Benign epithelioid peripheral nerve sheath tumors of the soft tissues: clinicopathologic spectrum of 33 cases

Benign epithelioid peripheral nerve sheath tumors (BEPNSTs) have not been fully characterized, and their relationship to conventional schwannoma and neurofibroma has not been satisfactorily established. Herein, we detail the clinicopathologic features of 33 examples of BEPNST. The study included 22 females and 11 males ranging in age from 2 to 68 years (median, 31.5 years). Only one patient probably has neurofibromatosis type 1. The tumors were predominantly dermal/subcutaneous in location (85%) and involved the lower limb (n=15), upper limb (n=11), trunk (n=4), and head/neck (n=3). The lesions ranged in size from 0.3 to 6.8 cm (median, 1.1 cm). Microscopically, the tumors were generally well-circumscribed, uninodular, or multinodular masses. Twenty-six lesions were encapsulated. Tumors consisted of trabeculae, loosely arranged nodules, and cohesive nests of epithelioid tumor cells immersed in collagenous, myxohyaline, or chiefly myxoid stroma. A bland spindled cell component comprising 5% to 40% of the tumor was noted in 15 cases. Mitotic activity ranged from 0 to 6 mitoses/50 high power fields (mean, 1.5 mitoses/50 high power fields) with no abnormal division figures identified. Five lesions were considered atypical based on presence of focal nuclear/nucleolar enlargement and hyperchromasia. Immunohistochemical reactivity for Schwann cell-related markers in tumor cells included S-100 protein (20 of 20 cases), collagen type IV (10 of 10), laminin (8 of 8), nerve growth factor receptor, p75(7 of 8), CD57 (6 of 9), and glial fibrillary acidic protein (8 of 15). CD34-positive fibroblast-like cells were identified in all 12 neoplasms tested. Anti-epithelial membrane antigen highlighted perineurial cells in 9 of the 11 encapsulated tumors. Anti-neurofilament protein did not identify intralesional neuraxons in the 10 tumors evaluated. Eighteen tumors were subtyped as epithelioid neurofibromas. The remaining 15 cases showed some histologic features suggestive of schwannoma, but their uniform cellularity, absence of nuclear palisading, and presence of a significant CD34-positive spindled cell population in 5 cases led to their classification as "BEPNST of indeterminate histogenesis." Evaluation for loss of heterozygosity in 2 cases demonstrated deletion of genetic material on chromosome 22q and 17q involving NF2 and NF1 loci. However, sequencing of NF2 coding sequences revealed no mutations. Follow-up for 18 patients (median interval, 13.5 years), including 4 patients with tumors exhibiting cytologic atypia, revealed a nondestructive recurrence or persistent disease in 3 patients whose tumors lacked atypia, but no evidence of metastatic spread or tumor-related death. BEPNSTs are usually small neoplasms located in superficial soft tissue and have an excellent prognosis after complete local excision. Accurate subclassification of some of these lesions is difficult based on currently available techniques.     

Sclerosing epithelioid fibrosarcoma: a study of 16 cases and confirmation of a clinicopathologically distinct tumor

Sclerosing epithelioid fibrosarcoma (SEF) is an uncommon tumor of deep soft tissues, originally described in 1995 by Meis-Kindblom et al. In the current study, the authors identified 16 cases of SEF in the pathology files of their institutions and studied their pathologic features and disease course. The group consisted of six male and 10 female patients (age range, 14-55 years; mean age, 40 years), and the tumors were located in a limb or limb girdle (n = 7), base of the penis (n = 1), back or chest wall (n = 3), and head and neck (n = 5). Tumor size ranged from 3.7 to 22 cm (mean, 8.9 cm). Histologically, the SEFs were composed predominantly of small to moderate-size round to ovoid, relatively uniform cells, often with clear cytoplasm, embedded in a hyalinized fibrous stroma. The only consistent immunohistochemical finding was a strong, diffuse reactivity of tumor cells for vimentin. Ultrastructural analysis performed in eight cases confirmed their fibroblastic nature. Bone invasion and tumor necrosis, features not reported before, were found in six cases each. Treatment consisted of intralesional excision (n = 2), attempted wide local excision (n = 11), and amputation (n = 3), with either adjuvant radiation therapy (n = 9) or chemotherapy (n = 3). Follow-up of at least 1 year in 14 cases revealed persistent disease or local recurrence in seven patients (50%), and distant metastasis in 12 patients (86%). Eight patients (57%) died of disease 16 to 86 months after diagnosis. Five patients were alive with disease as of last follow-up. SEF shares some pathologic features with two other fibrosing fibrosarcomas, low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes, but in the authors' experience behaves clinically as a fully malignant sarcoma.     

Epithelioid sarcoma-like hemangioendothelioma

We are reporting seven histologically identical cases of a distinctive, low-grade vascular tumor that closely mimics an epithelioid sarcoma because of growth in solid sheets and nests, the eosinophilia of the rounded to slightly spindled neoplastic cells, and the diffuse, strong cytokeratin expression. Termed epithelioid sarcoma-like hemangioendothelioma, all were diagnosed by the submitting pathologist or another expert consultant as epithelioid sarcoma. Although none displayed architectural evidence of vascular differentiation in the form of multicellular vascular channels, some displayed subtle cytologic features of vascular differentiation and all displayed immunohistochemical evidence of endothelial differentiation. The patients (four male; three female) ranged in age from 17 to 54 years (median 23 years). Ranging in size from 1 to 3.5 cm, they occurred in the extremities (n = 5), scalp (n = 1), and chest wall (n = 1), both in deep (n = 3) and superficial (n = 3) soft tissue or both (n = 1). The tumors were characterized by sheets, ill-defined nodules, or fascicles of deeply eosinophilic cells set within a desmoplastic stroma. Multicellular vascular channel formation and/or hemorrhage were absent in all cases. In four cases intracytoplasmic vacuolization suggestive of intracytoplasmic vascular lumen formation was noted. The typical neoplastic cell was large and rounded in shape but modulated in areas to a spindled or multipolar shape. Mitotic activity was low (<5 mitotic figures/50 high power fields), nuclear pleomorphism was mild to moderate, and necrosis was absent. The tumors were positive for cytokeratin (6 of 6), vimentin (6 of 6), CD31 (5 of 6), FLI-1 (6 of 6), but negative for CD34 (0 of 6). Within a follow-up period of 3-72 months (median 39 months), two patients experienced a local recurrence and one patient regional soft tissue metastases, but no distant ones. Two patients presented with multifocal lesions suggestive of regional metastases. Currently, two patients are alive with disease and five are disease free. Epithelioid sarcoma-like hemangioendothelioma appears to be a largely unrecognized epithelioid vascular tumor with an indolent course. Despite its similar clinical and histologic features, it differs from epithelioid sarcoma by the presence of endothelial markers and the absence to date of distant metastases. Its distinction from other epithelioid vascular lesions is discussed. We think this tumor fits best into the family of "hemangioendothelioma" or vascular lesions of intermediate malignancy.     

Primary cutaneous epithelioid angiosarcoma: a clinicopathologic study of 13 cases of a rare neoplasm occurring outside the setting of conventional angiosarcomas and with predilection for the limbs

Epithelioid angiosarcomas are rare aggressive neoplasms that occur most frequently in deep soft tissues. Primary cutaneous lesions are rare, and there are discrepant findings in the literature regarding their behavior. In this study, we report a series of 13 cases of primary cutaneous epithelioid angiosarcoma and analyze their clinicopathologic features. The tumors arising in the conventional settings for cutaneous angiosarcoma (ie, in the head and neck region of elderly patients, and those occurring postradiation or associated with lymphedema) were excluded. Primary cutaneous epithelioid angiosarcoma occurred in adults (mean age, 66 y) with an equal sex distribution, and presented as solitary (n=10) or multiple (n=3) nodules ranging in size from 8 to 80 mm, with a predilection for the limbs (n=10). Histopathologically, the tumors comprised infiltrative sheets of atypical epithelioid cells within the dermis with or without the involvement of the subcutis. Vascular channel formation and intracytoplasmic lumina were seen, at least focally, in most cases. Mitoses were readily identified and necrosis was seen in 40% of the cases. The tumors were immunoreactive for vascular markers, with CD31 and FLI-1 offering the highest sensitivity. Pancytokeratin was positive in two thirds of the cases, and epithelial membrane antigen was positive in one-quarter of the cases. There was rare focal expression of Melan-A (n=2) and smooth muscle actin (n=3). Follow-up information was available for 11 patients. Six patients died of metastatic disease after a median follow-up of 12 months (range, 3 to 36 mo), and 1 patient died of unrelated causes. These findings suggest that primary cutaneous epithelioid angiosarcoma occurring outside the conventional settings of angiosarcoma is a highly aggressive malignant tumor with mortality rates in excess of 55% after 3 years.     

Expanding the spectrum of malignant change in schwannomas: epithelioid malignant change, epithelioid malignant peripheral nerve sheath tumor, and epithelioid angiosarcoma: a study of 17 cases

Schwannomas (neurilemmomas) rarely undergo malignant change, most often in the form of either malignant peripheral nerve sheath tumor (MPNST) or angiosarcoma. We characterize the clinical features and the histopathologic spectrum of 17 schwannomas with evidence of malignant change. The study group comprised 7 males and 10 females with an age range of 16 to 76 years, (median, 40 yrs). None of the patients had neurofibromatosis. Lesions ranged in size from 0.6 to 10.5 cm (median, 4.0 cm) and arose mainly in the limbs/limb girdles (7 cases) or head and neck region (7 cases). All tumors contained areas of conventional benign schwannoma. Four cases of pure epithelioid malignant peripheral nerve sheath tumor (EMPNST) were identified, three of which showed immunopositivity for S-100 protein. Four angiosarcomas were identified, predominantly epithelioid-type. Ten schwannomas had an appearance that we have designated epithelioid malignant change (EMC) and, in one of these, EMC coexisted with EMPNST. Large epithelioid cells with abundant eosinophilic cytoplasm, vesicular chromatin, and prominent nucleoli (morphologically similar to cells of EMPNST) were distributed throughout the schwannoma--singly, in clusters, and in one case a microscopic nodule of such cells was also present. These large epithelioid cells were strongly positive for S-100 protein. Although follow-up data so far are limited, 1 of 5 patients with EMC in whom meaningful follow up was available developed repeated local recurrence (median follow up, 21 mos), one patient each with EMPNST and angiosarcoma died of local and metastatic disease. Pure EMPNST is rare; however, we confirm the tendency of MPNST to show epithelioid cytomorphology when arising in a benign schwannoma. We also confirm the distinctive (albeit infrequent) tendency of angiosarcoma to arise in schwannomas. We describe EMC in schwannomas and suggest that this represents a putative precursor lesion of EMPNST. At this time, we do not have an explanation for the tendency of schwannomas to show epithelioid cytomorphology when they undergo malignant change.     

Leiomyosarcoma of the penis: a clinicopathologic study of 14 cases with review of the literature and discussion of the differential diagnosis

Primary leiomyosarcomas of the penis are very rare. To date, less than 30 have been documented in the English language literature. In this report, we describe the clinical, histopathologic, and immunohistochemical findings in 14 cases retrieved from our files. The patients ranged in age from 43 to 62 years (mean age, 51 years) at the time of initial surgical resection. The tumors involved the prepuce (n = 1), prepuce and distal shaft (n = 1), circumcision scar line (n = 2), circumcision scar line and distal shaft (n = 1), shaft (n = 5), base of the penis (n = 3), and penis, not otherwise specified (n = 1). The lesions ranged in size from 0.5 to 6.0 cm (median size, 1.5 cm) in greatest dimension. Nine tumors were superficially located, two were of indeterminate depth, and three were deep-seated. The superficial tumors were relatively asymptomatic, and seven were reportedly present for 1 year to more than 20 years (median duration, 5 years) before medical attention was sought. In contrast, one deep-seated lesion caused dysuria and difficulty voiding, prompting the patient to seek a clinical opinion within only a few months of the apparent onset. Histologically, all tumors contained smooth muscle cells with both cytologic atypia and mitotic activity. Immunohistochemical studies were available for nine tumors, and immunoreactivity for desmin was present in all instances. All patients were initially treated with a local procedure. Follow-up information is available for 9 of the 14 patients (64%), with a median follow-up interval of 12 years 11 months. Three patients had multiple (two to four) local recurrences. Two of these patients were ultimately treated with a wide local excision or partial penectomy, and both were alive and well at last follow-up. In contrast, one patient, who had four local recurrences and refused a penectomy, developed a distant metastasis 10 months after the fourth recurrence. The best predictors of outcome are tumor depth and tumor size. Superficial leiomyosarcomas of the penis are optimally managed by wide local excision whenever this is technically feasible. Tumors with a deep-seated component may require more aggressive intervention to ensure complete removal.     

Benign lymphangioendothelioma (acquired progressive lymphangioma): a lesion not to be confused with well-differentiated angiosarcoma and patch stage Kaposi's sarcoma: clinicopathologic analysis of a series

The clinicopathologic features of 12 cases of benign lymphangioendothelioma (acquired progressive lymphangioma) are reported. There were five male and seven female patients. Age at diagnosis ranged from 17 to 90 years (median age, 54 yrs). Development of a single macular/papular hemangiomatous or pigmented lesion was the main presenting symptom. Symptom duration before diagnosis ranged from 2 months to 20 years (median, 5.5 yrs). Tumor size ranged from 0.3 cm to 10 cm (median. 1.5 cm). Location included skin of the head and neck (n = 5), back (n = 1), breast (n = 1), shoulder (n = 1), forearm (n = 1), plantar aspect of the foot (n = 2), and oral mucosa (n = 1). No patient had any other concomitant vascular anomaly (for example, lymphangiomatosis) or was suspected to have acquired immunodeficiency syndrome. Treatment consisted of excisional biopsy in nine patients, incisional biopsy in two, and wide excision in one. Follow-up information on nine patients (range, 4-40 mos; median, 12 mos) showed two local recurrences in one patient. Microscopically, the lesions consisted of anastomosing, often widely dilated vascular structures developing in the superficial dermis. As the lesion grew within deeper dermis, the vascular spaces collapsed and dissected the dermal collagen in an angiosarcoma-like pattern. The lining endothelium was flat and monolayered, with little or no cytologic atypia and no evident mitoses. Some vascular structures contained stromal papillary projections resembling papillary endothelial hyperplasia, and intravascular red blood cells were present occasionally. Immunohistochemistry performed in eight specimens showed variable endothelial cell reactivity for CD31 (7 of 8), CD34 (7 of 7), and factor VIII-related antigen (4 of 6). A smooth muscle cell layer was observed focally around the vascular spaces in six lesions. Benign lymphangioendothelioma (acquired progressive lymphangioma) is an uncommon benign lesion that, in view of major differences in treatment and prognosis, should be distinguished from well-differentiated angiosarcoma and Kaposi's sarcoma, especially the patch stage and lymphangioma-like variants of the latter.     

Papillary intralymphatic angioendothelioma (PILA): a report of twelve cases of a distinctive vascular tumor with phenotypic features of lymphatic vessels.

Six childhood vascular tumors were designated as "malignant endovascular papillary angioendothelioma" by Dabska in 1969. Since then, a few reports of similar cases were published, often called "Dabska tumors." Twelve similar cases were identified in review of vascular tumors from the authors' institutions. There were five men and seven women, including seven adults. Patient ages ranged from 8 to 59 years (mean, 30 years). The tumors occurred in the dermis or subcutis of the buttocks or thigh (n = 6), thumb or hand (n = 3), abdomen (n = 2), and heel (n = 1). The tumor sizes ranged from 1 to more than 40 cm (mean, 7.0 cm). The unifying feature of all cases was distinctive intravascular growth of well-differentiated endothelial cells presenting as a matchstick columnar configuration, sometimes with a large production of matrix that was positive for collagen type IV. In half the cases, these intravascular proliferations had an associated actin-positive pericytic proliferation. There was minimal cytologic atypia and rare to absent mitotic activity. Two cases had an adjacent lymphangioma, and two additional cases had clusters of lymphatic vessels adjacent to the tumor. All but two of the cases showed varying degrees of stromal or intraluminal lymphocytes. Occasional epithelioid endothelial cells were seen, but no cases had features typical of epithelioid, spindle cell, or retiform hemangioendothelioma. Tumor cells were positive for vimentin, von Willebrand factor, CD31, and focally for CD34 and were negative for keratins, epithelial membrane antigen, S-100 protein, and desmin. Vascular endothelial cell growth factor receptor type 3, a recently introduced marker for lymphatic endothelia, was positive in all eight cases that were studied, supporting a lymphatic phenotype. Follow-up in 8 of the 12 cases showed no evidence of recurrences, metastases, or residual disease during follow-ups ranging from 1 to 17 years (mean, 9 years). Based on the proliferative borderline features and the lymphatic phenotype, we propose to designate these tumors as papillary intralymphatic angioendothelioma. Additional cases with extensive follow-up should be studied to rule out variants with malignant potential.     

Pigmented epithelioid melanocytoma: a low-grade melanocytic tumor with metastatic potential indistinguishable from animal-type melanoma and epithelioid blue nevus

In the course of a study of borderline melanocytic tumors, we observed a distinctive group of lesions characterized by features very similar to those previously described in the literature as "animal-type melanoma" and epithelioid blue nevus of Carney complex. We have designated these lesions as pigmented epithelioid melanocytoma (PEM). Herein, we present a clinical-pathologic analysis of 41 consecutive PEM from 40 patients and compare them with 11 epithelioid blue nevi from patients with Carney complex. PEM occurred in both sexes of different ethnic backgrounds, including white, Hispanic, black, Asian, and Persian. The median age of occurrence was 27 years (range 0.6-78 years). Tumors had wide distribution with extremities being the most common site. The tumors were formed by deep dermal (mean Breslow's thickness 3.3 mm) proliferation of heavily pigmented epithelioid and/or spindled melanocytes. Five lesions were part of combined nevus. Ulceration was present in 7 cases. Tumor necrosis was present in 1 case. Regional lymph nodes were sampled in 24 cases (59%). In 11 cases, lymph nodes contained metastases (46%). Liver metastases occurred in 1 case. None of the patients died of disease. Clinical follow-up of more than a year (mean 32 months, range up to 67 months) was available in 27 cases (67%). We found no histologic criteria separating metastasizing and nonmetastasizing PEM. Ulceration was the only feature more common in PEM than epithelioid blue nevi of Carney complex. Otherwise, they were histologically indistinguishable. Our data show that PEM is a unique low-grade variant of melanoma with frequent lymph node metastases but indolent clinical course. We suggest that PEM be considered as a provisional histologic entity encompassing both animal-type melanoma and epithelioid blue nevus.     

Perivascular epithelioid cell tumor ('PEComa') of the uterus: a subset of HMB-45-positive epithelioid mesenchymal neoplasms with an uncertain relationship to pure smooth muscle tumors.

The family of lesions thought to be composed at least in part of perivascular epithelioid cells, characterized as HMB-45-positive epithelioid cells with clear to eosinophilic granular cytoplasm and a propensity for a perivascular distribution, includes some forms of angiomyolipoma and lymphangioleiomyomatosis, as well as clear cell "sugar" tumor (CC-SUGAR). When composed predominantly or exclusively of epithelioid cells, it has been suggested that these lesions be classified as "perivascular epithelioid cell tumors" (PEComa). Four cases of uterine PEComa have been described in the literature, three of which exhibited aggressive behavior. We report the clinical, histologic, and immunohistochemical features of eight more examples of uterine PEComa. Patients ranged in age from 40 to 75 years (mean 54 years). Most patients presented because of abnormal uterine bleeding, and grossly a mass was present in the uterine corpus. Morphologically, the tumors could be divided into two groups (A and B). Group A tumors demonstrated a tongue-like growth pattern similar to that seen in low-grade endometrial stromal sarcoma and were composed of cells that tended to have abundant clear to eosinophilic pale granular cytoplasm, diffuse HMB-45 expression, and focal muscle marker expression. Group B tumors were composed of epithelioid cells with less prominent clear cell features, smaller numbers of which were HMB-45-positive. They also featured extensive muscle marker expression and a lesser degree of the endometrial stromal sarcoma growth pattern seen in group A tumors. Two of the four patients with group B tumors had pelvic lymph nodes involved by lymphangioleiomyomatosis, and one of these patients had the tuberous sclerosis complex. Seven of the eight patients with PEComas were treated by hysterectomy. All eight patients are alive and well, although follow-up of >2 years was available only for two patients. Uterine epithelioid smooth muscle tumors and low-grade endometrial stromal sarcomas were compared with the PEComas. Group A PEComas, group B PEComas, and epithelioid smooth muscle tumors were all parts of a continuous histologic spectrum, with group A PEComa at one end of the spectrum and epithelioid smooth muscle tumors at the other, while group B tumors shared features of both. PEComa was histologically and immunohistochemically distinct from endometrial stromal sarcoma. Our data and a review of the literature indicate that PEComa is a subset of HMB-45-positive epithelioid mesenchymal tumors of the uterus with an uncertain relationship to pure smooth muscle tumors. Although none of the patients in this study experienced recurrence during a short follow-up period, some reported in the literature have had recurrences; consequently, we think uterine PEComa should be considered a tumor of uncertain malignant potential until long-term outcome data for a larger number of patients become available.     

Spindle cell and epithelioid cell nevi with atypia and metastasis (malignant Spitz nevus)

We report on the clinical and pathologic features of 32 lesions diagnosed as malignant spindle cell and epithelioid cell nevus (S&E nevus). Because of the clinical or initial histopathologic diagnosis of malignant melanoma, six patients had lymph node dissection. Three of these patients also had an enlarged lymph node. In all six cases, metastatic spindle or epithelioid cells were found in at least one of the resected lymph nodes. Of the 30 patients with follow-up information, including all six patients with lymph node metastases, all are alive and well. No recurrences or further metastases have been found. On histopathologic reevaluation, all the lesions had features of S&E nevi. Study of these cases suggests that although some lesions with features of S&E nevi may involve local lymph nodes, widespread metastases do not result.     

Pure epithelioid PEComas (so-called epithelioid angiomyolipoma) of the kidney: A clinicopathologic study of 41 cases: detailed assessment of morphology and risk stratification

Epithelioid angiomyolipomas (perivascular epithelioid cell tumors) of the kidney are defined as potentially malignant mesenchymal lesions that are closely related to classic angiomyolipoma. Although approximately 120 cases are published, mostly as case reports with variably used diagnostic criteria, the pathologic prognostic predictors of outcome are unknown. We analyzed the clinicopathologic parameters in a large series of 41 cases of pure epithelioid angiomyolipomas of the kidney, which we designate as pure (monotypic) epithelioid PEComas to contrast them from classic angiomyolipomas that are regarded by some as PEComas. We use the terminology "pure" to separate these cases from those that may have variable epithelioid components. The mean age of the patients was 40.7 years (range, 14 to 68 y). The male-to-female ratio was 1:1. Seventy-nine percent of patients were symptomatic at presentation with metastatic disease at onset in 12 cases. Follow-up and/or disease progression information were available for 33 of 41 cases (mean, 44.5 mo and median, 24.5 mo; range, 4 to 240); 9 patients had a history of associated tuberous sclerosis. Recurrence and metastasis were seen in 17% and 49% of patients; 33% of patients died of disease. Lymph node involvement was seen in 24% of patients; the liver (63%), lung (25%), and mesentery (18.8%) were the most common metastatic sites. Clinicopathologic parameters associated with disease progression (recurrence, metastasis, or death due to disease) in univariate analysis included associated tuberous sclerosis complex or concurrent angiomyolipoma (any metastasis, P=0.046), necrosis (metastasis at diagnosis, P=0.012), tumor size >7 cm (progression, P=0.021), extrarenal extension and/or renal vein involvement (progression, P=0.023), and carcinoma-like growth pattern (progression, P=0.040) (the 5 adverse prognostic parameters for pure epithelioid PEComas). Tumors with <2 adverse prognostic parameters (13 cases) were considered to be low risk for progression tumor, with 15% having disease progression. Tumors with 2 to 3 adverse prognostic parameters (14 cases) were considered to be "intermediate risk," with 64% having disease progression. Tumors with more than 4 or more adverse prognostic parameters (6 cases) were considered to be high risk, with all patients having disease progression. Of tumors with 3 or more adverse prognostic parameters, 80% had disease progression. An exact logistic regression analytic model showed that only carcinoma-like growth pattern and extrarenal extension and/or renal vein involvement were significant predictors of outcome (P=0.009 and 0.033, respectively). Our data of a large series with uniform definitional criteria confirm the malignant potential for pure epithelioid PEComas and provide adverse prognostic parameters for risk stratification in these patients.     

Pigmented (melanotic) neurofibroma: a clinicopathologic and immunohistochemical analysis of 19 lesions from 17 patients

Neurofibromas with melanin-laden pigmented cells are rare, accounting for less than 1% of all neurofibromas accessioned to the Soft Tissue Registry of the Armed Forces Institute of Pathology between the years 1970 and 1996. This study analyzes the clinicopathologic features associated with 19 specimens removed from 17 patients. Eleven males and six females, ranging in age from 2 to 61 years (median, 28 years), participated in the study. Nine of 15 patients whose race was provided were black. Eight patients (47%) are known to have neurofibromatosis, and two others (12%) are strongly suspected of having this disorder; two patients have similarly affected family members. Eight patients were noted to have multiple skin tumors, and in each of two cases, two pigmented neurofibromas were available for review. Two patients had hypertrichosis and cutaneous hyperpigmentation resembling a hairy nevus, and one had a café au lait spot directly overlying a pigmented neurofibroma. Tumors ranged in size from 1.7 to 50 cm in greatest dimension and involved the buttock or leg (n = 6), head or neck (n = 8), trunk (n = 2), wrist or hand (n = 2), and an unspecified site (n = 1). The neurofibromas exhibited diffuse (n = 15), combined diffuse and plexiform (n = 2), combined diffuse and intraneural epithelioid (n = 1), and nonspecific (n = 1) growth patterns. The process involved the skin (n = 14), subcutis (n = 18), and/or skeletal muscle (n = 3). Wagner-Meissner-like bodies were identified in 11 tumors, and mitoses (average, less than one mitosis per 10 high-power fields) were present in three lesions. All examples contained scattered pigmented cells with dendritic, tadpole-shaped, spindled or epithelioid morphology. These cells were positive with Fontana-Masson (nine of nine) and Warthin-Starry (pH, 3.2; four of four) stains, and were depigmented with a melanin bleach method (two of two). An iron stain was negative. The tumors had immunoreactivity for S-100 protein (11 of 11), HMB-45 ( 10 of 11), Melan-A (four of four), tyrosinase (four of four), and CD34 (four of four). Although recurrences are documented, none of the tumors are known to have undergone malignant transformation. A pigmented neurofibroma can be confused with a pigmented dermatofibrosarcoma protuberans (Bednár tumor) because the melanin-laden cells of both processes are similar. However, the latter entity exhibits a more extensive storiform growth, has greater immunoreactivity for CD34, and lacks a diffuse proliferation of S-100 protein-positive Schwann cells.     

Mucosal benign epithelioid nerve sheath tumors

Mucosal nerve sheath tumors have been well described in the gastrointestinal tract and other mucosal sites. In a series of mucosal biopsies, we have encountered a distinct subset of mucosal peripheral nerve sheath tumors characterized by small epithelioid cells and a benign clinical course. Such epithelioid nerve sheath tumors have been observed as a component of a larger study of colorectal "schwannomas," but herein we describe them in detail. A series of 7 of these lesions detected on mucosal biopsies (6 colonic, 1 bladder) was received by a single large institution in consultation material. The histologic and clinicopathologic features of the cases were reviewed. The mean age at presentation was 58.6 years with a slight female predominance (4 females, 3 males). Five of the colonic lesions were from the left colon and one from the right colon. The bladder biopsy was from the bladder neck. All of the colonic lesions were discovered as small (0.2-1.0 cm) polyps during the time of colonoscopy (3 at the time of routine screening, 2 for the workup of occult blood in the stool). The bladder neck mass was seen on bladder ultrasound after the patient presented with vaginal bleeding. None of the patients had a known history of neurofibromatosis. Histologically, the lesions showed an infiltrative growth pattern and were composed of spindled to predominantly epithelioid cells arranged in nests and whorls. The epicenters of the lesions were located in the lamina propria and extended to the superficial submucosa. The proliferating cells had uniform round to oval nuclei with frequent intranuclear pseudoinclusions and eosinophilic fibrillary cytoplasm. No mitoses were seen. All lesions expressed diffuse S-100 protein, and 3 of 5 lesions stained showed CD34 labeling in supporting cells. All were negative for CD117. All 5 lesions tested were negative for calretenin, while SM31 showed no intralesional neuraxons. One lesion was stained for epithelial membrane antigen and was negative. One lesion was associated with superficial mucosal erosion, and 1 had an inflammatory infiltrate predominantly composed of eosinophils. On follow-up of 5 patients, none has had any symptoms or recurrence of disease. Mucosal epithelioid nerve sheath tumors are a rare entity characterized by prominent epithelioid round to oval cells with an infiltrative growth pattern. These lesions are often discovered incidentally and have a benign clinical course.     

Uterine epithelioid leiomyosarcomas with clear cells: reactivity with HMB-45 and the concept of PEComa

In this study, we investigated HMB-45 expression in epithelioid uterine leiomyosarcomas with clear cell areas. From 12 epithelioid leiomyosarcomas, we selected 5 that had: 1) clear cell areas and 2) spindle cell areas that were at least focally positive for desmin and caldesmon. The patients' ages ranged from 47 to 82 years (mean 64 years). Presenting symptoms were uterine bleeding (three), abdominal pain (one), and a pelvic mass (one). There was no history of tuberous sclerosis or lymphangioleiomyomatosis. One patient had stage II disease, one stage III, and three stage IV. All were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy. Two received radiotherapy, and three were also treated with chemotherapy. The tumors ranged in size from 4 x 3 x 3 cm to 10 x 7 x 6 cm; all had significant cellular atypia, areas of coagulative necrosis, and between 10 and 90 mitoses per 10 high power fields. Vascular invasion was seen in three cases. The epithelioid component varied from 50% to 90% in each case; and the percentage of clear cells was < 1% in one case, 5% in one case, and 10% to 80% in three cases. Smooth muscle actin and desmin were positive in all cases. Four cases were positive for HMB-45 only in the clear cell areas. The tumor with < 1% of clear cells was negative for HMB-45. All were negative for S-100 and c-kit. Three patients died of disease at 9, 30, and 32 months; one patient is alive with progressive disease at 6 months, and one patient (stage II disease) is alive with no evidence of disease at 8 months. Unequivocal uterine epithelioid leiomyosarcomas may have clear cells positive for HMB-45. These tumors might belong to the group of lesion designated as PEComas; however, it is advisable to designate them as uterine leiomyosarcomas. In uterine smooth muscle tumors, some epithelioid cells most likely undergo clear cell changes and become positive for HMB-45. It would be advisable to perform this stain in all epithelioid smooth muscle tumors of the uterus.     

Giant epithelioid hemangioma of the hand

Epithelioid vascular tumors are a heterogeneous group characterized by epithelioid-appearing endothelial cells. Included are benign vascular tumors (epithelioid haemangioma), borderline tumors (epithelioid haemangioendothelioma), and malignant tumors (epithelioid angiosarcoma). We describe a case of epithelioid haemangioma.     

Schwannomas in the colon and rectum: a clinicopathologic and immunohistochemical study of 20 cases.

Schwannomas of the colon and rectum are uncommon and incompletely characterized tumors, and only a small number of cases have been reported. This study was undertaken to determine the clinicopathologic profile of such tumors. A total of 20 colorectal schwannomas were identified and analyzed in a review of 600 mesenchymal tumors of the colon and rectum from the files of the Armed Forces Institute of Pathology. The schwannomas occurred equally in men (n = 9) and women (n = 11) in a wide age range (18-87 years; median age 65 years). The most common location was cecum (n = 7), followed by sigmoid and rectosigmoid (n = 6), transverse colon (n = 3), descending colon (n = 2), and rectum (n = 1); the location of one tumor had not been specified. The tumors commonly presented as polypoid intraluminal lesions, often with mucosal ulceration. Rectal bleeding, colonic obstruction, and abdominal pain were the most common presenting symptoms. The most common histologic variant (n = 15) was a spindle cell schwannoma with a trabecular pattern and vague or no Verocay bodies. These tumors ranged from 0.5 to 5.5 cm in diameter. A lymphoid cuff with germinal centers typically surrounded these tumors and focal nuclear atypia was often present, but mitotic activity never exceeded 5 per 50 HPF. All four epithelioid schwannomas occurred in the descending colon or sigmoid, three of them as small submucosal tumors. There was one plexiform schwannoma in the sigmoid composed of multiple nodules of prominently palisading schwann cells similar to those seen in conventional soft tissue schwannomas. All tumors studied were strongly positive for S-100 protein and also for low affinity nerve growth factor receptor (p75), collagen IV, and GFAP. Three tumors had CD34-positive cells, but all were negative for CD117 (KIT), neurofilament proteins, smooth muscle actin, and desmin. The percentage of MIB-1-positive cells was usually less than 1% and never higher than 3%. Colorectal schwannomas behaved in a benign fashion with no evidence of aggressive behavior or connection with neurofibromatosis 1 or 2, based on follow-up information on 18 patients.