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Background
This soft tissue tumor is most common in the skin and subcutaneous tissue but it has been reported in many organ systems. Its most common presentation is a solitary small nodule. Although once thought to be derived from smooth muscle, pathologists have now correctly identified its origin from peripheral nerve.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Granular cell myoblastoma
PATHOGENESIS CHARACTERIZATION GROWTH FACTORS
Are epidermal growth factor and transforming growth factor responsible for pseudoepitheliomatous hyperplasia associated with granular cell tumors?Barkan GA, Paulino AF.
Department of Pathology, M. D. Anderson Cancer Center, Houston, TX; and the Department of Pathology, University of Michigan Hospitals, Ann Arbor, MI.
Ann Diagn Pathol 2003 Apr;7(2):73-7 Abstract quote Granular cell tumors (GCT) are uncommon benign neoplasms that have a predilection for the head and neck region. These tumors can frequently be associated with pseudoepitheliomatous hyperplasia (PEH), which in turn may be mistaken for squamous cell carcinoma. Although epidermal growth factors are overexpressed in squamous cell carcinomas of the head and neck, their presence in PEH, especially its relation to GCT, is unknown.
We hypothesize that the expression of epidermal growth factor receptor (EGFR), epidermal growth factor (EGF), and transforming growth factor alpha (TGFalpha) in GCT have a role in the development of PEH overlying some GCT. Sections from 13 cases of GCT (five with overlying PEH) were examined histologically and evaluated immunohistochemically using monoclonal antibodies for EGFR, EGF, and TGFalpha. These were compared with nine cases of PEH independent of GCT. Two of five GCT with overlying PEH and two of six GCT without overlying PEH stained positively for TGFalpha. None of the GCT stained with EGFR or EGF. All cases of PEH, whether or not associated with GCT, were reactive for EGFR and EGF. Four of the five cases of PEH overlying GCT stained with TGFalpha. The staining pattern and intensity of all three antibodies were comparable to that of the adjacent normal squamous mucosa.
Among the three antibodies, only TGFalpha in GCT appears to be related to the development of PEH. Epidermal growth factor receptor and EGF do not seem to be directly involved. The reason of PEH formation associated with GCT in the absence of growth factors is unknown.
HISTOLOGICAL TYPES CHARACTERIZATION General Poorly circumscribed dermal nodule composed of eosinophilic granular cells
Round to polygonal with small, central uniform nuclei and abundant granular cytoplasm
May be arranged in nests or sheets
In mucosal areas, overlying epithelium is usually hyperplastic
VARIANTS J Cutan Pathol 2001;28:49-52
Infiltrative lesion composed of granular cells
Overlying epidermis with elongation and hyperpigmentation of the rete ridgesEPIDERMAL INVOLVEMENT
Background: Cutaneous granular cell tumor (GCT) may present with extension into the junctional region of the epidermis and thus may mimic melanocytic neoplasms.
Methods: We reviewed three cases of cutaneous GCT where a melanocytic neoplasm was either initially diagnosed or considered in the differential diagnosis. Histopathology was evaluated in regards to features associated with melanocytic neoplasms. Immunohistochemistry was performed to delineate a panel useful in the distinction of these and other entities.
Results: All cases consisted of spindle and epithelioid cells with granular cytoplasm and bland nuclei and were centered in the superficial dermis with extension into the epidermis. Two cases resembled Spitz nevi and one case demonstrated lentiginous growth. All cases stained positively with calretinin and inhibin. Two of the three cases stained diffusely with S100 and 2/2 cases with CD56. HAM56 and CD68 were positive in one case and another showed positivity for NSE and PGP9.5. HMB-45, tyrosinase, and Melan-A were non-reactive in all cases tested.
Conclusions: GCT may involve the epidermis and has a growth pattern similar to melanocytic neoplasms. An immunohistochemical (IHC) panel including S100, Melan-A, tyrosinase, HMB-45, CD56, CD68, calretinin, inhibin, and PGP9.5 may aid in the distinction and may spare the patient from unnecessary morbidity.Am J Dermatopathol 1994;16:537 POLYPOID AND PRIMITIVE
- Primitive nonneural granular cell tumors of skin: clinicopathologic analysis of 13 cases.
Lazar AJ, Fletcher CD.
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Am J Surg Pathol. 2005 Jul;29(7):927-34. Abstract quote
A rare subset of distinctive cutaneous nonneural granular cell tumors was described by LeBoit et al in 1991 and termed "primitive polypoid granular-cell tumor."
Herein, we report our experience with 13 similar, distinctive nonneural granular cell tumors. Affected patients included 7 males and 6 females ranging in age from 5 to 83 years (mean, 25 years; median, 16 years). These cutaneous lesions involved the back (5 cases), neck, shoulder, thigh (2 cases each), chin, and elbow (1 case each).
Clinically described as smooth, nontender cutaneous nodules, the tumors ranged in size from 0.2 to 2.8 cm (median, 0.8 cm) and were present from months to years before excision. Mitoses numbered from 1 to 6 per mm (median, 2). Eight of the lesions were polypoid, based in the papillary dermis with extension to the superficial dermis and associated with an epithelial collarette. Five of the lesions were situated deeper in the reticular dermis with limited extension into the subcutis but clinically were also nodular. All the tumors were well circumscribed and composed of spindled to ovoid cells with abundant granular, eosinophilic cytoplasm and vesicular nuclei with small prominent nucleoli.
Immunohistochemistry revealed reactivity only for NKI-C3 (11 of 12 cases), CD68 (7 of 11 cases), and NSE (5 of 10 cases); S-100 protein as well as other melanocytic, epithelial, and myoid markers were uniformly negative. All 13 of the lesions were locally excised and in the 8 cases with adequate follow-up ranging from 13 to 126 months (mean, 68 months; median, 41 months), none has recurred locally. However, one tumor (case no. 11) gave rise to a local lymph node metastasis 25 months after presentation, but the patient is currently disease-free 70 months after lymphadenectomy.
These cutaneous granular tumors do not appear to be neural or Schwannian in nature, but their precise line of differentiation is unknown.Primitive polypoid granular-cell tumor and other cutaneous granular-cell neoplasms of apparent nonneural origin.
LeBoit PE, Barr RJ, Burall S, Metcalf JS, Yen TS, Wick MR.
Department of Pathology, University of California, San Francisco 94143-0506.
Am J Surg Pathol 1991 Jan;15(1):48-58 Abstract quote
Most cutaneous and noncutaneous granular-cell tumors are currently thought to be of Schwann-cell derivation.
We present seven unusual cutaneous granular-cell lesions in which Schwann-cell origin can be excluded or is inapparent. Four of these lesions are of a previously undescribed type, and, unlike conventional granular-cell tumors of the skin, show a polypoid configuration, numerous mitoses, cytologic atypia, and a primitive immunophenotype.
We propose the term "primitive polypoid granular-cell tumor" for these lesions. One occurred in a child, and three in adults. There have been no metastases to date, with follow-up periods of 2, 4, 4, and 16 years, respectively, although one tumor recurred locally. Additional cases and longer follow-up may be required to rule out the possibility that primitive polypoid granular-cell tumor is a low-grade malignancy. Two other granular-cell lesions represent variants of leiomyosarcoma, one of which widely metastasized. The last case is a granular-cell form of nodular basal-cell carcinoma.
Cutaneous granular-cell neoplasms can show varying differentiation and behavior. Pathologists should not equate the occurrence of cytoplasmic granularity in a cutaneous neoplasm with the diagnosis of granular-cell schwannoma.
SPECIAL STAINS/
IMMUNO-PEROXIDASECHARACTERIZATION Special stains Granules are PAS positive, diastase resistant Immunoperoxidase S100 and NSE positive Granular cell tumor: immunohistochemical assessment of inhibin-alpha, protein gene product 9.5, S100 protein, CD68, and Ki-67 proliferative index with clinical correlation.
Le BH, Boyer PJ, Lewis JE, Kapadia SB.
Department of Pathology, Penn State University College of Medicine, Hershey, Pa, USA.
Arch Pathol Lab Med. 2004 Jul;128(7):771-5. Abstract quote
CONTEXT: Granular cell tumor (GCT) is a rare tumor of nerve sheath origin with a predilection for upper aerodigestive tract, skin, and soft tissue. The neoplastic cells typically express S100 and CD68 (KP-1), the latter due to cytoplasmic lysosome content. However, the histogenesis of this tumor is unknown. Additionally, distinction between benign and malignant GCT is difficult because of histologic similarity and lack of reliable criteria that can predict clinical behavior.
OBJECTIVE: To perform a comparative, side-by-side immunohistochemical assessment of the traditional immunohistochemical markers for GCTs (S100, CD68), along with the newer markers (inhibin-alpha, protein gene product 9.5) for these tumors.
DESIGN: To address diagnostic and prognostic issues, we studied 30 specimens of GCT (27 primary and 3 recurrent tumors, 2 of which occurred consecutively in the same patient) for (1) nuclear pleomorphism, prominent nucleoli, necrosis, spindling, high nuclear-cytoplasmic ratio, and mitoses; (2) immunohistochemical expression of inhibin-alpha, protein gene product 9.5, S100, CD68 (KP-1), and Ki-67 using the avidin-biotin complex method on formalin-fixed, paraffin-embedded sections; and (3) correlation between tumor grade, proliferative fraction, and clinical data.
RESULTS: Twenty-seven of 27 primary GCTs and 1 of 3 recurrent GCTs had typical histologic features, while the 2 consecutive recurrent GCT specimens from the same patient were atypical (moderate nuclear atypia and prominent nucleoli alone). The mean age for primary GCT was 37.3 years (range, 5-67 years), and mean size was 1.89 cm. None of the cases metastasized. All 30 specimens showed diffuse (2+ to 3+) staining for S100, CD68, and inhibin-alpha, and 3+ staining for protein gene product 9.5; pseudoepitheliomatous hyperplasia was nonreactive. The Ki-67 proliferative index was less than 1% to 20% in typical nonrecurrent cases, 1% in the typical recurrent case, and 1% and 10% in 2 sequential recurrences of the atypical case.
CONCLUSION: Our study expands the immunophenotype of GCT (S100, CD68, protein gene product 9.5, and inhibin-alpha) regardless of location and supports a neural origin. Intensity of immunohistochemical staining had no prognostic significance. Although 1 of the 2 recurrent GCTs had atypical features, the Ki-67 proliferative index did not distinguish reliably between typical (nonrecurrent) and atypical or recurrent GCTs. The significance of inhibin expression with regard to cell differentiation and pathogenesis is unclear and warrants further investigation.Alveolar soft part sarcoma, granular cell tumor, and paraganglioma. An immunohistochemical comparative study.
Ogawa K, Nakashima Y, Yamabe H, Hamashima Y.
Acta Pathol Jpn 1986 Jun;36(6):895-904 Abstract quote
Five cases of alveolar soft part sarcoma, 5 cases of granular cell tumor, and 6 cases of paraganglioma were investigated immunohistochemically to examine the expression of tissue-specific intermediate filaments (cytokeratin, vimentin, desmin, and glial fibrillary acidic protein (GFAP], actin, myoglobin, and nervous tissue markers (S-100 protein, neuron-specific enolase, and Leu-7).
In alveolar soft part sarcomas, some of the tumor cells were positive for desmin, but negative for nervous tissue markers. The tumor cells of granular cell tumors were stained with anti-S-100 protein antibody, but not with anti-neuron-specific enolase antibody. In contrast, the tumor cells of paragangliomas were positive for neuron-specific enolase, but not for S-100 protein except for stellate cells surrounding the tumor cell nests. This immunohistochemical approach was valuable for the differential diagnosis of these three tumors. Furthermore, the complete absence of cytokeratin in all of the tumor cells may be helpful in distinguishing these three tumors from metastatic carcinoma in soft tissue. The histogenesis of alveolar soft part sarcoma is a matter of controversy.
The result that besides desmin actin was also demonstrated in some of the tumor cells may support the myogenic origin of this tumor.
Expression of Inhibin- by Granular Cell Tumors of the Gallbladder and Extrahepatic Bile Ducts
Linda A. Murakata, M.D.; Kamal G. Ishak, M.D., Ph.D.
From the Department of Hepatic & GI Pathology, Armed Forces Institute of Pathology, Washington, DC, U.S.A.
Am J Surg Pathol 2001;25:1200-1203 Abstact quote
This is the first report of inhibin- expression in granular cell tumors.
A Medline search of the literature revealed no case reports of granular cell tumors in any location of the body being tested for inhibin- immunohistochemically, by enzyme-linked immunosorbent assay, by radioimmunoassay, or by immunoprecipitation. Seventeen cases of previously diagnosed granular cell tumors of the gallbladder and extrahepatic bile ducts with hematoxylin and eosin-stained sections, and S-100 protein immunostain were retrieved from the archives of the Armed Forces Institute of Pathology.
All cases were reviewed for diagnostic accuracy and then immunostained for inhibin- (with endogenous biotin blocking). All 17 (100%) cases were diffusely positive for inhibin- immunostain. Previous studies of inhibin--positive lesions reported in the literature include sex cord stromal tumors (granulosa cell tumors, luteinized thecomas, Leydig cell tumors), placental and gestational trophoblastic lesions, and adrenal cortical tumors. This study adds the granular cell tumor to the list of inhibin-positive lesions and should prove helpful in differential diagnosis of these lesions.
Electron microscopy (EM) Cytoplasm stuffed with lysosomes
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES Granular cells have been noted in a number of neoplasms including: J Cutan Pathol 1991;18:376 Granular cell traumatic neuroma: a lesion occurring in mastectomy scars.
Rosso R, Scelsi M, Carnevali L.
Department of Pathology, University of Pavia and I.R.C.C.S. S. Matteo Hospital, Pavia, Italy.
Arch Pathol Lab Med 2000 May;124(5):709-11 Abstract quote
BACKGROUND: Granular cell changes can be observed in a variety of benign and malignant tumors, and are seen more commonly in granular cell tumors, which in about 5% of cases develop in the breast. Granular cells also have been observed in sites of previous trauma, such as surgery, and are found to be inflammatory reactions of histiocytic origin.
METHODS AND RESULTS: We investigated, morphologically and immunohistochemically, 2 granular cell lesions occurring in mastectomy scars after surgery for carcinoma. Both lesions were composed of strands and nests of large granular cells, haphazardly set in a background of fibrous tissue, with sparse inflammatory infiltrates. Several tortuous hypertrophic nerve bundles were also embedded in the fibrous tissue. A few of these nerve bundles showed degenerative changes and contained granular cells. Immunohistochemically, granular cells were positive for S100 protein, neuron-specific enolase, vimentin, and CD68 antigen.
CONCLUSIONS: We consider these proliferative lesions of peripheral nerves to have the features of both granular cell tumor and traumatic neuroma. These cases indicate that traumatic neuroma can undergo extensive granular cell changes and constitute a previously unrecognized entity, which we provisionally label granular cell traumatic neuroma. Granular cell traumatic neuroma has to be taken into consideration when evaluating lesions occurring at mastectomy scars and should be differentiated from malignant tumors with granular cells, such as apocrine carcinoma and alveolar soft part sarcoma.
MELANOMA
From the Department of Pathology, Brigham and Women's Hospital, Boston, MA; and Harvard Medical School, Boston, MA.
Granular cell tumors (GCTs), especially if atypical or malignant, may share cytomorphologic and architectural features with malignant melanoma, when the latter shows granular cell change. In many cases, these neoplasms can be differentiated from each other on histologic grounds, but distinction may sometimes be challenging. By immunohistochemistry, both tumors are strongly positive for S-100 protein and frequently express other nonspecific markers such as CD68, NSE, and NKIC3.
In the current study, we reviewed 60 cases of conventional cutaneous, mucosal, and visceral GCT and studied the use of immunoperoxidase staining for the differential diagnosis between malignant melanoma and GCT. Immunohistochemical stains for S-100 protein, A, HMB-45, and microphthalmia transcription factor (MITF) were performed in all cases. All of the tumors were positive for S-100 protein. MITF immunostaining was diffusely positive in 53 (88%) cases, focally positive in three (5%) cases, and negative in four (7%). Fifty-seven (95%) tumors were negative for Melan-A, one case was focally positive, and two cases showed rare positive tumor cells. None of the tumors expressed HMB-45.
In conclusion, GCT and malignant melanoma can be reliably differentiated on the basis of immunohistochemical stains in the majority of cases. Although not always positive in malignant melanoma, in this context, HMB-45 expression seems to be 100% specific for the diagnosis of melanoma. Melan-A is slightly less specific, with rare cases of GCT showing focal positivity. MITF is not useful in this differential-93% of the GCTs in our series showed nuclear reactivity for this marker. The latter finding highlights the limited specificity of this antibody in the diagnosis of melanocytic tumors.METASTATIC BREAST CANCER Metastatic breast carcinoma mimicking granular cell tumor.
Franzblau MJ, Manwaring M, Plumhof C, Listrom MB, Burgdorf WH.
Marin General Hospital, San Rafael, California.
J Cutan Pathol 1989 Aug;16(4):218-21 Abstract quote
Metastatic breast carcinoma may assume many patterns. We describe a case in which cutaneous, pulmonary and lymph node metastases of an adenocarcinoma of the breast all resembled granular cell tumor.
In all sites, the lesion stained positive with antibodies against EMA and cytokeratins, but failed to stain with anti-S100.
PROGNOSIS AND TREATMENT CHARACTERIZATON PROGNOSIS Malignant granular cell tumor metastatic to the orbit.
Callejo SA, Kronish JW, Decker SJ, Cohen GR, Rosa RH Jr.
Bascom Palmer Eye Institute, University of Miami School of Medicine, Florida 33101, USA.
Ophthalmology 2000 Mar;107(3):550-4 Abstract quote
OBJECTIVE: Malignant granular cell tumor is a rare type of soft tissue sarcoma. To our knowledge, ocular (eyelid) involvement has been described in only two cases. Herein, we report the clinicopathologic features of an unusual case of malignant granular cell tumor metastatic to the orbit.
DESIGN: Observational case report.
METHODS: Retrospective review of the medical record and the histopathologic and electron microscopic findings and review of the literature.
RESULTS: A 72-year-old man with biopsy-proven granular cell tumor in the cervical region was initially seen with proptosis and motility disturbance. A magnetic resonance imaging scan showed a large intraconal mass, and biopsy of the orbital mass revealed granular cell tumor. Histopathologic examination of the primary neck tumor and the orbital mass revealed increased nuclear atypia and pleomorphism in the consecutive lesions. The morphologic impression of granular cell tumor was also supported by the immunohistochemical demonstration of S-100 protein expression and ultrastructural findings typical of granular cell tumor. Six months after the orbital involvement, systemic workup revealed multiple apparent bony and lung metastases.
CONCLUSIONS: We report the first malignant granular cell tumor metastatic to the orbit and suggest the inclusion of this tumor in the differential diagnosis of metastatic orbital lesions.
TREATMENT Simple excision Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001
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Last Updated February 14, 2007
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