Andrew L. Folpe

Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin : A clinicopathologic study of 26 cases and review of the literature

PEComas, occasionally associated with the tuberous sclerosis complex, are defined by the presence of perivascular epithelioid cells that coexpress muscle and melanocytic markers. This family of tumors includes angiomyolipoma (AML), clear cell sugar tumor of the lung (CCST), lymphangioleiomyomatosis (LAM), and very rare tumors in other locations. Because non-AML/non-LAM PEComas are extremely rare and their natural history and prognostic features undefined, we present our experience with 26 PEComas of soft tissue and the gynecologic tract, the largest series to date. We also performed a detailed review of the literature, with special attention to features predictive of clinical behavior. All PEComas exclusive of AML and LAM were retrieved from our consultation files. Immunohistochemistry for pan-cytokeratin (CK), S-100 protein, smooth muscle actins (SMA), desmin, vimentin, HMB45, Melan-A, microphthalmia transcription factor (MiTF), TFE3, CD117, and CD34 was performed. Clinical follow-up information was obtained. Fishers exact test was performed. The median patient age was 46 years (range, 15-97 years); there was a marked female predominance (22 females, 4 males). Sites of involvement included the omentum or mesentery (6 cases), uterus (4 cases), pelvic soft tissues (3 cases), abdominal wall (2 cases), uterine cervix (2 cases), and vagina, retroperitoneum, thigh, falciform ligament, scalp, broad ligament, forearm, shoulder, and neck (1 case each). The tumors ranged from 1.6 to 29 cm in size (median, 7.8 cm). Tumors were epithelioid (N = 9), spindled (N = 7), or mixed (N = 10). Multinucleated giant cells were present in 18 cases. High nuclear grade was noted in 10 cases, high cellularity in 7 cases, necrosis in 8 cases, and vascular invasion in 3 cases. Mitotic activity was 0 to 50 mitotic figures (MF)/50 high power fields (HPF) (median, 0 MF/50 HPF) with atypical MF in 6 cases. IHC results were: SMA (20/25), desmin (8/22), HMB45 (22/24), Melan-A (13/18), MITF (9/18), S-100 protein (8/24), CK (3/23), vimentin (12/14), TFE3 (5/17), c-kit (1/20), and CD34 (0/7). Clinical follow-up (24 of 26 patients, 92%; median, 30 months; range, 10-84 months) showed 3 local recurrences and 5 distant metastases. At last available clinical follow-up, 2 patients (8%) were dead of disease, 4 patients (17%) were alive with metastatic or unresectable local disease, and 18 patients (75%) were alive with no evidence of disease. No patient in our series had a history of tuberous sclerosis complex. Recurrence and/or metastasis was strongly associated tumor size > median size (8 cm), mitotic activity greater than 1/50 HPF, and necrosis. We conclude that PEComas of soft tissue and gynecologic origin may be classified as “benign,” “of uncertain malignant potential,” or “malignant.” Small PEComas without any worrisome histologic features are most likely benign. PEComas with nuclear pleomorphism alone (“symplastic”) and large PEComas without other worrisome features have uncertain malignant potential. PEComas with two or more worrisome histologic features should be considered malignant. Occasional PEComas express unusual markers, such as S-100 protein, desmin, and rarely CK. The role of TFE3 in PEComas should be further studied.

Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature.

Oncogenic osteomalacia (OO) is a rare paraneoplastic syndrome of osteomalacia due to phosphate wasting. The phosphaturic mesenchymal tumor (mixed connective tissue variant) (PMTMCT) is an extremely rare, distinctive tumor that is frequently associated with OO. Despite its association with OO, many PMTMCTs go unrecognized because they are erroneously diagnosed as other mesenchymal tumors. Expression of fibroblast growth factor-23 (FGF-23), a recently described protein putatively implicated in renal tubular phosphate loss, has been shown in a small number of mesenchymal tumors with known OO. The clinicopathological features of 32 mesenchymal tumors either with known OO (29) or with features suggestive of PMTMCT (3) were studied. Immunohistochemistry for cytokeratin, S-100, actin, desmin, CD34, and FGF-23 was performed. The patients (13 male, 19 female) ranged from 9 to 80 years in age (median 53 years). A long history of OO was common. The cases had been originally diagnosed as PMTMCT (15), hemangiopericytoma (HPC) (3), osteosarcoma (3), giant cell tumor (2), and other (9). The tumors occurred in a variety of soft tissue (21) and bone sites (11) and ranged from 1.7 to 14 cm. Twenty-four cases were classic PMTMCT with low cellularity, myxoid change, bland spindled cells, distinctive “grungy” calcified matrix, fat, HPC-like vessels, microcysts, hemorrhage, osteoclasts, and an incomplete rim of membranous ossification. Four of these benign-appearing PMTMCTs contained osteoid-like matrix. Three other PMTMCTs were hypercellular and cytologically atypical and were considered malignant. The 3 cases without known OO were histologically identical to the typical PMTMCT. Four cases did not resemble PMTMCT: 2 sinonasal HPC, 1 conventional HPC, and 1 sclerosing osteosarcoma. Three cases expressed actin; all other markers were negative. Expression of FGF-23 was seen in 17 of 21 cases by immunohistochemistry and in 2 of 2 cases by RT-PCR. Follow-up (25 cases, 6-348 months) indicated the following: 21 alive with no evidence of disease and with normal serum chemistry, 4 alive with disease (1 malignant PMTMCT with lung metastases). We conclude that most cases of mesenchymal tumor-associated OO, both in the present series and in the reported literature, are due to PMTMCT. Improved recognition of their histologic spectrum, including the presence of bone or osteoid-like matrix in otherwise typical cases and the existence of malignant forms, should allow distinction from other mesenchymal tumors. Recognition of PMTMCT is critical, as complete resection cures intractable OO. Immunohistochemistry and RT-PCR for FGF-23 confirm the role of this protein in PMTMCT-associated OO.

Atypical and malignant glomus tumors : analysis of 52 cases, with a proposal for the reclassification of glomus tumors

Occasional glomus tumors display unusual features, such as large size, deep location, infiltrative growth, mitotic activity, nuclear pleomorphism, and necrosis. Although a small number of purportedly malignant glomus tumors have been described, histologic criteria for malignancy in glomus tumors have never been elaborated. The authors studied 52 unusual glomus tumors (retrieved from their consultation files) previously diagnosed as “atypical” or “malignant” by virtue of nuclear atypia, infiltrative growth, or mitotic activity. They evaluated size, depth, growth pattern, cellularity, nuclear grade, number of mitotic figures per 50 high-power fields (HPF), atypical mitotic figures, vascular space involvement, and necrosis to define criteria for malignancy in glomus tumors. Estimated relative risk was calculated and the Fisher exact test was used for statistical analysis. The 27 female patients and the 25 male patients ranged in age from 8 to 83 years (median age, 43 years). The tumors measured from 0.2 to 12 cm (median size, 2 cm) and occurred predominantly in the extremities, in both the superficial (n = 35) and deep (n = 17) soft tissues. Atypical features were usually observed centrally with a rim of benign-appearing glomus tumor. Follow-up information (n = 35; range, 5 months–23 years; mean 5.5 years) showed seven recurrences, eight metastases, and seven deaths from disease. Five-year cumulative metastatic risk increased significantly for tumors with a deep location (p = 0.005), with a size of more than 2 cm (p = 0.004), and with atypical mitotic figures (p = 0.004). Mitotic activity of more than 5 mitoses/50 HPF, high cellularity, the presence of necrosis, and moderate to high nuclear grade approached but did not reach significance. High nuclear grade alone, infiltrative growth, and vascular space involvement were not associated with metastasis. The authors propose the following classification scheme and criteria. Malignant glomus tumor: Tumors with a deep location and a size of more than 2 cm, or atypical mitotic figures, or moderate to high nuclear grade and ≥5 mitotic figures/50 HPF. Symplastic glomus tumor: Tumors with high nuclear grade in the absence of any other malignant feature. Glomus tumor of uncertain malignant potential: Tumors that lack criteria for malignant glomus tumor or symplastic glomus tumor but have high mitotic activity and superficial location only, or large size only, or deep location only. Glomangiomatosis: Tumors with histologic features of diffuse angiomatosis and excess glomus cells. Using this classification scheme, metastasis was observed in 38% of tumors fulfilling the criteria for malignancy. In contrast, metastatic disease was not seen in any specimen classified as symplastic glomus tumor, glomus tumor of uncertain malignant potential, or glomangiomatosis.

Thyroid Transcription Factor-1 Is Expressed in Extrapulmonary Small Cell Carcinomas but Not in Other Extrapulmonary Neuroendocrine Tumors

Thyroid transcription factor-1 (TTF-1) is a nuclear homeodomain transcription factor that is expressed in the developing thyroid, respiratory epithelium, and diencephalon. TTF-1 is thought to be expressed specifically in pulmonary or thyroid neoplasms, and it is expressed in a significant subset of pulmonary non–small cell carcinomas, small cell carcinomas, and carcinoids but not in nonpulmonary, non–small cell carcinomas. Neuroendocrine tumors from sites other than the lung have not been evaluated for TTF-1 expression. We examined TTF-1 expression using immunohistochemistry on formalin-fixed, paraffin-embedded sections of 49 gastrointestinal carcinoids; 15 pancreatic islet cell tumors; 21 paragangliomas; 8 medullary thyroid carcinomas; 7 small cell carcinomas of the uterine cervix; 4 prostate, 4 bladder, and 6 Merkel cell (primary cutaneous neuroendocrine) carcinomas; and 1 renal carcinoma. No gastrointestinal carcinoid tumor, pancreatic islet cell tumor, paraganglioma, or Merkel cell carcinoma expressed TTF-1. All of the medullary thyroid carcinomas strongly expressed TTF-1. However, 44% of nonpulmonary small cell carcinomas were also TTF-1 positive, including four of four prostate, two of four bladder, and one of seven cervical small cell carcinomas. We conclude that TTF-1 expression is not specific for small cell carcinomas of pulmonary origin and should not be used to distinguish primary from metastatic small cell carcinomas in extrapulmonary sites. However, TTF-1 expression may be useful in distinguishing Merkel cell carcinomas and cutaneous metastasis of small cell carcinomas. Among well-differentiated neuroendocrine tumors, TTF-1 expression seems to be present only in carcinoid tumors of the lung and medullary carcinomas of the thyroid and may be of differential diagnostic value when dealing with a metastatic well-differentiated neuroendocrine tumor.

Kaposiform hemangioendothelioma: a study of 33 cases emphasizing its pathologic, immunophenotypic, and biologic uniqueness from juvenile hemangioma.

Kaposiform hemangioendothelioma (KH) is a rare tumor of childhood often associated with Kasabach-Merritt phenomenon (KMP) and occasionally lymphangiomatosis. Although generally considered distinct from other vascular neoplasms, its rarity has precluded a thorough study of its immunophenotypic profile and long-term behavior. Thirty-three cases of KH were reviewed and immunostained for alpha-smooth muscle actin, various endothelial markers (CD31, CD34, vWf, FLI1), a platelet marker (CD61), and the juvenile hemangioma-associated markers GLUT-1 and Lewis Y antigen (LeY). In addition, the presence of HHV-8 was evaluated by RT-PCR. The patients (20 males and 13 females) ranged in age from 2 weeks to 20 years (mean 3 years 9 months). Tumors developed on the extremities (17 cases), head/neck (8 cases), and other sites (8 cases) and affected both superficial and deep soft tissue. Those in the skin presented as slightly raised blue-red lesions. More than half of the patients presented with KMP (14 of 25). Tumors consisted of irregular, infiltrating nodules of compressed vessels, which modulated between areas resembling a capillary hemangioma and Kaposi sarcoma (KS). Endothelial cells in nodules were CD31, CD34, and FLI1 positive but negative for GLUT1 and LeY. Scattered “epithelioid” or glomeruloid islands featuring endothelium associated with clusters of plump alpha-smooth muscle actin-positive pericytes, stippled hemosiderin, and CD61-positive fibrin thrombi likely represent the morphologic sites of platelet consumption. Small and large lymphatic channels occurred in 22 of 33 cases and were typically seen peripheral or deep to the main tumor mass. HHV-8 transcripts were not identified (0 of 3 cases). Follow-up information was available in 22 patients (range 8 months to 15 years; mean 2 years) and indicated that 3 died of disease, 8 were alive with disease, and 10 were alive without residual disease. Two patients developed regional perinodal soft tissue involvement, but none developed distant metastases. KH is a lesion having both a vascular and lymphatic component. Its common association with KMP probably relates in part to unique architectural features that favor turbulent blood flow and platelet activation. KH can also be reliably separated from JH by GLUT-1 and LeY immunostaining, indicating differences in the morphologic and functional attributes of the endothelium between the two lesions. The absence of HHV-8 in KH underscores a different pathogenesis from Kaposi sarcoma. Our study, the largest to date, emphasizes that mortality is due to KMP and not metastatic disease, which appears limited to regional perinodal soft tissue. Given this behavior, its continued classification as a vascular tumor of intermediate malignancy is warranted.

Clear Cell Myomelanocytic Tumor of the Falciform Ligament/ligamentum Teres: A Novel Member of the Perivascular Epithelioid Clear Cell Family of Tumors With a Predilection for Children and Young Adults

The perivascular epithelioid cell family of tumors (PEComas), defined by their co-expression of melanocytic and muscle markers, includes angiomyolipoma, lymphangioleiomyoma, and clear cell “sugar” tumors of the lung, pancreas, and uterus. We present seven cases of a unique and previously unrecognized tumor of children and young adults, which represents a new addition to the PEComa group of tumors. Culled from three institutions over a 50-year period, all cases occurred in or immediately adjacent to the ligamentum teres and falciform ligament. Six patients were female and one male; their ages ranged from 3 to 21 years (median, 11 yrs). Tumor sizes ranged from 5 to 20 cm (median, 8 cm). All cases consisted of clear to faintly eosinophilic spindled cells arranged in fascicular and nested patterns. The cells had small but distinct nucleoli and low mitotic activity. Immunohistochemically, all cases were positive with antibodies to gp100 protein (HMB-45) and negative for S-100 protein. In three of the seven cases studied immunohistochemically, the tumors expressed smooth muscle actin, melan-A, microphthalmia transcription factor (MiTF), and myosin, but not desmin. No expression of the TSC2 gene product, tuberin, was seen in three cases. One case studied cytogenetically disclosed a t(3;10). Follow-up data, available in six of seven cases (median duration, 18 mos), showed five patients to be free of disease and one to have a radiographically presumed lung metastasis. We think these tumors comprise a new entity for which we propose the term “clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres.” The differential diagnosis of these tumors includes clear cell sarcoma of tendons and aponeuroses, leiomyosarcoma, and angiomyolipoma.

Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes: a clinicopathologic study of 73 cases supporting their identity and assessing the impact of high-grade areas.

Low-grade fibromyxoid sarcoma (LGFMS) is a rare sarcoma characterized by bland histologic features and a paradoxically aggressive clinical course. The hyalinizing spindle cell tumor with giant rosettes (HSCT) is a closely related tumor characterized by the presence of giant collagen rosettes. Only a single example of a metastasizing HSCT has been reported. A small subset of both LGFMS and HSCT display areas of increased cellularity and atypia which qualify as intermediate-to high-grade sarcoma; the significance of these features has not been definitively assessed. We present the clinicopathologic features of 77 cases of LGFMS and HSCT to determine the degree of overlap of these two lesions, their biologic behavior, and the significance of the occasional presence of intermediate-to high-grade sarcoma within both. The patients (33 female, 40 male) ranged from 3 to 78 years of age (median, 34 yrs). Fourteen cases occurred in patients less than 18 years of age. The tumors measured from 1 to 23 cm (median, 4.5 cm) and occurred predominantly in the trunk and lower extremities in both the deep (66 cases) and superficial (7 cases) soft tissues. In 15 cases, the tumor was present >1 year before diagnosis. All tumors showed predominantly the typical hypocellularity and bland cytologic features of typical LGFMS; however, areas of hypercellularity and nuclear enlargement and hyperchromatism were identified in 12 of 73 (16%) and 7 of 73 (10%), respectively. Necrosis and mitotic activity >5/50 high-powered fields (HPF) were present in 6 of 73 (8%) and 5 of 73 (7%), respectively. Epithelioid areas were present in 33 of 73 (45%) and rosettes in 22 of 73 (30%). Follow up (54 cases; range, 2–192 mos; median, 24 mos; mean, 38 mos) showed 5 recurrences, 3 metastases, and 1 death. The diagnosis of LGFMS or HSCT was made prospectively in 51 patients; none had metastatic disease. Two of the metastatic tumors were LGFMS and one was a HSCT. LGFMS may occur more often in the pediatric population and show a much wider histologic spectrum than previously thought. A significant number of LGFMS possess inconspicuous collagen rosettes characteristic of HSCT, indicating that these two tumors are ends of a common spectrum rather than distinct entities. HSCT, like LGFMS, are low-grade sarcomas with metastatic potential. The presence of focal areas of intermediate-to high-grade sarcoma does not portend a worse outcome in the short term. The better prognosis reflected in this study compared with previous ones might reflect the fact that all were initially diagnosed as sarcomas and treated with aggressive surgery. The fact that the only three patients to develop metastatic disease were patients whose LGFMS or HSCT was identified retrospectively supports this concept.

Pathology of Peripheral Nerve Sheath Tumors: Diagnostic Overview and Update on Selected Diagnostic Problems

Peripheral nerve sheath tumors are common neoplasms, with classic identifiable features, but on occasion, they are diagnostically challenging. Although well-defined subtypes of peripheral nerve sheath tumors were described early in the history of surgical pathology, controversies regarding the classification and grading of these tumors persist. Advances in molecular biology have provided new insights into the nature of the various peripheral nerve sheath tumors, and have begun to suggest novel targeted therapeutic approaches. In this review, we discuss current concepts and problematic areas in the pathology of peripheral nerve sheath tumors. Diagnostic criteria and differential diagnosis for the major categories of nerve sheath tumors are proposed, including neurofibroma, schwannoma, and perineurioma. Diagnostically challenging variants, including plexiform, cellular and melanotic schwannomas are highlighted. A subset of these affects the childhood population, and has historically been interpreted as malignant, although current evidence and outcome data suggest they represent benign entities. The growing current literature and the authors experience with difficult to classify borderline or “hybrid tumors” are discussed and illustrated. Some of these classification gray zones occur with frequency in the gastrointestinal tract, an anatomical compartment that must always be entertained when examining these neoplasms. Other growing recent areas of interest include the heterogeneous group of pseudoneoplastic lesions involving peripheral nerve composed of mature adipose tissue and/or skeletal muscle, such as the enigmatic neuromuscular choristoma. Malignant peripheral nerve sheath tumors (MPNST) represent a diagnostically controversial group; difficulties in grading and guidelines to separate “atypical neurofibroma” from MPNST are provided. There is an increasing literature of MPNST mimics which neuropathologists must be aware of, including synovial sarcoma and ossifying fibromyxoid tumor. Finally, we discuss entities that are lacking from the section on cranial and paraspinal nerves in the current WHO classification, and that may warrant inclusion in future classifications. In summary, although the diagnosis and classification of most conventional peripheral nerve sheath tumors are relatively straightforward for the experienced observer, yet borderline and difficult-to-classify neoplasms continue to be problematic. In the current review, we attempt to provide some useful guidelines for the surgical neuropathologist to help navigate these persistent, challenging problems.

Expression of Fli-1, a nuclear transcription factor, distinguishes vascular neoplasms from potential mimics.

Fli-1 protein, a member of the ETS family of DNAbinding transcription factors, is involved in cellular proliferation and tumorigenesis. Approximately 90% of Ewings sarcoma/primitive neuroectodermal tumors (ES/PNET) have a specific translocation, t(11;22)(q24;q12), which results in fusion of EWS to Fli-1, and production of an EWS–Fli-1 fusion protein. We have recently shown that immunohistochemistry for the carboxy terminal of Fli-1 protein is sensitive and highly specific for the diagnosis of ES/PNET. In our earlier study we noted that among normal tissues only endothelial cells and small lymphocytes expressed Fli-1. Fli-1 expression in vascular neoplasms has not been previously studied. Formalin-fixed paraffin-embedded tissue from 54 vascular tumors and 75 nonvascular tumors were immunostained for Fli-1 (1:120, Sc 356, Santa Cruz Biotechnology, Santa Cruz, CA), after steam heat-induced epitope retrieval. Only cases with >10% of cells showing nuclear staining were accepted as positive. Cases without positive internal controls (endothelium and small lymphocytes) were not scored. Positive internal controls were present in 122 of 129 cases (95%). One vascular tumor (Kaposis sarcoma) and 7 nonvascular tumors (2 epithelioid sarcomas and 5 carcinomas) without internal controls were not scored. Fli-1 was expressed by 50 of 53 vascular tumors scored (94%), including 20 of 22 angiosarcomas, 11 of 12 hemangioendotheliomas, 7 of 7 hemangiomas, and 12 of 12 Kaposis sarcomas. In contrast, Fli-1 expression was absent in the 68 nonvascular tumors scored (0 of 68), including 16 sarcomas, 7 melanomas, and 45 carcinomas. The results of this study strongly suggest a role for Fli-1 as a novel marker of both benign and malignant vascular tumors. The sensitivity (94%) and specificity (100%) of Fli-1 with regards to the cases evaluated in this study equal or exceed those of the established vascular markers, CD31, CD34, and von Willebrand factor. As the first nuclear, rather than cytoplasmic or membranous marker of endothelium, Fli-1 immunostaining also generally lacks cytoplasmic staining artifacts that are the result of endogenous peroxidases or biotin.

Perivascular epithelioid cell neoplasms: pathology and pathogenesis

This review article summarizes our current understanding of the clinical, pathologic, immunohistochemical, and genetic aspects of perivascular epithelioid cell neoplasms, a rare group of related tumors defined by both morphologic and immunophenotypic criteria.