FUS rearrangements are rare in 'pure' sclerosing epithelioid fibrosarcoma.

Several recent reports have described low-grade fibromyxoid sarcoma with sclerosing epithelioid fibrosarcoma-like areas. We evaluated cases of pure sclerosing epithelioid fibrosarcoma lacking areas of low-grade fibromyxoid sarcoma for FUS rearrangement to determine whether this entity could be related to low-grade fibromyxoid sarcoma. Available formalin-fixed paraffin-embedded tissue of 27 sclerosing epithelioid fibrosarcoma from 25 patients was retrieved and tabulated with clinical information. Unstained slides from formalin-fixed paraffin-embedded blocks were prepared and fluorescence in-situ hybridization was performed using a commercial FUS break-apart probe. The median patient age at presentation was 50 (range, 14-78) years, with 14 males and 10 females. Sclerosing epithelioid fibrosarcoma most commonly involved the extremities (n=8) or chest (n=6). Sixteen patients had a median follow-up of 17 (range, 1-99) months; seven were alive and well at 12 (range, 5-30) months; three alive with disease at 28 (range, 9-99) months; five dead of disease at a median of 22 (range, 1-36) months and one was dead of unknown causes. Twelve patients were known to have metastases; the most common site was lung (n=7), followed by bone (n=3), lymph nodes (n=2) and peritoneum (n=1). Only 2 of 22 (9%) analyzable cases of sclerosing epithelioid fibrosarcoma showed rearrangement in the FUS locus by fluorescence in-situ hybridization. Although cytogenetically confirmed low-grade fibromyxoid sarcoma can have sclerosing epithelioid fibrosarcoma-like areas, FUS rearrangement, which is characteristic of low-grade fibromyxoid sarcoma, appears to be relatively rare in pure sclerosing epithelioid fibrosarcoma.

Dermatofibrosarcoma protuberans with unusual sarcomatous transformation: a series of 4 cases with molecular confirmation.

Dermatofibrosarcoma protuberans (DFSP) is a superficial sarcoma of intermediate malignancy usually composed of monotonous short spindle cells with storiform architecture. The tumor cells are diffusely reactive for CD34 and characterized by a translocation involving chromosomes 17 and 22 or a supernumerary ring chromosome that results in the fusion of exon 2 of platelet-derived growth factor beta (PDGFß; 22q13) to various exons of collagen type 1 alpha 1 (COL1A1; 17q22). In some tumors, fibrosarcomatous transformation can occur and is characterized by a monotonous spindle cell proliferation arranged in fascicles or a herringbone-type pattern. We report 4 DFSPs with unusual and pleomorphic sarcomatous transformation. They occurred on the back, scalp, shoulder, and forehead of women (ages 31,48, 48, and 27 year). In addition to areas of conventional DFSP that strongly expressed CD34, 2 cases showed pleomorphic areas mimicking undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma: 1 case had a patternless area and 1 case had combined round/spindled cells with myxoid areas. Reverse transcription--polymerase chain reaction was performed in 1 case, confirming the presence of a COL1A1-PDGFß fusion transcript. The remaining three cases were found to be positive for a PDGFß gene rearrangement by fluorescence in situ hybridization. This series illustrates that sarcomatous transformation in DFSP may occasionally display areas, which can mimic undifferentiated pleomorphic or unclassified sarcoma. Ancillary diagnostic testing may be helpful to confirm the diagnosis, especially in small biopsies.

Atypical lipomatous tumor, its variants, and its combined forms: a study of 61 cases, with a minimum follow-up of 10 years.

Sixty-one cases of neoplasms composed wholly or in part of atypical lipomatous tumor were reviewed. Minimum follow-up was 10 years. The cases were divided into 4 groups based on the findings in the initial excision specimen: conventional atypical lipomatous tumor (n=15), cellular atypical lipomatous tumor (n=21), dedifferentiated liposarcoma (n=24), and atypical lipomatous tumor with a pleomorphic liposarcoma-like component (n=1). The term "cellular atypical lipomatous tumor" was applied to atypical lipomatous tumors having areas of increased cellularity that when non-lipogenic lacked the 5 mitotic figures per 10 high-power fields (maximal rate) required for a dedifferentiated component and when lipogenic fell short of being truly pleomorphic liposarcoma-like. Myxoid regions within this spectrum sometimes had prominent or even plexiform vascularity, creating a resemblance to myxoid liposarcoma especially when interspersed small fat cells were present. The most important prognostic factor was tumor location, as none of the 12 patients with a subcutaneous or intramuscular neoplasm died of tumor. Among the 49 patients with neoplasms of central body sites (mostly retroperitoneum), those with dedifferentiated liposarcoma had significantly shorter survival (median 77 mo) than those with cellular (median 142 mo) or conventional (median 209 mo) atypical lipomatous tumor, whereas there was no statistically significant difference between the latter 2 categories. Patients with atypical lipomatous tumor (either cellular or conventional) in central body sites had significantly shorter survival if the tumor transformed into dedifferentiated liposarcoma in recurrence, and, conversely, those with central body site dedifferentiated liposarcoma had significantly longer survival if it recurred as atypical lipomatous tumor. Metastasis (7 cases) occurred only when the initial specimen or a recurrence demonstrated dedifferentiated liposarcoma.

Malignant Solitary Fibrous Tumor of the Pancreas.

Solitary fibrous tumor (SFT) arising in the pancreas is exceedingly rare, with only 11 cases reported in the English literature. All cases described thus far have exhibited benign histology. We report the first case of malignant SFT of the pancreas. The patient was a 52-year-old woman who presented with obstructive jaundice and a 15-cm pancreatic head mass. The mass showed areas with typical histologic features for SFT including small fibroblastlike cells arranged in the well-characterized "patternless pattern" of architecture, hemangiopericytomalike vessels, areas with dense collagen and infrequent mitoses (0-2 per 10 high-power fields [HPFs]). In addition, multiple areas with an overtly sarcomatous morphology were present, containing large spindle and epithelioid cells with nuclear pleomorphism, marked cellularity, up to17 mitoses per 10 HPFs, and necrosis. Immunohistochemical stains were positive for CD34 and B-cell CLL/lymphoma 2 (Bcl-2) in both benign and malignant components and showed strong, diffuse p53 and p16 staining in the malignant component. At last follow-up (40 months), the patient was alive and well without evidence of disease. However, given that the presence of a malignant component in extrapancreatic SFT has been associated with recurrence/metastasis and death, complete surgical resection and close long-term follow-up is required.

Multinucleated giant cells in plantar fibromatosis.

Specimens from 13 patients with plantar fibromatosis were reviewed with particular attention to the presence and number of multinucleated giant cells in the lesions. These were found in all specimens but one and ranged from very few to many. The nuclei of the giant cells were uniform, rounded to somewhat elongated, and arranged in circles, semicircles, ovals, clusters, chains, and V's. Aside from the giant cells, the lesions were composed of the usual uniform fibroblastic spindle cells. The growth pattern was almost always multinodular, with nodules having moderate to high cellularity. Maximal mitotic rate varied up to more than 10 mitotic figures per 10 high-power fields but was most often between 1 and 4 mitotic figures per 10 high-power fields. The patients were from 10 to 66 years of age; nine were male and four were female. Two had bilateral involvement. Five patients had recurrence, including three with multiple recurrences, and all but one of the remainder had only short follow-up. Judging from the available data, recurrence did not appear to be related to any specific clinical or pathologic feature.

Intraparenchymal nevus cell aggregates in lymph nodes: a possible diagnostic pitfall with malignant melanoma and carcinoma.

It is well documented that nevus cells can be found within the fibrous capsule and trabeculae of lymph nodes; however, it is less well known that nevus cells can also be found in the lymph node parenchyma. We report the findings in 13 cases of nevus cell aggregates located within the cortical and/or medullary parenchyma of lymph nodes. Seven of the 13 patients had a primary diagnosis of melanoma, three had no known malignancy, one had breast carcinoma, one had adnexal carcinoma of the skin, and one had squamous cell carcinoma of the tonsil. Of the seven patients with melanoma, four had axillary lymph node dissections and three had inguinal lymph node dissections. The patient with adnexal carcinoma had metastatic carcinoma in 14 of 20 lymph nodes that had been dissected; one of them also had intraparenchymal nevus cells. The patient with squamous cell carcinoma of the tonsil had an intraparenchymal nevus cell aggregate in one of the 21 dissected lymph nodes; all 21 were negative for carcinoma. Nests of intraparenchymal nevus cells ranged from clusters of only a few cells up to 2.1-mm aggregates. No mitotic figures, prominent nucleoli, or lymphatic-vascular invasion were detected in any of the melanocytic aggregates. The melanocytic cells of the nevus cell aggregates expressed S-100 protein and/or MART-1 but not gp100 protein (HMB-45). Less than 1% of the nevus cells expressed Ki-67. The purpose of this study was to draw attention to the finding of nevus cells in the parenchyma of lymph nodes and to alert pathologists to this as a potential diagnostic pitfall, especially in patients with concurrent melanoma or carcinoma. Awareness that nevus cells can be present in nodal parenchyma, analysis of their morphologic features (including comparison with any previous or existing melanoma or carcinoma), and immunophenotyping will help pathologists to establish the correct diagnosis in most instances.

Vascular tumors of bone: A study of 17 cases other than ordinary hemangioma, with an evaluation of the relationship of hemangioendothelioma of bone to epithelioid hemangioma, epithelioid hemangioendothelioma, and high-grade angiosarcoma.

Cases filed as vascular tumor of bone other than ordinary hemangioma were reviewed. They were included in the study if there was adequate histologic material and clinical information, clear evidence of bone origin, and at least 5 years follow-up. The study group comprised 17 cases, of which 13 were categorized as hemangioendothelioma of bone, 1 as epithelioid hemangioendothelioma, and 3 as high-grade angiosarcoma. Hemangioendothelioma of bone had growth patterns varying from vasoformative to solid, but well-formed vessels were present in at least some area in all cases. The cells generally had a rounded, epithelioid character, regular nuclei, and relatively few mitotic figures; occasional features included spindle cells and scattered enlarged, hyperchromatic or pleomorphic nuclei. Lymphoplasmacytic and eosinophilic inflammatory infiltrate ranged from prominent to slight or absent, and myxoid or hyaline stroma was never more than focal. Epithelioid hemangioma could not be separated from hemangioendothelioma of bone. The single epithelioid hemangioendothelioma for the most part had cords of relatively uniform epithelioid cells in a prominent myxoid stroma but focally demonstrated an angiosarcoma-like appearance, with irregular vascular spaces and marked nuclear pleomorphism. The high-grade angiosarcomas exhibited predominantly irregular vasoformation combined with solid areas, diffuse nuclear hyperchromatism and pleomorphism, and, in 2 cases, numerous mitotic figures (the third case had only a small biopsy and a postradiation amputation specimen). Of the hemangioendotheliomas of bone, 7 were unicentric and 6 were regionally multicentric either concurrently or sequentially. Three patients had intraosseous local recurrence, 2 had discontinuous regional skin or soft tissue involvement (including the popliteal artery in 1), and 1 had a solitary lung metastasis, but none died of tumor. The patient with epithelioid hemangioendothelioma had multicentric tumors in widely separated bones and died with liver and lung metastases. Two of the high-grade angiosarcomas were unicentric, and the third was regionally multicentric, with a popliteal artery-soft tissue component as well. All 3 of these patients died with metastases in various sites.

Sporadic superficial diffuse neurofibromas with repeated local recurrence over many years and a tendency toward malignant change: a report of 3 cases.

Sporadic superficial (cutaneous/subcutaneous) neurofibromas are normally small tumors that do not recur after excision or undergo malignant change. In contrast to this, I have encountered 3 cases in which a solitary sporadic superficial diffuse neurofibroma was large, recurred locally on multiple occasions extending over 30 years, and exhibited malignant change at least once. The first patient was a 44-year-old black woman who had a superficial diffuse neurofibroma with a focus of epithelioid malignant peripheral nerve sheath tumor (MPNST) excised from her left upper arm. The tumor recurred locally 14 times over a period of 38½ years; most specimens demonstrated only neurofibroma, but the 11th and 14th recurrences also had areas of epithelioid MPNST (extensive in the latter recurrence). There was no follow-up information after the last recurrence was excised except that the patient died of an unknown cause 3 years later. The second patient was a 39-year-old white woman who had a superficial neurofibroma excised from her scalp. A local recurrence was excised 30 years later and demonstrated a small focus of spindle cell MPNST in addition to neurofibroma. There were 6 further recurrences over the ensuing 14 years, of which the last 3 had components of spindle cell MPNST that extended into the skull bone and skeletal muscle. For these, radiotherapy was performed in addition to excision, and the patient had no evidence of tumor when last seen 1 year after the last recurrence was excised (she died 2 mo later of an unknown and presumably incidental cause). The third patient was a 28-year-old black woman who had a mass excised from her back that she was told was benign. A local recurrence was excised from the same area about 10 years later, again with a benign diagnosis (no details were available about these 2 specimens). Another recurrence was excised 36 years after the original excision; this demonstrated an extensive superficial diffuse neurofibroma with at least 2 small foci of spindle cell MPNST. A further recurrence was excised slightly >1 year later and showed superficial diffuse neurofibroma with some cellular areas but no definite MPNST. The patient was lost to follow-up after this. In addition to their diffuse infiltrative nature, a distinctive finding in the neurofibromas in all 3 cases was the presence of a focal to patchy lymphocytic chronic inflammatory infiltrate. Despite the difference in the character of the MPNST components (epithelioid in the first case, spindle cell in the other 2), the cases had sufficient histologic and clinical similarities to suggest that they represent a distinctive type of superficial neurofibroma.

Low-grade fibromyxoid sarcoma: a clinicopathologic study of 33 cases with long-term follow-up.

Cases listed in the U.T.M.D Anderson Cancer Center files as low-grade fibromyxoid sarcoma and originally diagnosed before 2004 were reviewed. They were included in the study if the diagnosis was confirmed and if there was adequate histologic material and clinical information with at least 5 years of follow-up. Thirty-three cases met the study criteria. The patients were 6 to 52 years old at the time of diagnosis (median, 29 y); 19 were male and 14 were female. The most common tumor locations were the shoulder area (5), thigh (5), and inguinal area (4). Tumor size varied from 1.5 to 16 cm (median, 9.4 cm) in those cases in which it was known. The typical histologic findings were contrasting fibrous and myxoid areas, moderate to low cellularity, bland-appearing spindle cells with no or slight nuclear pleomorphism and rare mitotic figures, and a swirling, whorled growth pattern. Prominent vascularity in myxoid areas and perivascular hypercellularity were fairly common, whereas larger hypercellular zones were sometimes seen in primary tumors but were more frequent in recurrences (local) and metastases. Hypercellular regions sometimes had round rather than spindle cells, a diffuse sheet-like cell arrangement, and/or a somewhat increased mitotic rate. Very hypocellular fibrotic areas were also observed and sometimes had thick collagen bundles. Pericollagenous rosettes were present in 6 cases but not in all specimens from these. Other growth pattern variations included storiform, fascicular-herringbone, and patternless areas; uncommonly noted were cell clusters, strands, palisades, and a retiform network. Additional unusual features were moderate nuclear pleomorphism (seen mostly in recurrent and metastatic tumors), cysts, osseous metaplasia, and a tigroid pattern with alternating fibrous and myxoid strips. One patient had a recurrence with features of sclerosing epithelioid fibrosarcoma, whereas 2 had dedifferentiated recurrences with anaplastic predominantly round cells and numerous mitotic figures. Fourteen patients died of tumor after 3 (this patient's tumor became dedifferentiated) to 42 years (median, 15 y). Nineteen patients were alive at last follow-up of 5½ to 70 years (median, 13 y), 6 with tumor and 13 without. Twenty-one patients had recurrence after intervals of up to 15 years (median, 3½ y), and 15 had metastases (mostly in the lungs and pleura) after periods of up to 45 years (median, 5 y). Except for dedifferentiation, which led to short survival after it occurred, histologic differences were not related to tumor behavior or patient survival. The 4 patients whose neoplasms measured <3.5 cm were all tumor free at last follow-up.

Multiple squamous cell carcinomas of the skin after therapy with sorafenib combined with tipifarnib.

BACKGROUND: Keratoacanthomas, as well as an actinic keratosis progressing to squamous cell cancer, have been reported in patients who were treated with sorafenib, a multikinase inhibitor known to suppress the actions of Raf kinase and vascular endothelial growth factor receptor. OBSERVATIONS: We describe a 70-year-old white woman with metastatic renal cell carcinoma who was treated with a combination of sorafenib and tipifarnib (a farnesyltransferase inhibitor). She had no history of skin cancer. However, within 3 months after starting this therapy, she developed 3 erythematous nodules on her legs. Pathologic examination showed deeply invasive, well-differentiated squamous cell carcinomas. The tumors were excised, and sorafenib-tipifarnib treatment was discontinued. No new lesions have developed to date. CONCLUSIONS: Targeted agents, such as sorafenib and tipifarnib, are increasingly being used in the management of visceral malignant neoplasms. A temporal relationship was observed between the initiation of the targeted treatments and the emergence of these cutaneous cancers. Further study of the mechanisms responsible for the rapid appearance of squamous cell cancers in this setting may provide insights into the pathogenesis of skin tumors.

Prognostic factors for patients with localized soft-tissue sarcoma treated with conservation surgery and radiation therapy: an analysis of 1225 patients.

BACKGROUND: Prognostic factors for patients with soft-tissue sarcoma who are treated with conservative surgery and radiation are documented poorly. METHODS: The clinicopathologic features and disease outcome for 1225 patients with localized sarcoma who were treated with conservative surgery and radiation were reviewed retrospectively. Actuarial univariate and multivariate statistical methods were used to determine significant prognostic factors for local control, metastatic recurrence, and disease specific survival. RESULTS: The median follow-up of surviving patients was 9.5 years. The respective local control rates at 5 years, 10 years, and 15 years were 83%, 80%, and 79%. Factors predictive of local recurrence were positive or uncertain resection margins; tumors located in the head and neck and the deep trunk; presentation with local recurrence; patient age > 64 years; malignant fibrous histiocytoma, neurogenic sarcoma. or epithelioid sarcoma histopathology; tumor measuring > 10 cm in greatest dimension; and high pathologic grade. Freedom from metastasis at 5 years, 10 years, and 15 years was 71%, 68%, and 66%, respectively. Factors that were predictive of metastatic recurrence were high tumor grade; large tumor size (> 5 cm); and leiomyosarcoma, rhabdomyosarcoma, synovial sarcoma, or epithelioid sarcoma. The respective disease specific survival rates at 5 years, 10 years, and 15 years were 73%, 68%, and 65%. Adverse factors for disease specific survival were high tumor grade; large tumor size (> 5 cm); tumors located in the head and neck and deep trunk; rhabdomyosarcoma, epithelioid sarcoma, or clear cell sarcoma; patient age > 64 years; and positive or uncertain resection margins. CONCLUSIONS: Soft-tissue sarcoma comprises a heterogeneous group of diseases. Prognostic factors for local recurrence, metastatic recurrence, lymph node recurrence, disease free survival, and disease specific survival are different, and optimal treatment strategies need to take this complexity into account.