanding, elevated pigmented lesion on her back.
Results: The biopsy showed a symmetrical, well circumscribed lesion. However, higher magnification revealed sheets of nevoid cells infiltrating deep into the dermis, lacking maturation, and exhibiting a high mitotic rate (average 5/10 high-power field) with deep mitoses. The possibility of nevoid melanoma was raised, and re-excision and sentinel lymph node (SLN) biopsy were recommended. Two SLNs were positive for melanoma, verified by immunohistochemical staining. In order to further characterize this melanoma, we performed immunohistochemistry for the tumor-suppressor p53, proliferation marker MIB-1, and oncogenes Bcl-2, cyclin D-1, and MDM-2. Staining for p53 was diffusely positive in the primary and the metastasis; MIB-1 showed moderate proliferative rate in the primary (approximately 10%); Bcl-2 was weakly positive in the primary and showed focal staining in the metastasis; cyclin D-1 was strongly positive in the primary and metastasis; and MDM-2 staining showed scattered positive cells in both lesions.
Conclusions: These findings are consistent with a metastatic nevoid melanoma arising in the absence of predisposing disease in a young child, a distinctly unusual occurrence.
Nevoid melanoma: a clinicopathological study of seven cases of malignant melanoma mimicking spindle and epithelioid cell nevus and verrucous dermal nevus.
Wong TY, Suster S, Duncan LM, Mihm MC Jr.
Department of Pathology, Brigham and Women's Hospital, Boston, MA.
Hum Pathol 1995 Feb;26(2):171-9 Abstract quote
We report seven cases of a distinctive type of malignant melanoma characterized by a deceptively benign histological appearance with an architecture resembling that of benign melanocytic nevi on scanning magnification.
Two predominant architectural patterns were observed: a dome-shaped pattern (two specimens) and a verrucoid pattern (five specimens).
The specimens with a dome-shaped pattern of growth were characterized by a smooth epidermal surface and a proliferation of epithelioid melanoma cells with an inconspicuous intraepidermal component resembling spindle and epithelioid cell nevi (Spitz nevi). Gradual diminution in the size of dermal nests toward the bases of the lesions simulating the maturation phenomenon of benign nevi was observed; however, the dermal organization in cords and strands of melanoma cells and the persistence of cellular atypia extending to the bases of the tumors allowed their recognition as malignant melanomas.
On the other hand, the specimens with a verrucoid growth pattern consisted of broad, exophytic tumors with a verrucous epidermal surface resembling that of papillomatous dermal nevi but distinguished from them by the presence of a continuous proliferation of melanocytes along the dermal-epidermal junction and by confluent sheets of melanoma cells in the dermis without evidence of true maturation.
Clinical follow-up showed local recurrence in three patients after intervals ranging from 5 months to 5 years and regional metastasis in one patient after 2 years.
The lesions described here may constitute a serious pitfall for diagnosis because of their innocent silhouette on scanning magnification and their superficial resemblance to spindle and/or epithelioid cell nevi and benign verrucous melanocytic nevi. Proper attention to cytological detail and subtle architectural features will aid in recognizing this unusual variant of malignant melanoma.
Nevoid malignant melanoma: morphologic patterns and immunohistochemical reactivity.
McNutt NS, Urmacher C, Hakimian J, Hoss DM, Lugo J.
Department of Pathology, New York Hospital, Cornell University Medical Center, New York 10021, USA.
J Cutan Pathol 1995 Dec;22(6):502-17 Abstract quote
The term "nevoid malignant melanoma" (nevoid MM) is used here to describe rare nodular malignant melanomas that may escape detection in routine histological sections due to the lack of a prominent intraepidermal component, sharp lateral circumscription and evidence of partial maturation with descent in the dermis.
Nevoid MM mimic ordinary compound or intradermal melanocytic nevi when the melanoma cells are small, or Spitz's nevi when the cells are large. The patterns of HMB-45 staining in 12 nevoid MM were compared with those in 107 melanocytic nevi. HMB-45 staining was strong in the dermal component of the nevoid MM, even in the absence of a junctional component. In common acquired and congenital nevi, the upper dermal component stained less than the junctional component of the lesion. The deepest components of these nevi were negative. Spitz nevi and cellular blue nevi had positive dermal cells, even without a junctional component. Additional staining for a proliferation marker, such as cyclin (PCNA) or Ki-67 (with the antibody MIB-1), can help further in distinguishing a nevoid MM from a Spitz's nevus. Melanoma has strong nuclear staining throughout the lesion. In contrast, Spitz's nevi have more staining at the top of the lesion than at the bottom.
The patterns of HMB-45 and MIB-1 staining can be used along with standard histologic criteria for the diagnosis of nevoid MM. Clinicopathologic correlation is needed to distinguish some metastatic melanomas from primary nevoid MM.
Morphological Analysis of Nevoid Melanoma A Study of 20 Cases With A Review of the Literature
Artur Zembowicz, M.D.; Margaret McCusker, M.D.; Concetta Chiarelli, M.D.; Angelo P. Dei Tos, M.D.; Scott R. Granter, M.D.; Eduardo Calonje, M.D.; Phillip H. McKee, M.D.
From the Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital (M.M., P.H.M., S.R.G.), and Department of Pathology, Dermatopathology Unit, Massachusetts General Hospital (A.Z.), Boston, Massachusetts; Department of Pathology, San Martino Hospital, Belluno (C.C.), and Department of Pathology, Regional Hospital, Treviso, Italy (A.P.D.); and Department of Dermatopathology, St. John's Institute of Dermatology, St. Thomas Hospital, London, United Kingdom (E.C.).
Am J Dermatopathol 2001;23:167-175 Abstract quote
Nevoid melanoma is a rare variant of melanoma characterized by deceptive morphologic features reminiscent of a benign melanocytic nevus.
Twenty (13 nodular, 7 verrucous) nevoid melanomas were reviewed with the goal of identifying the predominant architectural patterns, cytologic features, and prognostic indicators. Although at scanning magnification, many lesions showed a strong resemblance to banal compound or dermal nevi, careful inspection in all cases demonstrated subtle pleomorphism and impaired maturation with depth, invariably accompanied by multiple dermal mitoses.
Four tumors recurred and three metastasized, with subsequent death of the patients. Follow-up information for a period of at least 3 years was available in eight cases. In this group, mortality was 37.5%, the metastasis rate was 37.5%, and the local recurrence rate was 75%, with an average tumor thickness of 2.5 mm.
We conclude that nevoid melanoma may be distinguished from a benign melanocytic nevus by a high index of suspicion, a careful analysis of architecture, and attention to cytologic features. Our data and a review of the literature do not support the notion that nevoid melanoma has a better prognosis than ordinary melanoma.
Minimal deviation and/or naevoid melanoma: is recognition worthwhile? A clinicopathological study of nine cases.Stas M, van den Oord JJ, Garmyn M, Degreef H, De Wever I, De Wolf-Peeters C.
Department of Surgical Oncology, University Hospitals, Catholic University of Leuven, Belgium.
Melanoma Res 2000 Aug;10(4):371-80 Abstract quote One to two per cent of primary cutaneous melanomas share clinical features with benign melanocytic and non-melanocytic skin lesions, and even at histology recognition of their malignant nature is problematic, mainly due to the lack of an intraepithelial component, their nodular aspect and the monotonous cell population throughout the lesion. These tumours were termed minimal deviation melanomas (MDMs) by Reed et al. and later naevoid melanomas by Schmoeckel et al. The name MDM suggests the concept of a more favourable outcome for these melanomas that do not (yet) show the typical features of fully evolved lesions able to metastasize, although naevoid melanomas seem to behave like 'common' melanomas.
In a retrospective analysis of nine cases of MDM collected from our database and followed for a median duration of 112 months, we faced similar clinical and histological pitfalls and observed local recurrence following marginal resection.
Wide excision, even of local recurrence, and therapeutic node dissection could nevertheless provide survival comparable at least to that predicted by mathematical models for patients who initially had optimal treatment.
Multiple nevoid malignant melanomas in a patient with AIDS: The role of proliferating cell nuclear antigen in the diagnosis.
Pereira F, Carey W, Shibata H, Burnier MN Jr, Wang B.
Departments of Dermatology, Pathology, and Oncology, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
J Am Acad Dermatol 2002 Aug;47(2 Pt 2):S172-4 Abstract quote The rapid growth of lesions clinically resembling compound nevi in patients with HIV/AIDS should alert physicians to the possibility of malignant melanomas. Immunohistochemistry for proliferating cell nuclear antigen can be helpful in the diagnosis of these tumors.
A case of multiple primary nevoid melanomas in a patient with HIV/AIDS is reported.
OSTEOGENIC MELANOMA
Osteogenic melanoma. A rare variant of malignant melanoma.
Lucas DR, Tazelaar HD, Unni KK, Wold LE, Okada K, Dimarzio DJ Jr, Rolfe B.
Section of Surgical Pathology, Mayo Clinic, Rochester, Minnesota 55905
Am J Surg Pathol 1993 Apr;17(4):400-9 Abstract quote Osteogenic melanoma is a rare variant of malignant melanoma; only eight cases have been reported. To characterize this unusual neoplasm further, we present four new cases.
Two patients were men and two were women (average age, 56 years; range, 47-78 years). All tumors arose from acral lentiginous melanomas. Three were subungual finger lesions and one was on the sole of the foot. All four had been previously diagnosed as or were suspected to have been primary osseous lesions. The vertical growth components were high-grade, amelanotic sarcomatoid malignancies with abundant osteoid matrix. Two tumors also had chondroblastic differentiation. Cells with epithelioid features, including prominent eosinophilic nucleoli, were discernible in every tumor.
Regional lymph node metastases in two cases retained osteocartilaginous differentiation, whereas metastatic cells in another case were purely epithelioid. Tumor cells in every case were immunoreactive for S-100 protein and vimentin, and non-reactive for cytokeratin. Two tumors also expressed HMB-45. Melanosomes were identified ultrastructurally in every tumor. Follow-up information was available on every patient. Three developed regional lymph node metastases and are currently alive and well after 14, 39, and 101 months. The fourth patient died of metastatic uterine carcinoma 20 months postoperatively. The differential diagnosis of osteogenic melanoma includes osteosarcoma as well as atypical fibro-osseous proliferations.
Clinico-pathologic features that support a diagnosis of osteogenic melanoma include junctional activity, absence of primary bony involvement, regional nodal metastases, immunoreactivity for S-100 protein and/or HMB-45, lack of cytokeratin reactivity, and ultrastructural identification of melanosomes.
Osteoid and bone formation in a nasal mucosal melanoma and its metastasis.
Hoorweg JJ, Loftus BM, Hilgers FJ.
Department of Otolaryngology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Histopathology 1997 Nov;31(5):465-8 Abstract quote AIMS: To present a literature review and a case history concerning bone and osteoid formation by a metastasizing (mucosal) melanoma.
CASE DETAILS: Osteocartilaginous differentiation and production of osteocartilaginous structures in malignant melanoma have been described only in 12 previous cases (osteoid in 11. bone in four), all of which involved dermal melanomas. Five of these melanomas were recurrent and one was associated with neurofibromatosis. The case report concerns a 75-year-old man with a nasal mucosal melanoma which was treated surgically. One year later, the patient developed a local recurrence and a cervical lymph node metastasis. Both the recurrent tumour and the metastasis showed clear evidence of bone and osteoid formation.
CONCLUSIONS: This case is the first report in the literature, clearly demonstrating bone and osteoid formation by a mucosal melanoma, not only at the primary site, but even more convincingly in a cervical lymph node metastasis.
Diagnostic lessons of mucosal melanoma with osteocartilaginous differentiation.Banerjee SS, Coyne JD, Menasce LP, Lobo CJ, Hirsch PJ.
Department of Pathology, Christie Hospital NHS Trust, Manchester, UK.
Histopathology 1998 Sep;33(3):255-60 Abstract quote AIMS: To document the clinical, morphological and immunohistochemical features of two cases of primary mucosal melanoma with osteocartilaginous differentiation.
MATERIALS AND METHODS: Two cases of mucosal melanoma with cartilage and bone formation are reported, one arising in the vagina of a 79-year-old woman and one in the oral cavity of a 67-year-old man. The vaginal melanoma exhibited only cartilaginous differentiation. The oral cavity mucosal melanoma exhibited both bone and cartilage formation and was remarkable for its multifocality, long history not associated with metastases and its lengthy manifestation of dual morphologies: some of the tumours were typical in situ/invasive melanotic melanomas whilst the others were composed of amelanotic spindle and epithelioid cells with osteocartilaginous tissue. One of the lesions exhibited in situ and invasive melanoma with transition to an osteogenic tumour in places. The patient also developed nonosteogenic malignant melanomas in the nasal cavity and nasopharynx.
CONCLUSIONS: Malignant melanomas showing foci of osteocartilaginous differentiation are extremely rare with only 18 cases reported. Primary mucosal malignant melanomas of vagina and oral cavity showing osteocartilaginous differentiation have not previously been documented. Primary vaginal melanoma with cartilaginous differentiation must be distinguished from primary malignant mixed Mullerian tumour whilst malignant change in a pleomorphic adenoma, sarcomatoid carcinoma, osteogenic sarcoma and mesenchymal chondrosarcoma are included in the differential diagnosis of primary oral mucosal melanomas with osteocartilaginous differentiation. In this context, immunohistochemistry using antibodies to cytokeratin, S100 protein and MIC2 is of value.
PARADOXICAL MATURATION Malignant Melanoma With Paradoxical Maturation
Steven M. Ruhoy, M.D.; Victor G. Prieto, M.D., Ph.D.; Susan L. Eliason, M.D.; James M. Grichnik, M.D., Ph.D.; James L. Burchette Jr., H.T. (A.S.C.P.); Christopher R. Shea, M.D.
From the Departments of Pathology (S.M.R., V.G.P., S.L.E., J.L.B., C.R.S.) and Medicine (Dermatology; V.G.P., J.M.G., C.R.S.), Duke University Medical Center, Durham, North Carolina, U.S.A.
Am J Surg Pathol 2000;24:1600-1614 Abstract quote
Typically, melanocytic nevi ``mature'' (i.e., exhibit a morphologic shift to smaller or spindle cells with progressive depth in the dermis). In contrast, most malignant melanomas (conventional MMs) lack maturation, and are composed of large pleomorphic cells throughout.
The authors describe a series of melanomas with paradoxical maturation mimicking the pattern of nevi. Seventeen primary invasive melanomas with paradoxical maturation (IMPs), two epidermotropic metastatic melanomas with maturation (EMMMs), 13 compound nevi (CN), and 14 conventional MMs without apparent maturation were analyzed by histologic, cytomorphometric, and immunohistochemical techniques. With increasing dermal depth, both CN and IMPs had smaller nuclear and cellular areas, and decreased expression of Ki-67, glycoprotein (gp)100 (with HMB-45), and tyrosinase. IMPs had significant differences from conventional MMs; namely, smaller nuclear and cytoplasmic areas (deep), and decreased expression of Ki-67 (superficial and deep), gp100 (deep), and tyrosinase (deep). IMPs also had notable differences from CN: namely, larger nuclear and cellular areas, more confluence, more mitotic figures, increased Ki-67 and gp100 expression in both the superficial and deep portions, and more melanin (deep). The two EMMMs exhibited histologic and immunohistochemical features similar to the primary IMPs. IMP, because of its mimicry of nevus, can present a diagnostic hazard.
The authors propose histologic, morphometric, and immunohistochemical criteria that facilitate recognition and accurate diagnosis of this unusual variant of melanoma.
PSEUDO-EPITHELIOMATOUS HYPERPLASIA
- Oral malignant melanoma associated with pseudoepitheliomatous hyperplasia. Report of a case.
Meleti M, Mooi WJ, van der Waal I.
Unit of Oral Pathology and Medicine, Section of Odontostomatology, Department of ENT/Dental/Ophthalmological and Cervico-Facial Sciences, University of Parma, Parma, Italy.
J Cutan Pathol. 2006 Apr;33(4):331-3. Abstract quote
Background: Pseudoepitheliomatous hyperplasia (PEH), a histological mimic of squamous cell carcinoma, is an exuberant reactive epithelial proliferation that may be induced by a variety of infectious, traumatic, inflammatory and neoplastic conditions of the skin and mucous membranes. PEH has been described in association with Spitz nevi and intramucosal nevi but not with oral malignant melanoma.
Methods and results: A case of PEH in malignant melanoma of the palate in a 46-year-old female patient has been described. A search of the English literature did not disclose any previously reported case of such event.
Conclusions: PEH associated with oral malignant melanoma is apparently very rare and most likely originates from the surface epithelium. This is in contrast with PEH in cutaneous melanoma where follicular or eccrine units have been suggested to be the origin.
- Paratumoral epidermal hyperplasia: a novel prognostic factor in thick primary melanoma of the skin?
Drunkenmolle E, Marsch WCh, Lubbe D, Helmbold P.
From the Department of Dermatology, Martin Luther University, Halle-Wittenberg, Halle (Saale), Germany.
Am J Dermatopathol. 2005 Dec;27(6):482-8. Abstract quote
There is a lack of histopathological factors to sub-stratify prognosis in pT3/4 melanoma primaries. In the presented pilot study, the prognostic significance of different clinical and histopathological parameters was studied in thick primary melanoma taking paratumoral epidermal hyperplasia (PTEH) into consideration.
Of 1632 melanoma patients in the melanoma register of the Martin Luther University Halle-Wittenberg in the years 1980 to 1987, 16 cases with tumor thickness (TT) of the primary >/= 3 mm, documented metastasis-free follow-up of 10+ years after primary therapy and available histologic sections were compared with an adequate recurrence control group (n = 62) by PTEH and standard prognostic parameters. PTEH was demonstrable in 15 of 16 patients of the metastasis-free group (PTEH penetration depth 1.42 +/- 0.82 mm/mean +/- SD) and 27 of 62 of controls (0.29 +/- 0.46 mm), P </= 0.001. Of the standard prognostic parameters, TT, sex, location, and lack of nevus association also correlated with metastasis.
In multivariate analysis, PTEH >/= 1 mm was the single independent parameter with the highest (negative) association to recurrence (odds ratio 52.3). Occurrence of PTEH might predict a more moderate course of disease in thick melanoma.
Thus, it might become an easily determinable and effective tool to sub-stratify prognosis in thick primary melanoma of the skin. Further studies are necessary to prove these findings.Cutaneous malignant melanoma associated with extensive pseudoepitheliomatous hyperplasia. Report of a case and discussion of the origin of pseudoepitheliomatous hyperplasia
Andrew J.Hanly1, MerceJorda1 and George W.Elgart2
1Department of Pathology, Jackson Memorial Hospital, Miami, Florida, USA, 2Department of Dermatology and Cutaneous Surgery, Miami, Florida, USA
J Cutan Pathol 2000;27 (3), 153-156 Abstract quote
We report a case of cutaneous malignant melanoma associated with extensive pseudoepitheliomatous hyperplasia. Pseudoepitheliomatous hyperplasia may mimic squamous cell carcinoma and may complicate the diagnosis of cutaneous melanoma. This diagnostic pitfall is important to both recognize and be cognizant of, so as to avoid diagnostic errors.
The observation of the pseudoepitheliomatous hyperplasia, in this case with an extensive proliferation of eccrine ducts, provides further evidence that cutaneous pseudoepitheliomatous hyperplasia arises within the eccrine apparatus.
Melanoma associated with pseudoepitheliomatous hyperplasia: a case series and investigation into the role of epidermal growth factor receptor.Mott RT, Rosenberg A, Livingston S, Morgan MB.
Department of Pathology, University of South Florida College of Medicine, and Department of Pathology, James A. Haley Veteran's Hospital, Tampa, Florida, USA.
J Cutan Pathol 2002 Sep;29(8):490-7 Abstract quote BACKGROUND: Pseudoepitheliomatous hyperplasia (PEH) is a reactive epithelial proliferation that occurs in response to underlying infectious, inflammatory, and neoplastic conditions. The histologic features of PEH may simulate squamous cell carcinoma and may obscure an underlying malignant process. The association of PEH with benign melanocytic nevi is well described in the literature. However, reports documenting the association of PEH with melanoma are rare.
METHODS: We examined the demographic and histologic features in 13 cases of melanoma in association with PEH. In addition, we evaluated the possible pathogenic role of epidermal growth factor receptor (EGFR) using immunohistochemical methods.
RESULTS: In each case, histologic examination revealed epidermal hyperplasia with irregular cords of well-differentiated epithelial cells extending into the dermis and infiltrating the melanoma. Although overlap existed, two patterns of epidermal hyperplasia were noted. The majority of cases (69%) exhibited acanthosis, hyperkeratosis, papillomatosis, and irregular infiltrating epithelial cords with squamous eddies. The remaining cases demonstrated basaloid acanthosis, laminated orthokeratosis, and horn cysts. EGFR immunohistochemical studies revealed strong staining within the basal layer of the epithelium, with no discernible difference between the hyperplastic epithelium overlying the melanoma cells and adjacent normal skin. Immunostaining among the melanoma cells was absent to weak in each of the cases. All cases exhibited intense EGFR immunoreactivity in macrophages underlying the epidermal lesions.
CONCLUSIONS: Melanoma is capable of presenting in a variety of histologic guises, including a pattern with PEH. The etiology of PEH, as rarely seen in conjunction with melanoma, unlikely involves EGFR and remains to be elucidated.
PSEUDOGLANDULAR
Department of Medicine, New Jersey Medical School, Newark, NJ, USA.
We describe a 64-year-old man with a primary nodular melanoma showing unusual histologic features. It consisted entirely of markedly atypical melanocytes arranged in a well-structured glandular pattern. These atypical melanocytes were positive for S-100.
This is only the second report of such histology in melanoma, and to our knowledge, the first such case consisting entirely of these features.
We review the literature on this rare variant of melanoma.RHABDOID MELANOMA
Metastatic malignant melanoma with "rhabdoid" features.
Chang ES, Wick MR, Swanson PE, Dehner LP.
Lauren V. Ackerman Laboratory of Surgical Pathology, Barnes Hospital, Washington University Medical Center, St. Louis, Missouri 63110.
Am J Clin Pathol 1994 Oct;102(4):426-31 Abstract quote The authors propose the addition of malignant melanoma to the list of extrarenal neoplasms that may be predominantly composed of polygonal cells with the cytologic features of "rhabdoid" tumor.
A review of 313 metastatic melanomas disclosed 49 examples with rhabdoid features, from which 31 had sufficient material for further pathologic and immunohistologic characterization. A control group of 46 nonrhabdoid metastatic melanomas was examined in parallel fashion. In 39% of cases, rhabdoid melanomas manifested relative deletion of S100 protein compared with the control tumors. However, there were no differences in staining with HMB-45. Vimentin immunoreactivity was concentrated in the paranuclear cytoplasm of rhabdoid melanoma cells. However, ultrastructural studies of these cases failed to show corresponding whorls of intermediate filaments and instead demonstrated paracrystalline paranuclear inclusions in profiles of rough endoplasmic reticulum.
It is concluded that metastatic rhabdoid melanoma exhibits significant morphologic similarity to other rhabdoid tumors at a light-microscopic level. However, it usually retains enough melanocytic attributes to allow for accurate diagnostic recognition. Probably because patients with metastatic melanoma have an extremely poor prognosis overall, no worsening of biologic behavior was associated with rhabdoid cytomorphologic findings in this tumor type when compared with the control cases.
Primary malignant melanoma with rhabdoid features: a histologic and immunocytochemical study of three cases.Borek BT, McKee PH, Freeman JA, Maguire B, Brander WL, Calonje E.
Department of Histopathology, UMDS (St Thomas' Campus), London, UK.
Am J Dermatopathol 1998 Apr;20(2):123-7 Abstract quote Malignant rhabdoid tumors are morphologically characterized by the presence of sheets of large polygonal cells with abundant cytoplasm containing eosinophilic inclusions. They have vesicular nuclei, often with prominent central nucleoli.
The term rhabdoid tumor was originally coined to describe a group of rare, aggressive renal neoplasms of childhood. Since then, similar lesions, so-called extrarenal malignant rhabdoid tumors have been increasingly reported. The evidence to date suggests that, at least in extrarenal locations, rhabdoid tumors do not constitute a homogeneous entity, but rather represent the shared morphological pattern of a diverse range of malignant neoplasms.
Although such rhabdoid features are not uncommon in metastatic malignant melanoma, they have only once been briefly described in a primary lesion. We report three further cases of cutaneous primary malignant melanoma with rhabdoid morphology.
SIGNET RING CELL MELANOMA
Sikl's Department of Pathology, Medical Faculty Hospital, Charles University, Bioptical Laboratory, Pilsen, Czech Republic.
The authors report a 69-year-old man with a primary nodular malignant melanoma on the shoulder showing unusual histological features. It mostly consisted of markedly neoplastic melanocytes, which exhibited abundant clear cytoplasm compressing the nuclei to the periphery, resulting in a signet-ring appearance. In other areas of the melanoma, there were focally desmoplastic and pseudoglandular patterns and oncocytoid changes.
Immunohistochemical studies showed that the tumor cells were uniformly positive only for S-100 protein and vimentin. Signet-ring cell melanoma is a rare histopathological variant of malignant melanoma with only a few described cases.
To the best of our knowledge, this is the first case reporting a combination of the signet-ring cell melanoma with desmoplastic, pseudoglandular, and oncocytoid features.
Primary cutaneous signet-ring cell melanoma: a clinico-pathologic and immunohistochemical study of two cases.
Rutten A, Huschka U, Requena C, Rodriguez-Peralto JL, Requena L.
Dermatopathologisches Gemeinschaftpraxis, Friedrichshafen, Germany.
Am J Dermatopathol. 2003 Oct;25(5):418-22. Abstract quote
Signet-ring cell malignant melanoma is a rare histopathologic variant of malignant melanoma with only a few described cases. We report the clinical, histopathological, and immunohistochemical features of two cases of primary cutaneous signet-ring cell malignant melanoma.
Neoplastic melanocytes showed abundant clear cytoplasm compressing the nuclei to the periphery, sometimes resulting in a signet-ring appearance. Immunohistochemically, neoplastic melanocytes in both cases expressed immunoreactivity for the usual melanocytic markers S-100 protein and Melan-A, although only the second case resulted HMB-45 positive.We review the literature about this rare cytologic variant of malignant melanoma and discuss the differential diagnosis with other cutaneous neoplasms that may show a signet-ring cell appearance of their neoplastic cells.
Signet-ring cell melanoma. A rare morphologic variant of malignant melanoma.Sheibani K, Battifora H.
Division of Pathology, City of Hope National Medical Center, Duarte, California 91010.
Am J Surg Pathol 1988 Jan;12(1):28-34 Abstract quote We recently received in consultation a lymph node involved by metastatic malignant melanoma with unusual and previously undescribed morphologic features. The neoplastic cells had a striking signet-ring appearance, similar to the signet-ring cells normally seen in mucin-producing adenocarcinoma and signet-ring cell lymphoma. Review of our consultation files of malignant melanomas revealed an additional case in which the neoplastic cells had a signet-ring cell appearance.
Electron microscopic studies revealed that formation of signet-ring cells is caused by the presence of abundant vimentin filaments in the cytoplasm of neoplastic cells.
Immunologic studies using a series of monoclonal and polyclonal antibodies, including S-100 protein, HMB-45, vimentin, cytokeratin, leukocyte common antigen, and Leu-M1, on both cases clearly established the diagnosis of this morphologically unusual variant of malignant melanoma for which we propose the term "signet-ring cell melanoma."
Primary invasive signet-ring cell melanoma.Breier F, Feldmann R, Fellenz C, Neuhold N, Gschnait F.
Department of Dermatology, Vienna-Lainz, Austria.
J Cutan Pathol 1999 Nov;26(10):533-6 Abstract quote The histopathological variants of malignant melanoma include the common type (lentigo maligna, superficial spreading melanoma, nodular melanoma, acrolentiginous melanoma), spindle cell, desmoplastic, balloon cell, pleomorphic (fibrohistiocytic), myxoid, small cell melanoma and malignant blue nevus. Recently, signet-ring cell melanoma was introduced as an additional cytologic variant.
We describe a 72-year-old patient with a primary signet-ring cell melanoma of the skin located on the upper arm. Histopathologic examination disclosed a melanocytic tumor extending from the epidermis to the deep reticular dermis. Numerous pleomorphic tumor cells showed large, intracellular vacuoles and oval to spindle-shaped nuclei at their periphery. Mitotic figures and multinucleated melanocytes were also observed. Some of the signet-ring cells exhibited cytoplasmatic periodic acid-Schiff (PAS)-positivity.
Immunohistochemistry showed positive reaction of the tumor cells for S-100, HMB-45 protein and vimentin, confirming their melanocytic differentiation. Tumor cells were negative for cytokeratins, epithelial membrane antigen (EMA), and carcinoembryonic antigen (CEA). The signet-ring cell melanoma disclosed an invasion to Clark Level IV and tumor thickness of 2.2 mm.
Signet-ring cell melanoma is a rare morphologic variant of melanoma. Its recognition is important for differentiation from other tumors featuring signet ring cells.
SMALL CELL MELANOMA Small cell (naevoid) melanoma: a clinicopathologic study of 131 cases.
Kossard S, Wilkinson B.
Skin and Cancer Foundation, Sydney, Australia.
Australas J Dermatol 1997 Jun;38 Suppl 1:S54-8 Abstract quote
One hundred and thirty-one small cell melanomas were reviewed with respect to clinical data submitted with each specimen and the histological pattern of each tumour.
Of the small cell melanomas, 80% developed in individuals over the age of 50 years. There was a 2:1 male predominance with 58% of the tumours in men occurring on the back. All but one melanoma showed a lentiginous intraepidermal pattern. The dermal component was characterized by cords and nests of hyperchromatic melanocytes associated with interstitial fibrosis.
Small cell melanomas may be recognized as thin lesions and are commonly located in chronic sun-damaged skin of elderly individuals. They may represent a special naevoid variant of lentigo maligna melanoma.
Small cell malignant melanoma: a variant of naevoid melanoma. Clinicopathological features and histological differential diagnosis.
Blessing K, Grant JJ, Sanders DS, Kennedy MM, Husain A, Coburn P.
Department of Pathology, Aberdeen University, Foresterhill, UK.
J Clin Pathol 2000 Aug;53(8):591-5 Abstract quote
AIMS: To describe the clinical and histopathological features of a rare variant of naevoid melanoma, small cell melanoma, and discuss the histological differential diagnoses.
METHODS: The clinical and histological features of cases of malignant melanoma with the histological features of small (non-Merkel like) melanoma were reviewed and documented. In addition, five cases had available material for immunohistochemistry and this was performed using antibodies to the S100 protein and melan-A, and the HMB-45 antibody.
RESULTS: There were 15 cases of small cell melanoma from 14 (10 female, four male) patients, aged between 30 and 77 (mean, 48.6) years. The trunk was the most common location. In more than half the cases, the provisional diagnosis was melanoma/borderline lesion. All shared similar histological appearances of an intraepidermal component of in situ melanoma and a dermal component of nests of cells with hyperchromatic nuclei and scanty cytoplasm, usually in tightly packed nests. All components (junctional and intradermal) of the lesions investigated by immunohistochemistry were positive both for S100 protein and melan-A. All junctional components were positive with HMB-45, but with variable staining of the dermal components with this antibody.
CONCLUSIONS: Small cell malignant melanoma is postulated to be a distinct histopathological entity and a rare variant of naevoid melanoma. Such lesions can be difficult to interpret and easily missed at scanning magnification because the cells of the dermal component mimic benign naevus cells.
SPITZOID MELANOMA Spitzoid malignant melanoma in teenagers: an entity with no better prognosis than that of other forms of melanoma.
Fabrizi G, Massi G.
Department of Dermatology, Catholic University Medical School, Largo F. Vito, 1, Rome, Italy.
Histopathology 2001 May;38(5):448-53 Abstract quote AIMS: A rare form of melanoma in teenagers closely simulates Spitz naevus and is claimed to have a good prognosis. The aim of this study is to identify the clues for a confident diagnosis of this entity and to confirm the peculiarly good prognosis.
METHODS AND RESULTS: Two cases of melanoma with Spitzoid features were compared with Spitz naevus and it was found that the major distinctive criteria are: mitoses and single cell necrosis in the deepest part of the lesion, cellular and particularly nuclear and nucleolar pleomorphism, and growth pattern in solid sheets of cells. More subtle clues were the asymmetric distribution of pigment and the thinning of the epidermis with parakeratosis and exudate in the cornified layer. Both of the lesions reached the mid-dermis. There was a fatal outcome in both patients after generalized metastatic spread. The metastatic disease in one of the cases appeared 15 years after the excision of the primary lesion.
CONCLUSIONS: Spitzoid melanoma in teenagers can be distinguished from Spitz naevus if strict criteria are followed. Spitzoid melanoma does not show a better prognosis than other types of melanoma if the follow-up is prolonged enough.
SPECIAL STAINS/
IMMUNO-
PEROXIDASE/
OTHERCHARACTERIZATION TYPICAL MELANOMA MARKERS S-100
HMB-45
MART-1 (Melanoma associated with reactive T-cells)
Department of Pathology and Laboratory Medicine, Geffen/UCLA School of Medicine, Los Angeles, CA 90095-1732, USA.
Melanoma has a wide spectrum of histologic features which mimic epithelial, hematologic, mesenchymal, and neural tumors. Immunohistochemistry has been the primary tool to distinguish melanomas from these other tumors; it has also been studied for use as an adjunct to distinguish benign and malignant melanocytic tumors and to elucidate prognosis. Furthermore, there has been extensive effort to find a suitable marker to differentiate spindle cell and desmoplastic melanoma from other tumors.
We have reviewed the literature investigating melanocytic differentiation markers, proliferation markers, immunomodulatory markers, signaling molecules, and nerve growth factors and receptors. Despite the proliferation of immunohistochemical markers, S-100 remains the most sensitive marker for melanocytic lesions, while markers such as HMB-45, MART-1/Melan-A, tyrosinase, and MITF demonstrate relatively good specificity but not as good sensitivity as S-100.
No marker has proven useful in distinguishing spindle cell and desmoplastic melanomas from other tumors. Ki67 remains the most useful adjunct in distinguishing benign from malignant melanocytic tumors.
None of the markers reviewed has been shown conclusively to have prognostic value for melanocytic neoplasms.
Am J Dermatopathol. 2005 Oct;27(5):401-6. Abstract quote
The new monoclonal antibody SM5-1 has been shown to have significant advantages in immunohistochemistry of melanoma over currently used antibodies such as HMB-45 or anti-S100.
In this study we compared the immunohistological staining pattern of SM5-1 with that of the more recently described antibodies A103 (anti-MART-1) and T311 (anti-Tyrosinase) in 344 paraffin-embedded melanoma specimens, consisting of 101 primary melanomas (77 SSM, 16 NM, 6 ALM, 2 LMM) and 243 melanoma metastases. The overall reactivity of SM5-1 for all the specimens was 92% (318/344) compared with 83% (285/344) for MART-1 and 71% (245/344) for Tyrosinase. Staining of melanoma metastases with SM5-1 was found in 91% (222/243), but only in 77% (187/243) with A103 and 63% (154/243) with T311, respectively. Staining with SM5-1 was more homogenous with 196 of 243 (80%) of metastatic lesions showing 50% or more positively stained cells within the lesions, whereas A103 and T311 did so in 141 of 243 (58%) or 117 of 243 (48%) of the lesions.
With regard to staining intensity of SM5-1, 157 of 243 (64%) showed a strong or very strong staining intensity, whereas A103 and T311 did so in 85 of 243 (35%) or 70 of 243 (29%) of the lesions. Staining intensity and percentage positivity correlated well for SM5-1, because from the 58 very strong positive metastases 55 showed staining in more than 75% of the cells within a lesion. Importantly, 52 of 56 MART-1-negative metastases and 81 of 89 Tyrosinase-negative metastases were positive for SM5-1. Thirty-eight metastases (15.6%) were negative for both A103 and T311. Of those, 35 (92.1%) were positive for SM5-1, demonstrating the value of SM5-1 in identifying melanoma-associated antigen-negative lesions.
We conclude that SM5-1 could be of value in immunohistochemistry of melanoma.
False-positive Rate of the Immunoperoxidase Stains for MART1/MelanA in Lymph Nodes.
Yan S, Brennick JB.
Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH.
Am J Surg Pathol. 2004 May;28(5):596-600.
MART1 and MelanA are considered sensitive markers of melanocytic differentiation and are used to increase the detection of melanoma micrometastases in sentinel lymph nodes (SLNs). However, the false-positive rates of these two antibodies have not been adequately evaluated.
We examined 217 lymph nodes (LNs) from patients with no history of melanoma: 117 SLNs from breast cancer patients, 79 LNs from other nonmelanoma malignancy patients, and 21 reactive LNs. Capsular melanocytic nevi were identified in 5 SLNs from 5 breast cancer patients by both antibodies. Two of these 5 SLNs with capsular nevus also contain MART1- and MelanA-positive cells within the lymph node parenchyma. Individual immunoperoxidase-positive cells were also identified within the parenchyma of lymph nodes without capsular nevus (9 LNs with MART1 and 3 LNs with MelanA). The false-positive rate is 5.1% for MART1 and 2.4% for MelanA.
In conclusion, MART1- or MelanA-positive cells may be present in lymph nodes from patients without melanoma. Therefore, MART1- and MelanA-positive cells in SLNs from melanoma patients, without corresponding atypia or hematoxylin and eosin findings, should be interpreted with caution.
HMB-45, S-100, NK1/C3, and MART-1 in metastatic melanoma.
Zubovits J, Buzney E, Yu L, Duncan LM.
Department of Pathology, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada.
Hum Pathol. 2004 Feb;35(2):217-23. Abstract quote
The diagnosis of melanoma metastatic to lymph node remains a difficult problem given its histological diversity.
We examined the staining patterns of S-100, NK1/C3, HMB-45, and MART-1 (DC10) in melanoma metastases to lymph nodes. Immunohistochemical stains were performed on tissue sections of 126 formalin-fixed lymph nodes from 126 patients with an established diagnosis of metastatic melanoma. A total of 98% of cases (123 of 126) stained positive for S-100, 93% (117 of 125) stained positive for NK1/C3, 82% (103 of 126) stained positive for MART-1, and 76% (95 of 125) stained positive for HMB-45. The distribution and intensity of staining varied among these markers. A diffuse staining pattern, defined as >50% of tumor cells stained, was observed in 83% of MART-1-positive cases but in only 56% of S-100-positive cases, 48% of NK1/C3-positive cases, and 34% of HMB-45-positive cases. A maximally intense signal was almost always observed for MART-1 (83% of positive cases) but was rarely observed for NK1/C3 (20%). S-100 and HMB-45 showed maximally intense staining in 50% and 54% of cases, respectively. S-100 and NK1/C3 stained both histiocytes and melanocytes, whereas MART-1 and HMB-45 stained only melanocytes. Seventy-eight cases (63%) stained positive for all 4 markers, 17 cases (14%) stained for all markers except HMB-45, 13 cases (10%) stained for all markers except MART-1, 6 cases (5%) stained only with S-100 and NK1/C3, 4 cases (3%) stained only with S-100 and HMB-45, and 2 cases stained for all markers except S-100. One case each stained for the following: only S-100, only S-100 and HMB-45, and all markers except NK1/C3. One case exhibited absence of staining for any of these markers.
We demonstrate that lymph node metastases of melanoma are heterogeneous with regard to tumor marker expression. S-100 and NK1/C3 were the most sensitive stains for detecting metastatic melanoma; however, they both also stain other nontumor cells in lymph nodes. MART-1 did not stain histiocytes and exhibited a more frequently intense and diffuse staining pattern than NK1/C3. HMB-45 was less sensitive and demonstrated less diffuse staining than MART-1.Expression of Melanocytic Differentiation Markers in Malignant Melanomas of the Oral and Sinonasal Mucosa
Manju L. Prasad, etal.
Am J Surg Pathol 2001;25:782-787 Abstract quote
Malignant melanomas of the oral and sinonasal mucosa are rare tumors. Amelanotic variants can, on occasion, be difficult to recognize by routine light microscopy. Immunohistochemical studies may be needed for a final diagnosis. A number of new monoclonal antibodies to melanocytic differentiation antigens have been studied recently on primary cutaneous and metastatic melanoma. However, little is known about these antibodies for the diagnosis of mucosal melanomas.
In this study the authors analyzed 79 oral and sinonasal mucosal melanomas of 65 patients. A total of 35 tumors originated from the oral mucosa (21 primary tumors, eight local recurrences, and six metastases) and 44 melanomas were from the sinonasal tract (27 primary tumors, nine local recurrences, and eight metastases).
Immunohistochemical studies were performed on paraffin-embedded tissues, using the following antibodies: anti-S-100 protein, T311 (anti-tyrosinase), A103 (anti-Mart-1/Melan-A), D5 (antimicrophthalmia-associated transcription factor), and HMB-45 (anti-gp100). Of 35 oral mucosal tumors, 34 (97%) were positive with anti-S-100 protein, 33 (94%) with T311, 30 (85%) with A103, 26 (74%) with D5, and 25 (71%) with HMB-45. All five desmoplastic melanomas of the oral mucosa were positive for S-100 protein, four for tyrosinase, and one each for HMB-45 and A103. No desmoplastic melanoma was positive with D5. All 44 sinonasal melanomas were positive for tyrosinase and Mart-1/Melan-A (100%). Forty-three (98%) were positive with HMB-45, 42 (95%) with anti-S-100 protein, and 40 (91%) with D5.
These results reveal that T311 is the most sensitive marker for sinonasal melanomas and closely approaches the sensitivity of anti-S-100 protein for oral mucosal melanomas. For desmoplastic mucosal tumors, anti-S-100 protein remains the most sensitive marker.
Immunoprofile of MITF, Tyrosinase, Melan-A, and MAGE-1 in HMB45-Negative Melanomas
Xiaowei Xu, M.D. , Ph.D. ; Albert Y. Chu, M.D. , M.H.S. ; Terry L. Pasha, B.A. ; David E. Elder, M.B. , Ch.B. ; Paul J. Zhang, M.D.
From the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.
Am J Surg Pathol 2002;26:82-87 Abstract quote
A majority of desmoplastic melanomas and some of the other forms of melanomas are S-100 positive and HMB45 negative; this pattern of immunoreactivity is similar to certain nerve-derived tumors such as malignant peripheral nerve sheath tumor.
In this study the immunostaining profile of HMB45-negative malignant melanomas was evaluated by a panel of antibodies against markers associated with melanoma and melanocytic differentiation, including microphthalmia transcription factor, tyrosinase, Melan-A, and MAGE-1. Immunodetection was performed on paraffin sections of 22 cases of HMB45-negative malignant melanomas (including 8 spindle cell melanomas, 8 desmoplastic melanomas, and 6 epithelioid melanomas), 8 HMB45-and S-100-positive malignant melanomas, 15 malignant peripheral nerve sheath tumors, 16 schwannomas, and 11 neurofibromas.
Of eight HMB45-positive malignant melanomas, all were positive for Melan-A, tyrosinase, and melanocyte-specific transcription factor, and three were positive for MAGE-1.
In the 14 HMB-45 negative, nondesmoplastic melanomas, melanocyte-specific transcription factor was positive in 9, Melan-A in 9, tyrosinase in 6, and MAGE-1 in 11.
In eight desmoplastic malignant melanomas, MAGE-1 was positive in three, and all other markers were negative. The five markers tested were negative in all but two schwannomas, one with focal melanocyte-specific transcription factor and the other with tyrosinase and weak MAGE-1 reactivity.
MAGE-1, melanocyte-specific transcription factor, tyrosinase, and Melan-A are useful markers in the diagnosis of malignant melanocytic lesions when HMB45 is negative. MAGE-1 may be useful in differentiating melanocytic lesions from nerve-derived lesions, but its sensitivity is relatively low. The immunostaining profile of desmoplastic malignant melanomas more closely resembles that of malignant peripheral nerve sheath tumor than that of other types of malignant melanoma. Melanocyte-specific transcription factor is not a useful marker for desmoplastic melanoma.
Expression of melanocyte differentiation antigens and ki-67 in nodal nevi and comparison of ki-67 expression with metastatic melanoma.Lohmann CM, Iversen K, Jungbluth AA, Berwick M, Busam KJ.
Am J Surg Pathol 2002 Oct;26(10):1351-7 Abstract quote Nodal nevi represent a potential diagnostic pitfall in the analysis of lymph nodes. They may be confused with metastatic melanoma or carcinoma. Although several morphologic guidelines exist for the recognition of nodal nevi, on occasion immunohistochemical studies may be helpful for diagnosis, especially when melanocytes extend into the lymph node parenchyma.
To learn more about the immunohistochemical profile of nodal nevi we examined 15 nodal nevi for the expression of S-100 protein, gp100 (HMB-45), Melan-A/MART-1 (A103), and tyrosinase (T311), and we studied the expression of Ki-67 (MIB-1) in nodal nevi and 40 melanoma metastases (35 lymph node and five cutaneous metastases). All nodal nevi were homogeneously immunoreactive for S-100 protein, tyrosinase, and Melan-A/MART-1. Two nodal nevi were focally positive for gp100. Fourteen of 15 nodal nevi were completely negative for Ki-67. One large cellular nodal nevus showed nuclear labeling in <0.2% of melanocytes. All metastases showed MIB-1 labeling. However, the percentage of labeled tumor cells varied widely, ranging from 2% to 80%.
These results demonstrate that MIB-1 and HMB-45 are helpful reagents for the distinction of nodal nevi from melanoma. Immunohistochemistry for S-100 protein, Melan-A/MART-1, or tyrosinase facilitates the recognition of melanocytes but does not distinguish between nodal nevus and metastatic melanoma.
Matthew V. Sheffield, MD,1 Herman Yee, MD, PhD,2 Christine C. Dorvault, MD,3 Katherine N. Weilbaecher, MD,4 Isam A. Eltoum, MD,1 Gene P. Siegal, MD,5 David E. Fisher, MD,6 and David C. Chhieng, MDAm J Clin Pathol 2002;118:930-936 Abstract quote
We determined the sensitivity and specificity of 3 novel antibodies (microphthalmia transcription factor [Mitf], Melan-A, and tyrosinase) as markers for melanoma in cytologic preparations and compared the results with those of commonly used markers (S-100 protein [S-100] and HMB-45).We stained 72 cell blocks from 40 patients with melanoma and 32 with nonmelanocytic malignant neoplasms with antibodies against S-100, HMB-45, Mitf, Melan-A, and tyrosinase. Histologic correlation was available in more than 95% of cases. Nuclear staining for Mitf and cytoplasmic staining for S-100, HMB-45, Melan-A, and tyrosinase in more than 10% of tumor cells was considered positive. All 3 novel markers demonstrated sensitivity superior to S-100 and HMB-45. HMB-45, Melan-A, and Mitf demonstrated specificities of 97%. S-100 protein and tyrosinase were less specific.
Sensitivity and specificity for the combination Mitf+/Melan-A+ were 95% and 100%, respectively, whereas they were 80% and 100%, respectively, for S-100+/HMB-45+. Mitf, Melan-A, and tyrosinase are sensitive markers for epithelioid melanoma. Mitf and Melan-A seem more specific than S-100 and tyrosinase.
An antibody panel consisting of Mitf and Melan-A is superior to a panel of S-100 and HMB-45 in the diagnosis of melanoma in cytologic specimens.
CLUSTERIN
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Clusterin is a pleiotrophic glycoprotein that has been implicated in diverse physiologic processes. Recent studies of gene expression profiling found clusterin to be expressed in desmoplastic variants of malignant melanoma.
In this study, we extended those observations and examined clusterin expression in a larger number of primary as well as in metastatic melanomas and melanocytic nevi. We used tissue microarray panels as well as selected conventional sections from formalin-fixed and paraffin-embedded tissue blocks. Positive staining for clusterin was found in seven of 21 (30%) primary desmoplastic and three of 21 (7%) non-desmoplastic melanoma. Among metastatic tumors, clusterin expression was found in five of 37 tumors (13.5%). Clusterin expression was not seen in melanocytes of normal skin or in any of the 10 melanocytic nevi tested. Clusterin expression was not entirely restricted to melanoma; it was also seen in a few non-neoplastic tissues, including perifollicular fibroblasts, occasional sebocytes, and the epithelial cells lining sebaceous duct and the isthmus of the hair follicle.
Our findings confirm the observation that clusterin can be expressed in melanoma, in particular primary desmoplastic melanoma. However, clusterin appears to be present only in a minority of melanomas.HMB-45 Rapid HMB-45 staining in Mohs micrographic surgery for melanoma in situ and invasive melanoma
Gregg M. Menaker, etal.
J Am Acad Dermatol 2001;44:833-6. Abstract quote
Background: Accurate interpretation of frozen sections in the treatment of melanoma by Mohs micrographic surgery may be difficult.
Objective: Our purpose was to review the literature on the role of Mohs micrographic surgery in the treatment of melanoma and to demonstrate the added benefits of using rapid HMB-45 staining in Mohs micrographic surgery for the treatment of melanoma.
Methods: Twenty cases of melanoma were included in our study. Histologic diagnosis in each case was made by means of excisional biopsy specimens and permanent sections. Mohs micrographic surgery was performed with 3-mm margins used for each stage. Each Mohs frozen section was stained with HMB-45. In addition, routine frozen sections stained with hematoxylin-eosin were also prepared for comparison. All tissues were also sent for permanent sections. These permanent sections were cut similarly to Mohs-oriented sections because they were sectioned horizontally. Since they were serving as the standard, no staining with HMB-45 was performed on these permanent sections. Further stages with 3-mm margins were taken until tissues stained negative. Frozen sections were compared with permanent sections at each stage of resection.
Results: Eleven of the 20 cases stained positive with HMB-45 antibody on the first Mohs stage. These results were consistent with findings on permanent sections. Ten of the 11 cases were cleared by the first stage. One of the 11 cases required 3 stages because margins were not cleared and the specimens stained HMB-45 positive. However, permanent sections in this case revealed no tumor in the second stage. Nine of 20 cases did not stain with HMB-45 on the first layer of Mohs excision. This was consistent with findings on permanent sections.
Conclusion: HMB-45 staining serves as a rapid technique to aid in the interpretation of frozen sections during Mohs micrographic surgery in the treatment of melanoma.
MAGE (ANTI-MAGE ANTIBODY B27) Is MAGE-1 Expression in Metastatic Malignant Melanomas Really Helpful?
Gajjar NA, Cochran AJ, Binder SW.
Department of Pathology, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA.
Am J Surg Pathol. 2004 Jul;28(7):883-8. Abstract quote
Melanoma antigen-encoding gene (MAGE-1) has been introduced as a sensitive immunohistochemical marker to aid in the diagnosis of malignant melanomas, in particular, those that are HMB-45 negative.
Our goal was to determine the consistency of positive staining in melanomas on the basis of the usefulness of MAGE-1 in comparison with tyrosinase and MART-1. We studied 56 malignant melanomas using immunohistochemical markers to MAGE-1, tyrosinase, MART-1, HMB-45, and S-100. Six of 17 HMB-45-negative cases were strongly positive for MAGE-1 (35%), while 9 of 39 HMB-45-positive cases were positive for MAGE-1 (23%), overall, 27% positivity (n = 56). Tyrosinase and MART-1 were both strongly positive in 42 of 56 cases (75%). Fifty-two of 56 cases were strongly positive for S-100 (93%).
We found MAGE-1 to be less sensitive than described in other studies, and overall, not very helpful, especially as a predictor of aggressive behavior. Although MAGE-1 expression has been considered as a target for immunomodulation therapy, our findings do not indicate consistent expression of this epitope in a majority of melanomas. S-100 protein, tyrosinase, and MART-1 immunomarkers were more frequently positive in our melanoma cases and appear to constitute a useful panel of markers to aid in the diagnosis of metastatic malignant melanomas, especially in patients with an unknown primary.The anti-MAGE antibody B57 as a diagnostic marker in melanocytic lesions.
Kazakov DV, Kutzner H, Rutten A, Michal M, Requena L, Burg G, Dummer R, Kempf W.
Unit of Dermatopathology, Department of Dermatology, University Hospital, Zurich, Switzerland.
Am J Dermatopathol. 2004 Apr;26(2):102-7. Abstract quote
The differentiation of melanoma from certain benign melanocytic lesions on histologic grounds alone may sometimes be difficult. The anti-MAGE antibody 57B was suggested to be a useful adjunct in differentiating melanoma from nevi.
Our aim was to study MAGE immunoreactivity with B57 in benign melanocytic lesions that have not been investigated to this end so far. One hundred six benign melanocytic lesions were stained with the monoclonal antibody 57B. They included deep-penetrating nevus (n = 6), desmoplastic nevus (n = 9), halo nevus (n = 10), persistent melanocytic nevus (n = 12), common blue nevus (n = 17), cellular blue nevus (n = 8), cellular blue nevus with microalveolar pattern (n = 3), desmoplastic cellular blue nevus (n = 6), epithelioid blue nevus (n = 2), sclerotic blue nevus (n = 3), and clonal nevus (n = 30). Fifty-two lesions (49%) demonstrated various patterns of MAGE immunoreactivity, with clonal nevi and deep-penetrating nevi showing the most consistent staining.
In conclusion, MAGE immunoreactivity detected by the monoclonal antibody 57B in formalin-fixed, paraffin-embedded tissue can be observed in benign melanocytic lesions, and therefore this antibody cannot be used in the differential diagnosis between melanoma and nevi.MART-1 (MELAN-A) A comparative immunohistochemical study of MART-1 expression in Spitz nevi, ordinary melanocytic nevi, and malignant melanomas.
Bergman R, Azzam H, Sprecher E, Manov L, Munichor M, Friedman-Birnbaum R, Ben-Itzhak O.
Department of Dermatology, Rambam Medical Center, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
J Am Acad Dermatol 2000 Mar;42(3):496-500 Abstract quote
BACKGROUND: The histopathologic differential diagnosis of Spitz nevus (SN) from malignant melanoma (MM) may be difficult.
OBJECTIVE: We attempted to elucidate the pattern of expression of a newly recognized melanocyte-specific melanosomal protein MART-1 in routinely processed specimens of SNs, MMs, and ordinary melanocytic nevi (MNs) and to see whether it can help to differentiate between them.
METHODS: Twenty SN, 22 MM, and 27 ordinary MN were immunostained with anti-MART-1 monoclonal antibody (clone A103).
RESULTS: All SNs, MNs, and MMs demonstrated cytoplasmic staining for MART-1 in some of their tumor cells, of which 17 of 20 (85%) and 24 of 27 (89%) of SN and MN, respectively, demonstrated positive stainings in more than half of their tumor cells, as compared with only 10 of 22 (45%) of the MM (P <.05). The majority of lesions in all 3 types of tumors showed a homogeneous mode of staining, although MM tended to show a more heterogeneous pattern. A consistent pattern of stratification of staining with progressive descent into the dermis was not demonstrated in these tumors.
CONCLUSION: MART-1 does not differentiate between SN, MM, and ordinary MN in a consistent pattern, but it may be used as a marker for these tumors.
Staining of melanocytic neoplasms by melanoma antigen recognized by T cells.
Mehregan DR, Hamzavi I.
Pinkus Dermatopathology Laboratory, Monroe, Michigan 48161, USA.
Am J Dermatopathol 2000 Jun;22(3):247-50 Abstract quote
We stained benign melanocytic nevi and malignant melanoma with antibodies to melanoma antigen recognized by T cells (Mart-1) to determine if this was useful in differentiating benign from malignant melanocytic neoplasms.
Forty-five primary malignant melanomas and 71 benign melanocytic nevi were stained with antibodies to Mart-1. Two cases of malignant melanoma metastatic to lymph node and three cutaneous metastases of malignant melanoma were also stained. The degree of staining was graded into diffuse positive staining, focal positive staining, and negative staining. Thirty-six of 45 primary malignant melanomas stained diffusely positive with antibodies to Mart-1. This included three of five desmoplastic malignant melanomas that showed positive staining. Four melanomas showed faint or focal positive staining. One of two metastases to lymph node showed strong positive staining and one showed no staining. All three cutaneous metastases showed diffuse positive staining. Sixty-one of 71 melanocytic nevi showed no staining or faint staining with antibodies to Mart-1. Ten of 71 melanocytic nevi showed strong positive staining. The majority of these were congenital nevi. Staining with antibodies to Mart-1 antigen was a useful marker of malignant melanoma. However, staining may also be seen in benign melanocytic neoplasms.
The presence or absence of staining for Mart-1 antigen cannot be used to differentiate benign melanocytic nevi from malignant melanocytic tumors.
ADDITIONAL STAINS-ALPHABETICAL CD34
J Cutan Pathol. 2005 Nov;32(10):685-9. Abstract quote
Background: The histological diagnosis of malignant melanoma can be challenging. Immunohistochemical techniques may define a critical role in certain cases, specifically in establishing a primary diagnosis of melanoma. CD34 is a hemopoietic stem cell antigen expressed in bone marrow and endothelial cells, and may also be expressed in vascular and spindle cell tumors; it is generally negative in malignant melanoma.
Case report: An 83-year-old white female presented with a 3-4 mm area on her right upper back, which had been present for several years. Histologic sections showed a polypoid distortion by sheets and nodules of transformed amelanotic melanocytes lying in intimate apposition to an attenuated epidermis without a concomitant radial growth phase. Tumor cells were extensively S-100 and CD34 positive and showed focal immunoreactivity with melan-A and HMB-45.
Discussions: We present a case of malignant melanoma of nodular subtype, which strongly expressed CD34. The spectrum of abnormal phenotypes in malignant melanoma is reviewed, and a possible explanation for the presence of CD34 is discussed. This case demonstrates the potential of malignant melanoma to express CD34, defining an infrequently recognized aberrant phenotype. Whether or not expression of this marker is associated with a more aggressive clinical course remains to be determined.CD34 expression in desmoplastic melanoma
Mai P. Hoang1, M. Angelica Selim2, Rex C. Bentley2, James L. Burchette2 and Christopher R. Shea2
1 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA, 2 Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA
Journal of Cutaneous Pathology 2001;28 (10), 508-512 Abstract quote
Background: Primary and metastatic malignant melanoma can simulate various soft tissue tumors, including dermatofibrosarcoma protuberans (DFSP). Expression of CD34, a marker characteristic of DFSP, as well as other spindle cell tumors, has not been previously documented in malignant melanoma.
Methods: We present here an unusual case of metastatic malignant melanoma with a strong histologic resemblance to DFSP and also CD34 expression.
Results: The patient, a 72-year-old man with a history of an invasive malignant melanoma of the skin of the right lower abdomen, presented with a right axillary mass. Histologic sections revealed intersecting fascicles of spindle cells with nuclear pleomorphism and numerous mitotic figures, diffusely infiltrating the adipose tissue in a pattern closely simulating that seen in DFSP. In other foci, epithelioid neoplastic cells with abundant cytoplasm, prominent nucleoli, nuclear pseudoinclusions, and focal cytoplasmic melanin pigment were seen. The neoplastic spindle cells were strongly labeled by two anti-CD34 monoclonal antibodies. Some of the spindle cells and the majority of the epithelioid neoplastic cells expressed S-100 protein and focally tyrosinase. The tumor cells were negative for HMB-45 and MART-1. Melanosomes were not identified by electron microscopy.
Conclusion: This case demonstrates the potential of melanoma to simulate DFSP closely, on both morphologic and immunohistochemical grounds, and confirms the utility of employing a broad panel of immunohistochemical reagents in problematic cases.
CD99
Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Background: A true diagnostic marker differentiating Spitz nevi (SN) from spitzoid melanoma (sMM) has been elusive. CD99, a transmembrane glycoprotein, believed to play a role in many neoplastic processes, has yet to be investigated in this regard. Recently, the expression of CD99 has been shown in 60% of primary melanomas. Other studies exploring the expression of CD99 in melanocytic lesions have not been performed. Here, we evaluate the presence of CD99 in these two histologically difficult to differentiate entities.
Methods: Cases of sMM were selected based on the presence of key microscopic words: spitz, spindled and/or epitheliod. In addition, all the cases of SN over the past 7 years were retrieved. Each case was stained with anti-human CD99 and analyzed for the presence of CD99 staining.
Results: Fifteen of 27 cases (56%) of sMM expressed CD99 compared with only 3 of 58 cases (5%) of SN.
Conclusions: This study shows 56% of sMM and only 5% of SN express CD99. Eight of the sMM showed strong diffuse staining, a pattern not seen in any of the SN. This study does not elucidate the role that CD99 plays in these melanocytic processes; however, it does show that CD99 can be a useful tool in distinguishing sMM from SN.
Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Background: CD99, also known as p30/32, is a glycoprotein product of the MIC2 gene. It was originally utilized in immunohistochemistry as a unique marker for Ewing sarcoma, other primitive neuroectodermal tumors, and subsequently in other tumors. Its expression in malignant melanoma (MM) has not been well documented, with just two isolated cases of MM recently reported. Recent studies have documented CD99 expression in a significant percentage of atypical fibroxanthomas (AFX), posing potential diagnostic problems in differentiating these two entities. As mistaking MM for AFX based on immunohistochemical staining pattern has significant consequences, we sought to determine the percentage of invasive MM in our archives that have this staining pattern.
Methods: Seventy-eight cases of invasive melanoma were retrieved from our files. Each case was stained with mouse anti-human CD99 and evaluated for membranous expression. Results: Our evaluation revealed that 47 of 78 MM cases (60%) stain positive for CD99.
Conclusion: This study is the first to demonstrate, in a large series, the prevalence of CD99 expression in primary cutaneous melanoma. Additionally, this introduces in the histologic differential diagnosis of CD99 expressing dermal spindle cell lesions.CD117
- Utility of CD117 immunoreactivity in differentiating metastatic melanoma from clear cell sarcoma.
Garcia JJ, Kramer MJ, Mackey ZB, O'Donnell RJ, Horvai AE.
Department of Pathology, University of California, San Francisco, CA, USA.
Arch Pathol Lab Med. 2006 Mar;130(3):343-8. Abstract quote
CONTEXT: Clear cell sarcoma is a malignant soft tissue tumor with melanocytic differentiation. Molecular methods are sometimes necessary to identify the unique t(12; 22)(q13;q12) translocation and differentiate clear cell sarcoma from melanoma.
OBJECTIVE: To determine whether CD117 immunoreactivity may be useful in separating melanoma from clear cell sarcoma.
DESIGN: We identified 20 tumors listed in our surgical pathology files that were diagnosed as clear cell sarcoma or in which clear cell sarcoma was strongly considered. These were tested for the presence of the t(12;22) translocation by reverse transcriptase/polymerase chain reaction and sequencing from paraffin-embedded tissue. Tumors with a t(12;22) translocation were immunostained with an antibody to CD117 and compared with 16 similarly stained metastatic melanomas.
RESULTS: Twelve tumors from 9 patients demonstrated t(12;22). No metastatic melanomas demonstrated t(12;22). None of the 12 clear cell sarcomas showed membrane or cytoplasmic staining for CD117. Conversely, 10 (63%) of 16 metastatic melanomas were, at least focally, positive for CD117; this difference was significant (P < .001). Interestingly, 3 tumors in which clear cell sarcoma was initially considered as a diagnosis, but which lacked t(12;22), were also positive for CD117.
CONCLUSIONS: Reverse transcriptase/polymerase chain reaction, performed on paraffin-embedded tissue, is a useful, rapid tool for identifying the presence of t(12;22) in clear cell sarcoma. The CD117 immunoreactivity may prove useful in the differential diagnosis of deep soft tissue or visceral lesions with melanocytic differentiation; positive staining results exclude clear cell sarcoma, but are compatible with metastatic melanoma.
- Expression of c-kit (CD117) in Spitz nevus and malignant melanoma.
Isabel Zhu Y, Fitzpatrick JE.
Department of Dermatology, University of Colorado Health Science Center, Aurora, CO, USA.
J Cutan Pathol. 2006 Jan;33(1):33-7. Abstract quote
Background: CD117, the receptor for kit-ligand, which is a growth factor for melanocyte migration and proliferation, has shown differential staining in various benign and malignant melanocytic lesions. The purpose of this study is to compare CD117 immunohistological staining in Spitz nevus versus malignant melanoma, to determine whether CD117 can aid in the diagnosis of these two lesions.
Methods: CD-117 immunohistological staining was performed in 22 clinically and pathologically diagnosed pigmented lesions including 9 cases of Spitz nevus, 10 cases of primary MM and 3 cases of metastatic melanoma.
Results: There was no significant difference in CD117 staining in either epidermis or dermis between Spitz nevi and primary melanomas. However staining of metastatic melanomas is less than dermal staining of primary MM and Spitz nevus.
Conclusions: CD117 is unlikely a useful diagnostic tool in differentiating Spitz nevus from primary MM. On the other hand, CD 117 may be useful in differentiating metastatic melanoma from primary melanoma in patients who had a history of melanoma and who present with new dermal lesions. Isabel Zhu Y, Fitzpatrick JE. Expression of c-kit (CD117) in Spitz nevus and malignant melanoma.hTER
J Cutan Pathol. 2005 Nov;32(10):680-4. Abstract quote
Background: Telomerase plays a role in the immortalization of cells and carcinogenesis. Previous studies have yielded conflicting results on whether human telomerase RNA (hTER) expression differs in nevi, atypical nevi and melanomas using polymerase chain reaction-based telomeric repeat amplification protocol or in situ hybridization assays. The aim of this study was to evaluate human telomerase reverse transcriptase (hTERT) staining in melanocytic lesions on paraffin-embedded tissues.
Methods: Paraffin-embedded sections from 12 acquired nevi, seven dysplastic nevi, 11 Spitz nevi, eight primary invasive melanomas, and three metastatic melanomas were studied for staining intensity (0-3+) and percentage of labeled cells with anti-hTERT.
Results: hTERT staining was observed in most cells (>75%), in all but three lesions, and was of greater intensity in the nucleus, especially the nucleolus, compared with the cytoplasm. Spitz nevi tended to have weaker hTERT staining (mean = 1.7) compared with acquired nevi (mean = 2.2), dysplastic nevi (mean = 2.4), primary melanomas (mean = 2.4), or metastatic melanomas (mean = 3).
Conclusions: Although telomerase activity was weaker in Spitz nevi, there was overlap with other nevi and primary invasive melanomas in our small series. Thus, hTERT expression does not appear to be a reliable adjunct to the histological diagnosis of primary melanocytic lesions.
Human telomerase RNA component expression in Spitz nevi, common melanocytic nevi, and malignant melanomas.Guttman-Yassky E, Bergman R, Manov L, Sprecher E, Shaefer Y, Kerner H.
Department of Dermatology, Rambam Medical Center; Haifa, Israel The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology; Haifa, Israel Dermatopathology Unit, Rambam Medical Center, Haifa, Israel Department of Pathology, HaEmek Medical Center, Afula; Israel Department of Pathology, Rambam Medical Center, Haifa, Israel.
J Cutan Pathol 2002 Jul;29(6):341-346 Abstract quote BACKGROUND: Telomerase is a ribonucleoprotein DNA polymerase that is capable of synthesizing telomeres onto the ends of chromosomes. The cumulative loss of telomerase activity is believed to be associated with cell senescence. Telomerase activity has been shown to be higher in malignant melanomas than in common melanocytic nevi. The aim of the present study was to elucidate the pattern of expression of the human telomerase RNA (hTER) component in routinely processed specimens of Spitz nevi, malignant melanomas, and ordinary melanocytic nevi.
METHODS: Ten specimens of each type of tumor were studied, using an in situ hybridization technique.
RESULTS: All three types of tumors demonstrated moderate to high intensities of hTER expression, usually in more than half of the tumor cells, and the majority of the studied lesions in each group did not show stratification of staining. The hTER component was also detected in the epidermis, sweat glands, and pilosebaceous units.
CONCLUSIONS: hTER levels do not necessarily correlate with the level of telomerase activity, and the level and pattern of hTER expression are not useful as an adjunct to the histologic differential diagnosis of Spitz nevi from melanocytic nevi and malignant melanomas.
IMP-3
1Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Insulin-like growth factor-II messenger RNA (mRNA)-binding protein-3 (IMP-3), also known as K homology domain-containing protein overexpressed in cancer (KOC) and L523S, is a member of the insulin-like growth factor-II mRNA-binding protein family and is expressed during embryogenesis and in some malignancies. IMP-3 expression in melanocytic neoplasms has not been investigated.
Fifty-six melanocytic neoplasms from 48 subjects were immunohistochemically studied using a monoclonal antibody against L523S/IMP-3. IMP-3 expression in melanoma was significantly higher than in Spitz nevi (P<0.05), and the staining intensity in the Spitz nevi was weak.
IMP-3 expression in metastatic melanoma was significantly higher than in primary cutaneous melanoma with a Breslow depth </=1 mm (P<0.01). None of the benign nevi and dysplastic nevi expressed IMP-3.
Our study demonstrates that IMP-3 is expressed in malignant melanoma but not in benign nevi, even when dysplastic features are present; IMP-3 is expressed in a significantly higher proportion of melanomas than Spitz nevi; and IMP-3 is expressed in metastatic melanomas significantly more than in thin melanomas.
In conclusion, IMP-3 appears to be involved in the progression of malignant melanoma and may play an important role in the regulation of the biologic behavior of this tumor. Additionally, IMP-3 may have diagnostic utility in distinguishing melanoma from benign nevic cells, dysplastic nevi, and Spitz nevi.MELANOMA INHIBITORY ACTIVITY Hum Pathol 2000;31:1381-1388
Expression was analyzed by RT-PCR and immunohistochemistry in 23 melanoma cases and 25 nonmelanoma nonmalignant casesAccuracy was not greater than 71% raising concern about the specificity of this marker
MICROPHTHALMIA TRANSCRIPTION
FACTOR (MITF)Cell 1993;74:395-404
J Cell Biol 1998;142:827-835
The microphthalamia gene is a transcription factor essential for the development and survival of melanocytesEncodes a DNA binding protein in the helix-loop-helix transcription family
Acts as a promoter regulating the pigmentation enzyme genes tyrosinase, tyrosinase-related protein (TRP1 and TRP2)
Melanocyte stimulating hormone (alpha-MSH) upregulates the pigment enzyme gene through a signalling cascade that stimulates expression of MITF followed by secondary MITF-mediated activation of pigment enzyme expresion
Mutations in the mouse gene lead to accelerated age-dependent melanocyte death during the first months of life, attributed to a mutation in the helix-loop-helix motif of mi
MITF is also targeted biochemically by the c-kit signaling pathway in melanocytes, suggesting a connection to proliferation or survival
Homozygous mi-deficient mice have complete loss of melanocytes from the skin, choroid of the eye, and stria vascularis of the inner ear
Am J Surg Pathol 2001;25:58-64
Study of:
20 desmoplastic melanomas
10 scars
10 neurofibromas
12 MPNST
10 AFX
10 clear cell sarcomas
3 melanotic schwannomas
4 cellular blue nevi
Positive in 11/20 desmoplastic melanomas
7/10 clear cell sarcomas
3/3 melanotic schwannomas
3/4 cellular blue neviAm J Surg Pathol 2001;25:51-57
Study of:
62 benign nevi
58 primary melanomas
53 nonmelanocytic tumors
All primary cutaneous melanomas were positive, nevi, Spitz nevi were positive0/14 desmoplastic melanomas were positive
No nonmelanocytic tumors were positiveMITF and Mel-CAM coexpressed in 6/17 desmoplastic melanomas
Am J Surg Pathol 2001;25:197-204
Twenty cases of desmoplastic malignant melanoma were analyzed for immunohistochemical expression of Mitf (D5), S-100 protein, gp100 (HMB-45), and tyrosinase (T311)
All 20 melanomas were immunoreactive for S-100 protein
Six cases were positive for HMB-45, seven were positive for D5, and 11 were positive for T311A panel of 346 miscellaneous tumors was analyzed in tissue arrays. Positive staining in a number of nonmelanocytic tumors, including soft tissue tumors (e.g., angiomyolipomas, malignant peripheral nerve sheath tumors, leiomyosarcomas, and fibrosarcomas), lymphoid neoplasms (B- and T-cell lymphomas and Hodgkin's disease), and rare carcinomas, such as renal cell carcinoma
Anti-Mitf antibody D5 is less sensitive than S-100 protein and tyrosinase in the detection of desmoplastic melanoma and is not restricted to melanocytes
Positive staining of histiocytes/macrophages with D5 is of particular concern
Am J Surg Pathol 2001;25:205-211
Diagnostic usefulness of MITF compared with four other markers in 266 cases of conventional metastatic melanomas from different sites, 33 cases of desmoplastic melanomas, and 1 case of melanoma with rhabdoid features
Microphthalmia transcription factor with nuclear positivity was seen in 235 of 266 cases of conventional MMM (88%), usually in more than 30% of tumor cells
Only 1 of 30 desmoplastic melanomas (3%) had MITF-positive cells, representing epithelioid foci resembling conventional melanoma
Two cases had TYR in a similar pattern; all were HMB45-negative
One metastatic melanoma with rhabdoid features was negative for MITF and other markers except the S100 protein
Half of the S100 protein negative conventional melanomas (6 of 12) were MITF-positive, whereas 4 of 20 (20%) TYR-negative tumors had reactivity for MITF
The percentages of positive cases of MMM (10% or more tumor cells positive) diagnosed with the four other markers in descending order were:
90% (S100 protein and TYR)
78% (melan-A)
66% (HMB45)Microphthalmia transcription factor appeared to be specific, because significant reactivity was not found in 112 carcinomas, 20 lymphomas, 20 angiosarcomas, 20 fibrous histiocytomas, and 20 malignant peripheral nerve sheath tumors
Positive nuclei were found focally among reactive histiocytes, especially in osteoclasts, epithelioid histiocytes, and sporadic other histiocytesMicrophthalmia transcription factor may be a valuable addition to the marker panel used in diagnosing melanoma, in combination with S100, TYR, and the other markers, but it is not present in cases of desmoplastic melanomas.
Microphthalmia Transcription Factor Not A Sensitive or Specific Marker for the Diagnosis of Desmoplastic Melanoma and Spindle Cell (Non-Desmoplastic) Melanoma
Scott R. Granter, M.D.; Katherine N. Weilbaecher, M.D.; Catherine Quigley, FIBMS; Christopher D.M. Fletcher, M.D, F.R.C.Path; David E. Fisher, M.D., Ph.D.
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (S.R.G., C.D.M.F., C.Q.); Division of Pediatric Oncology, Dana Farber Cancer Institute and Children's Hospital, Boston MA (K.N.W., D.E.F.).
Am J Dermatopathol 2001;23:185-189 Abstract quote
Microphthalmia transcription factor (Mitf), a melanocytic nuclear protein critical for the embryonic development and postnatal viability of melanocytes, is a master lineage regulator and modulates extracellular signals. Recently, Mitf expression was shown to be both a sensitive and specific marker of epithelioid melanoma. Because loss of specific melanocytic markers in melanomas with spindle cell morphology is more common compared with those tumors with epithelioid morphology, we investigated the sensitivity of D5, an anti-Mitf antibody, for diagnosis in this diagnostically problematic subset of melanomas.
Twenty of 21 (95%) spindle cell and desmoplastic melanomas examined were reactive for S-100 protein. Only 4 of 21 (19%) spindle cell and desmoplastic melanomas were reactive for HMB-45. Six of 21 tumors (29%) were reactive for D5, including one case that was non-reactive for S-100 and HMB-45. Melan-A reactivity was seen in 2 of 13 cases (15%) studied. Eight of 24 (33%) non-melanocytic spindle cell tumors were reactive for D5, including 4 of 6 dermatofibromas, 1 of 6 schwannomas, 1 of 2 leiomyomas, and 2 of 6 leiomyosarcomas.
Although D5 was shown in a previous study to be a highly sensitive and specific marker for epithelioid melanomas, the results of this study show it is not a sensitive or specific marker of spindle cell and desmoplastic melanomas. Nevertheless, we believe that diffuse positive staining for D5 when taken in clinical, histologic and immunohistochemical context may be diagnostically useful in selected cases of melanoma.
Microphthalmia transcription factor immunohistochemistry: A useful diagnostic marker in the diagnosis and detection of cutaneous melanoma, sentinel lymph node metastases, and extracutaneous melanocytic neoplasms
Fiona M. O'Reilly, MD
Daniel J. Brat, MD, PhD
Barbara E. McAlpine, MD
Hans E. Grossniklaus, MD
Andrew L. Folpe, MD
Jack L. Arbiser, MD, PhDJ Am Acad Dermatol 2001;45:414-9 Abstract quote
Background: Melanoma is the most lethal form of skin cancer. Diagnosis of amelanotic melanoma and detection of micrometastases in sentinel lymph nodes pose diagnostic and therapeutic dilemmas for the dermatopathologist and clinician.
Objective: The purpose of this article is to determine the utility of immunohistochemistry using antibodies specific for microphthalmia in the identification of melanocytic lesions in the skin, eye, central nervous system, and sentinel lymph nodes.
Methods: Paraffin-embedded, formalin-fixed specimens of cutaneous melanoma, including amelanotic melanoma and lentigo maligna melanoma, were stained with antibodies specific for microphthalmia. In addition, paraffin sections of extracutaneous lesions, including sentinel lymph nodes, uveal melanoma, and central nervous system melanocytomas, were stained with the specific microphthalmia antibody.
Results: All cutaneous melanomas stained positively with microphthalmia, as did uveal melanomas and central nervous system melanocytomas. These findings confirm the melanocytic origin of melanocytomas and uveal melanomas and demonstrate that microphthalmia staining can be used to establish melanocytic origin of neoplasms. In addition, micrometastases were easily detected in sentinel lymph nodes.
Conclusion: Microphthalmia transcription factor immunohistochemistry is a valuable tool in the identification of melanocytic lesions in numerous sites. Use of this stain may facilitate detection of micrometastases in sentinel lymph nodes.
MELANOMA CELL ADHESION MOLECULE (MEL-CAM)
(Mel-CAM)Am J Surg Pathol 2001;25:58-64
Positive in:
14/17 desmoplastic melanomas
3/11 MPNST
4/10 neurofibromas
9/10 clear cell sarcomas
3/3 melanotic schwannomas
0/4 cellular blue neviMITF and Mel-CAM coexpressed in 6/17 desmoplastic melanomas
MUM1
Expression of the B-cell proliferation marker MUM1 by melanocytic lesions and comparison with S100, gp100 (HMB45), and MelanA.Sundram U, Harvell JD, Rouse RV, Natkunam Y.
Department of Pathology, Stanford University Medical Center, Stanford, California 94305, USA.
Mod Pathol. 2003 Aug;16(8):802-10. Abstract quote The diagnosis of malignant melanoma remains one of the most difficult to render in surgical pathology, partially because of its extreme histologic variability. Limits in the sensitivity and/or specificity of the currently available melanocytic markers such as anti-S100, HMB45, and anti-MelanA further complicate this problem. Previous work has demonstrated that the B-cell proliferation/differentiation marker MUM1/IRF4 is detected in malignant melanoma and hematolymphoid malignancies, but not in any other neoplasm tested (including colonic, lung, breast, and ovarian carcinomas).
In the current study, we have examined MUM1 protein expression in 61 melanocytic lesions and compared the diagnostic usefulness of this marker with that of anti-S100, HMB45, and anti-MelanA. The results indicate that MUM1 is positive in 33/36 (92%) cases of melanoma (21/22 [95%] conventional primary melanomas and 12/14 [86%] metastatic melanomas). In comparison, positivity was seen with anti-S100 in 36/36 cases (100%, 22 primary and 14 metastatic), HMB45 in 28 cases (78%, 17 primary and 11 metastatic), and anti-MelanA in 27 cases (75%, 19 primary and 8 metastatic). Although negative in schwannomas, neurofibromas, and malignant peripheral nerve sheath tumors, MUM1 is detected in only one in eight cases of spindle cell and desmoplastic melanomas.
With the exception of desmoplastic and spindle cell melanomas, MUM1 appears to be a sensitive and specific immunohistochemical stain for melanocytic lesions and may prove to be a useful addition to the current panel of melanoma markers.N-CADHERIN
- Differential expression of N-cadherin distinguishes a subset of metastasizing desmoplastic melanomas.
Attis MG, Burchette JL, Selim MA, Pham T, Soler AP.
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
Hum Pathol. 2006 Jul;37(7):899-905. Epub 2006 May 22. Abstract quote
SUMMARY: Desmoplastic melanoma is a variant of spindle cell melanoma considered at low risk for distant metastases when compared with other forms of melanoma. The emphasis in the differential diagnosis of desmoplastic melanomas has been placed mostly in distinguishing it from scars and other benign spindle cell proliferations. In contrast, recognizing a subset of desmoplastic melanomas with higher metastatic potential has proven more difficult.
We studied the expression of N-cadherin in 21 desmoplastic melanomas. The expression of N-cadherin was examined by immunohistochemistry using archive material and a mouse anti-N-cadherin monoclonal antibody previously shown to react in routinely processed paraffin-embedded tissues. Of 21 cases, N-cadherin was strongly positive in 10, only weakly or focally positive in 3, and negative in 8. Seven of 21 patients had distant metastases, and N-cadherin was strongly positive in 6 of those 7 cases. In contrast, only 1 of 11 patients within the group of N-cadherin-negative or weakly positive tumors had distant metastases.
Our results show that strong N-cadherin expression in desmoplastic melanoma correlates with distant metastases and potentially more aggressive behavior. In contrast, desmoplastic melanomas with low metastatic potential are mostly negative or only focally positive for N-cadherin. The data suggest that N-cadherin may be a useful marker in recognizing a subset of desmoplastic melanoma with higher metastatic potential.
NGFR
- NGFR-Positive Desmoplastic Melanomas with Focal or Absent S-100 Staining: Further Evidence Supporting the Use of Both NGFR and S-100 as a Primary Immunohistochemical Panel for the Diagnosis of Desmoplastic Melanomas.
Radfar A, Stefanato CM, Ghosn S, Bhawan J.
Dermatopathology Section, Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts.
Am J Dermatopathol. 2006 Apr;28(2):162-7. Abstract quote
The histologic diagnosis of desmoplastic melanoma can be challenging in circumstances in which biopsy specimens are small, or there are unsuspected clinical settings, re-excision scars, and unusual sites. This is particularly true when the overlying junctional component is absent or the spindle cells lack melanin pigment. In these instances, the importance of immunohistochemistry cannot be overemphasized. S-100 protein is the primary immunohistochemical stain used for this purpose, with a sensitivity approaching 90%. HMB-45, although a more specific marker for melanocytes, is less sensitive and often negative in these cases. In addition, NGFR, a marker of Schwannian differentiation, has been shown to be a useful confirmatory stain for desmoplastic melanoma, with staining intensity comparable with, or better than that of S-100 protein.
We report 2 cases of desmoplastic melanomas that stained only focally and weakly with S-100 protein, but showed diffuse and intense staining with NGFR. In both cases, S-100 staining could have been interpreted as non-confirmatory, thus misguiding the diagnosis.
We suggest that NGFR can be a useful complementary marker to S-100 in those desmoplastic melanomas in which staining for S100 protein is only focal or weak.The p75 Neurotrophin Receptor, Relative to Other Schwann Cell and Melanoma Markers, Is Abundantly Expressed in Spindled Melanomas
Satori Iwamoto, M.D., Ph.D. ; Robert C. Burrows, Ph.D.; S. Nicholas Agoff, M.D.; Michael Piepkorn, M.D., Ph.D.; Mark Bothwell, Ph.D.; Rodney Schmidt, M.D., Ph.D.
From the Department of Physiology and Biophysics (S.I., R.C.B.,M.B.); Department of Medicine/Dermatology and Dermatologic Surgery (S.I.,M.P.); Imaging Research Laboratory, Department of Radiology, Department of Pathology (S.N.A.,R.S.); Department of Pathology/Dermatopathology (M.P.), University of Washington, Seattle, Washington.
Am J Dermatopathol 2001;23:288-294 Abstract quote
Seventeen cases of spindled melanomas and eleven cases of epithelioid melanomas were immunolabeled with various melanoma and Schwann cell markers. Standard melanoma markers included S100, HMB45, HMB50, tyrosinase, and Melan A. Schwann cell markers included the p75 neurotrophin receptor (p75NTR), glial fibrillary acidic protein (GFAP), and the L1 adhesion protein. The degree of immunocytochemical labeling was scored by levels of both intensity and pervasiveness. The results confirmed a distinct difference in labeling between epithelioid and spindled melanomas. The p75NTR was strongly expressed in spindled melanomas and weakly expressed in the epithelioid melanomas. The usual melanoma markers, including HMB45, HMB50, MelanA, and tyrosinase had the reverse pattern, being strongly expressed in virtually all epithelioid melanomas, but rarely expressed in the spindled variants. S100 was unique among the markers in being expressed by both epithelioid and spindled melanomas. Glial fibrillary acidic protein and L1 adhesion protein were expressed moderately, with preferential labeling of the spindled melanomas. The greatest immunophenotypic difference between spindled and epithelioid melanomas was the high abundance of p75NTR expression in spindled melanomas.
The functional significance of the high level of p75 neurotrophin receptor expression may contribute to the high predisposition of perineural extension in the desmoplastic subset of spindled melanomas.
J Cutan Pathol. 1996 Jun;23(3):205-10. Abstract quote
Melanoma is a malignant tumor with a varied histologic appearance. Melanoma composed of spindle cells may include desmoplastic and neurotropic melanoma. The histologic diagnosis of desmoplastic and neurotropic melanoma can be difficult. Although S100 protein stains a majority of these melanomas, the staining may be weak or focal. HMB-45, a more specific marker of melanoma, is frequently negative in desmoplastic and neurotropic melanoma.
In order to aid the identification of desmoplastic and neurotropic melanoma, we stained 13 spindle cell melanomas (5 neurotropic melanomas, 5 desmoplastic melanomas, 3 spindle cell melanomas without either desmoplasia or neurotropism) with p75 NGF-R and compared the staining results with S100 and HMB-45. p75 NGF-R is the low affinity nerve growth factor receptor reported to be present on the surface of neural-crest-derived cells. Conventional melanoma as well as neurotized nevi, neurofibroma, spindle squamous carcinoma, atypical fibroxanthoma, dermatofibroma and scars were also stained with p75 NGF-R. p75 NGF-R stained all of the desmoplastic and neurotropic melanomas tested. In each of these cases, negative HMB-45 staining of the spindle cells was seen. In many cases the number and intensity of the spindle cells staining with p75 NGF-R was greater than with S100. Neurofibroma, neurotized nevi and focal cells in round cell melanoma also were stained with p75 NGF-R. All the squamous cell carcinomas, atypical fibroxanthomas, dermatofibromas and scars were negative for p75 NGF-R. Based on our results, p75 NGF-R may be useful as an additional confirmatory antibody in a melanoma panel, especially in differentiating desmoplastic and neurotropic melanomas from non-neural-crest-derived spindle cell lesions.
We feel it also can be helpful in better identifying margins of excision of these melanomas. p75 NGF-R, like S100 protein, will not differentiate desmoplastic and neurotropic melanomas from other neural-crest-derived lesions.
PNL2
- Immunohistochemical Analysis of Novel Monoclonal Antibody PNL2 and Comparison With Other Melanocyte Differentiation Markers.
Busam KJ, Kucukgol D, Sato E, Frosina D, Teruya-Feldstein J, Jungbluth AA.
From the *Department of Pathology and daggerLudwig Institute for Cancer Research, New York Branch, Memorial Sloan-Kettering Cancer Center, New York, NY.
Am J Surg Pathol. 2005 Mar;29(3):400-406. Abstract quote
PNL2 is a novel monoclonal antibody, which has recently been introduced as an immunohistochemical reagent to stain melanocyte and tumors derived thereof. In the present study, we analyzed the immunoreactivity of this mAb in various normal tissues, melanocytic nevi, primary and metastatic melanoma, nonmelanocytic tumors, including histologic mimickers of melanoma as well as angiomyolipoma, and multiple cell lines derived from different tumors types.
We used several tissue microarray panels as well as selected conventional sections from tissue blocks. For metastatic melanoma, immunoreactivity for PNL2 was compared with A103 (Melan-A/MART-1), T311 (tyrosinase), HMB45 (gp100), and D5 (MITF). Positive staining with PNL2 was found in normal melanocytes and neutrophils, but no other normal cell type. Among melanocytic lesions, both benign nevi as well as primary malignant melanomas, especially epithelioid variants thereof, were commonly immunopositive. Only 1 of 13 desmoplastic melanomas reacted with PNL2. PNL2 showed high sensitivity for metastatic melanoma (87%). In comparison, 82% of metastatic melanomas were positive for A103, 76% for HMB45, 92% for T311, and 84% for D5.
The combined use of all five reagents minimized the number of immunonegative cases. None of the selected nonmelanocytic tumors (carcinomas or soft tissue neoplasms) was positive for PNL2 in this series except for angiomyolipomas and chronic myeloid leukemias and 1 single case of a malignant peripheral nerve sheath tumor with heterologous differentiation (malignant Triton tumor).
Despite its reactivity with neutrophils, PNL2 appears to be a valuable supplementary reagent for the diagnosis of melanocytic tumors.
PNL2, a New Monoclonal Antibody Directed against a Fixative-Resistant Melanocyte Antigen.Rochaix P, Lacroix-Triki M, Lamant L, Pichereaux C, Valmary S, Puente E, Al Saati T, Monsarrat B, Susini C, Buscail L, Delsol G, Voigt JJ.
Laboratoire d'anatomie et cytologie pathologiques, Institut Claudius Regaud (PR, ML-T, J-JV).
Mod Pathol 2003 May;16(5):481-90 Abstract quote We report the production of a new monoclonal antibody, PNL2, directed against a fixative resistant melanocyte antigen. The analysis of PNL2 immunostaining on a broad range of normal or malignant human tissues and on various melanocytic lesions revealed its high specificity. PNL2 gave a strong cytoplasmic staining of skin and oral mucosae melanocytes, and staining of granulocytes when used at high concentration. PNL2 stained all intra-epidermal nevi irrespective of their histologic type, but common intradermal nevi and the dermal component of compound nevi were largely non-reactive as only scattered nevus cells in the papillary dermis were labeled. PNL2 labeled more than 70% of the neoplastic cells in all primary melanomas irrespective of their histologic type.
However, PNL2 did not label desmoplastic melanomas. All metastatic melanomas were also stained but the percentage of labeled cells was occasionally lower than the primary tumor. PNL2, as anti-Melan A and HMB-45 antibodies, stained most of the clear cell sarcoma cells, and a few cells in angiomyolipomas and lymphangioleiomyomatosis. None of the other non-melanocytic lesions tested were labeled. Proteomic approaches showed that the immunoaffinity purified PNL2-binding complexes isolated from melanoma cell lines comprise at least TAP1, Clathrin 17 and prealbumin proteins, but not the gp100 recognized by HMB-45.
In conclusion, this new monoclonal antibody, PNL2, is directed against a new fixative resistant melanocyte associated antigen. This antigen is chemically resistant and thus allows immunostaining after melanin bleaching or decalcification. We also demonstrate that it is different from Melan A and from gp100, even if PNL2 and HMB-45 staining patterns are sometimes similar.
S100
- Loss of S100 antigenicity in metastatic melanoma.
Aisner DL, Maker A, Rosenberg SA, Berman DM.
Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA.
Hum Pathol. 2005 Sep;36(9):1016-9. Abstract quote
Melanoma is a highly malignant disease that may initially present as a poorly differentiated metastatic tumor. Therefore, the S100 immunostain, immunoreactive in 96% to 99% of melanoma, is used to evaluate poorly differentiated malignant tumors.
To develop criteria for correctly diagnosing S100-negative melanomas, we studied the immunohistochemical profile of 1553 patients enrolled in ongoing National Cancer Institute clinical trials for melanoma. Seventeen patients (1%) had metastatic melanoma specimens that were negative for S100. Of the 17 S100-negative lesions, 10 (59%) were immunoreactive for both GP100 and MART-1. Of the 17 S100-negative cases, 13 had a documented primary melanoma. Twenty-four percent of the S100-negative cases had an ocular primary, whereas only 6% of all melanomas had an ocular origin. In 11 of the 17 cases with previous surgical specimens, a prior documented S100-immunoreactive specimen was identified in 9 cases (82%). The time interval for loss of S100 immunoreactivity ranged from 3 weeks to 3 years (average, 13.5 months). There was no association between S100-negative status and histological appearance or site of metastasis.
We conclude that all S100-negative melanomas could be correctly identified by negative workup for carcinoma, lymphoma, and sarcoma plus (1) GP100/MART-1 immunoreactivity and/or (2) prior documentation of melanoma.
S100A6 Protein Expression is Different in Spitz Nevi and Melanomas.Ribe A, McNutt NS.
Dermatopathology Division, Department of Pathology, New York Presbyterian Hospital-Cornell University Weill Medical College, New York, New York.
Mod Pathol 2003 May;16(5):505-11 Abstract quote The Spitz nevus is a benign melanocytic lesion that can be identified reliably in many cases by conventional histopathological criteria. However, there are subsets of Spitz nevi and of malignant melanoma that closely resemble each other and represent diagnostic challenges. S100 proteins are of interest because of their involvement in neoplastic processes and their genes are clustered in chromosome 1q21. Chromosome 1 contains mutations in several types of tumors, including melanomas.
The expression of different S100 proteins (A2, A6 and A8/A9 or A12) was examined in 42 Spitz nevi, 105 melanomas, and 73 melanocytic nevi to test the hypothesis that their expression differs among these entities and may contribute to the distinction between these entities.
The results showed an up-regulation of S100A6 protein in Spitz nevi, melanomas, and melanocytic nevi but with a different percentage of positivity and pattern of immunoreactivity. The differences between these three entities were statistically significant (P <.001). All 42 Spitz nevi (100%) showed strong and diffuse S100A6 protein expression, both in junctional and in dermal components of the nevi. Thirty-three percent of melanomas expressed S100A6 (35/105). The expression was mainly weak (30/35) and patchy in the dermal component and was negative or minimal in the junctional component. Fifty-six percent of different subtypes of melanocytic nevi (41/73) expressed S100A6, almost all of them weakly (40/41) and in the dermal component. Normal intraepidermal melanocytes were negative. The melanocytic cells in these three entities did not express S100A2, S100A8/A9 or A12. However, an up-regulation of S100A2 and S100A8/A9 or A12 proteins was observed in normal keratinocytes in the epidermis overlying Spitz nevi and melanomas, without differences. In summary, a simple immunohistochemical test for S100A6 protein differentiated between Spitz nevi, melanomas, and melanocytic nevi.
This marker could be used when the distinction is very difficult or controversial in routine studies, especially when there is a junctional component. Further molecular analyses of the S100A6 protein and gene should be performed to study the underlying genetic bases for such differences.
S100A Protein Expression in the Distinction Between Lentigo Maligna and Pigmented Actinic Keratosis.Ribe A, McNutt NS.
Am J Dermatopathol 2003 Apr;25(2):93-9 Abstract quote Lentigo maligna (LM), a type of malignant melanoma in situ, and pigmented actinic keratosis (PAK) may have similar clinical appearances but are different in prognosis and treatment.
Diagnosis is established by skin biopsy. In certain cases, microscopic features may be very similar in both entities, making it difficult to determine whether the pigmented atypical cells are keratinocytes or melanocytes. Immunohistochemical markers can be useful for the identification of melanocytes in these cases. There are limitations to the use of some standard immunohistochemistry markers, however. S100 proteins are a varied group of proteins that are of special interest because of their dysregulated expression in neoplastic disorders. Their expression is changed during malignant transformation, progression, and/or metastasis in various cell lines and tumors, including melanomas.
Our study analyzed the expression of several of the S100 protein subtypes (S100A2, S100A6, and S100A8/A9 or A12) in 38 LM cases and 44 PAK cases to define their potential value in the distinction between these entities together with their role in the development of early malignant melanoma of the skin.
The results showed an upregulation of S100A2 protein in atypical keratinocytes in PAK and in normal keratinocytes adjacent to melanoma cells in LM. There was also an upregulation of S100A8/A9 or A12 protein, as detected by the antibody MAC387, in normal keratinocytes adjacent to both atypical keratinocytes and melanocytes in PAK and LM, respectively. There were statistically significant differences in the level of positive cells and in the pattern of immunoreactivity for anti-S100A2 and MAC387 in each entity, however. Moreover, the findings of our study support the notion that melanocyte-keratinocyte interactions are abnormal in both of these disease entities and may be involved in their progression.TYROSINASE Melanocyte-specific antigen important in melanin synthesis and melanosome formation
Presented in association with HLA class I molecules to T lymphocytes
Homogenous, diffuse expression in stage I melanomas versus nevi which have a low percentage of labeled dermal cells and diminished expression toward their base
Tyrosinase expression in malignant melanoma, desmoplastic melanoma, and peripheral nerve tumors.Boyle JL, Haupt HM, Stern JB, Multhaupt HA.
Department of Pathology, Pennsylvania Hospital, Philadelphia, PA 19107, USA.
Arch Pathol Lab Med 2002 Jul;126(7):816-22 Abstract quote CONTEXT: Pathologists may encounter problems in the differential diagnosis of malignant melanoma, spindle and epithelioid neoplasms of peripheral nerves, and fibrohistiocytic tumors. Tyrosinase has been demonstrated to be a sensitive marker for melanoma.
OBJECTIVE: To determine the specificity of tyrosinase expression in the differential diagnosis of melanoma, desmoplastic melanoma, and peripheral nerve sheath tumors.
DESIGN: Immunoreactivity for tyrosinase, HMB-45 (anti-gp100 protein), S100 protein, CD34, and vimentin was studied in 70 tumors, including 15 melanomas (5 desmoplastic, 4 amelanotic, 6 melanotic), 13 malignant peripheral nerve sheath tumors; 10 schwannomas (1 pigmented), 12 neurofibromas (4 pigmented), and 20 fibrohistiocytic tumors (10 dermatofibrosarcoma protuberans and 10 dermatofibromas). Microwave-based antigen retrieval was performed in 10mM citrate buffer, pH 6.0, for 20 minutes at 121 degrees C.
RESULTS: All melanomas demonstrated positive immunostaining for tyrosinase, HMB-45, and S100 protein. Immunoreactivity for HMB-45 was generally stronger than that for tyrosinase in amelanotic lesions and significantly stronger in 1 of the desmoplastic lesions. The 4 pigmented neurofibromas were focally positive for tyrosinase, but did not stain for HMB-45. The pigmented schwannoma was focally positive for both tyrosinase and HMB-45. The malignant peripheral nerve sheath tumors, dermatofibrosarcoma protuberans, and dermatofibromas were nonreactive for tyrosinase and HMB-45.
CONCLUSIONS: Our results support the sensitivity of tyrosinase expression and demonstrate the relative specificity of tyrosinase as a marker for melanocytic lesions, including desmoplastic melanoma, although pigmented peripheral nerve tumors may demonstrate focal positive staining. Immunoreactivity for tyrosinase and HMB-45 may have been enhanced by the microwave-based antigen-retrieval technique used in this study.
WT-1
Perry BN,School of Medicine, Department of Dermatology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
BACKGROUND: Pigmented lesions are common, yet they present diagnostic and therapeutic challenges. They range from nevi, which are clinically stable, to melanomas, which are notorious for distant metastasis and death. Both nevi and melanomas arise from melanocytes, which are neural crest derivatives, and melanocyte precursors migrate from the paraspinal area to their eventual location at the dermoepidermal junction. Atypical nevi have been clinically considered to be precursors of melanoma, and recently, biochemical abnormalities have been found that are present in both nevi and melanomas, including inactivation of the p16INK4a tumor suppressor gene and mutations in B-raf. These mutations suggest not only that nevi and melanomas share a common origin but also that additional events are required for transformation to malignant melanoma.
OBSERVATIONS: We performed a Panomics protein array comparing a radial growth melanoma cell line with a vertical growth melanoma cell line and found that the transcription factor Wilms tumor 1 is highly expressed in the vertical growth cell line compared with the radial growth cell line. Using immunohistochemical analysis, we compared expression of archival nevi and melanomas in a tissue microarray.
CONCLUSION: We found that Wilms tumor 1 is expressed in most melanomas but is nearly absent in nevi. Immunohistochemical analysis for Wilms tumor 1 may be clinically useful in distinguishing nevi from melanoma.ELECTRON MICROSCOPY Melanocytes in nevi and melanomas synthesize basement membrane and basement membrane-like material. An immunohistochemical and electron microscopic study including immunoelectron microscopy
G.Schaumburg-Lever, I.Lever, B.Fehrenbacher, H.Möller, B.Bischof, E.Kaiserling, C.Garbe and G.Rassner
J Cutan Pathol 2001;27 (2), 67-75 Abstract quote
Light microscopic studies have shown that nevus cell nests and melanoma nests are surrounded by basement membrane (BM) material containing type IV collagen and laminin.
This study confirms this by electron microscopy and relates it to proteins which interact with the basement membrane.
Nevi except for dysplastic and Spitz nevi, malignant melanomas, and melanoma metastases were studied by immunohistopathology, routine electron microscopy (EM), and immunoelectron microscopy. The lesions were incubated with monoclonal antibody (moAb) against type IV collagen, laminin, and the integrin a6 and studied by light microscopy. In addition, melanomas were studied by immuno-EM after incubation with a moAb against matrix metalloproteinase-2 (MMP-2). Nevus cell nests and melanoma nests are surrounded by BM material containing type IV collagen and laminin by immuno-EM. The BM material various in thickness and is amorphous.
Type IV collagen, laminin, and MMP-2 are synthesized by melanoma cells as well as adjacent fibroblasts. Destruction or loss of the BM is not mandatory for melanoma invasion or even metastasis. Possibly the BM material is a protective wall for melanoma cells. Interactions between melanocytes and the extracellular matrix of which the BM is a part, can be traced back to the migration of melanocytes from the neural crest.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES AYTPICAL JUNCTIONAL MELANOCYTIC HYPERPLASIA Benign atypical junctional melanocytic hyperplasia associated with intradermal nevi: a common finding that may be confused with melanoma in situ.
Okamura JM, Barr RJ, Cantos KA.
Department of Dermatology, University of California, Irvine, USA.
Mod Pathol 2000 Aug;13(8):857-60 Abstract quote
Over the past few years, consultation cases thought to represent melanoma in situ have been received that consisted of otherwise normal intradermal nevi with an abnormal but benign junctional proliferation of melanocytes that we have termed benign atypical junctional melanocytic hyperplasia.
In order to evaluate the incidence of this feature, 400 cases of intradermal nevi were reviewed. Of these, 25 (6.2%) qualified for inclusion, making this a rather common phenomenon. Clinically, patient ages ranged from 18 to 64 years (mean, 35 years), with a male to female ratio of 1:1. Face (40%) and back (32%) were the most common locations. Histologically, the lesions were predominantly dome-shaped with an intradermal component consisting of conventional nevus cells. Most importantly, each lesion exhibited prominent individual nevomelanocytic cells dispersed at uneven intervals along the dermoepidermal junction in insufficient numbers to be considered compound nevi. The cells exhibited abundant pale to clear cytoplasm, an increased nuclear:cytoplasmic ratio, and often exhibited prominent nucleoli. However, these lesions could be distinguished from melanoma in situ by the lack of several features including lateral spread, upward epidermal migration, marked cytologic atypia, finely granular "smoky" melanin pigment, mitotic figures, and a subjacent host inflammatory response.
All cases behaved in a benign fashion. Although benign atypical junctional melanocytic hyperplasia is a relatively common histological curiosity, it is a potential pitfall in the diagnosis of pigmented lesions.
BASOMELANOCYTIC TUMOR
- Combined High-Grade Basal Cell Carcinoma and Malignant Melanoma of the Skin ("Malignant Basomelanocytic Tumor"): Report of Two Cases and Review of the Literature.
Rodriguez J, Nonaka D, Kuhn E, Reichel M, Rosai J.
From the *Department of Pathology, National Cancer Institute, Milan, Italy; and daggerDepartment of Dermatology, College of Physicians & Surgeons, Columbia University, New York, New York.
Am J Dermatopathol. 2005 Aug;27(4):314-318. Abstract quote
We describe two cases of a malignant cutaneous neoplasm with combined phenotypical features of high-grade basal cell carcinoma and malignant melanoma.
Some tumor cells showed a keratinocytic phenotype (cytokeratins, p63) and others a melanocytic phenotype (HMB-45, MART-1, Melan-A, S100-protein).
We favor the hypothesis of a tumor with bidirectional keratinocytic and melanocytic differentiation, an exceptionally rare event.
Malignant Basomelanocytic Tumor Manifesting as Metastatic Melanoma.
Erickson LA, Myers JL, Mihm MC, Markovic SN, Pittelkow MR.
Departments of *Laboratory Medicine and Pathology, daggerOncology, and double daggerDermatology, Mayo Clinic, Rochester, MN; and the section signDepartment of Pathology, Massachusetts General Hospital, Boston, MA.
Am J Surg Pathol. 2004 Oct;28(10):1393-1396. Abstract quote
We report a case of an unusual basomelanocytic tumor from the scalp of a 56-year-old man. A 56-year-old white man presented with a scalp lesion that was biopsied and interpreted as a basal cell carcinoma. Fourteen months later, metastatic melanoma was discovered in a cervical lymph node and the liver.
A subsequent biopsy from the area of the previously biopsied basal cell carcinoma of the scalp showed an invasive malignant melanoma. Immunohistochemical stains performed on the original scalp specimen showed biphasic immunohistochemical profile. A population of neoplastic cells was strongly positive for the melanocytic markers Melan-A, HMB-45, and tyrosinase and showed weak focal immunoreactivity for S-100. A second population of cells was strongly immunoreactive for keratin (wide-spectrum polyclonal antibody) and BerEp4.
To our knowledge, this is the first description of a malignant basomelanocytic tumor complicated by metastatic melanoma.BLACK SPOT POISON IVY Black spot poison ivy: A report of 5 cases and a review of the literature
Julia G. Kurlan, MD Anne W. Lucky, MD
Cincinnati, Ohio
J Am Acad Dermatol 2001;45:246-9. Abstract quote
Black-spot poison ivy dermatitis is a rare manifestation of a common condition. It occurs on exposure to the resins of the plants of the Rhus family also known as Toxicodendron. We describe 5 patients with black deposits on their skin and clothing after contact with poison ivy and review the literature reflecting different aspects of this phenomenon including clinical presentation, histologic findings, and historical background.
FERRUGINOUS FOREIGN BODY
Ferruginous foreign body: a clinical simulant of melanoma with distinctive histologic features.Paproski SM, Smith SL, Crawford RI.
Am J Dermatopathol 2002 Oct;24(5):396-8 Abstract quote A 53-year-old man reported a pigmented lesion on his forearm that he had first become aware of approximately 30 years previously. More recently, the lesion had become symptomatic and was excised because of concern of melanoma; however, during tissue processing, an embedded metallic object was found.
Histologic examination of the tissue surrounding the site of the metallic object confirmed an inner zone of iron deposition with a distinctive histologic appearance indistinguishable from rust, associated with a foreign body reaction. Surrounding this was an outer zone of siderophages with the more usual histologic appearance.
Chemical analysis of the foreign body confirmed its ferruginous nature. On subsequent questioning, the patient informed us that he had worked with heavy equipment in a mine at the time that he had first noticed the lesion.
MELANOCYTIC MATRICOMA METASTATIC EPIDERMOTROPIC MELANOMA
From the *Department of Dermatology, Northwestern University, Chicago, IL; daggerDepartment of Dermatology, University of Chicago, Chicago, IL; and double daggerDepartment of Pathology, University of Iowa, Iowa.
ABSTRACT:: The diagnosis of epidermotropic metastatic malignant melanoma (EMMM) can be extremely challenging for both clinicians and pathologists. The diffculties include distinguishing metastatic lesions with an epidermal component from residual incompletely excised primary melanoma, and multiple primary melanomas. This has great prognostic significance as the current American Joint Committee on Cancer guidelines consider localized metastatic disease such as satellites and intransits in the nodal (N) category of N2C or stage IIIB disease. In this report, we present a case of EMMM with angiotropism. Additionally, we discuss in detail the differential diagnosis for recurrence of malignant melanoma with an epidermal component within the scar. Angiotropism may be seen in lesions of EMMM and the current literature suggests that angiotropism is highly suggestive of metastatic melanoma.
The differential diagnosis of locally recurrent melanoma with an epidermal component can be extremely challenging and the presence of angiotropism may be a clue to the diagnosis of EMMM.
Pamela M. Guerriere-Kovach, MD, Edgar L. Hunt, MDk, etal.
Through careful clinicopathologic correlation, we identified 37 metastatic melanomas in the skin, all of which had intraepidermal components. These were compared with 43 microscopically similar primary melanomas with a predetermined panel of immunostains in general use in surgical pathology, including bcl-2 protein, mutant p53 protein, Ki-67 (MIB-1), proliferating cell nuclear antigen (PCNA), a-isoform actin, and CD117 (c-kit protein).
There was no significant difference in bcl-2 or a-isoform actin staining patterns of primary vs secondary cutaneous melanomas. The expression of Ki-67 generally was higher in metastatic melanomas than in primary lesions, and the same was true of mutant p53 protein labeling; however, some overlap was observed. CD117 staining was retained in 65% of metastatic melanomas (24/37) when they originated from ocular primary tumors; nevertheless, that marker was lost in virtually all of the other metastatic melanocytic neoplasms, whereas primary melanomas demonstrated consistent reactivity for c-kit protein.
Although they are not definitive, these trends in immunoreactivity could facilitate the process of distinguishing the multiple primary melanoma syndrome from melanomatous metastases to the skin. That undertaking is best approached with circumspection, because clinicopathologic discriminators for this diagnostic separation are still imperfect.NEVUS CELL AGGREGATES IN LYMPH NODES
Intraparenchymal nevus cell aggregates in lymph nodes: a possible diagnostic pitfall with malignant melanoma and carcinoma.Biddle DA, Evans HL, Kemp BL, El-Naggar AK, Harvell JD, White WL, Iskandar SS, Prieto VG.
Am J Surg Pathol 2003 May;27(5):673-81 Abstract quote It is well documented that nevus cells can be found within the fibrous capsule and trabeculae of lymph nodes; however, it is less well known that nevus cells can also be found in the lymph node parenchyma.
We report the findings in 13 cases of nevus cell aggregates located within the cortical and/or medullary parenchyma of lymph nodes. Seven of the 13 patients had a primary diagnosis of melanoma, three had no known malignancy, one had breast carcinoma, one had adnexal carcinoma of the skin, and one had squamous cell carcinoma of the tonsil. Of the seven patients with melanoma, four had axillary lymph node dissections and three had inguinal lymph node dissections. The patient with adnexal carcinoma had metastatic carcinoma in 14 of 20 lymph nodes that had been dissected; one of them also had intraparenchymal nevus cells. The patient with squamous cell carcinoma of the tonsil had an intraparenchymal nevus cell aggregate in one of the 21 dissected lymph nodes; all 21 were negative for carcinoma. Nests of intraparenchymal nevus cells ranged from clusters of only a few cells up to 2.1-mm aggregates.
No mitotic figures, prominent nucleoli, or lymphatic-vascular invasion were detected in any of the melanocytic aggregates. The melanocytic cells of the nevus cell aggregates expressed S-100 protein and/or MART-1 but not gp100 protein (HMB-45). Less than 1% of the nevus cells expressed Ki-67.
The purpose of this study was to draw attention to the finding of nevus cells in the parenchyma of lymph nodes and to alert pathologists to this as a potential diagnostic pitfall, especially in patients with concurrent melanoma or carcinoma.
Awareness that nevus cells can be present in nodal parenchyma, analysis of their morphologic features (including comparison with any previous or existing melanoma or carcinoma), and immunophenotyping will help pathologists to establish the correct diagnosis in most instances.NEVUS WITH SCHWANNIAN DIFFERENTIATION
Intradermal melanocytic nevus with prominent schwannian differentiation.Kroumpouzos G, Cohen LM.
Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Am J Dermatopathol 2002 Feb;24(1):39-42 Abstract quote Features of peripheral nerve sheath differentiation such as neuroid cords, nerve corpuscles, fascicle-like structures, and, exceptionally, palisading have been reported in melanocytic nevi.
We report an intradermal melanocytic nevus with prominent Verocay-like bodies. The upper portion of the neoplasm was composed of typical round intradermal nevus cells, many of which were pigmented. Within the deeper portion, there was a nonpigmented spindle cell proliferation with prominent Verocay bodies, simulating a neurilemmoma. Typical nevus nests merged with neurilemmoma-like areas. The entire lesion stained positively for S-100 and Mart-1 proteins and negatively for HMB-45 stain. Diffuse Mart-1 positivity excluded a collision of a melanocytic lesion with a neurilemmoma.
The histopathologic features of this nevus further support a close relation between nevus cells and Schwann cells.
PARAGANGLIOMA-LIKE DERMAL MELANOCYTIC TUMOR
- Paraganglioma-like Dermal Melanocytic Tumor: A Unique Entity Distinct From Cellular Blue Nevus, Clear Cell Sarcoma, and Cutaneous Melanoma.
Deyrup AT, Althof P, Zhou M, Morgan M, Solomon AR, Bridge JA, Weiss SW.
From the *Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA; daggerDepartments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE; and double daggerDepartment of Pathology, University of South Florida, Tampa, FL.
Am J Surg Pathol. 2004 Dec;28(12):1579-1586. Abstract quote
We are reporting a previously undescribed primary dermal melanocytic tumor identified by reviewing all dermal melanocytic tumors referred in consultation that did not qualify histologically as a previously described entity.
From these cases, 8 were remarkably similar. We termed them "paraganglioma-like dermal melanocytic tumor" (PDMT) based on their nested growth pattern. This term is used descriptively and does not imply any histogenetic or biologic similarity to true paraganglioma. PDMT is primarily a tumor of the extremities of adult females (18-53 years, mean 35 years; males 2; females 6) which present as a dermal nodule (range, 0.5-4.2 cm; mean, 1.4 cm) composed of nests of clear to amphophilic oval cells separated by delicate fibrous strands. Nuclear atypia was mild and mitotic activity low (1-4 mitoses/10 HPF). Melanin was not obvious on light microscopy.
Tumors expressed S-100 protein (8 of 8), Melan-A (4 of 8), HMB-45 (8 of 8), and microphthalmia transcription factor (8 of 8) and lacked pancytokeratin (8 of 8) and smooth muscle actin (8 of 8). FISH analysis of 5 cases revealed an intact EWS gene locus, supporting absence of the clear cell sarcoma 12;22 translocation.
Follow-up information in 8 patients (range, 35-92 months; mean, 54 months) indicated that all were alive without disease. PDMT comprises a clinically and pathologically unique subtype of dermal melanocytic tumors. Our study suggests a benign course, although a lesion of low malignant potential cannot be excluded.SCAR
Melanocytic hyperplasia in scars. A histopathological investigation of 722 cases.Duve S, Schmoeckel C, Burgdorf WH.
Dermatopathology Laboratory, Technical University of Munich, Germany.
Am J Dermatopathol 1996 Jun;18(3):236-40 Abstract quote We studied 722 reexcision scars of benign and malignant lesions (except melanocytic lesions) excised over a 24-month period. The formalin-fixed, paraffin-embedded tissue sections were examined histologically and immunohistochemically.
The histological features of melanocytic hyperplasia were present in 59 cases (8%), 56 from the sun-exposed skin of the face and neck and three from the trunk [p < 0.00001]. The most common sites were the nose and lower eyelids, but the forehead was also frequently involved. Of the 59 patients, 41 were women (p < 0.0001). Basal cell carcinoma was the most frequent original lesion in both sexes (80%). No melanocytic hyperplasia was found in 663 cases (298 on the trunk and extremities and 365 on the head and neck). We have seen this reaction pattern following reexcision of melanocytic lesions as well.
Thus, interpreting reexcision margins when lentigo maligna or similar lesions are reexcised may be fraught with difficulty. It is important for pathologists and dermatopathologists to recognize this phenomenon because histologically the presence of increased numbers of large melanocytes could be misinterpreted as melanoma in situ.
Atypical cells in human cutaneous re-excision scars for melanoma express p75NGFR, C56/N-CAM and GAP-43: evidence of early Schwann cell differentiation.Trejo O, Reed JA, Prieto VG.
University of Texas MD Anderson Cancer Center, Texas, USA Baylor College of Medicine, Houston, Texas, USA.
J Cutan Pathol 2002 Aug;29(7):397-406 Abstract quote BACKGROUND: A common problem in the routine examination of melanoma re-excision scars occurs when a few or rare mildly atypical cells are present within the scar, raising the question of residual disease. Little is known about the derivation of these cells. Because the normal cutaneous wound-healing process is reparative, we hypothesized that these atypical cells may be reactive proliferating Schwann cell precursors.
METHODS: The expression of the Schwann cell differentiation markers p75NGFR, CD56/N-CAM and GAP-43 was examined by immunohistochemistry in scars of wide local re-excisions for melanoma and non-melanoma tumors. Expression of S100, gp100 (with HMB45) and MART1 was also analyzed by immunohistochemistry.
RESULTS: All melanoma and non-melanoma re-excision specimens contained mildly atypical, spindled or epithelioid cells within the scar. They varied in number from case to case and expressed S100, p75NGFR, CD56/N-CAM or GAP-43 but not gp100 (with HMB45) or MART1. Rare epithelioid non-melanoma cells within the superficial dermis expressed MART-1.
CONCLUSIONS: Atypical cells are present in re-excision scars from melanoma and non-melanoma cases. They demonstrate early Schwann cell differentiation and appear to proliferate during the scarring process. The use of anti-MART-1 alone in the examination of melanoma re-excisions specimens may be inadequate as it may label rare, superficially located, non-melanoma cells within the scar.
S100-positive spindle cells in scars: a diagnostic pitfall in the re-excision of desmoplastic melanoma.Chorny JA, Barr RJ.
Dermatopathology Laboratory, University of California Irvine Medical Center, Orange, California, U.S.A.
Am J Dermatopathol 2002 Aug;24(4):309-12 Abstract quote Distinguishing desmoplastic melanoma (DM) from scar tissue on routine microscopy can be difficult, especially in re-excision specimens, and S100 immunohistochemistry has been recommended as a useful adjunct.
The purpose of this study is to evaluate the extent and nature of S100 positivity in scars. In this study, formalin-fixed paraffin archival tissues were evaluated with immunohistochemistry. Ten re-excision specimens of previously biopsied nonnevomelanocytic lesions were immunostained with the S100 and CD57 (Leu 7) antibodies. In 9 of the 10 cases, the scars contained S100-positive spindle cells, but there were no cases with CD57+ cells. Ten re-excised atypical nevi and 10 re-excised melanomas were also immunostained for the S100 protein, and all 20 cases contained S100-positive spindle cells within the scars. There was a trend toward quantitatively more S100-positive spindle cells in these nevomelanocytic re-excisions. To evaluate the nature of the spindle cells, scars from two of the nonnevomelanocytic re-excisions were further analyzed utilizing immunostains for glial fibrillary acidic protein, HMB-45, Melan-A, CD1a, factor XIIIa, and neuron specific enolase.
In both scars, neuron specific enolase diffusely stained the fibroblast population, but the remaining immunostains were negative in the scar. The presence of S100-positive spindle cells in scars represents a potential diagnostic pitfall, particularly in the evaluation of re-excision specimens of DM.
SCHWANNOMA Sinonasal mucosal malignant melanoma: report of an unusual case mimicking schwannoma.
Kardon DE, Thompson LD.
Department of Endocrine and Otorhinolaryngic-Head and Neck Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.
Ann Diagn Pathol 2000;4:303-307 Abstract quote
Primary mucosal melanoma of the sinonasal tract is a rare malignancy that has a more aggressive clinical course than its cutaneous counterpart.
The histology of these lesions varies, with differing degrees of melanin production and an epithelioid or spindle-cell growth pattern. Cutaneous melanocytic lesions may differentiate in accordance with their neural crest derivation and express morphology similar to nerve sheath tumors.
We believe the following case study reports the first instance of a mucosal melanoma with a Schwannian pattern of growth, arising from the nasal cavity of a 26-year-old man.
SEBORRHEIC KERATOSIS
Prevalence of melanoma clinically resembling seborrheic keratosis: analysis of 9204 cases.Izikson L, Sober AJ, Mihm MC Jr, Zembowicz A.
Dermatopathology Unit, Department of Pathology, Massachusetts General Hospital, Warren 820, 15 Fruit St, Boston, MA 02114.
Arch Dermatol 2002 Dec;138(12):1562-6 Abstract quote OBJECTIVE: To estimate the prevalence of melanoma clinically mimicking seborrheic keratosis.
DESIGN: Retrospective review of cases submitted for histological examination with a clinical diagnosis of seborrheic keratosis or with a differential diagnosis that included seborrheic keratosis.
SETTING: A tertiary medical care center-based dermatopathology laboratory serving academic dermatology clinics that have a busy pigmented lesion clinic.
MATERIALS AND METHODS: A total of 9204 consecutive pathology reports containing a diagnosis of seborrheic keratosis in the clinical information field were identified between the years 1992 and 2001 through a computer database search. Reports with a final histological diagnosis of melanoma were selected for further review and clinicopathological analysis.
MAIN OUTCOME MEASURE: Histological diagnosis, which was correlated with the preoperative clinical diagnosis.
RESULTS: Melanoma was identified in 61 cases (0.66%) submitted for histological examination with a clinical diagnosis that included seborrheic keratosis. Melanoma was in the clinical differential diagnosis of 31 cases (51%). The remaining lesions had a differential diagnosis of seborrheic keratosis vs melanocytic nevus (17 cases, 28%), basal cell carcinoma (7 cases, 12%), or a squamous proliferation (3 cases, 5%). In 3 cases (5%), seborrheic keratosis was the only clinical diagnosis. All histological types of melanoma were represented.
CONCLUSIONS: Our results confirm that melanoma can mimic seborrheic keratosis. These data strongly support the current policy of submitting for histological examination all specimens that have been removed from patients.
SPITZ NEVUS
- Consumption of the Epidermis: A Diagnostic Criterion for the Differential Diagnosis of Melanoma and Spitz Nevus.
Hantschke M, Bastian BC, Leboit PE.
From the *Dermatopathologische Gemeinschaftspraxis, Friedrichshafen, Germany; and the daggerDepartments of Pathology and Dermatology, and Comprehensive Cancer Center, University of California, San Francisco, CA.
Am J Surg Pathol. 2004 Dec;28(12):1621-1625. Abstract quote
The distinction between melanoma and its most important simulant, Spitz nevus, is usually made on microscopically. We point out "consumption of the epidermis" (COE) as an additional diagnostic criterion.
We defined COE as thinning of the epidermis with attenuation of the basal and suprabasal layers and loss of rete ridges in areas of direct contact with neoplastic melanocytes. We analyzed 102 unequivocal melanomas and 125 unequivocal Spitz nevi for the presence of COE. COE had not been used in arriving at the diagnosis of these cases because we were unaware of the criterion at the time that the cases were first evaluated. COE was found in 88 of 102 (86%) of melanomas but only 12 of 125 (9.6%) of Spitz nevi (P < 0.001). We then looked for COE in an independent set of 61 ambiguous melanocytic lesions with overlapping histopathologic features that could not be classified unequivocally as Spitz nevus or melanoma. The cases were analyzed by comparative genomic hybridization (CGH) for aberration patterns suggesting a benign or a malignant process, based on previous studies. COE was found in only 6 of 42 (14%) of the ambiguous cases in which CGH suggested a benign process and 14 of 19 (74%) of the ambiguous cases in which CGH suggested melanoma (P < 0.001).
Our data suggest that COE is a useful criterion in the evaluation of melanocytic neoplasms. Because COE was frequently found at the edges of ulcers in the majority of ulcerated melanomas, the thinning of the epidermis in COE may represent an early phase of ulceration. This may prove to be important in distinguishing ulceration due to an effect of the tumor from ulceration due to trauma, which would be expected not to have the same prognostic import. Future studies are required to analyze the prognostic value of COE itself.XANTHOGRANULOMA Xanthogranulomas With Inconspicuous Foam Cells and Giant Cells Mimicking Malignant Melanoma A Clinical, Histologic, and Immunohistochemical Study of Three Cases
Klaus J. Busam, M.D.; Juan Rosai, M.D.; Kristin Iversen, B.S.; Achim A. Jungbluth, M.D.
From the Department of Pathology (K.J.B., J.R.), Memorial Sloan-Kettering Cancer Center; and the Ludwig Institute for Cancer Research (K.I., A.A.J.), New York Branch, New York, NY, U.S.A.
Am J Surg Pathol 2000;24:864-869 Abstract quote
Histiocytic proliferations can mimic melanocytic tumors and vice versa. The authors describe the clinical, histologic, and immunohistochemical findings of three predominantly mononuclear xanthogranulomas that were misdiagnosed as malignant melanoma by experienced pathologists.
All lesions occurred in male patients ranging in age from 14 to 75 years. The tumors presented as dermal nodules, two of which were surrounded by an epidermal collarette and were ulcerated focally. The tumors were composed of a mixed population of large epithelioid and plump spindle cells with pink or pale cytoplasm arranged in nests and short fascicles. Occasional mononuclear cells had cytoplasmic vacuolar changes, but none had well-developed foamy cytoplasm. Rare, multinucleated giant cells were present, but they were not of the Touton type. Mitotic figures were found in all lesions.
Immunohistochemically, most tumor cells (80%–90%) were strongly positive for CD68 and a minority of cells (10%–15%), located typically at the periphery of the tumor, was positive for factor XIIIa. Two tumors contained rare cells positive for S-100 protein (5% of tumor cells or less). All tumors were completely negative for tyrosinase (T311), gp100 (HMB-45), and Melan-A (A103).
Giant and foam cell-poor variants of juvenile xanthogranuloma have been reported previously, mainly in young children. Their occurrence in adolescents and adults is underrecognized. Knowledge of this variant is important to avoid misdiagnosing a benign tumor as malignant melanoma.
Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008
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