Malignant Melanotic Nerve Sheath Tumor.

Malignant melanotic nerve sheath tumors are uncommon pigmented tumors of Schwann cell origin, most often found along the spinal nerves. Although well-described in the literature, the tumors are quite rare, making up <1% of nerve sheath tumors. Physicians are, therefore, often unfamiliar with both the appearance and the optimal treatment of such tumors. Morphologically, many imaging features overlap with schwannomas and neurofibromas. Nevertheless, the malignant melanotic nerve sheath tumors are crucial to identify. They can be extremely aggressive, and the management of these tumors is considerably different from their benign counterparts. In this radiology-pathology review, we will highlight the imaging appearance, histologic features, surgical resection, and subsequent therapeutic strategies in a patient with a lumbar malignant melanotic nerve sheath tumor.

A Retrospective Case Series of Synovial Sarcoma of the Upper Extremity.

PURPOSE: Previous studies have grouped the treatment of axial and appendicular synovial sarcomas. The purpose of this study was to assess the prognostic variables of upper extremity synovial sarcomas (UESS) and compare the outcomes of those who underwent a nononcologic or inadvertent excision prior to definitive resection to those who underwent an initial oncologic resection. METHODS: We reviewed the records of 23 UESS treated with definitive surgery at our institution between 1990 and 2014. There were 13 women and 10 men with a median age of 30 years (6-60) and median follow-up of 63 months (15-248). Prognostic variables, recurrence-free survival (RFS), and overall survival (OS) were then assessed. RESULTS: Fifteen patients (65%) had a prior unplanned excision. Five patients required an amputation to obtain local control of disease. There were 3 observed local recurrences and 2 distant metastases at a median of 45 months from presentation. We found no difference in need for amputation, RFS, or OS between those who had undergone a planned excision and those who had an unplanned excision. CONCLUSION: While we were unable to find a significant difference in outcomes or amputation rates between those who underwent reexcision of a previously unplanned excision and those who underwent an initial planned resection, the high rate of unplanned excision is troubling and should remind practitioners to consider sarcoma in the differential of all upper extremity masses.

Phosphaturic mesenchymal tumors: what an endocrinologist should know.

Tumor-induced osteomalacia (TIO), also known as "oncogenic osteomalacia", is a rare cause of osteomalacia. TIO often has an insidious onset characterized clinically by progressive muscle weakness and bone pain with fractures. The hallmark biochemical finding is a persistent low serum phosphorus concentration due to renal phosphate wasting. The vast majority of cases of TIO result from production of the phosphaturic hormone fibroblast growth factor 23 (FGF23) by a histologically distinctive mesenchymal tumor, termed "phosphaturic mesenchymal tumor" (PMT). Circulating FGF23 induces internalization of renal sodium/phosphate co-transporters resulting in reduced proximal tubular phosphate reabsorption. FGF23 also inhibits production of 1α,25-dihydroxyvitamin D which is inappropriately low or normal in the context of hypophosphatemia. Diagnosis is often delayed owing to the rarity of the condition and an underappreciation for the role of phosphorus as a cause for the constellation of symptoms. Primary treatment for TIO is identification of the offending tumor and surgical removal. However, these tumors are notoriously difficult to find, precluding the opportunity for a curative surgery in many. In such cases, phosphate and calcitriol therapy is used to improve symptoms and heal the osteomalacia. Recently, molecular genetic studies have shown recurrent genetic events in PMT, including the novel fusions FN1-FGFR1 and less commonly FN1-FGF1. These fusion events are hypothesized to result in autocrine/paracrine signaling loops within the tumor, spurring tumorigenesis. This review will cover the clinical features, imaging characteristics, pathologic features, molecular genetic aspects, and therapy of PMT, with a brief discussion of other neoplasms that may cause TIO.

Massive localised lymphoedema: a clinicopathological study of 22 cases and review of the literature.

BACKGROUND: Massive localised lymphoedema (MLL) is a rare, relatively recently described pseudosarcoma most often occurring in morbidly obese patients. AIM: To perform a retrospective review of all cases diagnosed as MLL. METHODS AND RESULTS: Clinical information was obtained. 22 morbidly obese adults (mean patient weight 186 kg) presented with unilateral, large soft tissue lesions of longstanding duration. Most lesions involved the thigh, but also occurred in the posterior calf and lower leg. Clinically, most lesions were regarded as representing benign processes, including pedunculated lipoma, lymphocoele or recurrent cellulites, although soft tissue sarcoma was also suspected in two cases. Grossly, all masses showed markedly thickened skin with a "cobblestone" appearance, and were ill-defined, unencapsulated, lobulate, and very large (mean size 31 cm, range 15-61.5 cm, mean weight 3386 g, range 1133-10,800 g). Histologically, all 22 cases showed striking dermal fibrosis, expansion of the fibrous septa between fat lobules with increased numbers of stromal fibroblasts, lymphatic proliferation and lymphangiectasia. Multinucleated fibroblastic cells, marked vascular proliferation, moderate stromal cellularity and fascicular growth raised concern among referring pathologists for atypical lipomatous tumour/well differentiated liposarcoma, angiosarcoma, and a fibroblastic neoplasm such as fibromatosis in 10, 2 and 1 case, respectively. CONCLUSION: The diagnosis of MLL continues to be challenging, in particular for pathologists. Awareness of this entity, clinical correlation and gross pathological correlation are essential in the separation of this distinctive pseudosarcoma from its various morphological mimics.

Alveolar soft-part sarcoma: a review and update.

Alveolar soft-part sarcoma (ASPS) is a rare, distinctive sarcoma, typically occurring in young patients. Although it displays a relatively indolent clinical course, the ultimate prognosis is poor and is often characterised by late metastases. Recently, our understanding of the genetic events underlying the pathogenesis of ASPS has greatly increased. The historical, histopathological, ultrastructural, immunohistochemical and genetic aspects of ASPS are reviewed in this article.

Lingual alveolar soft part sarcoma; 14 cases: novel clinical and morphological observations.

AIMS: Alveolar soft part sarcoma (ASPS) is a rare sarcoma in the buttocks or thigh of young adults, often with metastases to lung, brain, or bone. This study examines the morphological and clinical features of lingual ASPS. METHODS AND RESULTS: Fourteen cases, in eight males and six females (ages 3-21 years, median 5 years), ranged from 8 to 50 mm, median 25 mm. All tumours were intramuscular, circumscribed and multinodular. Tumours from all but the oldest patient exhibited a predominantly solid (non-alveolar) growth pattern. Vascular invasion was common. Crystals varied in number from none or extremely rare to nearly 100% of tumour cells. Immunohistochemical results: Fifty percent desmin positive, all focally smooth muscle antigen (SMA) positive; negative for vimentin, neural/melanocytic, myoid, histiocytic, and epithelial markers. All tumours were surgically excised; only two patients received chemotherapy. Follow-up on 10 patients showed that all patients were alive without disease (4-32, median 22 years). Only one patient had a microscopic metastasis to lung (3 years) but was without disease at 11 years. CONCLUSIONS: Lingual ASPS is a tumour of childhood with a distinctive, predominantly solid growth pattern. Despite typical vascular invasion, the early diagnosis and small tumour size may explain its relatively good outcome.

Intra-abdominal synovial sarcoma: a clinicopathological study.

AIMS: To evaluate a series of synovial sarcomas arising in the abdomen, pelvic cavity, or retroperitoneum. Synovial sarcoma is rare within the abdomen. In this location, it can be confused with other biphasic tumours and with other spindle and round cell sarcomas. METHODS AND RESULTS: Cases were retrieved from archives. There were 11 intra-abdominal tumours among 300 synovial sarcomas in two referral practices (3.7%). Three were pelvic (two midline, one sidewall) and eight were retroperitoneal. They occurred in six males and five females aged from 25 to 75 years (mean 49 years, median 46 years), and ranged in diameter from 65 to 470 mm (mean 210 mm, median 150 mm). Six examples were biphasic, five were monophasic and seven had poorly differentiated areas. Monophasic tumours displayed at least one epithelial marker. One biphasic tumour had a SYT-SSX2 fusion gene. Seven sarcomas were high-grade and four of intermediate grade malignancy. Follow-up data were available in 10 patients. In all but one case, tumour recurred or metastasized within the abdomen. The pelvic sarcomas also metastasized outside the abdomen. Eight of 10 patients (80%) died of disease with survival from 4 to 36 months (mean 17 months, median 18 months). Two patients were alive with disease at 43 and 48 months. CONCLUSIONS: Synovial sarcomas rarely arise within the abdomen and pelvis. They occur mainly in middle age, attain a large size, are difficult to excise and recur locally. Pelvic tumours metastasize distantly. Retroperitoneal tumours remain confined to the abdomen and, unlike synovial sarcomas elsewhere, do not metastasize remotely, although mortality is high.

P504S immunohistochemical detection in 405 prostatic specimens including 376 18-gauge needle biopsies.

P504S is a recently described, prostate cancer-specific gene that encodes a protein involved in the beta-oxidation of branched chain fatty acids. A recent study has shown that immunohistochemical detection of P504S gene product is a sensitive and specific marker of prostatic carcinoma in formalin-fixed, paraffin-embedded tissues. We performed a detailed analysis of P504S protein expression in a large series of prostate and bladder specimens with special emphasis on staining in specific morphologic patterns of prostatic adenocarcinoma, posthormonal and radiation therapy cases, and invasive urothelial carcinoma. A total of 366 prostate needle core biopsies from 124 patients with prostate cancer, 10 biopsies from 2 patients without prostate cancer, 28 prostatectomy specimens (16 with specific morphologic patterns, 7 posthormonal therapy and 5 postradiation therapy specimens), 5 bladder specimens with invasive urothelial carcinoma, and a single transurethral resection specimen from a patient with hormonally treated prostate cancer and invasive urothelial carcinoma were stained with P504S monoclonal antibody at a 1:250 dilution using standard heat-induced epitope retrieval and avidin-biotin technique. Extent (0, no staining; 1+, 1-10% staining; 2+, 11-50% staining; 3+, > or =51% staining) and location (luminal, subluminal, and diffuse cytoplasmic) of immunoreactivity in carcinoma and benign tissues were recorded. A total of 153 of 186 biopsies (82%) with prostatic adenocarcinoma stained for P504S. Pseudohyperplastic, atrophic, ductal, and mucinous prostatic carcinomas stained similarly, as did cases treated with hormone or radiotherapy. In 81 of 377 (21%) foci of benign prostatic tissue there was staining that was almost always focal, faint, and noncircumferential. Seminal vesicles did not stain for P504S. Five of six (83%) specimens with invasive urothelial carcinoma had 2+ staining and one case had focal staining. We conclude that immunohistochemistry for P504S has potential utility in the diagnosis of prostate cancer, including those treated by hormones and radiation. Circumferential luminal to subluminal and diffuse cytoplasmic staining is the most specific staining pattern for prostatic carcinoma and is almost never associated with benign prostatic tissue. However, a negative P504S immunostain does not automatically rule out prostate cancer, as 18% of cases were negative. Additionally, occasional benign glands, high-grade prostatic intraepithelial neoplasia, atypical adenomatous hyperplasia, and urothelial carcinoma may express P504S. Therefore, we think that P504S is best used only in conjunction with strict light microscopic correlation and preferably with high molecular weight cytokeratin immunostaining.

Do leiomyomas of deep soft tissue exist? An analysis of highly differentiated smooth muscle tumors of deep soft tissue supporting two distinct subtypes.

There is a prevailing view that leiomyomas of deep soft tissue are rare or nonexistent, but there are limited data on this subject in the form of large clinical studies with long follow-up information. We reviewed 36 consultation cases that had been diagnosed as leiomyoma or probable leiomyoma based on absence of nuclear atypia, necrosis, and no/minimal mitotic activity. Follow-up information was obtained to determine whether these stringent histologic criteria could identify a biologically benign group of smooth muscle tumors of deep soft tissue. The tumors occurred in two distinct locations. The first (n = 13) occurred in deep somatic soft tissue of the lower extremity (7), upper extremity (2), trunk (2), axilla (1), and back (1) and affected the sexes equally (7 male, 6 female). Composed of a circumscribed mass of mature smooth muscle cells, they were frequently calcified with a mean mitotic activity of <1 mitosis/50 high power fields (HPF) (range 1-4 mitoses/50 HPF). Estrogen receptor and progesterone receptor proteins were negative in the three cases tested. No tumors recurred or metastasized (mean follow-up 58.7 months, range 5-97 months). The second group (n = 23) occurred within the retroperitoneum (20) or abdominal cavity (3) of women (1 male, 22 female). Resembling uterine leiomyomas, they were always distinct from the uterus, occasionally multiple (n = 4), and sometimes occurred up to years after hysterectomy (n = 3). Four cases occurred with synchronous uterine leiomyomas. In the six cases tested, five of six were positive for the estrogen receptor protein and all were positive for progesterone receptor protein. Mean mitotic activity was 1 mitosis/50 HPF (range <1-10 mitoses/50 HPF). None developed metastasis within the follow-up period (mean 42.5 months, range 6-120 months); one tumor with a positive margin recurred at 10 months. We conclude that clinically benign smooth muscle tumors of deep soft tissue are rare but can be identified using stringent histologic criteria. They comprise two distinct subtypes: leiomyomas of somatic soft tissue and retroperitoneal-abdominal leiomyomas. The latter probably arise from hormonally sensitive smooth muscle. Although similar to uterine leiomyomas, they are located at sites removed from the uterus and are likely independent soft tissue primaries rather than parasitic leiomyomas of the uterus. We suggest that these two groups of smooth muscle tumors be diagnostically approached in a site-specific fashion.

CD31 expression in intratumoral macrophages: a potential diagnostic pitfall.

CD31 (platelet endothelial adhesion molecule, PECAM-1) is generally regarded to be the most sensitive and specific endothelial marker in paraffin sections. We have recently encountered several cases in which intratumoral CD31-positive macrophages were misinterpreted as evidence of a vascular sarcoma. We therefore reviewed our last 1950 consultation cases with respect to cases in which CD31 immunostains were performed, to determine the frequency of CD31 expression in macrophages in formalin-fixed, paraffin-embedded tissue and how often the presence of these cells was a source of diagnostic confusion. CD31 immunohistochemistry had been performed on 59 of 1950 (3%) of cases. These 59 cases consisted of both vascular (20 cases) and nonvascular tumors (39 cases). CD31-positive macrophages were distinguished from endothelial or tumor cells by correlation with the morphologic features and the immunohistochemical staining pattern of the cells of interest. In no case was CD31 positivity seen in the lesional cells of a nonvascular tumor. CD31-positive macrophages were identified in 48 of 59 (81%) cases. CD31-positive macrophages were present in 34 of 39 (87%) nonvascular tumors. A vascular tumor was diagnosed or favored by the referring pathologist in 15 of these 39 cases (38%). In 14 of these 15 cases CD31 immunostains were performed by the referring pathologist; 13 (93%) showed CD31-positive macrophages. In 4 of these 14 cases (29%) the misdiagnosis of a vascular tumor was based primarily or in part on the misinterpretation of CD31-positive macrophages as tumor cells. In all cases with CD34 and CD68 immunostains, the CD31-positive macrophages were CD34 negative and CD68 positive. We conclude that CD31 expression is very common in macrophages. Misinterpretation of CD31-positive macrophages as tumor cells may result in the erroneous diagnosis of a primary vascular neoplasm. Recognition of the characteristic granular, membranous pattern of CD31 expression in macrophages and careful distinction from tumor cells should allow the accurate interpretation of CD31 immunohistochemistry in possible vascular neoplasms. CD31 may also be useful as a nonlysosomal marker of macrophages in formalin-fixed, paraffin-embedded sections.

Consultative (expert) second opinions in soft tissue pathology. Analysis of problem-prone diagnostic situations.

We reviewed 500 consecutive soft tissue lesions referred for expert consultation to determine types of lesions and/or situations in which major discrepancies occur. Of 266 cases (53.2%) accompanied by a diagnosis, essential agreement with the second opinion was noted in 68%, minor discrepancy in 7%, and major discrepancy in 25%. The 65 major discrepancies were distributed proportionally to the referring sources and could be divided into 4 groups: benign mesenchymal lesions diagnosed as sarcomas (45%), sarcomas diagnosed as benign tumors (23%), nonmesenchymal lesions diagnosed as sarcoma (20%), and major grading discrepancies (12%). Relatively few lesions accounted for a major proportion of major discrepancies. Problematic lesions were lipoma and fasciitis and their variants and desmoplastic-neurotropic melanoma. Needle biopsy specimens were somewhat more likely to be associated with a discrepant opinion. With the exception of nonmesenchymal lesions, the diagnosis for all major discrepant cases could be made on the basis of the H&E-stained slides, suggesting that failure to perform immunostains did not account for discrepancies. Lack of familiarity with rare or unusual lesions is probably more significant in explaining diagnostic discrepancies than is the increasing use of needle biopsy or the failure to perform immunohistochemical analysis.

Diagnostic utility of microphthalmia transcription factor in malignant melanoma and other tumors.

The diagnosis of malignant melanoma is sometimes challenging. Immunohistochemistry for specific markers of melanocytic differentiation such as HMB-45 and Melan-A can be very valuable in proving melanocytic differentiation in poorly differentiated or spindled forms of melanoma. Microphthalmia-associated transcription factor (MiTF) is the most recently described and the only nuclear melanocytic marker. This article reviews the biology of MiTF and those published studies that have addressed its diagnostic sensitivity and specificity. MiTF may be very valuable for the diagnosis of melanoma, including desmoplastic variants; melanocytic soft tissue tumors, such as clear cell sarcoma; and the unusual group of tumors that show combined melanocytic and myoid differentiation, the perivascular epithelioid cell family of tumors (PEComas).

Microphthalmia transcription factor immunohistochemistry: a useful diagnostic marker in the diagnosis and detection of cutaneous melanoma, sentinel lymph node metastases, and extracutaneous melanocytic neoplasms.

BACKGROUND: Melanoma is the most lethal form of skin cancer. Diagnosis of amelanotic melanoma and detection of micrometastases in sentinel lymph nodes pose diagnostic and therapeutic dilemmas for the dermatopathologist and clinician. OBJECTIVE: The purpose of this article is to determine the utility of immunohistochemistry using antibodies specific for microphthalmia in the identification of melanocytic lesions in the skin, eye, central nervous system, and sentinel lymph nodes. METHODS: Paraffin-embedded, formalin-fixed specimens of cutaneous melanoma, including amelanotic melanoma and lentigo maligna melanoma, were stained with antibodies specific for microphthalmia. In addition, paraffin sections of extracutaneous lesions, including sentinel lymph nodes, uveal melanoma, and central nervous system melanocytomas, were stained with the specific microphthalmia antibody. RESULTS: All cutaneous melanomas stained positively with microphthalmia, as did uveal melanomas and central nervous system melanocytomas. These findings confirm the melanocytic origin of melanocytomas and uveal melanomas and demonstrate that microphthalmia staining can be used to establish melanocytic origin of neoplasms. In addition, micrometastases were easily detected in sentinel lymph nodes. CONCLUSION: Microphthalmia transcription factor immunohistochemistry is a valuable tool in the identification of melanocytic lesions in numerous sites. Use of this stain may facilitate detection of micrometastases in sentinel lymph nodes.

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 Ewing's 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 (Kaposi's 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 Kaposi's 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.

Concurrent angiomyolipoma and renal cell neoplasia: a study of 36 cases.

Little is known about the association of angiomyolipoma and adult renal-cell neoplasia. We studied the clinicopathologic features of 36 patients with concurrent angiomyolipoma and renal-cell neoplasia from the consultation and surgical pathology files of nine institutions. HMB-45 immunoreactivity was analyzed in both neoplasms. Twenty-five sporadic cases of patients with angiomyolipoma and renal-cell neoplasia and 11 cases of patients with tuberous sclerosis, as defined by Gomez' criteria, had mean ages of 59 and 53 years, respectively, and female-male ratios of 2:1 and 5:1, respectively. The mean size of the angiomyolipomas was 1 cm in the sporadic cases and 3 cm in those patients with tuberous sclerosis (medians: 0.5 and 3 cm, respectively, P =.002). The mean sizes of the renal-cell neoplasms were 5 cm in sporadic cases and 6 cm in patients with tuberous sclerosis (medians: 4 and 5 cm, respectively; P =.88). In both clinical settings, angiomyolipoma was more commonly the incidental tumor. Clear-cell (conventional) renal-cell carcinoma was the most common renal-cell neoplasm in both groups of patients, accounting for approximately two thirds of the tumors. In patients with tuberous sclerosis, 27% of renal-cell neoplasms were oncocytomas, compared with 8% in sporadic cases (P =.15). Papillary neoplasia, chromophobe, and collecting-duct renal-cell carcinoma were found only in sporadic cases. All of the 22 renal-cell neoplasms studied were negative for HMB-45, whereas all 25 angiomyolipomas studied were positive.

Spindle cell lipoma of the oral cavity. Report of a rare intramuscular case with fine needle aspiration findings.

BACKGROUND: Spindle cell lipoma (SCL) is a benign neoplasm characterized by a mixture of mature fat, bland spindle cells and wiry collagen in a variably myxoid background. Oral SCLs are rare, and only four cases of intramuscular SCL exist in the literature. We report the first case of intramuscular SCL of the oral cavity with fine needle aspiration (FNA) findings. CASE: A 61-year-old woman presented with a 3-cm mass in the right gingivobuccal sulcus. Papanicolaoustained FNA smears were hypocellular and contained loose collections of spindle cells in a myxoid background, numerous mast cells, rare capillary fragments and portions of skeletal muscle. The spindle cells had mild nuclear enlargement, focal nuclear irregularities, rare intranuclear inclusions and occasional small nucleoli. No lipoblasts or mitoses were identified. There was intermingling of the spindle cells with the skeletal muscle fragments. CONCLUSION: Intraoral SCL is a rare lesion but should be considered in the differential for a benign spindle cell neoplasm in the oral cavity. Clues to diagnosis on cytology include mature fat, bland spindle cells, a myxoid background and mast cells.

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 > or =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.

Immunohistochemical study of microphthalmia transcription factor and tyrosinase in angiomyolipoma of the kidney, renal cell carcinoma, and renal and retroperitoneal sarcomas: comparative evaluation with traditional diagnostic markers.

Angiomyolipoma has a unique immunophenotype with co-expression of muscle-specific actin and melanocytic markers such as HMB-45 and Melan-A. The most recently developed melanocytic markers, microphthalmia transcription factor and tyrosinase, have not been studied in the diagnosis of angiomyolipoma. We tested 29 renal angiomyolipomas (21 classic histology, 4 epithelioid variants, 2 lipomatous variants, and 2 leiomyomatous variants) with an immunohistochemical panel, including microphthalmia transcription factor, tyrosinase, HMB-45, Melan-A, and muscle-specific actin. Results were compared with 15 renal cell carcinomas (9 conventional types, 6 with sarcomatoid change), 2 leiomyosarcomas, 5 liposarcomas, and 1 unclassified high-grade sarcoma. Microphthalmia transcription factor expression was seen in 22 of 29 angiomyolipomas, one renal cell carcinoma, and one well-differentiated liposarcoma (that is, 2 of 23 non-angiomyolipomas; sensitivity 75%, specificity 91%). Tyrosinase expression was seen in 4 of 29 angiomyolipomas and 0 of 23 non-angiomyolipomas (sensitivity 14%, specificity 100%). HMB-45 was positive in 24 of 29 angiomyolipomas and 0 of 23 non-angiomyolipomas (sensitivity 83%, specificity 100%). Melan-A was expressed by 25 of 29 angiomyolipomas and 0 of 23 non-angiomyolipomas (sensitivity 86%, specificity 100%). Muscle-specific actin was expressed by 29 of 29 angiomyolipomas and 2 of 23 non-angiomyolipomas (both leiomyosarcomas; sensitivity 100%, specificity 91% [100% excluding leiomyosarcomas]). Microphthalmia transcription factor showed the most widespread staining in angiomyolipoma (50% of cases staining more than half of the tumor cells) followed by Melan-A (24% of cases staining more than 50%). Only three cases showed positivity for all four melanocytic markers, while in one case each only microphthalmia transcription factor and Melan-A were positive. We conclude that microphthalmia transcription factor, but not tyrosinase immunostaining, has a sensitivity and specificity that rivals those of the established markers, HMB-45 and Melan-A, in the diagnosis of angiomyolipoma. Our data supports the use of a panel in difficult cases that includes antibodies to microphthalmia transcription factor, either Melan-A or HMB-45, and muscle-specific actin to provide the best mix of high sensitivity, high specificity, nuclear and cytoplasmic immunolocalization, and widespread staining of cells within a given tumor.

Microphthalmia transcription factor and melanoma cell adhesion molecule expression distinguish desmoplastic/spindle cell melanoma from morphologic mimics.

Desmoplastic/spindle cell melanoma is a rare variant of melanoma. A number of factors complicate the diagnosis of desmoplastic/spindle cell melanoma, including the variable absence of a lentiginous component, its spindle cell morphology, and its many morphologic mimics, including scars, malignant peripheral nerve sheath tumor, neurofibroma, atypical fibroxanthoma, and spindled carcinoma. The immunohistochemical confirmation of desmoplastic/spindle cell melanoma may also be difficult, because the majority of tumors are negative for specific melanocytic markers such as HMB-45 and Melan-A, despite their usual expression of S-100 protein. Two new and potentially promising melanocytic markers, microphthalmia transcription factor (MiTF) and melanoma cell adhesion molecule (Mel-CAM), have been shown to be sensitive markers of epithelioid melanoma, but have not been tested in desmoplastic/spindle cell melanoma or in other rare melanocytic neuroectodermal tumors such as clear cell sarcoma. We immunostained 79 tumors (20 desmoplastic/spindle cell melanomas, 10 scars, 10 neurofibromas, 12 malignant peripheral nerve sheath tumors, 10 atypical fibroxanthomas, 10 clear cell sarcomas, 3 melanotic schwannomas, and 4 cellular blue nevi) for MiTF and Mel-CAM. MiTF expression was seen in 11 of 20 desmoplastic/spindle cell melanomas, 0 of 10 scars, 2 of 10 neurofibromas, 0 of 12 malignant peripheral nerve sheath tumors, 1 of 10 atypical fibroxanthomas, 7 of 10 clear cell sarcomas, 3 of 3 melanotic schwannomas, and 3 of 4 cellular blue nevi. Mel-CAM expression was present in 14 of 17 desmoplastic/spindle cell melanomas, 0 of 10 scars, 4 of 10 neurofibromas, 3 of 11 malignant peripheral nerve sheath tumors, 0 of 10 atypical fibroxanthomas, 9 of 10 clear cell sarcomas, 3 of 3 melanotic schwannomas, and 0 of 4 cellular blue nevi. MiTF and Mel-CAM were coexpressed in 6 of 17 desmoplastic/spindle cell melanomas and in no other tumor. Regarding desmoplastic/spindle cell melanoma, scar, neurofibroma, malignant peripheral nerve sheath tumor, and atypical fibroxanthoma, the sensitivity and specificity of MiTF for desmoplastic/spindle cell melanoma were 55% and 91%, respectively. For this same group of tumors, Mel-CAM had a sensitivity of 82% and a specificity of 83%. We conclude that the sensitivity and specificity of MiTF for desmoplastic melanoma equals or exceeds that of such markers as HMB-45 or Melan-A, and that MiTF should be part of the initial immunohistochemical panel for the work-up of such cases. Mel-CAM, while very sensitive, is relatively nonspecific, because it is also expressed in a variety of mesenchymal tumors and carcinomas. Mel-CAM is best reserved for cases morphologically suspected to be desmoplastic/ spindle cell melanoma, in which S-100 is positive and MiTF and other melanocytic markers are negative. These markers may also be helpful in certain other differential diagnoses, such as distinguishing clear cell sarcomas from epithelioid malignant peripheral nerve sheath tumors.

Immunohistochemical detection of FLI-1 protein expression: a study of 132 round cell tumors with emphasis on CD99-positive mimics of Ewing's sarcoma/primitive neuroectodermal tumor.

The histologic and immunohistochemical differentiation of Ewing' s sarcoma/primitive neuroectodermal tumor (ES/PNET) from other small, blue, round cell tumors may be difficult. Despite initial promise, CD99 (MIC2) has not proven to be a specific marker. Approximately 90% of ES/PNET have a specific t(11; 22)(q24;q12) that results in fusion of the EWS and FLI-1 genes, and overexpression of FLI-1 protein. A recent study has shown immunohistochemical FLI-1 expression in five of seven of the ES/PNET cases tested. We evaluated FLI-1 expression in 132 well-characterized small, blue, round cell tumors. All tumors were immunostained for FLI-1 (1:40, Sc 356 polyclonal, Santa Cruz Biotechnology) using steam heat for epitope retrieval. Only nuclear staining was accepted as positive. Endothelial cells were strongly positive in all cases and served as an internal control. In many cases, a subset of lymphocytes also stained positive. No staining was seen in any other normal tissue. FLI-1 expression was seen in 29 of 41 (71%) ES/PNET, 7 of 8 (88%) lymphoblastic lymphomas, 0 of 8 poorly differentiated synovial sarcomas (PDSS), 0 of 32 rhabdomyosarcoma (RMS), 0 of 30 neuroblastomas, 0 of 8 esthesioneuroblastomas, 0 of 3 Wilms' tumors, 0 of 1 mesenchymal chondrosarcoma, and in 1 of 1 desmoplastic round cell tumor. This last case was known to have an EWS/WT-1 fusion. Although the EWS/FLI-1 fusion gene is specific for ES/PNET, FLI-1 protein expression is not. Significantly, the great majority of lymphoblastic lymphomas (also CD99-positive) are strongly FLI-1-positive. Immunohistochemical detection of FLI-1 may be valuable in confirming the diagnosis of ES/ PNET in cases in which molecular genetic evaluation is not feasible. FLI-1 protein expression is also helpful in distinguishing ES/PNET from other tumors that may be CD99-positive, such as PDSS and RMS. It is not surprising that some ES/ PNET are FLI-1-negative, because not all ES/PNET have the classic EWS/FLI-1, and some cases of ES/PNET may produce either low levels of protein or idiotypically different protein.