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Charcot neuropathic arthropathy is a degenerative, debilitating disease that affects the foot and ankle in patients with diabetes and peripheral neuropathy, often resulting in destruction, amputation. Proposed etiologies include neurotraumatic, inflammatory, and neurovascular. There has been no previous animal model for Charcot. This study proposes a novel rodent model of induced neuropathic arthropathy to understand the earliest progressive pathologic changes of human Charcot. High-fat-diet-induced obese (DIO) Wild-type C57BL/6J mice (n = 8, diabetic) and age-matched low-fat-diet controls (n = 6) were run on an inclined high-intensity treadmill protocol four times per week for 7 weeks to induce mechanical neurotrauma to the hind-paw, creating Charcot neuropathic arthropathy. Sensory function and radiologic correlation were assessed; animals were sacrificed to evaluate hindpaw soft tissue and joint pathology. With this model, Charcot-DIO mice reveals early pathologic features of Charcot neuropathic arthropathy, a distinctive subchondral microfracture callus, perichondral/subchondral osseous hypertrophy/osteosclerosis, that precedes fragmentation/destruction observed in human surgical pathology specimens. There is intraneural vacuolar-myxoid change and arteriolosclerosis. The DIO mice demonstrated significant hot plate sensory neuropathy compared (P < 0.01), radiographic collapse of the longitudinal arch in DIO mice (P < 0.001), and diminished bone density in DIO, compared with normal controls. Despite exercise, high-fat-DIO mice increased body weight and percentage of body fat (P < 0.001). This murine model of diet-induced obesity and peripheral neuropathy, combined with repetitive mechanical trauma, simulates the earliest changes observed in human Charcot neuropathic arthropathy, of vasculopathic-neuropathic etiology. An understanding of early pathophysiology may assist early diagnosis and intervention and reduce patient morbidity and mortality in Charcot neuropathic arthropathy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Challenging emerging entities with distinctive molecular signatures may benefit from algorithms for diagnostic work-up., Methods: Fusion sarcomas (2020-2021, during pandemic) were diagnosed by clinicoradiology, morphology, phenotype, and next-generation sequencing (NGS)., Results: Six fusion sarcomas in two males and four females involved the chest-wall, neck, or extremities; ages ranged 2-73, median 18 years. Sizes ranged 5.3-25.0, median 9.1 cm. These include high grade 1) TPR-NTRK1 of proximal femur with a larger rounded soft tissue mass, previously considered osteosarcoma yet without convincing tumor matrix. A pathologic fracture necessitated emergency hemipelvectomy (NED) and 2) novel KANK1-NTRK2 sarcoma of bone and soft tissue with spindled pleomorphic to epithelioid features (AWD metastases). 3) Novel ERC1-ALK unaligned fusion, a low grade infiltrative deep soft tissue hand sarcoma with prominent-vascularity, myopericytoid/lipofibromatosis-like ovoid cells, and collagenized stroma, was successfully treated with ALK-inhibitor (Crizotinib), avoiding amputation. These NTRK and ALK tumors variably express S100 and CD34 and were negative for SOX10. 4) and 5) CIC-DUX4 round cell tumors (rapid metastases/demise), one with COVID superinfection, were previously treated as Ewing sarcoma. These demonstrated mild pleomorphism and necrosis, variable myxoid change and CD99 reactivity, and a distinctive dot-like-Golgi WT1 immunostaining pattern. 6) A chest wall/thoracic round cell sarcoma, focal CD34/ keratins/CK7, revealed nuclear-STAT6, STAT6-NAB2 by NGS, confirming malignant solitary fibrous tumor, intermediate-risk-stratification (AWD metastases)., Conclusions: Recent fusion sarcomas include new KANK1-NTRK2 and ERC1-ALK, the latter successfully treated by targeted-therapy. ALK/NTRK fusion partners TPR and KANK1 suggest unusual high-grade morphology/behavior. Clinicoradiologic, morphologic, and phenotypic algorithms can prompt molecular-targeted immunostains or NGS for final classification and promising inhibitor therapy., (Copyright © 2021. Published by Elsevier Inc.)

Background: Charcot neuropathic arthropathy is a debilitating, rapidly destructive degenerative joint disease that occurs in diabetic, neuropathic midfoot. Clinicoradiologic assessment for Charcot neuropathic arthropathy previously relied on Eichenholtz stage. There is limited histopathologic data on this entity. We wanted to independently develop a histopathologic scoring system for Charcot neuropathic arthropathy., Design: Retrieval of surgical pathology midfoot specimens from Charcot patients (2012-2019) were analyzed to evaluate joint soft tissue and bone. Considering progression from large (≥half 40× hpf) to small (

We present 19 cases of primary breast malignant fibrous histiocytoma (MFH) or myxofibrosarcoma/pleomorphic sarcoma not otherwise specified, the largest series to date, and compare our results with those in the literature to better define MFH in this anatomical location. Twenty-seven cases (MFH, myxofibrosarcoma, or pleomorphic sarcoma not otherwise specified) were reviewed using World Health Organization and French Federation of Cancer Centers criteria. Inclusion required location within breast parenchyma without extensive chest wall involvement. Morphological features were recorded, and immunohistochemistry was applied. Clinical data were extracted from patients' medical records. Clinically, there was 1 male patient. Of 15 patients with follow-up, 5 (33% overall) died of disease within an average of 7 months after diagnosis. Distant metastases and older patient age were associated with poor survival. Storiform-pleomorphic subtype was most common (10/19) with myxofibrosarcoma (6/19) and giant cell subtype (1/19) also observed. Unique lymphocyte-rich (1/19) and pleomorphic hyalinizing angiectatic tumor-like (1/19) morphologies are presented. Immunohistochemistry demonstrated expression of CD68 (71%), focal smooth muscle actin (36%), with rare focal estrogen and progesterone receptor immunoreactivity. All cases were negative for CD34, S-100 protein, desmin 33, and keratins, including CK7, CK20, CK5/6, and CK18. Malignant fibrous histiocytoma occurs as a primary lesion in breast parenchyma. Attention to morphological detail and immunohistochemistry avoids misdiagnosis. Entrapped breast ductal epithelium should not be misinterpreted as the epithelial component of a biphasic tumor. A florid lymphoid response should not be confused with metaplastic carcinoma. Pleomorphic hyalinizing angiectatic tumor-like features may be observed in MFH. Our study confirms the presence of MFH in breast and presents unique morphological observations of primary breast MFH., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Congenital epulis of the newborn (CEN) is a rare benign lesion that exclusively occurs in the oral and maxillofacial regions of newborns. The clinicopathologic features of CEN were examined and reviewed from the files of the Armed Forces Institute of Pathology from 1970 to 2000. Ten cases were included. Patient lesions were all present at birth but were surgically excised between 2 days and 6 weeks (median, 5.5 days). Nine lesions were in females; 1 case did not designate patient sex. Locations included 6 on the maxilla, 2 on the mandible, 1 on the designated maxillary lip, and 1 unknown. The cases included a patient with 2 lesions: 1 on mandibular and 1 on maxillary alveolar ridges, respectively. All other lesions were solitary and polypoid. Microscopically, these were pedunculated and nodular, composed of sheets to grouped clusters of medium-sized, ovoid-to-polygonal cells with abundant granular cytoplasm, distinct cell membranes, vascular-rich stroma, and attenuated overlying mucosa. Two cases also demonstrated spindled cells. The nuclei were vesicular and focally stippled, with distinct and slightly convoluted nuclear membranes; nucleoli were visible but not prominent. Mitotic activity was not observed. The vascular channels ranged from capillary-sized to venous, some staghorn-like with rare perivascular long-term inflammation. The venules exhibited a perivascular pericytic proliferation. Odontogenic epithelial rests were present in 2 cases. No cases demonstrated cytoplasmic hyaline globules. The lesional cells in all cases were negative for S-100 protein, CD68, CD34, CD31, keratins, desmin, calponin, and smooth muscle actin. Perivenular pericytes were positive for smooth muscle actin. Congenital epulis of the newborn is a rare oral entity with characteristic clinicopathologic features. It predominately affects girls, mainly on the maxillary alveolar ridge. It may be separated from "granular cell tumor" by location, patient age, absence of cytoplasmic hyaline globules, solid growth pattern, pericytic proliferation, attenuated overlying epithelium, and negativity for S-100 protein., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Soft tissue Rosai-Dorfman disease (STRDD) is rare, previously reported only as single cases and few series. Simian virus 40 (SV40), a polyomavirus, has been identified in lymphoid processes and has a controversial role in neoplasia etiology. Occasional cytoplasmic pink granular inclusions and nuclear changes led us to explore a viral etiology. Only unpublished STRDD from our files with adequate material, soft tissue location, and diagnostic confirmation were included. Immunohistochemistry and follow-up were obtained. Eighteen STRDD patients, 4 male and 14 female, had 29 lesions; 5 with 2 or more lesions. Ages ranged from 8 to 81 years (mean 42.6 years and median 42.5 years). Soft tissue Rosai-Dorfman disease locations include trunk or proximal extremity (n = 19), distal extremity (n = 5), "abdominal" (n = 3), face (n = 1), and unknown subcutaneous site (n = 1). Sizes ranged from 0.5 to 13.7 cm (median, 2.4 cm). Previous disease included lymphoma, buttocks injection site, diabetes and hypothyroidism, and radiation for chronic dermopathy. No patients had a preceding or concurrent known viral infection; none had lymphadenopathy at present. None were known to be immunocompromised. Soft tissue Rosai-Dorfman disease was rapidly progressing. Initial pathologic diagnosis ranged from Rosai-Dorfman disease or inflammatory pseudotumor to inflammatory malignant fibrous histiocytoma. Grossly STRDDs were multilobulated, tan-yellow, and firm; morphologically, circumscribed, and subcutaneous-based. All had sheets of polygonal histiocytes with abundant pale eosinophilic cytoplasm, emperipolesis, plasma cells, and lymphocytes scattered and within clusters. Focal spindle cell change and mild pleomorphism were each observed in 3 patients; 2 had focal necrosis, none with mitoses. Small granular pink cytoplasmic inclusions and nuclear viral-like changes were observed. By immunohistochemistry, all STRDDs were positive for S100 protein, negative for CD1a, Epstein-Barr virus, and latent membrane protein, yet 3 (all abdominal, 1 multicentric) of the 9 studied were focally positive for cytoplasmic and nuclear SV40 polyomavirus. All were treated by local excision. Follow-up on 14 patients older than 8 to 16 years revealed recurrence in 3 patients with persistent multiple lesions, one with abdominal location. There were no metastases or death from disease. Soft tissue Rosai-Dorfman disease is a rapidly evolving, mostly solitary and nonrecurrent trunk and proximal extremity subcutaneous lesion in middle-aged females. More than one third can have persistent multicentric disease. It is important to recognize STRDD, to separate it from malignancy. Epstein-Barr virus/latent membrane protein was negative but polyomavirus was positive in 3 patients with abdominal STRDD, one with multicentric persistent disease. The relationship of polyomavirus to the evolution of abdominal STRDD should be further explored., (Copyright © 2010. Published by Elsevier Inc.)

Cutaneous angiosarcoma (AS) is a rare malignant neoplasm of dermis composed of infiltrating cells of endothelial phenotype with overall poor prognosis. Although autocrine stimulation by vascular endothelial growth factor secretion may play a role in the pathogenesis of angiosarcoma, its mechanism has not been fully established. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that mediates cellular and systemic homeostatic responses to hypoxia.. The stability of HIF can regulate key proteins in angiogenesis and the alpha-subunit has been found in epithelial tumors, only 1 case of human retroperitoneal angiosarcoma, and rare vascular proliferations and tumors in knockout mice. We wanted to observe the utility of HIF-1alpha as a marker or explanatory factor in AS. Cases coded as "angiosarcoma" of dermis were culled and re-reviewed for inclusion as AS, based on patient folder, slides, and obtained immunohistochemistry including CD31 and smooth muscle actin (SMA). Hypoxia-inducible factor-1alpha was performed on a subset of cases, with additional available material. Forty-five cases met the criteria for AS; there were 17% females and 83% males, with a mean age at presentation of 67 years (range, 27-88 years). Tumors presented most commonly in the skin of the scalp followed by the left lower leg, face, nose, lower arm, neck, thigh, eyelid, ear, and temple. Associated basal cell carcinoma was noted in 1 patient; no others had other neoplasms or unrelated surgeries. There was no history of other primary, lymphedema, radiation, breast-associated, or thorotrast-induced angiosarcoma. The tumors ranged in size from 0.4 up to 9.5 cm, with a mean size of 2.4 cm. Histopathologically, most tumors were vasoformative, with either solid architecture (n = 35) or papillary endothelial hyperplasia-like foci (n = 7). All cases demonstrated infiltrative growth pattern, cytologic atypia, and mitotic activity, including atypical forms. Surface ulceration was present in 44% and solar elastosis in the most evaluable cases. Epithelioid morphology was present in 29% (n = 13) cases. Mild to moderate lymphocytic inflammatory response was noted in 62% (n = 28) cases. CD31 highlighted malignant endothelial cells. SMA (for pericytes) was generally absent. Hypoxia-inducible factor 1alpha was focally positive in cytoplasm of 3 of 18 (17%) cases studied. Treatment and follow-up data were only available on 4 cases: 2 died of disease within 4 years, 2 others had known recurrence within 2 years. Cutaneous angiosarcoma is largely found on the scalp of older individuals. Requirement for diagnosis includes extravascular proliferation of atypical endothelial cells with mitotic activity in vasoformative, solid, and papillary patterns. Absence of SMA can prove extravascular extension of tumor, outside their normal vessel confines. Cutaneous angiosarcoma generally lacks HIF-1alpha expression. Accordingly, the hypoxic response pathway is not thought to be a documentable common mechanism of angiogenesis in this entity., (Published by Elsevier Inc.)

Mesenchymal chondrosarcoma is a rare malignant tumor in the differential diagnosis of other small, round blue cell tumors, including atypical teratoid tumor in the central nervous system (CNS) and rhabdomyosarcoma in the musculoskeletal (MSK) locations. We reviewed the morphology of CNS and MSK cases and applied a panel of immunostains. Archival cases were pulled from our files. Immunohistochemistry and follow-up were obtained. Twenty-two cases included 5 CNS (all female; mean age, 30.2) and 17 MSK (11 female and 6 male; mean age, 31.1). Both CNS and MSK examples had similar round cells, staghorn vascular pattern, increased mitotic activity, and centrally located hyaline cartilage islands. The CNS examples demonstrated more spindling and the MSK cases more necrosis. INI1 was retained in all tumors studied. Epithelial membrane antigen (EMA) and desmin were expressed focally in 35% and 50% of cases, respectively. The round cells of all cases were negative for MyoD1, myogenin, smooth muscle actin (SMA), glial fibrillary acid protein (GFAP), keratins, and estrogen receptor, as well as a panel of other antiobodies. Eighty percent of patients with follow-up had pulmonary metastases and/or died within a mean of 5 years. The CNS and MSK mesenchymal chondrosarcoma predominantly affects adult females with poor prognosis. There are only subtle morphologic differences between the CNS and MSK groups. By immunohistochemistry, mesenchymal chondrosarcoma occasionally expresses aberrant desmin and EMA but is negative for SMA, myogenin MyoD1, GFAP, and keratins, refuting true smooth or skeletal muscle, epithelial, or meningothelial phenotype. Retained INI1 separates these tumors from atypical teratoid tumor. Despite marked female predominance in our series, estrogen receptor is negative in mesenchymal chondrosarcoma., (Published by Elsevier Inc.)

Myositis ossificans (MO) is a reactive zonal fibroosseous lesion in skeletal muscle of the proximal extremities and trunk of young patients. It generally matures over several weeks to form a peripheral rim of bone. Fibroosseous pseudotumor of the digits (FOPD) is a similar reactive lesion of the digits, which is reportedly less well organized. Cases up to year 1980 were previously reported from our institution. We examined new cases of FOPD since 1980 and addressed the relationship of this lesion to both myositis ossificans and other distal extremity fibroosseous lesions. Fifty-two cases coded as FOPD or MO limited to the hands and feet, from 1980 to the present, were retrieved from our files. Nine cases were excluded due to incomplete material or rediagnosis as other lesion. Materials reviewed included radiologic images and pathologic material. Forty-three cases of FOPD were included. All cases were in the fingers, except for 1 toe case, with the proximal phalanx of the index finger the most commonly affected site. Duration of lesions was radiologically estimated to range from 2 to 6 weeks. Age of patients ranged from 10 to 64 years (mean and median of 40 years). Sixty percent of cases occurred in women. Morphologically, half of these lesions had a zonal organization, with mature woven bone peripherally and immature woven bone centrally; all bone demonstrated osteoblastic rimming. Clinically, 6 patients had known antecedent trauma, yet edema and pain of the digit were noted in all. Novel findings were that patients often had occupations requiring repetitive manual labor. Cases of FOPD were diagnosed and treated by simple excision. Three patients had residual disease, subsequently resected, without any recurrences. Fibroosseous pseudotumor of the digits is a distinctive, benign, reactive myofibroblastic and osseous zonal lesion that occurs in the finger of mainly adult patients, many with occupations that require repetitive manual use. Imaging can date these lesions, determine their exact location, and help with diagnosis. These lesions are the superficial and distal counterparts of MO. It is important to understand the morphology of FOPD to distinguish this type of lesion from other benign and malignant fibroosseous lesions.

The seminal article of Drs Franz Enzinger and Renyuan Zhang in 1988 defined plexiform fibrohistiocytic tumor (PFHT) as a distinctive entity. They described 65 cases (from 1965 to 1985) in children and young adults, with female and upper extremity predominance. These tumors were morphologically divided into 3 groups: fibroblastic, histiocytic (often with osteoclast-type giant cells), and mixed. Most tumors exhibited a plexiform and infiltrative arrangement of cells at the dermal/subcutaneous junction. Two fibroblastic PFHT had a metaplastic bone formation. Absence of cellular pleomorphism, low mitotic activity, dense hyalinization, hemorrhage, and chronic inflammation were observed. Vascular invasion was present in 1 recurrent, yet nonmetastatic, case. Tumors were negative for S100 protein, desmin, cytokeratin, factor VIIIrag, and lysozyme. Most patients were without disease up to 60 years after excision; 32 (37.5%) cases with follow-up recurred and 2 of those patients had regional lymph node metastasis at 9 and 36 months, respectively, yet there were no systemic metastases. In the interim, there have been additional studies on PFHT. We wanted to update the literature and add 66 new PFHT cases (1986-present) from the Armed Forces Institute of Pathology, since this seminal article, in honor of Dr Franz Enzinger. There were 37 men and 29 women; patient age ranged from 1 to 77 years (median, 20 years; 53% of patients were younger than 20 years). Twenty-eight cases occurred in the upper extremity (mostly forearm), 16 in lower extremity, 11 in trunk, 9 in head and neck, and 2 of unknown site. Although most cases were observed at the dermal/subcutaneous interface, 22 cases were predominantly dermal, and the rest predominantly subcutaneous, with 4 superficially involving skeletal muscle. Except for 12 predominantly dermal cases, most cases had an infiltrative growth pattern. Thirty-four cases were predominantly histiocytic, 16 predominantly fibroblastic, and the remaining 16 mixed. Two fibroblastic cases demonstrated the microfat cells (probably secondary to subcutis infiltration). All cases exhibited a plexiform growth pattern of small- to medium-sized nodules; 41 cases had giant cells, mainly osteoclast type, often the predominantly histiocytic type. The purely fibroblastic often had surrounding inflammation, 2 cases with marked inflammation. Perineural growth was observed in 5 cases, peri-Pacinian corpuscle growth in 2 cases, adnexal trapping in several, and, increased hyalinized collagen in 17 cases. Eight cases demonstrated focal myxoid change. Only 1 case, a histiocytic, had bone formation. Although increased cytologic atypia and mitotic activity were noted in a few cases, an atypical mitosis was only observed in 1 case. No cases demonstrated vascular or lymphatic invasion or necrosis. The tumors were generally positive for CD68 and SMA, occasionally for MSA, and negative for keratin, desmin, HMB45, S100 protein, and CD34. Overall, the findings were very similar to the original observations made by Dr Enzinger and his colleague, with the minor exceptions of roughly equal sex distribution (possibly due to timely referral bias), and additional morphologic features of myxoid change, adnexal sparing, increased inflammation, and microfat similar to recently described lipofibromatosis. The relationship between PFHT and cellular neurothekeoma is also explored.

Primitive neuroectodermal tumor/Ewing sarcoma (PN/ES) is a single clinical, morphologic, and molecular small round cell tumor entity. These are generally found in deep soft tissue or bone of young male patients, with poor behavior. Location in dermis is unexpected; only rare cases are reported. Cases coded as "dermal," "cutaneous," or "skin" PN/ES were retrieved from our consultation files. Only primary dermal cases were included. Those otherwise diagnosed or with incomplete material were excluded. There were 13 dermal PN/ES cases, consisting of 10 women and 3 men. Ages ranged from 2 to 67 years (mean, 28 years). Locations included groin or thigh (4), back or shoulder (3), neck (1), chest (1), scalp (1), forehead (1), hand (1), and foot (1). Most cases were small (0.5-2.3 centimeters) and painful, and persisted for less than 1 year. All were located within the dermis. Three caused pedunculation; 9 also involved superficial subcutis. All but 1 of the metastasizing tumors were round and encapsulated. All were composed of round to oval cells with a vague rosetting pattern, slightly overlapping nuclei, finely stippled chromatin, clear to eosinophilic cytoplasm, and collagenous stroma. Median mitotic activity was 8 per 10 high-power fields. Necrosis was present in three cases. All had globular periodic acid Schiff positivity and distinctive cytoplasmic membrane CD99 reactivity. One case studied was positive for Fli-1. All were negative for leukocyte common antigen, Tdt, CD3, CD20, CD79, CK20, pankeratin, epithelial membrane antigen, chromogranin, neurofilament protein, carcinoembryonic antigen, desmin, actin, diffuse S100 protein, and HMB45. Nine cases with material for reverse transcription-polymerase chain reaction revealed 1 positive type 2 translocation (EWS exon 7 to Fli-1 exon 5), 4 negative, and 4 "unable to amplify." Treatment was by wide excision; 9 received chemotherapy and 6 radiation. Follow-up of 11 (85%) cases revealed the following: 1 metastasis to stomach and death at 3 years; 10 years without disease (median, 9.0 years). Cutaneous PN/ES is a superficial round cell tumor in older women, with better prognosis than deep PN/ES. These may have a hitherto unrecognized variant genetic abnormality.

A quarter of a century ago at the International Academy of Pathology in Boston, Mass, Drs Enzinger and Shmookler's seminal abstract on giant cell fibroblastoma (GCF) included 20 GCFs on the back and thigh of mostly male children. These tumors involved dermis and subcutis, and had parallel fascicles of wavy uniform spindled cells with wiry collagen, dense sclerosis, and gaping spaces with scattered and rimming pleomorphic giant cells. EM suggested fibroblastic phenotype. All cases had benign behavior, but almost half recurred. The caveat was mistaking this tumor for a malignancy. In 1989, Drs Enzinger, Shmookler, and Weiss published this abstract as 28 cases from the AFIP (1960-1981), including 4 adults up to 55 years old. They proposed a relationship of this childhood tumor to dermatofibrosarcoma protuberans (DFSP). Since these original descriptions of GCF, there has been additional immunohistochemical and molecular support for a relationship between DFSP and GCF. We reviewed additional AFIP cases of GCF since 1981, in honor of Dr Enzinger. These new cases included 60 males and 26 females, whose ages ranged from 6 months to 62 years (median, 6 years; 62%, younger than 10 years; 77%, younger than 20 years; and only 10 patients were older than 40 years). Thirty-nine GCF cases with evaluable epidermis were observed to be protuberant, one with superficial ulceration. Most cases were dermal and subcutaneous, 3 purely dermal, and 5 involved superficial skeletal muscle. Almost all cases demonstrated a honeycomb pattern, and several, a parallel pattern of infiltration. Several cases spared adnexa. Pure GCF areas ranged from solid and collagenized to angiectoid and myxoid, the latter with small to large cystlike spaces. Most cases were relatively hypocellular, except one case with more atypia and mitotic activity. GCF demonstrated myoid whorls in 2 cases, a feature previously described in DFSP. Most remarkable is the peculiar perivascular lymphocytes in an onionskin pattern in GCF, not observed in DFSP. Furthermore, histologic intralesional hemorrhage seems to be common in GCF, particularly near the fascia. Fourteen of our 86 cases demonstrated 5% to 70% (median, 20%) dense nongiant cell storiform areas, interpreted as hybrid GCF-DFSP. Three of these cases demonstrated hypercellular DFSP. One hybrid case had fibrosarcomatous transformation. Two cases of pure GCF recurred as a hybrid tumor with DFSP areas, one of these with hypercellular DFSP. In all but one case, the DFSP was adjacent to GCF with an abrupt transition. Most cases studied were positive for CD34 (more intense in DFSP than relatively hypocellular GCF areas) and negative for smooth muscle actin, desmin, HMB-45, keratin, and S100 protein. GCF is exactly clinically and morphologically the same as Dr Enzinger and colleagues originally described it. Additional observations of marked perivascular and onionskin-like chronic inflammation and consistent hemorrhage may aid in the diagnosis of this previously well-described tumor. Collectively, we now have even more convincing morphologic, immunophenotypic, and molecular evidence that GCF is on a spectrum with DFSP.

Hemangioma is a common soft tissue tumor that frequently occurs in the oral and maxillofacial region including salivary glands, but is rarely biopsied and is therefore often unfamiliar to the surgical pathologist. Our study examined the subclassification and histologic features of salivary gland hemangioma (SGH). Consultative cases coded as hemangioma and located in salivary gland from 1970 to 2000 were retrieved from the Registry of Oral and Maxillofacial Pathology of the Armed Forces Institute of Pathology (Washington, DC). Only cases with histologic evidence of salivary gland involvement were included. Slide material and patient history for all cases were reviewed, subclassification assigned, and histologic features were noted. Ten cases coded as hemangioma with slides and history met our inclusion criteria. Seven cases were the "juvenile hemangioma" subtype in the parotid of infants, ranging in age from 3 to 10 months (mean age, 5.3 months) with a male predominance. These SGH had a distinctive histologic appearance of a cellular proliferation of capillary sized vessels around retained salivary gland ducts. Mitoses were easily identified. Three additional cases in females included an arteriovenous hemangioma of a lip minor salivary gland since birth in a 15-month-old infant and two parotid gland lesions: a lobular capillary hemangioma of a 10-year-old and a cavernous hemangioma in a 51-year-old. The latter three cases grew as replacing masses and lacked retained salivary gland ducts within the lesion, despite glandular tissue at the periphery of the tumor. No SGH cases in our series were identified in the submandibular or sublingual glands. Despite its common occurrence, SGH is relatively rare in our surgical pathology files. The parotid gland is the most common location (90%). Salivary gland hemangioma includes usual hemangioma subtypes, mainly in females, and a distinctive infantile subtype of capillary hemangioma (juvenile hemangioma), displaying distinctive histology and found predominately in males. The cellularity, mitotic activity, and retained salivary gland ducts in the latter lesion should not make one consider malignancy., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Nodular fasciitis (NF), uncommon in the auricular area, is a benign reactive myofibroblastic proliferation that may be mistaken for a neoplastic proliferation. Fifty cases of NF of the auricular region were identified in the files of the Otorhinolaryngic-Head and Neck Tumor Registry of the Armed Forces Institute of Pathology. The patients included 22 females and 28 males, aged 1 to 76 years (mean, 27.4 years). The patients usually presented clinically with a mass lesion (n = 49). Five patients recalled antecedent trauma. The lesions were dermal (n = 28) or subcutaneous (n = 11) in those cases where histologic determination was possible, measuring 1.9 cm on average. The majority of the lesions were circumscribed (n = 38), composed of spindle-shaped to stellate myofibroblasts arranged in a storiform growth pattern, juxtaposed to hypocellular myxoid tissue-culture-like areas with extravasation of erythrocytes. Dense, keloid-like collagen and occasional giant cells were seen (n = 18). Mitotic figures (without atypical forms) were readily identifiable. By immunohistochemical staining, myofibroblasts were reactive with vimentin, actins, and CD68. All patients had surgical excision. Four patients (9.3%) developed local recurrence and were alive and disease free at last follow-up. All patients with follow-up (n = 43) were alive or had died of unrelated causes, without evidence of disease an average 13.4 years after diagnosis. Nodular fasciitis of the auricular area occurs most often in young patients. Because NF is more often dermally situated than extremity NF, it may present with superficial ulceration and/or bleeding. Local recurrence is more frequent because of the difficulty in obtaining complete surgical excision around the ear.

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.

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.

Central nervous system hemangioblastomas are uncommon tumors of controversial etiology that are usually found in the posterior fossa of the cranial cavity, retina, and spinal cord. Peripheral involvement is rare; only isolated case reports have been identified. We report an unusual case of hemangioblastoma involving the retroperitoneum. A 47-year-old African-American man presented with polycythemia on routine laboratory testing. Computed tomography revealed a large retroperitoneal mass near the pancreas, in a left suprarenal location, without adrenal involvement and without attachment to a nerve. Although hemangioblastoma may be associated with the von Hippel-Lindau syndrome, this patient did not have any of the stigmata of this disease. The histologic features included a highly vascular tumor with cellular areas composed of plump, pleomorphic spindled and epithelioid (stromal) cells with variable cytoplasmic lipid vacuoles and hypocellular areas with inflammatory cells and collagenous fibrils. Immunohistochemical staining showed that the tumor (stromal) cells were positive for vimentin, calponin, S-100 protein, neuron-specific enolase, and CD57 and negative for glial fibrillary acidic protein, cytokeratins, epithelial membrane antigen, CD34, HMB-45, desmin, and the actins. These morphologic and immunohistochemical findings are consistent with hemangioblastoma. To our knowledge this is the first reported case of a hemangioblastoma in this location. Based on this case we conclude that hemangioblastoma may occur in the retroperitoneum and outside of the central nervous system in a patient without von Hippel-Lindau syndrome. The immunoprofile of this case suggests that hemangioblastomas are mesenchymal neoplasms exhibiting both neural and myofibroblastic differentiation.

Malignant fibrous histiocytoma (MFH) is one of the most common soft tissue sarcomas of adulthood. Although it is usually intramuscular and pseudocapsulated, we have recently observed MFHs with extremely infiltrative growth margins, which are predominantly located in the subcutis. These lesions are often associated with incomplete primary surgical excision, the subsequent need for additional surgery or adjuvant therapy, and an increased risk for local recurrence. To further analyze the growth pattern and clinical implication of the subcutaneous infiltrative MFHs, we reviewed a series of 24 subcutis and 21 intramuscular MFHs of the extremities. Morphologically, we defined "infiltrative" as tumor extension along normal tissue planes for a minimum measurable distance of 2 mm from the edge of the main mass. Radiographic findings were correlated with pathologic findings. Of the 24 subcutis MFHs, 83% showed an infiltrative growth pattern, involving 5% to 90% (mean, 51%) of the evaluable margin. Fifty percent of patients with subcutaneous MFH had both an infiltrative growth pattern and positive surgical resection margin on initial resection. Only 25% noninfiltrative subcutaneous MFHs had a positive initial surgical resection margin. Of the 21 intramuscular MFHs, only 5 (24%) had an infiltrative growth pattern that involved 5% to 90% (mean, 40%) of the evaluable margin. One of the five tumors had 90% margin infiltration with multiple positive surgical resection margins. Of 16 noninfiltrative intramuscular MFHs, 3 (19%) had positive resection margins. Magnetic resonance imaging (MRI) and/or computed tomography (CT) scan correctly identified the growth pattern in 87% of subcutaneous and 88% of intramuscular MFHs. Patient follow-up evaluation showed that four (17%) patients with subcutaneous MFHs had resection-proven recurrences, 6 to 57 months after diagnosis. All four of these tumors had infiltrative growth patterns and positive margins on the original surgical resection. There were no local recurrences of the intramuscular MFHs. Two patients of 20 in the infiltrative subcutaneous MFH group and two patients of four in the well-circumscribed subcutaneous MFH group had biopsy-proven metastases, which developed within 5 years after diagnosis. Six patients had metastases in the intramuscular MFH group. A group of MFHs, predominantly subcutaneous, have an extremely infiltrative growth pattern. This growth pattern, documented by radiographic methods and/or light microscopic examination of biopsy specimens, should indicate that a wider margin on initial resection is necessary to entirely excise the lesion. The presence or absence of an infiltrative growth pattern is not predictive of the tumor's metastatic potential.

Rhabdoid tumor is a well-accepted clincopathologic entity among childhood renal neoplasms; similar tumors have been described in extrarenal locations. We present the clinicopathologic profile and the immunohistochemical features of a series of soft tissue rhabdoid tumors. Twenty-eight cases coded as extrarenal rhabdoid tumor (ERRT), RT, possible ERRT, and "large cell sarcoma" were retrieved from the Armed Forces Institute of Pathology soft tissue registry. The tumors were reclassified according to strict criteria by light microscopy, clinical information, immunohistochemistry, and, in some cases, electron microscopy. Soft tissue rhabdoid tumor (STRT) was defined as (1) a tumor composed of noncohesive single cells, clusters, or sheets of large tumor cells with abundant glassy eosinophilic cytoplasm, an eccentric vesicular nucleus, and an extremely large nucleolus; (2) positivity for vimentin and/or cytokeratin or other epithelial markers by immunostaining; and (3) exclusion of other tumor types with rhabdoid inclusions (melanoma, other sarcomas, carcinoma). Eighteen cases met our criteria for soft tissue rhabdoid tumors. The median patient age was 13 years (range, 6 months to 56 years). Ninety-four percent of STRT cases were positive for vimentin and 59% for pan-cytokeratin. Sixty-three percent and 60% were positive for CAM 5.2 and EMA, respectively. Seventy-nine percent stained for at least one epithelial marker; 76% stained for both vimentin and epithelial markers simultaneously. Forty-two percent stained for MSA, and 14% for CEA and SMA. CD99, synaptophysin, CD57 (Leu-7), NSE, and focal S100 protein were identified in 75%, 66%, 56%, 54%, and 31% of the STRT cases, respectively. All STRT cases examined were negative for HMB-45, chromogranin, BER-EP4, desmin, myoglobin, CD34, and GFAP. Follow-up examination in 61% of the STRT patients revealed that 64% of patients died of disease within a median follow-up interval of 19 months (range, 4 months to 5 years); 82% had metastases to lung, lymph nodes, or liver; 22% had local recurrences before metastasis; and 18% were alive without known disease status (median, 5.5 years). Soft tissue rhabdoid tumor is a highly aggressive sarcoma, predominantly of childhood. Besides having nearly consistent coexpression of vimentin and epithelial markers, STRTs show positivity for multiple neural/neuroectodermal markers that overlap with those of primitive neuroectodermal tumor.