Bone and soft tissue tumors: clinicoradiologic-pathologic molecular-genetic correlation of novel fusion spindled, targetable-ovoid, giant-cell-rich, and round cell sarcomas.

BACKGROUND: New entities in the classification of bone and soft tissue tumors have been identified by use of advanced molecular-genetic techniques, including next-generation sequencing. Clinicoradiologic and pathologic correlation supports diagnostic classification. METHODS: Tumors from four morphologically grouped areas are selected to enhance diagnosis and awareness among the multidisciplinary team. These include select round cell tumors, spindle cell tumors, targetable tyrosine kinase/RAS::MAPK pathway-ovoid (epithelioid to spindled) tumors, and giant-cell-rich tumors of bone and soft tissue. RESULTS: Round cell tumors of bone and soft tissue include prototypical Ewing sarcoma, newer sarcomas with BCOR genetic alteration and CIC-rearranged, as well as updates on FUS/EWSR1::NFATc2, an EWSR1 non-ETS tumor that is solid with additional amplified hybridization signal pattern of EWSR1. This FUS/EWSR1::NFATc2 fusion has now been observed in seemingly benign to low-grade intraosseous vascular-rich and simple (unicameral) bone cyst tumors. Select spindle cell tumors of bone and soft tissue include rhabdomyosarcoma with FUS/EWSR1::TFCP2, an intraosseous high-grade spindle cell tumor without matrix. Targetable tyrosine-kinase or RAS::MAPK pathway-tumors of bone and soft tissue include NTRK, ALK, BRAF, RAF1, RET, FGFR1, ABL1, EGFR, PDGFB, and MET with variable ovoid myopericytic to spindled pleomorphic features and reproducible clinicopathologic and radiologic clues to their diagnosis. Giant-cell-rich tumors of bone, joint, and soft tissue are now respectively characterized by H3F3A mutation, CSF1 rearrangement (targetable), and HMGA2::NCOR2 fusion. CONCLUSION: This article is an update for radiologists, oncologists, surgeons, and pathologists to recognize these novel ovoid, spindled, giant-cell-rich, and round cell tumors, for optimal diagnostic classification and multidisciplinary team patient care.

Feline peripheral nerve sheath tumors: histologic, immunohistochemical, and clinicopathologic correlation (59 tumors in 53 cats).

Feline peripheral nerve sheath tumors are uncommonly reported, and their clinical behavior has not been well documented. Fifty-nine peripheral nerve sheath tumors were collected from 53 cats. All of the tumors involved skin, subcutis, skeletal muscle, and/or mucous membranes. Histologically, the tumors were composed of compact to loosely arranged streams and fascicles of spindled cells with eosinophilic, often wavy cytoplasmic processes; small to occasionally moderate amounts of collagenous to myxoid matrix; and nuclear palisading. Immunohistochemically, all tumors were positive for vimentin and S-100 protein, 44 of 59 were positive for glial fibrillary acidic protein (GFAP), and all were negative for muscle specific actin. The tumors fell into 3 histologic categories: 34 benign tumors with Antoni A areas that were S-100 protein and GFAP positive, 9 benign tumors that lacked Antoni A areas and were S-100 protein positive and GFAP negative, and 16 tumors with features of malignancy. Seventy-five percent of these cases involved the head, neck, or limbs. Recurrent tumors were submitted or tumors were reported to have recurred in 9 cases. Tumor recurrence was reported for all 3 of the histologic subtypes. None was documented as having metastasized.

Exploration of the APC/beta-catenin (WNT) pathway and a histologic classification system for pulmonary artery intimal sarcoma. A study of 18 cases.

APC, a tumor suppressor gene in the Wnt pathway, stabilizes beta-catenin and controls cell growth. Mutation of APC or beta-catenin leads to nuclear accumulation of beta-catenin and transcription of cyclin D1/cyclin A. Pulmonary artery sarcoma (PAS) were studied by morphologic, immunohistochemical, and molecular genetic methods of the Wnt pathway. Eighteen cases were included: mean age 52 years, primary intraluminal location with typical clinical presentation. PAS were classified as epithelioid (n = 4) or malignant fibrous histiocytoma (MFH; spindled/pleomorphic, n = 4), myxofibrosarcoma (n = 8), and one each hemangiopericytoma-like or malignant inflammatory myofibroblastic tumor-like. The tumor cells demonstrated vimentin, focal actins, and rare focal desmin positivity. All but one were grade 2 or 3 by FNCLCC grading. Alteration in chromosome 5q21 (APC) was found in 4/14 PAS by LOH, mostly epithelioid-type; an MFH-type case demonstrated microsatellite instability (MSI) and nuclear beta-catenin. Cyclin D1 was expressed in seven tumors, all myxofibrosarcoma-type. No mutations were detected in APC or beta-catenin. In summary, PAS are predominantly intermediate grade myxofibrosarcoma in middle-aged males, and fatal in two-thirds of patients. Despite myofibroblastic phenotype, APC/beta-catenin pathway changes are rare. Cyclin D1, only expressed in the myxofibrosarcoma-type, is likely transcribed via factors other than beta-catenin.

The morphologic spectrum of hibernoma: a clinicopathologic study of 170 cases.

Hibernoma, an uncommon tumor of brown fat, has been described only in a few case reports and small series. The authors reviewed 170 cases of hibernoma and evaluated the morphologic features and the behavior of this tumor. The records from the Soft Tissue Registry of the Armed Forces Institute of Pathology from 1970 were searched for cases coded as "hibernoma." Clinical information and available slides from 170 hibernomas were reviewed. Immunohistochemical staining for S-100 and CD34 was performed on select cases. Follow-up information was obtained from the patients' medical records, the patients' physicians, and the patients themselves. Of 170 patients with hibernoma, 99 were men and 71 were women. The tumor occurred most commonly in adults, with a mean age of 38.0 years (age range, 2-75 years). Nine tumors occurred in pediatric patients. The most common anatomic locations included the thigh (n = 50), shoulder (n = 20), back (n = 17), neck (n = 16), chest (n = 11), arm (n = 11), and abdominal cavity/retroperitoneum (n = 10). The average duration of the tumor was 30.6 months. Tumor size ranged from 1 to 24 cm with an average dimension of 9.3 cm. All tumors were composed partly or principally of coarsely multivacuolated fat cells with small, central nuclei and no atypia. Four morphologic variants of hibernoma were identified: typical, myxoid, spindle cell, and lipoma-like. "Typical" hibernoma (n = 140) included eosinophilic cell, pale cell, and mixed cell types based on the tinctorial quality of the hibernoma cells. The myxoid variant (n = 14) contained a loose basophilic matrix. Spindle cell hibernoma (n = 4) had features of spindle cell lipoma and hibernoma; all occurred in the neck or scalp. The lipoma-like variant (n = 12) contained only scattered hibernoma cells. Immunohistochemically, 17 of 20 cases (85%) were positive for S-100 protein. Only one hibernoma of 20, a spindle cell variant, was positive for CD34, whereas other hibernoma variants were negative. Follow-up was obtained for 66 cases (39%) over a mean period of 7.7 years (range, 6 months-28 years). None of the patients with follow-up had a recurrence or metastasis, including eight with intramuscular tumors. No patient died of disease. Hibernoma is a tumor found most often in adults and most commonly in the thigh, with several morphologic variants. It is a benign tumor that does not recur with complete excision. Hibernomas should not be confused with atypical lipomas or well-differentiated liposarcoma.

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.

Dendritic cell neurofibroma with pseudorosettes: a report of 18 cases of a distinct and hitherto unrecognized neurofibroma variant.

The authors present 18 cases of a hitherto unrecognized variant of cutaneous neurofibroma. The tumors presented in adults (10 occurred in men and eight occurred in women) as a solitary, well-circumscribed, superficial lesion located in the dermis measuring 3 to 17 mm (mean size, 6.2 mm). The tumors formed oval-shaped masses that ran perpendicular to the epidermis. In the deep part of the tumor there was multinodular arrangement with two types of cells: Type I cells were small, dark, lymphocyte-like cells with a slightly irregular nucleus and inconspicuous cytoplasm. Type II cells were larger, with pale-staining vesicular nuclei, with frequent invaginations and intranuclear inclusions, and had copious clear eosinophilic cytoplasm that formed a stellate growth pattern, which was poorly visible on hematoxylin and eosin staining. Type I cells were grouped concentrically around type II cells and formed pseudorosettes. Most of the type I and type II cells were S-100 protein and CD57 positive, and various proportions of both cell types were CD56 and PGP9.5 positive. All cells were chromogranin A, synaptophysin, glial fibrillary acidic protein, cytokeratins, CD1a, CD21, CD31, alpha-smooth muscle actin, muscle-specific actin, desmin, and HMB-45 negative. CD34 stained intralesional fibroblasts. Antibody to epithelial membrane antigen stained only the perineurium around the tumor masses, suggesting that the tumors arose inside the nerve sheath. No signs of neurosecretory granules were present at ultrastructural level. None of the lesions recurred and none metastasized over a mean follow-up of 8.1 years.

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.

Multiple spindle cell lipomas: a report of 7 familial and 11 nonfamilial cases.

Spindle cell lipoma, a variant of a benign lipoma, usually occurs as a solitary, subcutaneous, circumscribed lesion in the posterior back, neck, or shoulders of older men. Multiple lesions are exceedingly rare. To our knowledge, there have been no previous series reported of patients with multiple subcutaneous spindle cell lipomas. We examine the clinicopathologic findings of a group of patients with multiple spindle cell lipomas, including seven with a familial occurrence of this disease. The Soft Tissue Registry of the Armed Forces Institute of Pathology and the consultation files of one of the authors (S.W.W.) from the Department of Pathology at the University of Michigan were searched for patients with multiple spindle cell lipomas. All patients' records, clinical history, and pathology were reviewed. All patients had a minimum of two tumors that met strict morphologic criteria for spindle cell lipoma. Pleomorphic cells, typical of pleomorphic lipoma, were observed in some cases and were acceptable as part of the spectrum of spindle cell lipomas. Associated lesions, family history, ethnic background, daily habits, and natural progression of disease were recorded and compared. Eighteen patients in our files met the criteria for multiple spindle cell lipomas; 4 of the 18 patients were from the same family. Three additional patients had a family history of multiple spindle cell lipomas. The ratio of patients with multiple spindle cell lipomas to all patients with spindle cell lipoma in the two consultation files was 0.5 and 3%, respectively. All of the patients in our study were male; three had a family history of females with less severe disease (fewer and smaller spindle cell lipomas); however, no material from these female patients was available for review. All but four patients presented in their sixth through eighth decades of life; yet, several older patients stated that their first lesion occurred in their fifth decade. Patients had between 2 and >220 lesions, which usually commenced on the posterior neck or back, commonly followed by additional bilateral lesions on the shoulders and upper torso. The natural history of this disease revealed development of multicentric lesions over several years, for both familial and nonfamilial cases. The tumors became more cellular as the disease progressed, often with features of pleomorphic lipoma; however, no patients developed spindle cell liposarcoma. Multiple spindle cell lipomas are rare. The clinical presentation may mimic Madelung's disease (symmetrical lipomatosis). As mentioned above, some cases are familial. Genetic predisposition must be further examined. There appears to be no common ethnic background, environmental exposure, medical condition, or syndrome of associated lesions with multiple spindle cell lipomas.

Malignant granular cell tumor of soft tissue: diagnostic criteria and clinicopathologic correlation.

Seventy-three cases of malignant, atypical, and multicentric granular cell tumors of soft tissue were studied to clarify criteria for malignancy and prognostic factors. Six histologic criteria were assessed: necrosis, spindling, vesicular nuclei with large nucleoli, increased mitotic activity (> 2 mitoses/10 high-power fields at 200x magnification), high nuclear to cytoplasmic (N:C) ratio, and pleomorphism. Neoplasms that met three or more of these criteria were classified as histologically malignant; those that met one or two criteria were classified as atypical; and those that displayed only focal pleomorphism but fulfilled none of the other criteria were classified as benign. Hence, 46 cases were classified as histologically malignant, 21 as atypical (3 were multicentric), and 6 as benign (all were multicentric). The patients with benign multicentric and atypical granular cell tumors had no metastases and there were no tumor deaths. In contrast, 11 of 28 patients (39%) with malignant granular cell tumor with follow-up information died of disease at a median interval of 3 years; 8 of 28 (29%) were alive with disease, and 9/28 (32%) were disease free (median intervals, 2 and 7 years, respectively). There were local recurrences in 9 of 28 malignant cases (32%) and metastases in 14 of 28 (50%) (median intervals, each 2 years). Forty-eight cases were studied immunohistochemically; 100% expressed vimentin, 98% S-100 protein, 98% neuron-specific enolase, 69% CD57, and 65% CD68. Alpha-smooth muscle actin, desmin, epithelial membrane antigen (EMA), cytokeratins (with CAM 5.2 and KL-1), chromogranin, and HMB45 were not detected. The proliferative index with Ki67 (MIB 1) was 10-50% in 14 of 25 malignant tumors (56%), and immunostaining for p53 was detected in 50% or more of tumor cells in 17 of 25 (68%); both of these factors were statistically significant with regard to the histologic classification as benign, atypical, or malignant. Ultrastructural examination of 13 benign, atypical, and malignant granular cell tumors showed engorgement of the cytoplasm with complex granules and lysosomes, as well as Schwannian features. By flow cytometric DNA analysis, two of six malignant tumors were aneuploid, two were hyperdiploid, and two were diploid. One atypical tumor was aneuploid and all 11 benign tumors were either diploid (9 cases) or hyperdiploid (2 cases). Statistically significant adverse prognostic factors with regard to survival included local recurrence, metastasis, larger tumor size, older patient age, histologic classification as malignant, presence of necrosis, increased mitotic activity, spindling of tumor cells, vesicular nuclei with large nucleoli, and Ki67 values greater [corrected] than 10%. This study defines clinical and morphologic criteria for malignancy in granular cell tumors and shows that malignant granular cell tumor is a high-grade sarcoma with a high rate of metastases and a short survival.

Precursor B-Lymphoblastic lymphoma presenting as a solitary bone tumor and mimicking Ewing's sarcoma: a report of four cases and review of the literature.

Precursor B-lymphoblastic lymphoma (B-LBL) may present as a solitary bone tumor. Fewer than 10 cases with a proven precursor B-cell phenotype have been reported in the English literature. In this report, we describe four cases of B-lymphoblastic lymphoma presenting as a localized intraosseous mass, which clinically and histologically mimicked Ewing's sarcoma. Three tumors occurred in the tibia and one in the humerus. In all four cases, the initial diagnosis was either "Ewing's sarcoma" or "consistent with Ewing's sarcoma." All four patients were female. Three were children and one was an adult; mean age was 12.5 years (range, 4 to 31 years). All had extremity pain without significant constitutional symptoms. In three cases, the tumors were osteolytic on radiographic evaluation, and in one case, osteosclerotic. Immunohistochemical stains on paraffin-embedded tissue showed that the neoplastic cells expressed terminal deoxynucleotidyl transferase, CD43, vimentin, and CD99 (MIC2 gene product) in all cases. Three cases were negative for CD45. CD79a was positive in all four cases studied; however, CD20 (L26) was positive in only two of four cases. CD3 was negative in all cases. Two cases showed focal granular cytoplasmic staining for keratin. Two cases analyzed by polymerase chain reaction (PCR) revealed clonal rearrangement of the immunoglobulin heavy chain (IgH) gene. Follow-up revealed that the three pediatric patients, who received a high-dose multiagent chemotherapy regime for LBL, are disease free at follow-up intervals of more than 1, 11, and 12 years, respectively. The adult patient died two years after diagnosis with disseminated disease. Although rare, B-lymphoblastic lymphoma should be considered in the differential diagnosis of small round cell tumors of bone. A diagnosis of Ewing's sarcoma should be made only after complete immunophenotyping and, if necessary, molecular diagnostic tests to exclude lymphoblastic lymphoma. A limited panel of antibodies can lead to an erroneous diagnosis; B-lymphoblastic lymphoma may be negative for CD45 and CD20 but positive for CD99 and even for keratin, mimicking Ewing's sarcoma. Correct diagnosis is extremely important because LBL usually is curable in the pediatric age group with appropriate therapy.

Low-affinity nerve growth factor receptor (p75) in dermatofibrosarcoma protuberans and other nonneural tumors: a study of 1,150 tumors and fetal and adult normal tissues.

Low-affinity nerve growth factor receptor (p75) is a member of the tumor necrosis factor receptor family. It may modulate the binding of nerve growth factor (NGF) to the functional high-affinity receptor tyrosine kinase (trk) A. NGF is thought to be responsible for growth, apoptosis, and function of the nervous system. The presence of this receptor (p75) was determined in a large group of neural and nonneural tumors and fetal and adult tissues. One thousand one hundred fifty tumors were analyzed with monoclonal antibody for p75, along with selected normal fetal and adult tissues. Immunoreactivity for p75 was present in adult pericytes, perivascular fibroblasts, basal cells of several types of epithelia, perineurial cells, and dendritic reticulum cells. Additionally, a wide zone of subepithelial mesenchyme and skeletal muscle were positive in the first-trimester fetus, but were diminished or negative in the adult. Consistently positive nonneural mesenchymal tumors included dermatofibrosarcoma protuberans (DFSP), embryonal and alveolar rhabdomyosarcoma, synovial sarcoma, and spindle cell hemangio(endotheli)oma. Schwann cell tumors, ganglioneuroma, granular cell tumor, and malignant peripheral nerve sheath tumor (MPNST) were also p75 positive. Mesenchymal nonneural tumors that were variably positive (32% to 69%) for p75 included fibrosarcoma variants, solitary fibrous tumor, hemangiopericytoma, spindle cell lipoma, Ewing's sarcoma, mesenchymal chondrosarcoma, and malignant melanoma. Nervous system tumors such as paragangliomas, neuroblastoma, meningioma, and perineurioma and nonneural mesenchymal tumors, including extraskeletal osteosarcoma, benign fibrous histiocytomas, fibromas, alveolar soft part sarcoma, epithelioid sarcoma, smooth muscle and gastrointestinal stromal tumors, and angiosarcomas, were almost always negative for p75. Epithelial tumors that were consistently positive included mixed tumor and adenoid cystic carcinoma, whereas mesothelioma, adenocarcinomas, and most squamous cell carcinomas were negative. p75 is not a specific marker for nerve sheath tumors. It is present in a variety of other mesenchymal tumors including synovial sarcoma and in CD34-positive tumors such as DFSP, spindle cell lipoma, and hemangiopericytoma. The presence of p75 in nonneural tumors such as DFSP and rhabdomyosarcoma mimic its presence in early fetal mesenchyme and skeletal muscle, suggesting oncofetal expression in these tumors. p75 may be useful to distinguish DFSP from benign fibrous histiocytoma.

Angiomatoid "malignant" fibrous histiocytoma: a clinicopathologic study of 158 cases and further exploration of the myoid phenotype.

Angiomatoid "malignant" fibrous histiocytoma (AMFH) has been considered to be a low-grade sarcoma of childhood, and, with its fibrous pseudocapsule, angiomatoid change, dense lymphoplasmacytic response, and proliferation of spindled or round cells, has been classified as a fibrohistiocytic neoplasm. We wanted to study the clinicopathologic and immunophenotypic features of a large number of these tumors and to especially further explore their myoid differentiation. Cases coded as AMFH from 1979 to 1995 were retrieved from the Soft Tissue Registry of the AFIP. Only cases that met the criteria for AMFH by light microscopy were included, a total of 158 cases. Immunohistochemistry was obtained on 98 cases. Clinical history on 92% of all cases revealed a gender ratio of 1.3 females: males, age range of 2 to 71 years, median size of 2.0 cm, and a distribution of extremities > trunk > head and neck, with 66% lesions occurring in areas of normal lymphoid tissue. All tumors with available margins were well-circumscribed. Eighty percent of cases had some degree of lymphoplasmacytic infiltration; 50% cases had pseudovascular spaces filled with blood. Fifty-two percent had predominantly round cell morphology; 48% had a predominantly spindle cell pattern. Desmin positivity was noted in 51% cases and occurred in both predominantly round cell and spindle cell tumors. Most of the desmin-positive cases with adjacent lymphoid infiltrate (67%) showed scattered similar, desmin-positive cells in the surrounding lymphoid infiltrate, adjacent to the tumor. Muscle-specific and smooth-muscle actins were seen in 14% cases. Heavy-caldesmon was strongly positive in 3%, and calponin was focally positive in 73% and extensively positive in 12% cases. MyoD1, myoglobin, and myogenin (myf4) were negative in all tumors studied. Forty-five percent of cases were positive for CD99; 52% of these had round cell morphology. Fifteen percent of cases were positive for KP-1. All tumors were positive for vimentin and negative for CD21, CD35, S100 protein, CD34, keratins 8/18, and lysozyme. Clinical follow-up on 86 patients indicated that only 1 patient was alive with a local nodal metastasis (1% frequency of metastasis) within 1 year, and 2 others had local recurrence, all over a mean follow-up period of 6 years. The myoid, primarily myofibroblastic, phenotype of these lesions is supported by desmin, calponin, and occasional actin positivity. The occasional heavy-caldesmon and smooth muscle actin additionally suggest rare smooth muscle phenotype; however, lack of skeletal muscle markers indicate no relationship of AMFH to skeletal muscle tumors. The resemblance of these lesions to lymph nodes, clinically and morphologically, the finding of similar desmin positive cells in the adjacent lymphoid infiltrate, and the fact that 66% cases were found in sites of normal lymphoid tissue raise the possibility that some of these lesions may arise from or be related to myoid cells of lymphoid tissue. AMFH has an almost invariably benign behavior, but the 1% metastatic rate warrants its classification as low-grade "malignant." The predominantly round cell, CD99-positive and desmin positive AMFH cases, respectively, should not be confused with Ewing's sarcoma/PNET or rhabdomyosarcoma, respectively.

Osteocalcin and osteonectin immunoreactivity in extraskeletal osteosarcoma: a study of 28 cases.

Extraskeletal osteosarcoma (EOSA), a rare malignant soft tissue tumor, is by definition unattached to the skeleton and composed of malignant cells of osteoblastic phenotype which produce osseous matrix (ie, neoplastic bone). Because of its location, it can mimic other soft tissue tumors, and its matrix can be mistaken for hyalinized collagen. Antiosteocalcin (OC) and antiosteonectin (ON), antibodies against two abundant human bone proteins, are explored in the diagnosis of EOSA. Twenty-eight cases coded as EOSA (n=24) or probable EOSA (n = 4) were identified from the Soft Tissue Registry of the Armed Forces Institute of Pathology (Washington DC). All cases had paraffin blocks available for immunohistochemistry. OC and ON (Biodesign International, Kennebunk, ME, clones OC1 and OST1) immunostaining for tumor cells and matrix was graded on a four-tiered grading system: 1 = focal (< 50%) weak staining; 2 = focal strong staining; 3 = diffuse (> or = 50%) weak staining; and 4 = diffuse strong staining. Patient ages ranged from 9 to 80 years, with a mean age of 57 years. There were 9 female patients and 19 male patients. The tumor sizes ranged from 1.5 to 15 centimeters, with a mean size of 5.8 centimeters. Locations included the lower extremity (n=14), trunk (n=9), upper extremity (n=4), and head and neck (n=1). Subtypes included 12 osteoblastic, 4 fibroblastic, 2 chondroblastic, 2 well differentiated, 1 telangiectatic, 1 small cell, and 6 giant cell rich EOSAs; the latter resembled giant cell rich malignant fibrous histiocytomas with neoplastic bone formation. All tumors had both neoplastic cells and bony tumor matrix to evaluate. OC was 82% sensitive for EOSA neoplastic cells (1 to 4+), with immunostaining of neoplastic cells away from bone in 91% of cases, and 75% for bony tumor matrix (2 to 4+). ON was 93% sensitive for EOSA neoplastic cells (2 to 4+), yet only 39% for bony tumor matrix (1 to 4+). In 100% giant cell rich EOSA, neoplastic cells were positive for OC and ON (2 to 4+). OC showed 100% specificity for osteoblasts as it was nonreactive in all nonbone cells. ON was not specific for osteoblasts but consistently immunostained other cell types in our EOSA tumors: fibroblasts (100%), pericytes (96%), endothelial cells (92%), chondrocytes (5/5), basal layer of skin epithelium (1/4), nerves (2/2), and osteoclastic giant cells (64%). ON also stained several other cell types in normal and neoplastic tissues in our battery of preliminary stainings; OC was negative in all nonosteoblastic tissues and tumors. Both OC and ON were specific for osteoid matrix as they were nonreactive in both collagen and cartilage matrix. OC is a sensitive and specific marker for bone cells and would be helpful in identifying EOSA, even in the absence of neoplastic bone on small biopsies. ON and OC (more sensitive) will both distinguish malignant bone from collagen and cartilage matrix, essential to the diagnosis of EOSA.

Epithelioid sarcoma: an immunohistochemical analysis of 112 classical and variant cases and a discussion of the differential diagnosis.

Epithelioid sarcoma (ES) is a distinctive soft tissue neoplasm with a predilection for the distal extremities of young adults. This tumor typically contains nodular aggregates of epithelioid and spindle cells with zonal necrosis. The neoplastic cells are generally reported to coexpress keratin and vimentin and are often stated to be positive for CD34. However, there is no large series with extensive immunohistochemical data, there are few data with regard to expression of different keratin subtypes, and there are no large series discussing the epithelioid sarcoma subtypes. In the current study, we immunohistochemically evaluated 88 typical and 24 variant (8 angiomatoid, 9 large cell/rhabdoid, and 7 "fibroma-like") ESs. Nearly all ESs with typical histology (94%) were positive for keratin 8 (K8), whereas 72% were positive for K19, 48% for intermediate- and high-molecular-weight keratins (34betaEH12), and 22% for K7; reactivity with the latter two antibodies was usually seen in only a minority of tumor cells. Vimentin reactivity was present in all cases, EMA in 96% of cases and muscle-specific actin and CD34 were noted in 41% and 52% of the cases, respectively. A few ESs (7%) showed focal cytoplasmic CD31 reactivity, but none exhibited a distinctive membrane staining pattern, and examples tested for FVIIIRAg were negative. The angiomatoid, fibroma-like, and large cell-rhabdoid ES variants had immunohistochemical profiles similar to the classic cases, supporting a common pathogenesis. Although not consistently expressed in ES, the presence of CD34 is helpful in distinguishing this entity from primary and metastatic carcinomas and other sarcomas such as malignant rhabdoid tumor.

Splenic inflammatory myofibroblastic tumor (inflammatory pseudotumor): a clinicopathologic and immunophenotypic study of 12 cases.

CONTEXT: Inflammatory pseudotumor is an uncommon and enigmatic lesion. The spindle cells found in this tumor have features of myofibroblasts. Because of the indefinite relationship of these lesions with inflammatory fibrosarcoma and their indefinite biologic behavior, inflammatory pseudotumor is currently classified as inflammatory myofibroblastic tumor (IMT). To date, only case reports or small series have been published on these tumors, which are primary in the spleen. DESIGN: In this study, we describe the clinical, morphologic, and immunophenotypic findings of 12 cases of splenic IMT and examine their relationship to Epstein-Barr virus (EBV). RESULTS: The patients included 8 women and 3 men, ranging from 19 to 77 years of age (mean, 53 years; median, 60 years). Demographic data were unavailable for 1 patient. Patients generally presented with abdominal pain (n = 5) and fever (n = 4). Associated lesions included renal cell carcinoma (n = 2), colonic adenocarcinoma (n = 1), and cholecystitis (n = 1). All tumors were composed of a bland spindle cell proliferation in association with a variable mixed inflammatory component. There were 2 growth patterns, namely, a cellular spindle cell pattern and a hypocellular fibrous pattern. An immunohistochemical panel confirmed the myofibroblastic nature of the spindle cells. The spindle cells of 2 cases were immunoreactive for EBV latent membrane protein 1, whereas 6 of 10 cases were positive for EBV-encoded RNA using in situ hybridization. Follow-up was available for 8 patients; 6 were alive with no evidence of recurrence and 2 were dead of other causes. CONCLUSION: Splenic IMTs are uncommon lesions that can be distinguished from other conditions using a combination of clinical, histologic, and immunophenotypic findings. Epstein-Barr virus may play a role in the pathogenesis of splenic IMT, and there may be an association of splenic IMT with concomitant disease or malignancy. Most splenic IMTs have an excellent long-term prognosis.

Liposarcoma with meningothelial-like whorls: a study of 17 cases of a distinctive histological pattern associated with dedifferentiated liposarcoma.

AIMS: We reviewed 17 cases of liposarcoma with peculiar meningothelial-like whorls to determine the pathological and clinical significance of this distinctive morphological finding. METHODS AND RESULTS: Seventeen liposarcomas with concentric whorls simulating the whorls seen in meningioma, were retrieved from the soft tissue registry of the Armed Forces Institute of Pathology. There were 10 males and seven females with a mean age of 53 years (range 24-76 years). Twelve of the 17 cases were large retroperitoneal tumours (mean 170 mm in greatest dimensions). All 17 cases had whorls. Three cases were classified as well-differentiated liposarcoma with whorls and bone formation. Five cases showed coalescing of whorls into areas which may be interpreted as low to intermediate grade dedifferentiation. Five cases had spindled areas associated with the whorls which correlate with classical intermediate to high-grade dedifferentiation. Finally, four cases had a predominant spindle cell component resembling malignant fibrous histiocytoma with focal residual possible sclerosing well-differentiated liposarcoma (scattered adipocytes, adipocytic atypia and/or floret-type giant cells). The meningothelial-like whorls were clustered or scattered throughout the tumours and ranged from 0.09 mm to over 10 mm in diameter in cases with coalescent whorls. Metaplastic bone was present within the whorls or in their immediate vicinity in 10 of 17 cases. Immunohistochemically, the whorl-forming spindle cells showed alpha-smooth muscle actin reactivity in three of seven cases but were negative for epithelial membrane antigen, CD21, and CD35 indicating lack of relationship with meningioma and dendritic reticulum cell sarcoma, other tumours that may contain whorls. Whorls with bone formation revealed cells adjacent to the bone to be positive for osteocalcin, a marker of osteoblastic phenotype. The spindle cells of the whorls were negative for CD34 and CD31, yet these highlighted numerous capillaries inside the whorls in a concentric manner. The whorl-forming cells showed moderate to high MIB-1-index and showed p53 immunoreactivity similar to the dedifferentiated areas but differed from the areas of well-differentiated liposarcoma, which were p53-negative and showed a low MIB-1-index. Follow-up (available in 65% cases) revealed seven patients with metastases or dead of the disease and five patients with one or more recurrences. CONCLUSIONS: The meningothelial-like whorls represent a mesenchymal proliferation which may undergo pericytic or myofibroblastic, or occasionally osteoblastic, differentiation in liposarcoma. These whorls do not represent dendritic or perineurial/meningothelial differentiation. The significant proliferative activity, p53 reactivity and tendency to coalesce and associate with dedifferentiated liposarcoma suggest that the meningothelial whorls may represent an early sign of dedifferentiation of liposarcoma.

Pleomorphic rhabdomyosarcoma in children: four cases in the pediatric age group.

Pleomorphic rhabdomyosarcoma is considered rare and controversial, especially in children. Although pleomorphic rhabdomyosarcoma has been observed in children, its sparcity has taken it out of current childhood rhabdomyosarcoma classifications. We report four pediatric cases of pleomorphic rhabdomyosarcoma, review morphologic, immunohistochemical, and ultrastructural features, and discuss the rare need to include this category in children. The Soft Tissue Registry of the Armed Forces Institute of Pathology was searched for cases coded as "pleomorphic rhabdomyosarcoma" from 1970 to the present. Only cases in patients less than 21 years old were included. Clinical data, morphology, and immunohistochemical stains were reviewed and follow-up was obtained. Electron microscopy was performed on two cases. Molecular analysis by polymerase chain reaction was performed on one case with available material. Of four patients included, there were three boys and one girl. Patient ages ranged from 9 months to 10 years (median, 4.5 years). Tumors were located on the chest wall (n = 2) and one each on the upper and lower extremities. Tumor size ranged from 4.0 to 10.0 cm (median, 7 cm). Grossly, the tumors were lobulated and circumscribed. Microscopically, architectural patterns varied from solid to fascicular or storiform. All tumors had large, often multinucleated, polygonal, spindled or strap-like rhabdomyoblasts with abundant eosinophilic cytoplasm. Nuclear characteristics ranged from hyperchromatic to vesicular. Most tumor cells had large prominent nucleoli. Background rhabdomyoblasts varied from spindled to polygonal. No tumors displayed areas typical of embryonal or alveolar rhabdomyosarcoma. All tumors exhibited atypical mitotic figures. Immunohistochemistry revealed that the tumors were positive for the following markers: desmin (3/4), myoglobin (4/4), myoD1 (3/3), myf4 (3/3), and MSA (4/4). The two cases studied by electron microscopy both showed evidence for skeletal muscle differentiation. One case showed no evidence for a t(2;13) or t(1;13) translocation. Two patients were alive with no evidence of disease at 12 and 25 years. One patient was dead of disease at 9 years. Pleomorphic rhabdomyosarcoma is rare but exists in children. The diagnosis should be considered in pleomorphic sarcomas exhibiting skeletal muscle differentiation, which are otherwise devoid of typical areas or chromosomal changes of embryonal or alveolar rhabdomyosarcoma.

Fibrohistiocytic lipoma: twelve cases of a previously undescribed benign fatty tumor.

A lipoma with a spindled proliferation within it, resembling known (myo)fibroblastic lesions such as fibrous histiocytoma or dermatofibrosarcoma protuberans, (ie, fibrohistiocytic lipoma), has not been previously reported. This tumor varies from other classic lipoma variants, including spindle cell lipoma, myolipoma, angiolipoma, and fibrolipoma. We examine the clinicopathologic findings of this new lipoma variant. The Soft Tissue Pathology Registry of the Armed Forces Institute of Pathology was searched for patients with "lipoma with fibrohistiocytic proliferation." Lesions that were better classified as other entities were excluded. Patient slides and clinical history, including associated lesions, family history, duration of symptoms, history of trauma, natural progression, and treatments, were reviewed. Immunohistochemistry was performed on cases with available material (n = 6). Twelve patients with fibrohistiocytic lipoma were included. All tumors revealed a well-distributed quilt-like proliferation or solid focus of slightly plump to relatively bland spindled cells with collagenous stroma in short fascicular and storiform growth patterns. These spindled cells resembled those seen in either fibrous histiocytoma or dermatofibrosarcoma protuberans. However, the spindled proliferation was all within a well-circumscribed lipoma. The lesions lack the dermal involvement or plump pleomorphism of fibrous histiocytoma and the dermal involvement or infiltrative growth pattern of dermatofibrosarcoma protuberans. The fatty component demonstrated heterogeneously sized adipocytes, as those seen in other lipomas. Inflammation and hemosiderin were minimal. Mast cells were not identified. The tumors were typically found in the subcutis of the trunk of men (10 of 12; one each on the wrist and leg; mean age, 31 years). The average size of the lesions was 3.0 cm, and they were present for a mean duration of 10 months prior to surgical excision. One patient had two concurrent lesions; all others had solitary tumors. Another patient had a intracranial dermoid cyst removed during childhood. Four patients had a personal or family history of hypercholesterolemia, hypertension, or myocardial infarction. There was no history of antecedent trauma. Cases studied were positive for vimentin, calponin (5 of 5), CD34 (3 of 5), and occasionally KP-1 or lysozyme in the spindled component, and all cases studied were negative for the actins, caldesmon, S-100 protein, desmin, cytokeratins, and epithelial membrane antigen. Although the actins were negative in our laboratory, the more sensitive calponin positivity suggests myofibroblastic phenotype of the spindled component of this lesion. CD34-positive fibroblasts were present in three of five cases. Of eight patients with follow-up, there were no recurrences; all patients were alive and free of disease over a mean of 10 years (range, 2 months to 31 years). We have identified a lipoma variant, fibrohistiocytic lipoma, that has not been previously described. In our experience the morphology and calponin positivity suggest myofibroblastic phenotype for the spindled cells, within a lipoma. This entity can be distinguished from fibrous histiocytoma, fibromatosis, dermatofibrosarcoma protuberans, spindle cell lipoma and other lipoma, and liposarcoma variants.

Pleomorphic rhabdomyosarcoma in adults: a clinicopathologic study of 38 cases with emphasis on morphologic variants and recent skeletal muscle-specific markers.

Pleomorphic rhabdomyosarcoma (PRMS) is a rare and controversial tumor of skeletal muscle phenotype. Diagnostic criteria for PRMS by combined histology and currently available immunohistochemistry have not been clearly defined. We report 38 pleomorphic rhabdomyosarcomas in adults, explore morphologic variants, and discuss our experience with both specific and nonspecific skeletal muscle markers in these tumors. Clinical data, morphology, and immunohistochemistry were reviewed. Electron microscopy was performed. Of 38 cases, there were 28 males and 10 females. Patient ages ranged from 21 to 81 years (median = 54 y; mean = 51 y). Tumors were located in the lower extremity (n = 18), abdomen/retroperitoneum (n = 6), chest/abdominal wall (n = 5), spermatic cord/testes (n = 4), upper extremity (n = 3), and one each in the mouth and orbit. Tumor sizes ranged from 1.5 to 15.0 cm (mean = 7.3 cm; median = 6.8 cm). The cases were divided into three variants, each with large, atypical, pleomorphic polygonal rhabdomyoblasts (PRMB) with abundant eosinophilic cytoplasm in varying numbers and different morphologic backgrounds of round or spindled rhabdomyoblasts (RMB). 1. Classic PRMS: Predominantly atypical PRMB in sheets (n = 8). 2. Round cell PRMS: Clusters of PRMB throughout the tumor with a background of slightly atypical, medium-sized, round, blue RMB (n = 13). 3. Spindle cell PRMS: Scattered PRMB in a predominance of atypical spindled RMB arranged in a storiform growth pattern (n = 17). Immunohistochemistry revealed the following: myoglobin (37/38), MyoD1 (19/36), skeletal muscle myogenin (myf4; 19/34), fast skeletal muscle myosin (4/5), desmin (36/38), muscle-specific actin (MSA; 25/35), smooth muscle actin (SMA; 15/33), and muscle specific myogenin (myf3; 25/35). Immunohistochemistry was supportive of skeletal muscle differentiation with at least one positive skeletal muscle-specific marker (myoglobin, MyoD1, fast skeletal muscle myosin, or myf4). In addition, all cases had some positivity for nonspecific muscle markers (desmin, MSA, SMA, myf3). Electron microscopy (EM), performed on eight selected cases from all three morphologic groups, demonstrated definitive skeletal muscle differentiation in all cases. Follow-up, available on 30 (79%) cases, revealed that 70% of patients died of disease (mean 20 months, range 1 month-108 months), 3% were alive with disease at 12 months (n = 1); and 27% had no evidence of disease (mean, 83 mo; range, 18 to 108 mo). PRMS, a tumor of predominantly middle-aged adult males in the lower extremity, can be diagnosed by the morphologic presence of scattered PRMB with immunohistochemical evidence of at least one skeletal muscle-specific marker. There are three morphologic variants of PRMS. The appropriate diagnosis of PRMS is significant as it is a high-grade sarcoma, with an aggressive clinical course.

Hemosiderotic fibrohistiocytic lipomatous lesion: ten cases of a previously undescribed fatty lesion of the foot/ankle.

We address the clinicopathologic features of a previously undescribed heavily-pigmented spindle cell proliferation within a circumscribed benign lipomatous lesion that occurs mainly in the ankle region of older females. Patients with "lipoma with fibrohistiocytic proliferation" were retrieved from our files. Slides and clinical information were reviewed, and immunohistochemistry was performed (n = 5). Ten patients with hemosiderotic fibrohistiocytic lipomatous lesions were identified. All cases demonstrated a well-circumscribed fatty lesion with random focal proliferations of plump, slightly pleomorphic spindled cells, scattered inflammatory cells, and abundant iron pigment. The spindled cells had vesicular nuclei with indistinct nucleoli; occasional hyperchromatism was observed. No nuclear cytoplasmic inclusions were identified. The spindled component had a reactive appearance. In most cases, the fatty component, with homogeneously sized adipocytes, predominated. The lesions occurred in the foot/ankle region (8/10, one each cheek and hand) of primarily females (8/10) with a mean age of 50.6 years (range 42-63 years), size of 7.7 cm (range 2.5-17 cm), and prior duration of 3.1 years. Seven of eight patients had a history of prior trauma. The spindled component was positive for vimentin, calponin, CD34, and occasionally KP-1 or lysozyme and negative for caldesmon, S100, and desmin. Follow-up on eight patients revealed four with recurrences or residual disease over three years, requiring re-excision. No cases metastasized or caused patient death (mean 12 years, range 1-23 years). We describe a predominantly fatty lesion that is hemosiderin rich with a "fibrohistiocytic" proliferation, composed of histiocytes, myofibroblasts, and C34-positive fibroblasts, which occurs predominantly in the ankle region of middle-aged females. We believe that this is a reactive process due to antecedent trauma, the inflammatory cells, hemosiderin, mixed spindled cells, and homogeneous non-neoplastic appearance of the fat. HFLL can be distinguished from previously described lesions. Correct identification of hemosiderotic fibrohistiocytic lipomatous lesion is important, as it may locally recur.