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Background
Sophie Spitz, M.D. described this nevus in 1948 as a benign juvenile melanoma. This unfortunate appellation has remained in the minds of many physicians who treat this benign, yet histologically alarming nevus. It usually occurs in children and young adults presenting as a raised flesh-colored or pink-red nodule. It is common on the face, trunk, and extremities. Occasionally, multiple clustered (agminate) or disseminated lesions can occur.
The pathologist is faced with the sometimes daunting task of distinguishing the Spitz nevus from a melanoma. If isolated histologic fields are examined out of context, the diagnosis of melanoma may be difficult if not impossible to exclude. As in every diagnosis, the entire lesion must be evaluated histologically. The difficulty lies in the fact that the melanocytes comprising the Spitz nevus are atypical. The melanocytes vary from spindled to epithelioid. Unlike melanomas, Spitz nevi are symmetrical and show maturation (diminution of the size of the cells) as the melanocytes descend into the underlying dermis. Additional criteria include the lack of mitotic figures deep in the dermal melanocytes and junctional cleavage. There is no magic formula to establish the diagnosis and there is occasional disagreement even amongst expert dermatopathologists. Cases of Spitz nevi metastasizing are probably misdiagnosed melanomas. These experiences have left some clinicians wary of the ability of pathologists to make a distinction between the Spitz nevi and melanoma. As a rule, a pathologist should always think thrice before diagnosing a Spitz nevi in an adult over 40 years of age.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Spindled and epithelioid cell nevus AGE RANGE-MEDIAN J Am Acad Dermatol 1993;29:667-778
May occur at any age but 50% or more are <20 years
- Spitz Nevus Is Relatively Frequent in Adults: A Clinico-Pathologic Study of 247 Cases Related to Patient's Age.
Cesinaro AM, Foroni M, Sighinolfi P, Migaldi M, Trentini GP.
From the Dipartimento Integrato di Servizi Diagnostici, di Laboratorio e di Medicina Legale, Sezione di Anatomia Patologica, Universita di Modena e Reggio Emilia, Italy.
Am J Dermatopathol. 2005 Dec;27(6):469-75. Abstract quote
Spitz nevus is a clinico-pathologic entity that can cause diagnostic concern, particularly in adults. Many studies have been performed to establish reliable histologic criteria, in the attempt to differentiate this lesion from melanoma.
A series of 247 Spitz nevi, 6 of which were formerly classified as melanomas, were reviewed for clinical and histopathological parameters. Patients older than 20 comprised 66% of cases, with a predominance of women. The lower extremity was more affected in females of any age, whereas the trunk was more frequently involved in men over 40.
Histopathologic examination showed the following differences among Spitz nevi related to age: acanthosis, parakeratosis, pagetoid infiltration, and Kamino bodies were more frequent in young people, whereas multinucleated melanocytes were more frequent in adults. The latter also had lesions that were less pigmented, with less maturation and more desmoplasia. At a mean follow-up of 94 months (range 52-172), recurrence at the site of biopsy or metastases were absent. In our study, a greater proportion of Spitz nevi occurred in adults than in previous series. Moreover, the relative incidence of Spitz nevus compared with melanoma in our population was higher than in other studies.
Histopathologic criteria elaborated to diagnose Spitz nevus, applied to our cases, appeared reliable, allowing a correct diagnosis, even in adults.
PATHOGENESIS CHARACTERIZATION GENOMIC ANALYSIS Allelic imbalance in the diagnosis of benign, atypical and malignant Spitz tumours.
van Dijk MC, Rombout PD, Mooi WJ, van de Molengraft FJ, van Krieken JH, Ruiter DJ, Ligtenberg MJ.
Department of Pathology, University Medical Centre Nijmegen, Nijmegen, The Netherlands.
J Pathol. 2002 Jun;197(2):170-8. Abstract quote
To test the diagnostic usefulness of allelic imbalance (AI) analysis based on routinely paraffin-embedded tissue, a series of 55 benign Spitz naevi, Spitz tumours with uncertain malignant potential, and malignant Spitzoid melanomas was investigated.
Laser microdissection was used to ensure representative sampling of lesional cells and to investigate AI in separate tumour areas of four melanomas. AI was found in 2/12 (17%) typical Spitz naevi, 3/9 (33%) atypical Spitz tumours, 12/17 (65%) atypical Spitz tumours suspicious for melanoma and 15/17 (88%) Spitzoid melanomas. Additional immunohistochemical staining for Ki-67 using the MIB-1 antibody revealed positive deeply situated lesional cells in 0/6 (0%) Spitz naevi, 1/8 (13%) atypical Spitz tumours, 5/14 (35%) atypical Spitz tumours suspicious for melanoma, and 7/14 (50%) Spitzoid melanomas, respectively. Two of the melanomas examined for AI in separate tumour areas showed intratumoural genetic heterogeneity.
In view of the finding of AI and deeply situated Ki-67 positive cells not only in melanomas but also in Spitz tumours with uncertain malignant potential, these approaches appear to have no direct diagnostic applicability for the distinction between benign and malignant Spitz tumours. Further molecular studies will be required to determine whether Spitz tumours and Spitzoid melanomas are unrelated entities, or whether there is a true spectrum of tumour progression.Molecular cytogenetic analysis of Spitz nevi shows clear differences to melanoma.
Bastian BC, Wesselmann U, Pinkel D, Leboit PE.
Cancer Genetics Program, Cancer Center, University of California San Francisco, 94143-0808, USA.
J Invest Dermatol 1999 Dec;113(6):1065-9 Abstract quote
Spitz nevus is a benign neoplasm of melanocytes that can be difficult or impossible to distinguish from melanoma by clinical and histopathologic examination.
We studied genomic DNA from 17 Spitz nevi by comparative genomic hybridization (CGH).
Thirteen lesions showed no chromosomal aberrations, three cases had a gain involving the entire p-arm of chromosome 11, and one case showed a gain of chromosome 7q21-qter. Fluorescence in situ hybridization (FISH) on lesional tissue with a probe for the p-arm of chromosome 11 showed 6-10 p-arm signals per nucleus in those cases with a CGH-detected gain of chromosome 11p. One case with a normal CGH profile also showed increased copy number of 11p by FISH.
Thus, the majority of Spitz nevi have a normal chromosomal complement at the level of CGH resolution; however some may contain gains, with 11p apparently being the most frequently involved location. These findings differ significantly from the previously reported changes in primary cutaneous melanoma, which show frequent deletions of chromosomes 9p (82%), 10q (63%), 6q (28%), and 8p (22%), as well as gains of chromosomes 7 (50%), 8 (34%), 6p (28%), 1q (25%) by CGH analysis.
These clear differences in the location and frequencies of chromosomal aberrations in Spitz nevi and primary cutaneous melanomas could represent a basis for developing adjunctive techniques for refining accuracy in the difficult differential diagnosis of spitzoid melanocytic neoplasms.
Differentiation between Spitz nevi and malignant melanomas by interphase fluorescence in situ hybridization.
Wettengel GV, Draeger J, Kiesewetter F, Schell H, Neubauer S, Gebhart E.
Institute of Human Genetics, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany.
Int J Oncol 1999 Jun;14(6):1177-83 Abstract quote
Spitz nevi are benign melanocytic neoplasias which have distinct pathological features that make the pathological differential diagnosis from malignant melanomas extremely difficult. The Spitz nevi may be misdiagnosed as malignant melanoma and vice versa.
Therefore, interphase fluorescence in situ hybridization (I-FISH) was used for a possible discrimination between Spitz nevi and malignant melanomas on the basis of numerical aberrations of the chromosome complement in interphase nuclei of thin sections.
Previous studies had shown changes in malignant melanomas which were not found at the same level in normal tissue or benign tumors. Thin sections of archival paraffin material from 42 Spitz nevi with different histological type and grade of anomaly were subjected to FISH-analyses using commercially available biotinylated and/or digoxigenated alphoid DNA probes of chromosomes 1, 6, 7, 9, 17 and 18, which were applied in combinations in a two- or three-color-FISH. Unaffected epithelial areas from the same sections served as. The obtained data were compared with those collected previously from thin sections of malignant melanomas prepared in the same way. Due to the sometimes limited nevus area investigated, the number of evaluable nuclei was lower than expected from previous experiences with malignant melanomas.
Therefore, only 20 nevi could be reliably evaluated. The comparison of the group of Spitz nevi with the group of controls did not show any significant difference regarding chromosomes 1, 6, 7, 9 and 17 (Wilcoxon test). The method used to detect chromosomal loss or gain in the individual Spitz nevi demonstrated only two nevi (one of the spindle cell type with a low to middle grade of anomaly, the other of the epitheloid cell type with a middle grade of anomaly) with a gain of chromosome 7 and chromosome 17, respectively. So, with respect to the histological type and grade of anomaly, no numerical aberrations could be detected in Spitz nevi.
The comparison of the group of Spitz nevi with subgroups of malignant melanomas (metastatic, non-metastatic, melanomas with a thickness <1.5 mm and melanomas with a thickness >2. 0 mm) and with the whole group of malignant melanomas showed significant differences concerning chromosome 9 (Mann-Whitney U test), signal indices, which were higher in the melanomas than in the Spitz nevi.
Regarding chromosomes 6, 7 and 17 no significant differences could be shown, although a trend of gain in melanomas and of loss in Spitz nevi was observed of these chromosomes.
Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features.Bastian BC, LeBoit PE, Pinkel D.
Departments of Dermatology and Pathology and UCSF Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143-0808, USA.
Am J Pathol 2000 Sep;157(3):967-72 Abstract quote
Spitz nevus is a benign melanocytic neoplasm that can be difficult or impossible to histologically distinguish from melanoma.
We have recently described copy number increases of chromosome 11p in a subset of Spitz nevi. To study the molecular and histological features of this group, we studied 102 Spitz nevi for 11p copy number increases using fluorescence in situ hybridization (FISH) on tissue arrays. Copy number increases of at least threefold were found in 12 cases (11.8%) and involved the HRAS gene on chromosome 11p. Sequence analysis of HRAS showed frequent oncogenic mutations in cases with copy number increase (8/12 or 67%), contrasting with rare HRAS mutations in cases with normal HRAS copy numbers (1/21 or 5%, P: < 0.0001). Tumors with 11p copy number increases were larger, predominantly intradermal, had marked desmoplasia, characteristic cytological features, and had an infiltrating growth pattern. Proliferation rates in the majority of these cases were low to absent. HRAS activation by either mutation or copy number increase alone could explain several of the histological features that overlap with those of melanoma.
We speculate that HRAS activation in the absence of co-operating additional genetic alterations drives the partially transformed melanocytes of these Spitz nevi into senescence or a stable growth arrest.
Although there is no data suggesting that Spitz nevi with HRAS activation are at risk for progression to melanoma, future studies are warranted to assess their biological behavior more accurately.
Spitz Nevi Display Allelic Deletions
Inja Bogdan, MD; Günther Burg, MD; Roland Böni, MD
Arch Dermatol. 2001;137:1417-1420 Abstract quote
Background
Spitz nevi are acquired benign melanocytic lesions that occur in childhood and adolescence. Histologically, they resemble malignant melanoma and were first termed benign juvenile melanoma. Several studies have attempted the difficult task of establishing diagnostic criteria to differentiate between Spitz nevi and malignant melanoma.Objective
To elucidate sets of diagnostic criteria for differentiation between the 2 lesions.Design
We aimed to search for allelic deletions in Spitz nevi and to evaluate whether loss of heterozygosity (LOH) or microsatellite instability (MSI) would be a valuable diagnostic tool to differentiate between Spitz nevi and malignant melanoma.Setting
Two areas within each of 5 lesions were microdissected, and LOH and MSI were evaluated at chromosomes 6q (using polymorphic DNA marker D6S305), 9p21 (D9S171, IFNA, D9S265, and D9S270), 10q (D10S185), and 14q (D14S53).Patients
Five Swiss patients with Spitz nevi.Interventions
None.Main Outcome Measure
Allelic deletions may serve as a diagnostic tool to distinguish Spitz nevi from melanoma. Results All lesions were informative, displaying LOH or MSI with at least one marker. No LOHs were found at 14q. At 6q, MSI was found in 2 dissected areas from the same lesion; the remaining lesions were noninformative. Loss of heterozygosity was found in 2 of 6 areas at D9S171, 2 of 6 at IFNA, 3 of 6 at D9S270, 3 of 4 at D9S265, and 1 of 4 at D10S185. Microsatellite instability was found in 1 of 4 areas at D9S265.Conclusions
With the markers used in our study, Spitz nevi display LOH and MSI similar to those in melanoma. Analysis of LOH or MSI is therefore not a suitable diagnostic tool in distinguishing Spitz nevi from melanoma.BRAF GENE
Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead, NSW, Australia.
Melanocytic lesions, including Spitz nevi (SN), common benign nevi (CBN) and cutaneous metastatic melanoma (CMM), were analyzed for activating mutations in NRAS, HRAS and BRAF oncogenes, which induce cellular proliferation via the MAP kinase pathway.
One of 22 (4.5%) SN tested showed an HRAS G61L mutation. Another lesion, a 'halo' SN, showed a BRAF V600E (T1796A) mutation. BRAF V600E mutations were found in two thirds (20/31) of CBN, while a further 19% (6/31) showed NRAS codon 61 mutations. One third of CMM (10/30) had various BRAF mutations of codon 600, and a further 6% (2/31) showed NRAS codon 61 mutations. Seventeen SN tested for loss of heterozygosity (LOH) at 9p and 10q regions, known to be frequently deleted in melanoma, showed LOH at the 9p loci D9S942 and IFNA. A further lesion was found with low-level microsatellite instability at one locus, D10S214. The low rate of RAS-RAF mutations (2/22, 9.1%) observed in SN suggests that these lesions harbor as yet undetected activating mutations in other components of the RAS-RAF-MEK-ERK-MAPK pathway.
Germline DNA from members of 111 multiple-case melanoma families, representing a range of known (CDKN2A) and unknown predisposing gene defects, was analyzed for germline BRAF mutations, but none was found.
[1] 1Department of Pathology, University of Michigan, Ann Arbor, MI, USA [2] 2Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
BRAF mutations are common events in a variety of melanocytic nevi and primary cutaneous melanomas. We have previously found BRAF mutations in 82% of nevi, consisting of congenital, common acquired and dysplastic types, and 33% of primary cutaneous melanomas other than the spitzoid type, similar to other published reports. A small number of studies have evaluated Spitz nevi and have failed to detect any lesions possessing a BRAF mutation. Only one study included categories of atypical Spitz nevus and borderline lesions suspected to be spitzoid melanomas, along with classic Spitz nevi and spitzoid melanomas.
We examined a spectrum of spitzoid lesions that included 48 Spitz nevi, some with atypical features, seven atypical (borderline) Spitz tumors, and 13 spitzoid melanomas. BRAF mutations were detected in 12 of 68 spitzoid lesions, of which two were spitzoid melanomas and 10 were Spitz nevi. Five of the 10 Spitz nevi with BRAF mutations were altered by more than usual cytologic atypia and/or architectural atypia overlapping with dysplastic nevi, or irritation/inflammation; one desmoplastic Spitz nevus had a BRAF mutation.
These results indicate that a small subset of Spitz nevi, some with atypical histologic features, possess BRAF mutations. Therefore, the BRAF mutational status does not separate all Spitz nevi from spitzoid melanomas and non-Spitz types of melanocytic proliferations, contrary to previous reports.
The T1796A mutation of the BRAF gene is absent in Spitz nevi
Gabriele Palmedo1, Markus Hantschke, Arno Rütten, Thomas Mentzel, Heino Hügel, Michael J. Flaig, Amir S. Yazdi, Christian A. Sander and Heinz Kutzner
Journal of Cutaneous Pathology
Volume 31 Issue 3 Page 266 - March 2004 Abstract quote
Background: BRAF, a serine/threonine kinase, is a component of the retrovirus-associated sequence (RAS)-RAF-extracellular-regulated protein kinase (ERK)-MAP kinase signal transduction pathway mediating signals from RAS to ERK.The T1796A single point mutation in exon 15 of the BRAF gene has recently been reported in a high percentage of malignant melanomas and benign melanocytic lesions such as congenital nevi, compound nevi, intradermal nevi and dysplastic nevi. The T1796A mutation has been shown to promote cell proliferation.
Methods: We screened 21 Spitz nevi and six spitzoid malignant melanomas for the presence of the T1796A BRAF mutation.
Results: The T1796A BRAF mutation could not be detected in any of the 21 Spitz nevi but was present in two of the six spitzoid malignant melanomas.
Conclusions: Our results, in conjunction with data from a previous investigation, suggest that the melanocytic proliferation of Spitz nevi might be induced by components of the RAS-RAF-ERK-MAP kinase pathway different from BRAF, possibly combined with other genetic aberrations. The lack of the T1796A BRAF mutation might be of practical importance in distinguishing Spitz nevi from other melanocytic lesions simulating Spitz nevi as a part of a future complex diagnostic assay.
ONCOGENES J Cutan Pathol 1997;24:219-222
Probably does not play a signficant role found in equal numbers in Spitz nevi, melanocytic nevi, and melanomaIn general, no significant difference with melanoma Am J Dermatopathol 1999;21:115-120
Strongly expressed in superficial cells but not in the deeper cellsIn contrast, melanomas have overexpression
Am J Dermatopathol 1995;17:547-550
Show weak staining except in rapidly growing lesions
Strong staining favors melanoma
CHARACTERIZATION DERMOSCOPY
Department of Dermatology, University of Modena and Reggio Emilia, Modena, Italy.
BACKGROUND: Spitz nevi are benign melanocytic tumors, sometimes misdiagnosed as malignant melanoma (MM).
OBJECTIVE: We sought identification of characteristic in vivo microscopic features of Spitz nevi, their histopathologic correlates, and diagnostic usefulness.
METHODS: Forty Spitz nevi were studied by in vivo confocal microscopy and dermatoscopy, evaluating histopathologic correlates, and compared with 40 MMs and 40 Clark nevi.
RESULTS: Some histologic aspects characteristic for Spitz nevus diagnosis were correlated with confocal features, comprising some that can be useful for atypical Spitz nevus classification. The most striking features for differentiating Spitz nevi from MMs were the presence of sharp border cut-off, junctional nests, and melanophages.
LIMITATIONS: No correlates were found for other aspects, such as Kamino bodies, hyperkeratosis, acanthosis, mitoses, and maturation with depth. The impossibility of exploring deeper aspects hampered an accurate distinction from MMs in some cases.
CONCLUSION: Confocal and dermatoscopic examination enabled the identification of different Spitz categories with different histologic substrates.
- In vivo confocal scanning laser microscopy of pigmented Spitz nevi: comparison of in vivo confocal images with dermoscopy and routine histopathology.
Pellacani G, Cesinaro AM, Grana C, Seidenari S.
Department of Dermatology, University of Modena and Reggio Emila. Italy.
J Am Acad Dermatol. 2004 Sep;51(3):371-6. Abstract quote
BACKGROUND: Spitz nevus is a benign melanocytic lesion sometimes mistakenly diagnosed clinically as melanoma.
OBJECTIVE: Our aim was to evaluate in vivo reflectance-mode confocal scanning laser microscopy (CSLM) aspects of globular Spitz nevi and to correlate them with those of surface microscopy and histopathology.
METHODS: A total of 6 Spitz nevi, with globular aspects on epiluminescence observation, were imaged with CSLM and subsequently excised for histopathologic examination.
RESULTS: A close correlation among CSLM, epiluminescence, and histopathologic aspects was observed. Individual cells, observed in high-resolution confocal images, were similar in shape and dimension to the histopathologic ones. Lesion architecture was described on reconstructed CSLM images. Melanocytic nests corresponded to globular cellular aggregates at confocal microscopy and to globules at epiluminescence observation. Melanophages were clearly identified in the papillary dermis both by confocal microscopy and histopathology.
CONCLUSION: In vivo CSLM enabled the identification of characteristic cytologic and architectural aspects of Spitz nevi, correlated with histopathology and epiluminescence microscopy observation.
Morphologic changes of a pigmented Spitz nevus assessed by dermoscopy.Pizzichetta MA, Argenziano G, Grandi G, de Giacomi C, Trevisan G, Soyer HP.
Division of Medical Oncology C-Oncology Prevention, National Cancer Institute, Aviano, Italy.
J Am Acad Dermatol 2002 Jul;47(1):137-9 Abstract quote Pigmented Spitz nevus may simulate cutaneous melanoma clinically and histopathologically.
In an effort to characterize Spitz nevi using dermoscopy, we documented the dermoscopic features of a single pigmented Spitz nevus over a 6-month period. A 3-year-old boy had a brownish black papule, 3 mm in diameter, on the dorsum of the first finger of his left hand, clinically diagnosed as a Reed nevus. Two follow-up examinations were performed after 3 and 6 months, when the lesion finally was excised for histopathologic examination. Dermoscopically, a globular pattern was recognized during the initial examination, whereas a starburst pattern was identified 3 months later. After 6 months, a variation of the starburst pattern was still detectable.
Based on our observation, the globular and the starburst patterns might be considered different morphologic expressions corresponding to the evolutionary phases of pigmented Spitz nevi.
MICROFLUOROMETRY Successful differentiation of Spitz naevus from malignant melanoma by microfluorometric analysis of cellular DNA content.
Otsuka F, Chi HI, Umebayashi Y.
Department of Dermatology, University of Tsukuba, Japan.
Clin Exp Dermatol 1993 Sep;18(5):421-4 Abstract quote
Two cases of presumed Spitz naevus, whose diagnosis on clinical and histological grounds was uncertain, were examined for cellular DNA content using the technique of DAPI-DNA microfluorometry.
They were compared with 20 cases, respectively, of clinically and histologically confirmed, Spitz naevus, malignant melanoma and acquired pigmented naevus. The two Spitz naevi showed a diploid pattern in a distribution histogram of cellular DNA content. The pattern was similar to that of confirmed Spitz naevi and of acquired pigmented naevi but different from the aneuploid pattern of malignant melanomas. DNA index values of the two cases were within the range of confirmed Spitz naevi and different from those of malignant melanomas.
The DAPI-DNA microfluorometric method thus provided confirmatory evidence for the diagnosis of Spitz naevus. The method appears to reflect sensitively the biological behaviour of tumour cells, and is a useful aid to the diagnosis of uncertain Spitz naevi.
FLOW CYTOMETRY J Cutan Pathol 1990;17:342-347
Large cells are usually hyperdiploidIMAGE ANALYSIS J Invest Dermatol 1987;88:753-757
Increased DNA content in large cells which in some cases overlap with melanomaPredominance of diploid cells near the base of a Spitz nevus but a predominance of hyperdiploid cells near the base of most melanomas
Measurement of the maturation parameter by using computer-assisted interactive image analysis may be helpful in the differential diagnosis between compound Spitz nevus and malignant melanoma.
Bergman R, Sabo E, Schafer I.
Department of Dermatology, Rambam Medical Center, Haifa, Israel.
Am J Dermatopathol 1996 Dec;18(6):567-70 Abstract quote
The so-called maturation parameter (MP) (that is, the ratio of the mean nuclear areas in the deep portion and in the superficial portion of a tumor) was measured and calculated using a computer-assisted interactive image analysis system in 29 compound Spitz nevi (SNs) and 37 primary invasive cutaneous malignant melanomas (MMs), of which 16 and 14 lesions, respectively, measured up to 1 mm in Breslow thickness (that is, thin).
The MPs of the SNs and MMs were found to be 0.37-0.89 (mean +/- SD, 0.64 +/- 0.1) and 0.81-1.16 (mean +/- SD, 0.96 +/- 0.1), respectively (p < 0.001). The MPs of the subgroups of thin SNs and MMs were 0.56-0.87 (mean +/- SD, 0.67 +/- 0.1) and 0.86-1.10 (mean +/- SD, 0.98 +/- 0.1), respectively (p < 0.001). Most of the SNs and MMs had MP values of < 0.81 and > 0.89, respectively. This pattern of distribution prevailed in the subgroup of thin lesions. Thus, the previously shown difference in MPs between SN and MM for thicker lesions (> or = 1.0 mm) was demonstrated in this study in thin lesions (< or = 1.0 mm) as well.
Although a relatively small area of overlap in MP values exists between compound SNs and MMs, including the thin ones, below this area the lower the MP value the more likely the diagnosis is SN, and vice versa.
COMPARITIVE GENOMIC HYBRIDIZATION Science 1992;258:818-821
J Invest Dermatol 1999;113:1065-1069
Majority of Spitz nevi do show a normal pattern. However, about 25% have an amplification of 11p, an abnormality which does not occur in melanomas
Need to perform on relatively thicker lesions and ones that lack a significant lymphocytic infiltrate which have a normal DNA component
DNA in situ hybridization as a diagnostic tool in the discrimination of melanoma and Spitz naevus.
De Wit PE, Kerstens HM, Poddighe PJ, Van Muijen GN, Ruiter DJ.
Department of Pathology, University Hospital Nijmegen, The Netherlands.
J Pathol 1994 Jul;173(3):227-33 Abstract quote
As the clinical and histological differential diagnosis between Spitz naevus and cutaneous melanoma may be very difficult, we have investigated whether DNA in situ hybridization maybe helpful in resolving this problem.
To this end, routinely-processed paraffin sections of 15 typical Spitz naevi, 15 typical nodular melanomas, and five cases originally misdiagnosed as Spitz naevi but which later metastasized and were reclassified as melanoma were analysed using a method previously described (De Wit et al., J Invest Dermatol 1992; 98: 450-458).
Microscopical semi-quantitative evaluation revealed that the number of nuclei with supernumerary aberrations of the centromere region of chromosome 1, suggestive of aneuploidy, was significantly different in Spitz naevi and nodular melanoma. The mean number of aberrant nuclei per high power field was 0.41 and 4.01, respectively (P = 0.0001). On applying the results of the typical lesions to the equivocal, originally misdiagnosed lesions, three out of five could be identified as melanoma.
These results suggest that the application of DNA in situ hybridization may contribute to the positive identification of histologically equivocal pigmented lesions. The advantages of this technique are that it is cheap, requires little tissue, and can be applied on routinely-processed paraffin sections.
VIDEOMICROSCOPY Morphological features of Spitz naevus as observed by digital videomicroscopy.
Pellacani G, Cesinaro AM, Seidenari S.
Department of Dermatology, University of Modena, Italy.
Acta Derm Venereol 2000 Mar-Apr;80(2):117-21 Abstract quote
A characteristic epiluminescence pattern of pigmented epithelioid and/or spindle cell naevus, or Spitz naevus, has been described previously.
The aim of this study was (i) to evaluate the characteristic morphological features both of pigmented and non-pigmented epithelioid and/or spindle cell naevi observed employing a videomicroscope, (ii) to identify their histopathological correlates and (iii) to assess the improvement in diagnostic accuracy for epithelioid and/or spindle cell naevi obtained by means of this new instrumental device. Clinical, videomicroscopic and histopathological diagnoses were performed on 26 epithelioid and/or spindle cell naevi. Moreover, the videomicroscopic pattern of each lesion was described using appropriate morphological parameters.
Based on their morphological aspect detected by digital videomicroscopy, epithelioid and/or spindle cell naevi can be subdivided into three main groups: (i) darkly pigmented lesions, (ii) red or light brown ESC naevi, and (iii) lesions with dark or brown areas on a light-brown background. Whereas most epithelioid and/or spindle cell naevi of the spindle cell type belonged to the morphological group I and group 3, most epithelioid cell lesions appeared as red or light-brown coloured naevi. Finally, instrumental observation by means of a videomicroscope enabled an improvement in diagnostic accuracy with respect to the naked eye observation, with an increase in sensitivity from 15% to 58%.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL Dermatopathol: Practical and Conceptual 1999;5:9-13
Hum Pathol 1998;29:1105-1112
One must apply strict histologic criteria to ensure that the diagnosis of Spitz nevi do not overlap with other diseases including melanomaRelatively even distribution of melanocytes along the dermoepidermal junction
Monomorphous cytology of the large melanocytes
Abundant eosinophilic cytoplasm
Many multinucleated melanocytes
Clefts between melanocytes and neighboring keratinocytes
Slight epidermal hyperplasia overlying the melanocytic proliferationGently domed contour
Irregular epidermal hyperplasia, with jagged rete ridges, a thickened granular layer, and thickened compact cornified layer
Kamino bodies
Clefts around nests of melanocytes and between melanocytes within each nest
Sharp lateral circumscription-usually ends with a nest rather than with single cells
Nests of melanocytes predominate over single melanocytes at the junction
Few single melanocytes are present above the basal layer, usually in the center of the lesionNests within the papillary dermis are usually the same size or smaller than those at the junction and often do not extend within the dermis to the same width as the junctional nests
There may be dense lymphocytic infiltrates with junctional and early compound Spitz nevi
Nucleoli are brightly eosinophilic in the upper part of the lesion but in the deeper reticular dermis, the nuclei should have bluish hue, unlike melanomas-in addition, if these nucleoli are about the size of an erythrocyte and are bright red, a melanoma should be considered
Wedge shaped with a domed surface with melanocytes extending into the reticular dermis
Maturation of melanocytes as melanocytes descend deeper in the dermis in the form of:
Diminution in the sizes of aggregates of cells
Decreases in the sizes of the cells themselves
Loss of cytoplasmic volume with diminished pigmentation
Decrease in nucleolar sizeNOTE: If the aggregations of cells near the base of a Spitz nevus are large, a melanoma should be considered
Like most melanocytic nevi, Spitz nevi become intradermal neoplasms characterized by:
Wedge shape with apex in the deep dermis
Discrete nests of melanocytes throughout the lesion
Nests at each level of the dermis are approximately the same size, with cells of the same pigmentation and cytologic appearance
Thick collagen bundles throughout the neoplasm, not focalEventually resembles a dermatofibroma, histologically
Am J Dermatopathol 1979;1:319-324
Dull pink globules found in many Spitz neviNot brightly eosinophilic as dyskeratotic cells and had scalloped borders
Stain with PAS with diastase digestion
Composed of basement membrane material (laminin and collagen type IV)
EM shows filaments which may represent debris from necrotic melanocytes and keratinocytesAm J Dermatopathol 1998;20:551-554
TUNEL revealed no evidence for apoptosisVARIANTS Suprabasilar scatter of single cells usually occurring in the center of the nevus and not at the edges ANGIOMATOID Angiomatoid Spitz nevus: a distinct variant of desmoplastic Spitz nevus with prominent vasculature.
Diaz-Cascajo C, Borghi S, Weyers W.
Center for Dermatopathology, Freiburg, Germany.
Am J Dermatopathol 2000 Apr;22(2):135-9 Abstract quote
Five cases of a distinctive variant of desmoplastic Spitz nevus are reported. To the best of our knowledge, this tumor has never been described previously.
Clinically, it presents itself as a solitary papule on the extremities of young adults. Microscopically, it shows predominance of solitary melanocytes with epithelioid appearance over cell nests. They are embedded in a prominent fibrous stroma with many densely arranged, small blood vessels with plump endothelia not seen in other Spitz nevi.
Because of its resemblance to a vascular tumor, the name angiomatoid Spitz nevus is proposed for this lesion. Absence of recurrences or metastases after complete excision in all cases supports the benign nature of the tumor.
ATYPICAL SPITZ
- Spitz nevi and atypical Spitz nevi/tumors: a histologic and immunohistochemical analysis.
Kapur P, Selim MA, Roy LC, Yegappan M, Weinberg AG, Hoang MP.
1Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Mod Pathol. 2004 Oct 01; Abstract quote
A subset of Spitz nevi poses substantial diagnostic difficulty, even among experts, due to its resemblance to malignant melanoma. These lesions are termed atypical Spitz nevi/tumors and there is currently a lack of objective criteria for predicting their biologic behavior.
We compared the expression of Ki-67, p21, and fatty acid synthase by immunohistochemistry in 10 atypical Spitz nevi, 28 typical Spitz nevi, 19 compound melanocytic nevi and 18 invasive malignant melanomas. There was a progressive increase in fatty acid synthase cytoplasmic expression with statistically significant differences observed between Spitz nevi and atypical Spitz nevi (P=0.003) and between atypical Spitz nevi and malignant melanoma (P<0.050). Ki-67 nuclear staining was lower in both typical and atypical forms of Spitz lesions than in malignant melanoma (P<0.001). The degree of P21 nuclear expression in atypical Spitz nevi was not significantly different than in Spitz nevi, but was significantly greater than expression in conventional nevi and approached significance after multiple comparisons corrections for malignant melanoma.
Thus, a high level of P21 expression makes a tumor more likely to be a typical or atypical Spitz nevus than a malignant melanoma, especially when coupled with a low Ki-67 index and weak expression of fatty acid synthase. These immunohistochemical observations support the concept that atypical Spitz nevi are distinct lesions of borderline biologic behavior residing between Spitz nevi and malignant melanoma.
The study also compared a large array of histologic features of 16 cases of typical Spitz nevi in children with 12 typical Spitz nevi in adults. The adult lesions were significantly more likely to be intradermal and to display dermal fibroplasia, but were histologically similar to their pediatric counterparts in all other respects."Atypical" Spitz's nevus, "malignant" Spitz's nevus, and "metastasizing" Spitz's nevus: a critique in historical perspective of three concepts flawed fatally.
Mones JM, Ackerman AB.
Ackerman Academy of Dermatopathology, New York, New York, USA.
Am J Dermatopathol. 2004 Aug;26(4):310-33. Abstract quote
Our purpose in undertaking this Arbeit was to review all articles published about "atypical" Spitz's nevus, "malignant" Spitz's nevus, and "metastasizing" Spitz's nevus, to criticize them in a fashion that illuminates, and to come to conclusions compellingly about those subjects.
We found that an overwhelming majority of neoplasms that claimed to be "atypical Spitz's nevus," "metastasizing Spitz's nevus," and "malignant Spitz's nevus" were, in fact, melanomas ( Table 1). Moreover, in our estimation, those designations, and variants of them, like "atypical Spitz's lesion," "atypical dermal melanocytic lesion with features of Spitz's nevus," "atypical Spitzoid melanocytic neoplasm," and "problematic Spitzoid melanocytic lesion," are mere evasions from a diagnosis, straightforwardly, of either Spitz's nevus or melanoma.
Diagnoses in pathology equally bogus are "minimal deviation melanoma," "borderline melanoma," "nevoid melanoma," "potentially low-grade melanocytic neoplasm," and "melanocytic lesion of uncertain biologic potential." Rather than admit uncertainty forthrightly, those who employ circumlocutions like those just mentioned resort to linguistic maneuvers that, at first blush, seem to be "academic" and constructed in such a way as to appear to convey confidence, rather than tentativeness, on the part of a histopathologist.
On further scrutiny, however, each of those cliches is revealed to be devoid of content. For example, "malignant" Spitz's nevus and "metastasizing" Spitz's nevus not only are contradictions in terms, but they are outrageous violations of fundamental principles of classic Virchowian pathology, and "atypical" Spitz's nevus not only is a redundancy because the neoplasm was so atypical to Spitz, herself, she insisted (from the time she spawned the idea in 194 through 1951 it was a "malignant melanoma," but is abject intellectually, those who invoke it never setting forth, in clear-cut fashion, criteria for what constitutes a "typical" Spitz's nevus in contradistinction to an "atypical" one.Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome.
Barnhill RL, Argenyi ZB, From L, Glass LF, Maize JC, Mihm MC Jr, Rabkin MS, Ronan SG, White WL, Piepkorn M.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Hum Pathol 1999 May;30(5):513-20 Abstract quote
The biological nature of Spitz nevi/tumors and their diagnostic distinction from, or relationship to, melanoma remain unresolved issues.
In this report, a series of 30 melanocytic lesions removed from 28 patients, including atypical Spitz nevi/tumors and metastasizing Spitzoid tumors/melanomas, were evaluated by a panel of dermatopathologists to evaluate interobserver diagnostic concordance and to assess the prognostic power of histological criteria.
For inclusion in the study, each lesion had to display some criteria for the Spitz nevus, and in addition one of the following was required: (1) definitive clinical outcome such as metastasis or death of disease, or (2) long-term follow-up if the patient remained disease free.
Each lesion was reviewed independently and blinded as to the clinical data by 10 pathologists, who categorized them as (1) typical Spitz nevus/tumor, (2) atypical Spitz nevus/tumor, (3) melanoma, (4) tumor with unknown biological potential, or (5) other melanocytic lesion. There was limited discussion of criteria before the review.
Evaluation of 17 Spitzoid lesions yielded no clear consensus as to diagnosis; in only one case did six or more pathologists agree on a single category, regardless of clinical outcome. Notably, however, some lesions that proved fatal were categorized by most observers as either Spitz nevi or atypical Spitz tumors. Conversely, seven or more pathologists scored 13 lesions as melanoma.
These results illustrate (1) substantial diagnostic difficulties posed by many Spitz tumors, especially those with atypical features, even among experts, and (2) the lack of objective criteria for their distinction from melanoma and for gauging their malignant potential. Nevertheless, our observations do suggest that a biological relationship exists between the Spitz nevus/tumor and melanoma.
Am J Dermatopathol 1985;7:61S-78S
Spitz nevus is combined with other forms of melanocytic nevi including:
Congenital type
Blue nevusCongenital spitz nevus.
Harris MN, Hurwitz RM, Buckel LJ, Gray HR.
Dermatopathology Laboratory, Inc., Indianapolis, Indiana 46260, USA.
Dermatol Surg 2000 Oct;26(10):931-5 Abstract quote
BACKGROUND: Congenital Spitz nevus has been reported previously in the literature, but the histopathologic features have not been examined in detail.
OBJECTIVE: To histologically examine and report on congenital Spitz nevus.
METHOD: We examined 10 clinically submitted congenital melanocytic nevi that were histopathologically identified as congenital Spitz nevi and compared them to the characteristics seen in acquired Spitz nevus and superficial congenital melanocytic nevus.
RESULTS: Of the 10 congenital Spitz nevi, 9 were compound and 1 was dermal. Two showed features of combined Spitz nevus (Spitz and blue). Six cases showed all 16 listed characteristics of acquired Spitz nevus, with two cases having 15 and two cases having 14 characteristics. Of the superficial congenital melanocytic nevus characteristics, all except three cases had all 12 attributes. The one dermal lesion had all the characteristics of the acquired Spitz nevus and all but one of the characteristics of the superficial congenital melanocytic nevus in regards to intradermal findings.
CONCLUSIONS: Congenital Spitz nevi are true congenital lesions, with histopathologic features of both acquired Spitz nevus and superficial congenital melanocytic nevus.
DESMOPLASTIC NEVUS Desmoplastic nevus: a distinct histologic variant of mixed spindle cell and epithelioid cell nevus.
Barr RJ, Morales RV, Graham JH.
Cancer 1980 Aug 1;46(3):557-64 Abstract quote
From a series of 75 cases of mixed spindle cell and epithelioid cell nevi, 14 were designated as desmoplastic nevi. Junctional activity, theque formation, and pigmentation were uncommon features. As a result, desmoplastic nevi may be confused with a variety of fibrohistiocytic lesions.
Well defined intranuclear invaginations of cytoplasm occurred in 12 cases, and were helpful in differentiating desmoplastic nevi from these lesions.
Desmoplastic malignant melanoma must also be considered in the microscopic differential diagnosis, but distinguishing features of desmoplastic melanoma include the presence of preexisting lentiginous melanoma, and necrosis of tumor cells and collagen.
Desmoplastic nevus was compared to the ordinary variants of mixed spindle cell and eipthelioid cell nevus in an attempt to define etiologic factors responsible for a desmoplastic reaction. No satisfactory explanation could be found since the clinical variables examined were not statistically different.
Cancer 1980;46:557-564
Histopathology 1992;20:207-211
Some have used this term to describe lesions with intradermal Spitz features and prominent collagen bundlesA key is the presence of a wedge shaped infiltrate with apex pointing in reticular dermis
Clefts are present between melanocytes in superficial dermis and thickened collagen bundles separate small nests
Melanocytes at the base are positioned singly or in small discrete aggregations, an important differential point with melanomas which tend to lack this dispersal with descentHALO REACTION Spitz's nevi with halo reaction: a histopathologic study of 17 cases.
Harvell JD, Meehan SA, LeBoit PE.
Department of Pathology, University of California, San Francisco, School of Medicine, 94143-0506, USA..
J Cutan Pathol 1997 Nov;24(10):611-9 Abstract quote
Halo reactions to melanocytic nevi are a well-recognized phenomenon. In contrast, halo reactions to Spitz's nevi have been reported only infrequently. Halo reactions may cause misdiagnosis of an otherwise benign nevus as melanoma because inflammatory cells sometimes obscure the architectural features of the underlying nevus, and may induce cytologic atypia. For Spitz's nevus where the distinction between malignancy and benignancy is already challenging, halo reactions compound the problem.
We describe 17 examples of Spitz's nevus with halo reaction, and compare their immunohistochemical features with those of "ordinary" halo nevi. Only 2 of 17 lesions demonstrated clinically apparent halos. Clinical follow-up was available for 12 of 17 cases. None of the 12 has persisted at the biopsy site or metastasized after an average 3.6-year follow-up period. Junctional, compound, intradermal, and combined types of Spitz's nevi were represented. All were characterized by symmetrical lymphocytic infiltrates which permeated the full thickness of the nevus, including junctional nests. Combined Spitz's nevi constituted more than one-half of examples in this series (9/17 cases). The combined Spitz's nevus included a combination of Spitz's nevus with either an ordinary (common, banal) nevus or a superficial congenital type nevus. In these combined Spitz's nevi, the lymphocytic response was often directed exclusively to the Spitz's nevic component.
Important distinguishing features from malignant melanoma arising in a pre-existing nevus included symmetry and lateral circumscription of the spitzoid component, no large expansile-appearing aggregates of melanocytes, a decrease in size of nests with increasing dermal depth, a lack of mitotic figures among melanocytes at the base, and a symmetrical and diffusely permeative lymphocytic response. Although the combined Spitz's nevus with halo reaction sometimes appeared asymmetrical at scanning magnification, each component of the combination was symmetrical, when examined independently. Probably because of reactive atypia, nuclear maturation with progressive descent into the dermis was sometimes absent.
There were no obvious differences in immunohistochemical staining patterns among 4 Spitz's nevi with halo reaction, 5 regressing melanomas, and 5 benign halo nevi when stained with antibodies to S100, HMB-45, OPD4, CD8, TIA-1, CD1a, CD68, and Ki-67.
Scatter of melanocytes above the basal layer
Related to increased epidermopoiesis, secondary to such varied insults as ultraviolet light and trauma
If a scale crust, parakeratosis, or hemorrhage and fibrin are identified, especially with deeper levels, it may be inferred that this is focal phenomenonMYXOID
Myxoid Spitz nevus.
Hoang MP.
Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
J Cutan Pathol. 2003 Oct;30(9):566-8 Abstract quote.
BACKGROUND: The deposition of extracellular mucin has not been described in Spitz nevus and herein such a case is reported.
METHODS: A 6-year-old male presented with a growing 1.0-cm pigmented lesion on his left anterior knee. The lesion was excised.
RESULTS: The histologic sections demonstrated a symmetrical and dome-shaped proliferation of spindle and epithelioid melanocytes with sharp lateral demarcation at the dermal-epidermal junction and within the superficial dermis. Features of Spitz nevus such as retraction from the epidermis, eosinophilic bodies, and uniform cytologic atypia were seen. Of interest, there was marked mucin deposition within the epidermal clefts and between the neoplastic cells. The mucin was highlighted by alcian blue and colloidal iron stains, and it was negative with mucicarmine and periodic acid-Schiff stains.
CONCLUSION: Awareness that soitz nevi can rarely have extracellular mucin helps in avoiding diagnostic pitfalls.PAGETOID SPITZ Pagetoid Spitz nevus. Intraepidermal Spitz tumor with prominent pagetoid spread.
Busam KJ, Barnhill RL.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Am J Surg Pathol 1995 Sep;19(9):1061-7 Abstract quote
A distinctive variant of melanocytic growth pattern is described, which appears to be related to Spitz nevus and is characterized by a mainly intraepidermal proliferation of large epithelioid melanocytes with a predominantly pagetoid distribution.
This melanocytic lesion appears clinically as a small (< 0.4 cm) pigmented macule in young patients. Histologically, this lesion needs to be distinguished primarily from in situ or microinvasive malignant melanoma with pagetoid spread.
Features favoring nevus over melanoma include small size, circumscription, symmetry, even distribution of cells, and lack of marked cytologic atypia.
See file. PLEXIFORM Plexiform spitz nevus: an intradermal spitz nevus with plexiform growth pattern.
Spatz A, Peterse S, Fletcher CD, Barnhill RL.
Department of Pathology, Institut Gustave-Roussy, Villejuif, France.
Am J Dermatopathol 1999 Dec;21(6):542-6 Abstract quote
Two cases of a distinctive variant of Spitz (spindle and epithelioid cell) nevus are described.
One lesion developed on the lower leg of a 17-year-old boy and the other lesion on the back of a 52-year-old man.
The microscopic appearance was characterized by a plexiform arrangement of bundles and lobules of enlarged spindle to epithelioid melanocytes throughout the superficial and deep dermis. Intraepidermal melanocytic proliferation was unappreciated. Some lobules were circumscribed by a thin rim of compressed fibrous tissue. In both cases a myxoid stroma was present. The cells had abundant eosinophilic cytoplasm with well-defined borders. The nuclei were enlarged, consistently ovoid and vesicular, with small nucleoli. Both cases contained scattered multinucleate giant cells similar to those observed in classical form of Spitz nevi. No melanin pigment was detectable by light microscopy. No mitoses were observed in one case and a rare mitosis was present in the other. Tumor cells were strongly immunoreactive for S-100, but not for HMB-45, desmin, and actin.
The differential diagnosis of this distinctive tumor includes desmoplastic/neurotropic melanoma, plexiform spindle cell nevus, cellular blue nevus, plexiform neurofibroma, and cellular neurothekeoma.
The designation of "plexiform Spitz nevus" is chosen to emphasize its distinctive plexiform growth pattern.
Plexiform spitz nevus.Clarke B, Essa A, Chetty R.
Department of Pathology, Nelson R. Mandela School of Medicine, University of Natal, Durban, South Africa.
Int J Surg Pathol 2002 Jan;10(1):69-73 Abstract quote In 1999, Spatz et al. reported the first 2 cases of a plexiform variant Spitz nevus.
We describe another case of this variant on the upper thigh of a 10-year-old boy and discuss the differential diagnosis. Histologically, it comprised nodules of epithelioid cells with a plexiform arrangement distributed throughout the superficial and deep dermis. The cells had moderate eosinophilic cytoplasm with vesicular nuclei and prominent nucleoli. Intranuclear inclusions were present focally.
The tumor nodules were embedded in a myxoid stroma with intratumoral and peritumoral inflammatory cells including both lymphocytes and eosinophils. There were occasional melanin-containing spindle-shaped cells. An intraepidermal component could not be assessed, since the lesion was ulcerated.
The differential diagnosis includes both melanocytic and nonmelanocytic lesions exhibiting a plexiform pattern of growth as well as myxoid lesions.
POLYPOID Polypoid Spitz naevus: the benign counterpart of polypoid malignant melanoma.
Fabrizi G, Massi G.
Department of Dermatology, *Department of Pathology, Catholic University Medical School, Largo F. Vito, 1, 0168 Rome, Italy.
Br J Dermatol 2000 Jan;142(1):128-32 Abstract quote
Polypoid malignant melanoma is a peculiar morphological variant of melanoma with a distinct exophytic pattern of growth. This form of melanoma is usually very thick and the prognosis is accordingly poor.
We present here a previously undescribed form of Spitz naevus which had a similar polypoid exophytic silhouette and marked cytological atypia. Despite these close morphological similarities, polypoid Spitz naevus evolves in a completely benign manner.
Morphologically, polypoid Spitz naevus can be distinguished from polypoid melanoma by the absence of mitoses and by the prominent stromal reaction throughout the lesion.
RECURRENT SPITZ Arch Dematol 1990;126:1582-1583
Lesions that have been interrupted by surgery are no longer symmetrical and may display considerable pagetoid scatter of single melanocytesThere may be nodular aggregations of melanocytes adjacent to a zone of scar
Single melanocytes may be positioned between thickened collagen bundles in dermis beneath the scar
Recurrent Spitz's nevus.
Omura EF, Kheir SM.
Am J Dermatopathol 1984 Summer;6 Suppl:207-12 Abstract quote
A recurrence of a spindle- and epithelioid-cell nevus following partial removal is described.
Clinical and histologic photographs of the original and recurrent lesion and an immunohistochemical stain (S-100) which highlights melanocytic cells and their pattern of growth are included. This nodular recurrence of a Spitz's nevus is contrasted with macular recurrence of ordinary melanocytic nevi that may follow partial removal by shaves.
It is presented in order to promote recognition and prevent misdiagnosis of such a recurrence as a malignant melanoma.
Persistent (recurrent) Spitz nevi: a histopathologic, immunohistochemical, and molecular pathologic study of 22 cases.Harvell JD, Bastian BC, LeBoit PE.
Department of Pathology, Stanford University Medical Center, Stanford, California, USA.
Am J Surg Pathol 2002 May;26(5):654-61 Abstract quote This report describes 22 Spitz nevi that seemed to have been clinically removed but persisted and clinically recurred at the biopsy site. These were evaluated in terms of histopathology, immunohistochemistry, and molecular pathology using comparative genomic hybridization (CGH) and fluorescent in situ hybridization.
One of these 22 lesions was originally reported as an atypical melanocytic proliferation with some features of a Spitz nevus and was included in the study set at an early stage but was later recognized as melanoma after metastasis to regional lymph nodes 3 years after the local recurrence.
We noted four histopathologic patterns in the recurrent lesions: 1) a predominantly intraepidermal pattern resembling "pseudomelanoma" as seen in recurrent "common" melanocytic nevi, 2) a compound, mostly nested pattern above or within a scar that was nearly identical to the originally biopsied Spitz nevus, 3) a nodular growth pattern that closely simulated invasive melanoma, and 4) a desmoplastic pattern resembling an intradermal desmoplastic Spitz nevus. Although the majority of recurrent lesions exhibited asymmetry and pagetoid spread, the dermal component usually had a low mitotic rate and retained architectural and cytologic maturation, which allowed distinction from invasive melanoma. Except for the metastasizing melanoma, the immunostaining pattern with S-100 and HMB-45 was identical to that previously reported for Spitz nevi. Ki67 revealed a very low proliferation rate in all cases, including the melanoma.
CGH performed in 10 cases yielded results consistent with Spitz nevi in eight cases. The remaining two cases showed CGH profiles more typical of melanoma, and one of these was the above-referenced case of melanoma, proven by metastasis. Although ancillary molecular techniques such as CGH are of great help in distinguishing these from melanoma, until such techniques become widely available we advocate complete but conservative excision of any recurrent Spitz nevus.
SPECIAL STAINS/
IMMUNOPEROXIDASECHARACTERIZATION 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.CD117
- 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.c-FOS C-fos protein expression in Spitz nevi, common melanocytic nevi, and malignant melanomas.
Bergman R, Kerner H, Manov L, Friedman-Birnbaum R.
Department of Dermatology, Rambam Medical Centre, and the Bruce Rappaport Faculty of Medicine, Technion-Israel of Technology, Haifa.
Am J Dermatopathol 1998 Jun;20(3):262-5 Abstract quote
The expression of c-fos protein was studied in formalin-fixed, paraffin-embedded sections of 11 compound Spitz nevi (SNs), 16 ordinary compound melanocytic nevi (MNs), and 17 malignant melanomas (MMs) using monoclonal antibody MAB1283 and an immunoperoxidase technique.
Eleven (100%) SNs, 15 (94%) MNs, and 16 (94%) MMs showed positive reactions in some of the tumor cells (p = nonsignificant). In the majority of the tumors the staining was located in nuclei and graded as moderate to strong in intensity. The percentages of positively stained cells did not differentiate the three types of tumor, although they were higher in the melanocytic nevi. Most of the lesions with a significant dermal component did not show stratification of staining with progressive descent into the dermis. Positive staining for c-fos was also frequently found in the normal skin constituents within and adjacent to the melanocytic tumors.
In conclusion, the pattern of expression of c-fos in routinely processed specimens does not differentiate between SNs, MNs, and MMs.
CYCLIN D1 Cyclin D1 overexpression in Spitz nevi: an immunohistochemical study.
Nagasaka T, Lai R, Medeiros LJ, Brynes RK, McCourty A, Harada T, Saddik M.
Division of Pathology, Nagoya University Hospital, Japan.
Am J Dermatopathol 1999 Apr;21(2):115-20 Abstract quote
The morphologic distinction between Spitz nevus and malignant melanoma can be difficult. Because cyclin D1 has been reported to be overexpressed in malignant melanomas, but not in common acquired nevi, we hypothesized that cyclin D1 might be a useful marker to distinguish Spitz nevi from malignant melanoma.
Thus, we assessed for cyclin D1 expression in 11 Spitz nevi (10 compound and 1 intradermal) and 9 malignant melanomas (4 Clark stages I-III and 5 Clark stages IV-V) using an immunohistochemical method and routinely fixed and processed tissues. The cyclin D1 results were arbitrarily divided into three groups: 0% to 10%, >10% to 25%, and >25%. We confirmed the observations reported previously by others that cyclin D1 is expressed in malignant melanomas but not in common acquired nevi. Unexpectedly, a relatively high number of cyclin D1-positive cells (i.e., >10%) was also found in all cases of Spitz nevus. However, unlike malignant melanoma, the cyclin D1 positivity in Spitz nevi was present in a zonal pattern. In other words, the number of cyclin D1-positive cells decreased as the lesion extended more deeply, with the number of positive cells in the reticular dermis being less than that in the papillary dermis. Fluorescence in situ hybridization methods were used to assess amplification of 11q13, the locus harboring the cyclin D1 gene, in four cases of Spitz nevus; all were disomic.
Using the antibody MIB-1, we compared cyclin D1 expression to the proliferation rate in Spitz nevi. Despite the high cyclin D1 positivity, all Spitz nevi had a relatively low number of MIB-1-positive cells (mean=3.2%), which was significantly lower than that of malignant melanomas (mean=15.3%) (p < 0.001).
Thus, unlike malignant melanoma, there appears to be a dissociation between cyclin D1 overexpression and cell proliferation in Spitz nevi.
Ki-67
Immunohistochemical markers for distinguishing Spitz nevi from malignant melanomas.Kanter-Lewensohn L, Hedblad MA, Wejde J, Larsson O.
Department of Tumor Pathology, Karolinska Institutet, Stockholm, Sweden.
Mod Pathol 1997 Sep;10(9):917-20 Abstract quote In this study, we demonstrate that immunostaining with MIB-1 and anti-bcl-2 is a useful tool to distinguish compound Spitz nevi from malignant melanomas. Forty-six cases of Spitz nevi and 50 cases of vertical growth-phase melanomas (Clark III-V) were compared for the immunoreactivity of MIB-1 and bcl-2 in the intradermal component of the lesions.
As many as 76% of the Spitz nevus cases showed a low percentage (0-2%) of MIB-1 immunoreactivity. In the malignant melanomas, such a low MIB-1 index was shown in only 2% of the cases. The average MIB-1 index in malignant melanomas and Spitz nevi was 29.7 and 4.0%, respectively. bcl-2 was negative in only 4% of the melanoma cases, whereas the corresponding value was 72% in Spitz nevi. Statistical analyses using Students t test showed that the differences were highly significant (P < 0.001).
By considering the immunoreactivity for MIB-1 and bcl-2 in the individual cases, we found that as many as 96% of the melanomas both expressed a bcl-2 positivity and exhibited a MIB-1 index exceeding 2% in the dermal component. The corresponding value was as low as 6% in the Spitz nevi.
A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions.Li LX, Crotty KA, McCarthy SW, Palmer AA, Kril JJ.
Department of Pathology, University of Sydney, and Centre for Education and Research on Ageing, Concord Hospital, New South Wales, Australia.
Am J Dermatopathol 2000 Dec;22(6):489-95 Abstract quote Differentiation between malignant melanomas and benign nevi can sometimes be difficult by conventional histopathology, and additional diagnostic markers may be helpful.
This study investigated the immunoreactivity of the cell proliferation marker MIB1-Ki67 in 23 compound nevi, 17 dysplastic nevi, 8 Spitz nevi (SN), and 24 malignant melanomas (MMs) and evaluated its ability in separating benign nevi from MMs. In each lesion, the average number (percentage) of MIB1-positive nuclei (%MIB1-Mean) and the maximal number (percentage) of MIB1-positive nuclei (%MIB1-Max) were determined from each of the superficial, middle, and deep dermal zones of the lesion as well as from the entire lesion. The %MIB1-Max was determined from subjectively selected area(s) of high count. Malignant melanomas had a significantly greater %MIB1-Mean and %MIB1-Max than all benign nevi in all individual zones and in the entire lesion (p < 0.05). Discriminant analysis showed that the %MIB1-Mean and %MIB1-Max counted from the whole lesions had better discriminating abilities than from the individual zones.
By using the %MIB1-Mean from all zones, all lesions except 1 SN and 3 MMs could be correctly classified as benign or malignant. When using the %MIB1-Max from all zones, all but 2 SN could be correctly separated as benign or malignant. Thus, MIB1-Ki67 immunoreactivity closely correlates with the benignancy or malignancy of melanocytic lesions and may assist in the differentiation of benign nevi from MMs.
p27
Expression of p-27 (kip1) in nevi and melanomas.Morgan MB, Cowper SE.
Department of Pathology and Laboratory Medicine, James A. Haley Veterans' Administration Medical Center, Tampa, Florida 33612, USA.
Am J Dermatopathol 1999 Apr;21(2):121-4 Abstract quote Histopathologic criteria are usually sufficient for the accurate distinction of benign from malignant melanocytic lesions of the skin. A minority of cases, however, particularly Spitz nevi, continue to pose a vexing diagnostic challenge. Recent research, however, suggests that p27 (kip1), a cell cycle inhibitory protein, may prove helpful in predicting the biologic behavior of a diverse array of human neoplasms.
We analyzed 63 melanocytic lesions of the skin (21 Spitz compound nevi, 21 compound nevi, 21 melanomas, and a variety of other benign and malignant cutaneous neoplasms as a control group) for expression of p27 (kip1). The distribution of immunoreactivity was analyzed by quantifying nuclear staining in each case without knowledge of the diagnosis or outcome. Clinical history and follow-up information were obtained by chart review. There was no difference in the expression of p27 between Spitz nevi (labeling index=38.4+/-4.0), compound nevi (labeling index=40.1+/-4.8), and melanoma (labeling index=42.3+/-5.1). Logistic regression failed to show any difference in p27 labeling index between the nevi and melanoma (p=0.736).
These results indicate that antibodies to p27 are not useful in distinguishing between these melanocytic lesions.
p53
Immunohistochemical study of p53 protein expression in Spitz nevus as compared with other melanocytic lesions.Bergman R, Shemer A, Levy R, Friedman-Birnbaum R, Trau H, Lichtig C.
Department of Dermatology, Rambam Medical Center, Haifa, Israel.
Am J Dermatopathol 1995 Dec;17(6):547-50 Abstract quote The accumulation of p53 protein was studied immunohistochemically on paraffin-embedded sections of 26 Spitz nevi (SNs), 26 primary invasive cutaneous malignant melanomas (MMs), 20 metastases of MM, and 17 ordinary compound nevi (CNs), using monoclonal antibody BP53-12.
Positive reactivity was detected in some of the tumor cells in seven (35%) metastatic MMs, all exhibiting strong nuclear staining; eight (31%) primary MMs, of which seven showed strong nuclear staining; two (7%) SNs, of which only one showed strong nuclear staining; and none of the CNs. The frequencies of the positively stained lesions in general, and the strongly positively stained lesions in particular, in the MM and metastatic MM groups were each statistically significantly higher than the respective frequencies in the SN and CN groups.
We believe that the immunohistochemical detection of p53 protein with the use of monoclonal antibodies such as BP53-12 on paraffin sections, especially when strong nuclear reactivity is demonstrated, may prove to be an adjunctive tool in the histopathologic differentiation of MM from SN.
Concurrent Ki-67 and p53 immunolabeling in cutaneous melanocytic neoplasms: an adjunct for recognition of the vertical growth phase in malignant melanomas?Kaleem Z, Lind AC, Humphrey PA, Sueper RH, Swanson PE, Ritter JH, Wick MR.
Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University Medical Center, St. Louis, Missouri, USA.
Mod Pathol 2000 Mar;13(3):217-22 Abstract quote Ki-67 labeling of paraffin sections has been correlated with the number of cells in non-G(o) phases of the replicative cell cycle, and this immunohistochemical technique has been applied to the evaluation of a variety of human neoplasms. Similarly, immunolabeling for p53 protein has been used to detect mutations in the corresponding gene, as a reflection of possible cellular transformation in the same context. Both of these techniques were applied to 253 melanocytic tumors of the skin to assess their possible utility in the diagnosis and subcategorization of such lesions.
They included 76 banal (common) nevi (CN), 39 Spitz nevi (SN), 62 superficial spreading malignant melanomas in radial growth (SSMMs), 32 nodular malignant melanomas (NMMs), 21 lentigo maligna melanomas in radial growth (LMMs), and 23 melanomas arising in association with preexisting compound nevi (MCN). One hundred cells were counted randomly in each tumor, and dark, exclusively nuclear reactivity was scored as positive labeling; results were recorded as percentages.
Negligible Ki-67 and p53 labeling was seen in CN and SN, at a level that was similar to that obtained in cases of LMM and MCN. The largest proportion of Ki-67-positive and p53-positive cells was observed in NMMs, followed by SSMMs. Radial growth-phase SSMMs and LMMs demonstrated immunoprofiles that were similar to those of melanocytic nevi, and MCN did so as well. The prototypical malignant melanocytic tumor representing the vertical growth phase-nodular melanoma--demonstrated a statistically significant difference from all other lesions in this study with respect to Ki-67 index (P = .008, chi2) and p53 reactivity (P < .000001, chi2). Subsequent concurrent use of a Ki-67 threshold index of 10% and a p53 index of 5% correctly indicated the presence of vertical growth in 75% of NMMs, whereas only 8% of radial growth phase melanomas of other types were colabeled at the same levels of reactivity for the two markers (P < .00001, chi2).
Thus, although the distinction between benign and malignant melanocytic tumors could and should not be based on immunohistology for Ki-67 and p53, these results suggest that the latter determinants may, in fact, be used as an adjunct to morphology in the recognition of the vertical growth phase in cutaneous malignant melanomas.
J Pathol 1990;161:41-45
More weakly expressed in Spitz nevus cells rather than 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.J Cutan Pathol 1995;22:502-517
Am J Surg Pathol 1999;23:786-794
Am J Dermatopathol 1995;17:542-546
Usually just marks the uppermost cells of Spitz nevus unlike the diffuse expression by neoplastic melanocytes deep in the dermisThe pattern of HMB-45 antibody staining in compound Spitz nevi.
Bergman R, Dromi R, Trau H, Cohen I, Lichtig C.
Department of Dermatology, Rambam Medical Center.
Am J Dermatopathol 1995 Dec;17(6):542-6 Abstrac quote
We studied the staining pattern of HMB-45 antibody in 29 compound Spitz nevi (SNs) of the epithelioid cell variety, 17 of which showed extension of nevus cells into the reticular dermis (i.e., "deep"); 20 ordinary compound nevi (CNs), all with a deep dermal component; and 22 primary cutaneous invasive malignant melanomas (MMs) (excluding the desmoplastic and spindle cell types), 12 of which extended into Clark level IV or V. Of the 29 SNs, eight (28%) stained negatively; five (17%), including two deep SNs, stained in the epidermal component only; and 16 (55%), including 10 deep SNs, stained in both the epidermal and dermal components.
Of the latter 10 deep SNs, eight stained in the upper dermis only, and in the remaining two lesions, a smaller number of positively stained nevus cells were detectable in the lower dermis as well; these two SNs were not atypical histologically. Of the 20 CNs, four (20%) stained negatively, two (10%) stained in the epidermal component only, and 14 (70%) stained in the epidermal component and the upper dermis only. Of the 22 MMs, one stained negatively, and 21 (95%) stained positively in both the epidermal and dermal components. The pattern was variable in frequency of both staining and distribution, but showed no stratification.
We conclude that the majority of our positively stained deep compound SNs showed a stratified pattern of HMB-45 staining, similar to ordinary CNs and different from MMs, and that this pattern might be used as an adjunct in the histopathologic differential diagnosis of compound SN and MM, in the proper clinicopathological context.
hTER
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.
MIB-1 J Am Acad Dermatol 2001;44:500-4
Twenty-five compound SNs, 27 MMs, and 26 compound nondysplastic melanocytic nevi (MNs) were immunostained with the MIB-1 antibody.
Results: The mean counts of MIB-1-stained tumor cells of the epidermal and dermal components, both alone and together, were significantly lower in SNs and MNs than in MMs (P < .0001). The dermal counts showed the best discriminating power. In addition, the mean dermal/epidermal count ratios for MIB-1 in SNs and MNs (0.25 and 0.23, respectively) were significantly lower than the corresponding ratio (0.94) in MMs (P < .0001).
Conclusion: MIB-1-stained tumor cell counts, especially of the dermal component, and dermal/epidermal MIB-1 count ratios may be helpful as an adjunct to the histopathologic differential diagnosis of SN.
Mod Pathol 1997;10:917-920
Am J Dermatopathol 1993;15:311-314
Proliferation rate is lower as compared to melanoma with 75% of cases having proliferation rate of <2% and only 2% of melanomas having this low a proliferation rate
PCNA may overestimate the number of proliferating cells because of its long half life and also shows a striking increase in proliferating cells over conventional nevi with a small overlap with melanomap53 Immunohistochemical study of p53 protein expression in Spitz nevus as compared with other melanocytic lesions.
Bergman R, Shemer A, Levy R, Friedman-Birnbaum R, Trau H, Lichtig C.
Department of Dermatology, Rambam Medical Center, Haifa, Israel.
Am J Dermatopathol 1995 Dec;17(6):547-50 Abstract quote
The accumulation of p53 protein was studied immunohistochemically on paraffin-embedded sections of 26 Spitz nevi (SNs), 26 primary invasive cutaneous malignant melanomas (MMs), 20 metastases of MM, and 17 ordinary compound nevi (CNs), using monoclonal antibody BP53-12.
Positive reactivity was detected in some of the tumor cells in seven (35%) metastatic MMs, all exhibiting strong nuclear staining; eight (31%) primary MMs, of which seven showed strong nuclear staining; two (7%) SNs, of which only one showed strong nuclear staining; and none of the CNs. The frequencies of the positively stained lesions in general, and the strongly positively stained lesions in particular, in the MM and metastatic MM groups were each statistically significantly higher than the respective frequencies in the SN and CN groups.
We believe that the immunohistochemical detection of p53 protein with the use of monoclonal antibodies such as BP53-12 on paraffin sections, especially when strong nuclear reactivity is demonstrated, may prove to be an adjunctive tool in the histopathologic differentiation of MM from SN.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS Benign if accurate histopathologic criteria are applied GRADING SYSTEMS Some authors have advocated a grading system to assess atypical Spitz nevi in children and adolescents Taken from Basitan BC, etal. Am J Pathol 2000;157:967-972 Parameter Score Age (Years) 0 1 Diameter (mm) 0 1 Involvement of subcutaneous fat 0 2 Ulceration 0 2 Mitotic activity (mm2) 0 2 5 This grading system is by no means universally accepted but is reproduced here as an example of a system that some pathologists have utilized to stratify Spitz nevi into atypical categories
Using this system, the risk for metastasis is as follows:
0-2 Low risk
3-4 Intermediate risk
5-11 High riskAgNOR COUNTS
Argyrophilic staining of nucleolar organizer region count and morphometry in benign and malignant melanocytic lesions.Li LX, Crotty KA, Palmer AA, Kril JJ, Scolyer RA, Thompson JF, McCarthy SW.
Am J Dermatopathol. 2003 Jun;25(3):190-7. Abstract quote Differentiation between malignant melanomas (MMs) and benign nevi based on histologic features can sometimes be difficult.
This study evaluated the diagnostic effectiveness of argyrophilic staining of nucleolar organizer regions (AgNORs) in separating benign nevi from MMs by assessing 27 compound nevi (CN), 20 dysplastic nevi (DN), 10 Spitz nevi (SN), and 24 MMs. Both AgNOR count and morphology variables were measured from the superficial, middle, and deep zones of the lesions using video image analysis. Malignant melanomas had a significantly greater AgNOR number per nucleus, mean AgNOR area per nucleus, and variation in AgNOR area per nucleus compared with all types of benign nevi (p < 0.05). In multivariate discriminant analysis using a combination of four AgNOR counts and morphometric parameters, all CN and DN, 8 of 10 SN, and 23 of 24 MMs could be correctly classified as benign or malignant.
The results suggest that both AgNOR count and morphology help to separate benign and malignant melanocytic lesions and that the combination of both sets of parameters improves their discriminating ability.
CHILDREN Spitz tumors in children: a grading system for risk stratification.
Spatz A, Calonje E, Handfield-Jones S, Barnhill RL.
Department of Pathology, Institut Gustave-Roussy, Villejuif, France.
Arch Dermatol 1999 Mar;135(3):282-5 Abstract quote
OBJECTIVE: To describe a grading system for risk stratification of atypical Spitz tumors in children and adolescents. In some circumstances, unequivocal distinction between Spitz nevus and melanoma is practically impossible. It is likely that these lesions for which we lack specific diagnostic criteria represent a broad histological continuum extending from benign to malignant tumors. Therefore, we propose that Spitz tumors be categorized into low-, intermediate-, or high-risk categories based on the accumulation of abnormal features.
DESIGN: Retrospective study.
SETTINGS: Institutional practice.
PATIENTS: We present 30 cases of atypical Spitz tumors in patients younger than 18 years evaluated for at least 3 years or in whom a metastatic event developed during this period. I
NTERVENTION: None.
MAIN OUTCOME MEASURE: The grading system was formulated after data collection.
RESULTS: Among the parameters studied, only diagnosis at age greater than 10 years, diameter of the lesion greater than 10 mm, presence of ulceration, involvement of the subcutaneous fat (level V), and mitotic activity of at least 6/mm2 carried a likelihood ratio greater than 1.50 and were therefore used for the grading system.
CONCLUSION: The application of an objective grading system, such as the one described herein for the first time, is the first step in providing useful information for the management of atypical Spitz tumors.
VASCULARITY Quantification of vascularity in nodular melanoma and Spitz's nevus.
Binder M, Steiner A, Mossbacher U, Hunegnaw M, Wolff K, Pehamberger H.
Department of Dermatology, University of Vienna Medical School, Austria.
J Cutan Pathol 1997 May;24(5):272-7 Abstract quote
Spitz's nevi are acquired benign melanocytic skin tumors. Usually they are differentiated from nodular melanoma by clinical and histopathological criteria. Since Spitz's nevi are one of the most common simulators of nodular melanomas their bizarre histopathology may cause diagnostic confusion and make it difficult to differentiate these two melanocytic tumors. One of the histologic features shared by Spitz's nevus and nodular melanoma is prominent vascularity. The ability of malignant melanoma to induce angiogenesis is well established whereas benign melanocytic tumors do not have a prominent overall vascularity.
The purpose of this study was to find out whether the degree of vascularity of nodular melanomas differs significantly from that of benign Spitz's nevi. In this study the number of microvessels and the vessel area were determined in 23 Spitz's nevi and 16 nodular melanomas. The number of microvessels and the vessel area were determined on Ulex Europaeus agglutinin I-stained sections by computer-assisted image analysis. Two methods of measurement were used, namely systematic and selective sampling. Measurement of the whole tumor specimen (systematic sampling) revealed a vessel count of 10.83/field (SD +/-5.97) for Spitz's nevi whereas nodular melanomas exhibited a significantly lower (p=0.04) vessel count of 6.44/field (SD +/-3.85). This difference was even more pronounced when the vessel area (Spitz's nevi: 17.85x10-4mm2, SD +/-10.32; nodular melanomas: 7.88x10-4mm2, SD +/-5.23) was investigated (p < 0.001). The difference in vessel area and vessel count was insignificant for areas exhibiting the greatest vascularity (selective sampling).
Measurement of vessel count and vessel area lead us to conclude that Spitz's nevi have a significantly higher vascularity than do nodular melanomas.
Our results thus indicate that angiogenesis in these pigmented lesions is not correlated with malignancy.
RECURRENCE Arch Dematol 1990;126:1582-1583
Rare-see histology outline
Spindle and epithelioid cell nevus (Spitz nevus). Natural history following biopsy.Kaye VN, Dehner LP.
Department of Dermatology, University of Minnesota Hospital and Clinic, Minneapolis.
Arch Dermatol 1990 Dec;126(12):1581-3 Abstract quote
A clinical follow-up study of 49 cases of spindle and epithelioid cell nevus is presented to address the question about the potential for local recurrence.
Only 19 (39%) of the 49 lesions were initially excised en toto, and the remainder (30 cases) had positive margins; six of the latter spindle and epithelioid cell nevi were reexcised, and no evidence of a residual nevus was found in five of the six cases. There were no recurrences in the 49 patients during an average follow-up period of 5.0 years (range, 1 to 10 years).
The rarity of recurrent spindle and epithelioid cell nevus would justify a conservative approach to management, with clinical follow-up alone recommended after a subtotal excision, when the pathologic diagnosis is unequivocal.
METASTASIS Arch Dermatol 1979;115:1416-1420
Am J Surg Pathol 1989;13:931-939
Am J Surg Pathol 1990;14:53-68
Hum Pathol 1999;30:513-520
Arch Dermatol 1999;135:282-285
These cases that are cited have been diagnosed as:
Malignant Spitz nevus
Metastasizing Spitz nevi
Atypical Spitz nevi
Spindle cell and epithelioid cell nevi with atypia and metastases
Minimal deviation melanoma-Spitz nevus type
If one examines these papers, the majority of these cases utilize diagnostic criteria which differ from those of conventional Spitz nevi including:
Extension into subcutis
Ulceration
Sheets of melanocytes rather than discrete nests
Confluence of melanocytes disposed as nests with markedly irregular shapes
Sheets of melanocytes and cells with gigantic nucleoli
Presence of mitotic figures in melanocytes deep in the dermis
Plasma cells around nearby vesselsIn addition, one article cited several clinical and histologic features that may predict malignant behavior:
Age >10 years
Lesional diameter >1.0 cm
Ulceration
Extension into subcutis
Mitotic rate of >6/mm2
All of the cases cited, however, did share some histologic similarity with Spitz nevi including a vertically oriented silhouette, sharp lateral circumscription, irregular epidermal hyperplasia, and clefts between melanocytes and epidermis
Even Sophie Spitz described a case in her original series which metastasized. In review, this case was present in a child and histologically extended into the subcutaneous fat of the foot. In retrospect, this case was probably a melanoma, especially if strict modern histologic criteria are utilized
If a Spitz nevus metastasizes, the correct diagnosis is malignant melanoma and not a metastasizing Spitz nevus. A Spitz nevus, in spite of cases which may be difficult to diagnose, is still a benign neoplasm
One caveat should be mentioned regarding lymph node metastasis of melanocytic neoplasms
In examining lymph nodes which drain the lesional skin, there may be occasional subcapsular nests of melanocytes. These may be benign and represent:
Normal migration of benign melanocytes, presumably a embryonic migration
Normal draining of benign melanocytes, especially from a congenital nevusOnly if the lymph node is nearly totally replaced by melanocytes can a diagnosis of metastastic melanoma be made with confidence
- Sentinel lymph node biopsy in patients with "atypical Spitz tumors." A report on 12 cases.
Urso C, Borgognoni L, Saieva C, Ferrara G, Tinacci G, Begliomini B, Reali UM.
Department of Anatomic Pathology, Dermatopathology Section, S. M. Annunziata Hospital, Florence, Italy.
Hum Pathol. 2006 Jul;37(7):816-23. Epub 2006 May 19. Abstract quote
The distinction between Spitz nevus and melanoma is currently possible, applying a set of definite histological criteria. However, in certain lesions deviating from the stereotypical morphology of classic Spitz nevi ("atypical Spitz tumors"), the differentiation between benign and malignant cases appears problematic because objective criteria for a reliable diagnosis are lacking.
We report the clinicopathologic findings of 12 patients with atypical Spitz tumors, who underwent sentinel node biopsy. All the tumors, composed of spindle and/or epithelioid cells, histologically showed features referable to Spitz nevi mixed to features generally found in malignant melanomas. Nine patients were females and three males, ranging in age from 2 to 48 years (mean, 23.2 years). The size of lesions ranged from 5 to 9 mm, the thickness from 1.12 to 5.70 mm. Nodal micrometastases were found in 4 (33.3%) patients.
Among the patients with positive sentinel node, two showed minimal nodal involvements; one patient showed additional tumor deposits in one nonsentinel regional node. All patients are alive and free of disease with a follow-up of 2 to 90 months (mean, 26.3 months). Metastasizing and nonmetastasizing cases appeared clinically and histologically indistinguishable. The statistical analysis showed no significant difference between the two groups.
Results suggested that all the reported cases may constitute a relatively homogeneous morphological group of lesions with a relevant metastatic potential that may be underdiagnosed.
Sentinel Lymph Node Biopsy in Patients With Diagnostically Controversial Spitzoid Melanocytic Tumors
Christina M. Lohmann, M.D. ; Daniel G. Coit, M.D. ; Mary S. Brady, M.D. ; Marianne Berwick, Ph.D. ; Klaus J. Busam, M.D.
From the Departments of Pathology (C.M.L., K.J.B.), Surgery (D.G.C., M.S.B.), and Epidemiology and Biostatistics (M.B.), Memorial Sloan-Kettering Cancer Center, New York, NY, U.S.A.
Am J Surg Pathol 2002;26:47-55 Abstract quote
Melanomas can be difficult to diagnose histologically if they deviate in their growth pattern or cytology only minimally from a nevus. On occasion, even experts on melanocytic lesions may not reach a consensus on whether a lesion is a benign but unusual nevus or a malignant melanoma mimicking a nevus. This diagnostic dilemma is particularly well known for the distinction of Spitz nevus from melanoma. Diagnostic uncertainty and disagreement among consultant pathologists lead to confusion about the prognosis and clinical management of patients.
In this study we present the clinical and pathologic findings of 10 patients with diagnostically controversial melanocytic tumors, who underwent sentinel lymph node biopsy. In all of these cases, the diagnostic controversy among experts was between Spitz nevus and melanoma. Seven patients were female, and three were male, ranging in age from 7 to 46 years (mean 21 years). Histologic examination of the sentinel lymph nodes revealed tumor deposits in the lymph node parenchyma in 5 of 10 patients. Among patients with positive sentinel lymph nodes, two had satellite nodules and one showed additional tumor deposits in three nonsentinel regional lymph nodes. All patients are alive and free of disease with a follow-up of 10–54 months (mean 34 months).
Our study illustrates the role of a sentinel lymph node biopsy in the evaluation of patients with diagnostically controversial melanocytic tumors. Although the presence of metastatic tumor deposits in the sentinel lymph node supports the diagnosis of malignant melanoma, further studies are needed to determine the prognostic significance of the sentinel lymph node findings in such patients.
TREATMENT There is great controversy regarding adequate treatment for a Spitz nevus. Although this is definitely a benign proliferation of melanocytes, there may be hesitation on the part of both the dermatologist or treating physician to accept the diagnosis as well as the pathologist/dermatopathologist in making the diagnosis
At the very least, the diagnosis should be made only if most of the lesion is visualized and if the biopsy is a superficial shave or punch biopsy which does not completely or nearly completely visualize the entire lesion, a re-excision should be recommended
Having said that, if an experienced dermatopathologist or pathologist makes the diagnosis on an adequate excision, a reexcision is not necessary.
From a practical standpoint, a reexcision may be reasonable even if the diagnosis is confident. This is because if a Spitz nevus were to recur in a previously biopsied area, the distortion and treatment related atypia may make an accurate diagnosis very difficult, keeping in mind that Spitz nevi are already histologically atypical
GENERAL
Management of Spitz nevi: a survey of dermatologists in the United States.Gelbard SN, Tripp JM, Marghoob AA, Kopf AW, Koenig KL, Kim JY, Bart RS.
Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York 10016, USA.
J Am Acad Dermatol 2002 Aug;47(2):224-30 Abstract quote BACKGROUND: There is no consensus concerning management of Spitz nevi.
OBJECTIVE: This study was carried out to ascertain how dermatologists manage Spitz nevi.
METHODS: A questionnaire was sent to 997 fellows of the American Academy of Dermatology, 284 pediatric dermatologists, and 27 directors of pigmented-lesion clinics. The results are based on the 381 questionnaires returned.
RESULTS: The vast majority of responding dermatologists (93%) recommend biopsies of suspected Spitz nevi. Of this group, 43% recommend total biopsies and 55% recommend partial biopsies; 2% would recommend either total or partial biopsies, depending on the clinical situation. Sixty-nine percent of physicians would completely excise a lesion that was histologically diagnosed as an incompletely removed Spitz nevus. Seventy percent of general dermatologists and 80% of pediatric dermatologists would recommend excision with a 1- to 2-mm margin of normal-appearing skin around a Spitz nevus. Nine percent of general dermatologists would recommend margins of 4 mm or more; however, all pediatric dermatologists surveyed would recommend margins less than 4 mm. Physicians were less likely to monitor patients whose Spitz nevi were completely removed. Three fourths (74%) of respondents believe Spitz nevi are entirely benign, 4% believe they are precursors to melanoma, and 22% are not sure. Seven percent of general dermatologists and 4% of pediatric dermatologists have seen metastatic melanomas arise at sites of lesions initially diagnosed histologically as Spitz nevi; 40% of pigmented-lesion clinic directors have seen such lesions.
CONCLUSIONS: We believe that the lack of consensus, both in our survey and in the medical literature, reflects to some extent the lack of certainty in the histologic differentiation of Spitz nevi from melanomas and that concern about melanoma influences management. At the pigmented-lesion clinic of the New York University Skin and Cancer Unit, because of this concern about melanoma, it is usually recommended that Spitz nevi be completely excised.
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Kamino bodies-Coalescent eosinophilic globules usually located at the dermal-epidermal junction.
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