Unique case of a GLI1 amplified biphasic mesenchymal tumor of the orbit.

GLI1-altered mesenchymal tumors are an emerging entity in soft tissue pathology. In the head and neck region, they are most commonly in the tongue. Limited published data indicate a propensity for local recurrence, regional spread, and distant metastasis in both GLI1-rearranged and GLI1-amplified tumors. The purpose of this report is to present the rare case of a GLI1-amplified spindle cell tumor of the orbit and a focused review of the literature. A 54-year-old woman presented with proptosis, eye pain, and ocular motility restriction in the left eye. Imaging demonstrated a tumor occupying the superomedial intraconal orbit that was distinct from the extraocular muscles, optic nerve, and globe. The tumor was totally resected with a combined open transorbital and endoscopic, endonasal approach. Pathological analysis demonstrated a spindled and epithelioid mesenchymal tumor with diffuse nuclear GLI1 expression. PCR-based, next*-generation sarcoma fusion panel was negative for GLI1 fusions, including GLI1::ACTB fusions; however, DDIT3 breaks apart fluorescence in situ hybridization (FISH), which can be used as a surrogate for GLI1 alterations due to proximity to 12q13.3, showing amplification. Post-operatively, the patient had recovered visual acuity. She received adjuvant radiation therapy (60 Gy in 30 fractions). Surveillance for recurrence, regional spread, and distant metastasis has been negative at a 6-month follow-up. Ultimately, we report the first case of a GLI1-amplified mesenchymal neoplasm of the intraconal orbit managed with gross total resection via a combined approach followed by adjuvant radiation therapy.

A derived neutrophil to lymphocyte ratio predicts survival in patients with cancer.

BACKGROUND: The neutrophil lymphocyte ratio (NLR) has prognostic value in patients with a variety of cancers. Many chemotherapeutic trial databases hold information on white cell and neutrophil counts only. The aim of the present study was to compare the prognostic value of the NLR with a derived score (dNLR), composed of white cell and neutrophil counts. METHODS: Patients (n=27,031) who were sampled incidentally between 2000 and 2007 for neutrophil, lymphocyte and white cell counts, and also had a diagnosis of cancer (Scottish Cancer Registry), were identified. Of this group, 12,118 patients who had been sampled within 2 years of their cancer diagnosis were studied. RESULTS: On follow-up, there were 7366 deaths, of which 6198 (84%) were cancer deaths. The median time from blood sampling to diagnosis was 2.1 months. The area under the receiver-operating characteristic (ROC) curve for cancer-specific survival was 0.650 for the NLR and 0.640 for the dNLR. The NLR and dNLR were independently associated with survival in all cancers studied (all P<0.001). The optimal thresholds, on the basis of hazard ratios and area under the curve, were 4 : 1 for the NLR and 2 : 1 for the dNLR. CONCLUSION: The results of the present study show that the dNLR has similar prognostic value to the NLR. Therefore, the universally available dNLR is to be commended for use in the risk stratification of patients undergoing chemotherapy.

Epithelioid hemangioendothelioma, an ultra-rare cancer: a consensus paper from the community of experts.

Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication.

KIT oncoprotein interactions in gastrointestinal stromal tumors: therapeutic relevance.

Most gastrointestinal stromal tumors (GISTs) express oncogenic and constitutively active forms of the KIT or platelet-derived growth factor receptor alpha (PDGFRA) receptor tyrosine kinase proteins, and these kinase oncoproteins serve as targets for effective therapies. Given that mutant KIT oncoproteins serve crucial transforming roles in GISTs, we evaluated interactions with the KIT oncoproteins and determined signaling pathways that are dependent on KIT oncogenic activation in GISTs. Tyrosine-phosphorylated KIT oncoproteins interacted with PDGFRA, PDGFRB, phosphatidylinositol 3-kinase (PI3-K) and PKCtheta in GIST cells, and these interactions were abolished by KIT inhibition with imatinib or PKC412 or KIT RNAi. Notably, tyrosine-phosphorylated PDGFRA was prominent in frozen GIST tumors expressing KIT oncoproteins, suggesting that KIT-mediated PDGFRA phosphorylation is an efficient and biologically consequential mechanism in GISTs. Activated signaling intermediates were identified by immunoaffinity purification of tyrosine-phosphorylated proteins in GIST cells before and after treatment with KIT inhibitors, and these analyses show that GRB2, SHC, CBL and MAPK activation are largely KIT dependent in GISTs, whereas PI3-K, STAT1 and STAT3 activation are partially KIT dependent. In addition, we found that phosphorylation of several tyrosine kinase proteins - including JAK1 and EPHA4 - did not depend on KIT activation. Likewise, paxillin activation was independent of the KIT oncogenic signal. These studies identify signaling pathways that can provide both KIT-dependent and KIT-independent therapeutic synergies in GIST, and thereby highlight clinical strategies that might consolidate GIST therapeutic response to KIT/PDGFRA inhibition.

Translocation t(12;16)(q13;p11) in myxoid liposarcoma and round cell liposarcoma: molecular and cytogenetic analysis.

Translocation t(12;16)(q13;p11) is regarded as a diagnostic marker for myxoid liposarcoma. Cytogenetic data on round cell liposarcomas and combined myxoid and round cell tumors is scarce, and the genetic basis of progression of myxoid tumors to high grade, round cell lesions is unknown. We have accumulated six round cell, four combined myxoid and round cell, and three myxoid liposarcomas for analysis. t(12;16)(q13;p11) was present in three round cell lesions and was detectable in all of the tumors by DNA analysis. In each tumor type, the CHOP gene in 12q13 was rearranged and fused to the TLS gene in 16p11. A variant TLS-CHOP RNA transcript was detected by polymerase chain reaction but did not correlate with clinicopathological data. No distinguishing cytogenetic or molecular markers for round cell or mixed lesions were found. The histogenic and genetic relatedness of myxoid and round cell liposarcomas is apparent from these data.

KIT activation is a ubiquitous feature of gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, and they are generally resistant to chemotherapy and radiation therapy. Most GISTs express the KIT receptor tyrosine kinase protein, and a subset of GISTs contain activating mutations within the KIT juxtamembrane region. We evaluated 48 GISTs, including 10 benign, 10 borderline, and 28 malignant cases, to determine whether KIT expression and activation are general properties of these tumors. Immunohistochemical KIT expression was demonstrated in each case. Somatic KIT mutations were found in 44 tumors (92%), of which 34 (71%) had juxtamembrane region mutations. Other GISTs had KIT mutations in the extracellular region (n = 6) and in two different regions in the tyrosine kinase domain (n = 4). Contrary to previous reports, KIT mutations were not identified preferentially in higher-grade tumors: indeed, they were found in each of 10 histologically benign GISTs. Notably, mutations in all KIT domains were associated with high-level KIT activation/phosphorylation, and KIT activation was also demonstrated in the four GISTs that lacked detectable KIT genomic and cDNA mutations. These studies underscore the role of KIT activation in GIST pathogenesis, and they suggest that activated KIT might represent a universal therapeutic target in GISTs.

STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications.

Mutations in the c-KIT receptor occur somatically in many sporadic Gastrointestinal Stromal Tumors (GIST), and similar mutations have been identified at the germline level in kindreds with multiple GISTs. These mutations activate the tyrosine kinase activity of c-KIT and induce constitutive signaling. To investigate the function of activated c-KIT in GIST, we established a human GIST cell line, GIST882, which expresses an activating KIT mutation (K642E) in the first part of the cytoplasmic split tyrosine kinase domain. Notably, the K642E substitution is encoded by a homozygous exon 13 missense mutation, and, therefore, GIST882 cells do not express native KIT. GIST882 c-KIT protein is constitutively tyrosine phosphorylated, but tyrosine phosphorylation was rapidly and completely abolished after incubating the cells with the selective tyrosine kinase inhibitor STI571. Furthermore, GIST882 cells evidenced decreased proliferation and the onset of apoptotic cell death after prolonged incubation with STI571. Similar results were obtained after administering STI571 to a primary GIST cell culture that expressed a c-KIT exon 11 juxtamembrane mutation (K558NP). These cell-culture-based studies support an important role for c-KIT signaling in GIST and suggest therapeutic potential for STI571 in patients afflicted by this chemoresistant tumor.

Mutation of the p53 gene in human soft tissue sarcomas: association with abnormalities of the RB1 gene.

Soft tissue sarcomas have been examined for alterations in the p53 gene. In six sarcomas, loss or rearrangement of both alleles of this gene was detected while in a further seven sarcomas, point mutation or absence of transcription of the p53 gene was observed. Abnormalities of the p53 gene were found in several classes of soft tissue sarcoma, including leiomyosarcomas, rhabdomyosarcomas and malignant fibrous histiocytomas. Our studies also show that abnormalities of the RB1 suppressor gene and of the p53 gene frequently occur together. These results are consistent with the idea that the p53 gene is a tumour suppressor gene and indicate that coincident inactivation of more than one tumour suppressor gene may, in some cases, be required for tumour development.

Clinicopathologic re-evaluation of 100 malignant fibrous histiocytomas: prognostic relevance of subclassification.

PURPOSE: Malignant fibrous histiocytoma (MFH) has been regarded as the most common soft tissue sarcoma (STS) in adults. Yet its true nature and the validity of this diagnostic concept have increasingly been questioned. Available data suggest that most patients with MFH can be subclassified into specific STS types, but the clinical relevance of such categorization has been argued. In a retrospective study, we reclassified 100 tumors of the extremity and trunk wall primarily diagnosed as MFH and analyzed the outcome. PATIENTS AND METHODS: Patients were adults (median age, 70 years; range, 32 to 94 years). The median tumor size was 8 cm (range, 1 to 30 cm), and the thigh was the most common tumor location (n = 31). Median follow-up was 8 years (range, 3 to 16 years). The overall 5-year metastasis-free survival rate was 0.64. The tumors were reanalyzed histologically, immunohistochemically, and, where available, ultrastructurally, and were classified according to strict diagnostic criteria. Patients were staged according to the American Joint Committee on Cancer system, and prognoses were compared among different groups of the reclassified diagnoses, paying special attention to myogenic tumors. RESULTS: In 84 of 100 tumors, a specific line of differentiation was either proved or strongly suggested. The most common diagnoses were myxofibrosarcoma (n = 22) and leiomyosarcoma (n = 20). Overall, 30 tumors could be grouped as some form of myogenic sarcoma. These tumors had a worse prognosis, even within the same American Joint Committee on Cancer stage, and a shorter time to metastasis than nonmyogenic tumors. CONCLUSION: This retrospective study confirms that most so-called MFH can be subclassified by defined criteria; it provides evidence that such classification is clinically important. Specifically, pleomorphic STS showing myogenic differentiation are significantly more aggressive, a finding that allows planning future therapeutic trials.

Long-term outcomes after function-sparing surgery without radiotherapy for soft tissue sarcoma of the extremities and trunk.

PURPOSE: To define the rate of local recurrence (LR) and identify prognostic factors for LR for patients with soft tissue sarcoma (STS) treated with function-sparing surgery (FSS) without radiotherapy (RT). PATIENTS AND METHODS: Between 1970 and 1994, 242 patients with STS of the trunk and extremity presented with primary localized disease, 74 of whom were treated with FSS without RT (31%). The median tumor size was 4 cm (range, 0.5 to 31 cm). There were 40 patients with grade 1 tumors and 34 with grade 2 and 3 tumors. Median follow-up was 126 months. RESULTS: The 10-year actuarial local control rate was 93% +/- 4%. Resection margin status was a significant predictor for LR. Patients with closest histologic resection margins of less than 1 cm had a 10-year local control rate of 87% +/- 6% compared with 100% for patients with closest histologic resection margins of >/= 1 cm (P =.04). There was no significant association between LR and tumor grade, size, site (truncal v extremity), or depth (superficial v deep). For all patients, the 10-year actuarial survival rate was 73% +/- 6%. CONCLUSION: The 7% LR rate after treatment of STS with FSS without RT reported herein is comparable to published rates following treatment where adjuvant RT is used. These results suggest there may be a select subset of patients with STS in whom carefully performed FSS may serve as definitive therapy and in whom adjuvant RT may not be necessary. However, further study is needed to carefully define this subset of patients and to identify the optimal surgical approach and technique for patients treated without RT.

Prognostic information in soft tissue sarcoma using tumour size, vascular invasion and microscopic tumour necrosis-the SIN-system.

We have earlier devised a system for soft tissue sarcoma (STS), based on three negative prognostic features: large tumour size, vascular invasion, and microscopic tumour necrosis, the SIN-system. Tumours which exhibit 2 or 3 of these features are categorised as high-risk, the others as low-risk. We have now tested this system for reproducibility both as regards recognition of its components, and as regards prognostic strength in patients from another institution. We have also compared it with the American Joint Committee on Cancer (AJCC) system. 200 patients with STS were analysed, all had been treated by surgery, in 97 patients combined with radiotherapy. The median follow-up for the 117 survivors was 10 (1.5-27) years. Without knowledge of the clinical data, three groups of pathologists independently reviewed original slides from all of the tumours. Based on the factors, the tumours were classified as high-risk or low-risk. The prognostic strength was compared using the results obtained by the different observers. Concordance in recognition of vascular invasion, tumour necrosis, and overall grading was seen in 156 (78%), 154 (77%), and 167 (84%) of the 200 tumours, respectively. Based on the different observers' grading, the cumulative 5-year metastasis-free survival rate (MFSR) varied for patients with low-risk tumours between 0.85 and 0.80, and for patients with high-risk tumours between 0.48 and 0.43. The Kappa-value for grading between all three groups of observers was 0.77. The SIN-system gave more clinically useful prognostic information than the AJCC system. Useful prognostic information in STS can be obtained by using tumour size, vascular invasion and microscopic tumour necrosis. This system provides two distinct prognostic groups, and has a high reproducibility.

Effects of postmenopausal hormone replacement therapy on lipoproteins including lipoprotein(a) and LDL subfractions.

The purpose of this study was to examine the effects on lipoprotein risk markers for CHD of oestradiol given alone and in combination with the androgenic progestogen, norethisterone. Eighty postmenopausal women were randomly allocated to receive oestradiol (2 mg/day) alone or with continuous norethisterone (1 mg/day). Serum lipoprotein levels, including lipoprotein(a), were monitored during 12 months on treatment in all the women, and in a sub-set of 32 patients cholesterol was measured in the two major density subfractions of LDL. Oestradiol caused a transient rise in triglycerides, a small decrease in LDL cholesterol (significant only at 3 and 6 months, P < 0.05) and a consistent significant increase in HDL cholesterol (16%, P < 0.01). There was a downward trend in lipoprotein(a) levels which did not achieve statistical significance. The combined preparation caused significant, sustained decreases in triglycerides (31%, P < 0.01), total cholesterol (15%, P < 0.001), VLDL (42%, P < 0.01), LDL (9%, P < 0.05) and HDL (11%, P < 0.001). Lipoprotein(a) was also reduced (39%, P < 0.05). In the sub-set of patients in which LDL subfractions were measured, the reduction in LDL induced by oestradiol monotherapy was significant only at the 3-month visit (6%, P < 0.05). This was due to a decrease in the 'light' (1.025 < d < 1.044 g/ml) subfraction (10%, P < 0.05) and resulted in an apparent shift in subfraction distribution towards the 'heavy' (1.044 < d < 1.060 g/ml) subfraction, although there was no absolute increase in the latter. None of these changes was statistically significant at 12 months. Oestradiol/norethisterone caused sustained decreases in both 'light' (15%, P < 0.05) and 'heavy' (29%, P < 0.05) subfractions, with no significant change in the relative amounts. The changes in 'light' and 'heavy' LDL in this group were highly correlated with changes in triglyceride levels (r = -0.57, P < 0.05 and r = 0.82, P < 0.01 respectively). Therefore, at the end of 1 year's treatment with unopposed oestradiol the only statistically significant change was an increase in HDL cholesterol. Addition of norethisterone to the preparation reversed this potentially beneficial change, but favourably influenced triglycerides, VLDL, LDL subfraction profile and lipoprotein(a), which may counteract the adverse effect on HDL.

Pleomorphic malignant fibrous histiocytoma: fact or fiction? A critical reappraisal based on 159 tumors diagnosed as pleomorphic sarcoma.

Pleomorphic malignant fibrous histiocytoma (MFH) is regarded as the most common soft tissue sarcoma of adulthood, but no definable criteria exist for its diagnosis. Possibly its only distinctive feature is its apparent lack of specific differentiation. To determine the validity of pleomorphic MFH, 159 tumors diagnosed as pleomorphic sarcomas have been reassessed morphologically, immunohistochemically, and ultrastructurally, where possible. Of these 97 cases (63%) proved to be specific sarcomas other than MFH, 20 proved to be nonmesenchymal neoplasms, and 42 were unclassifiable (of which 21 were either small biopsies or subtotally necrotic). Only 13% of these cases were eligible for consideration as MFH, but these showed no reproducible histological differences from the other tumors studied, nor was this group morphologically consistent. These tumors showed no evidence of true monocyte/macrophage differentiation. It is postulated that pleomorphic MFH is a noncohesive heterogeneous group of poorly differentiated neoplasms, a term that has become a meaningless diagnosis of convenience. With sufficient effort, a specific line of differentiation can be identified in the majority of pleomorphic malignant soft tissue tumors; with advances in investigative technology, the proportion that remain unclassifiable is very likely to diminish further in the future.

Solitary circumscribed neuroma of the skin (so-called palisaded, encapsulated neuroma). A clinicopathologic and immunohistochemical study.

Solitary, circumscribed neuroma is a distinctive benign cutaneous tumor that was first described under the name "palisaded, encapsulated neuroma" over 15 years ago. Despite the fact that it is not uncommon, it has received minimal attention and is very poorly known among pathologists. We have studied the clinicopathologic and immunohistochemical features of 39 cases. These lesions almost always present on the face or close to a mucocutaneous junction in middle-aged adults. Most examples measure less than or equal to 0.5 cm and are composed of a partially encapsulated mass of bland Schwann cells and innumerable tiny axons arranged in interlacing fascicles. The capsule is composed of perineural cells that show epithelial membrane antigen positivity. Solitary, circumscribed neuroma is not associated with von Recklinghausen's neurofibromatosis, nor is there evidence to support its possible relationship to the type IIb multiple endocrine neoplasia syndrome. This entity warrants wider recognition.

Benign fibrous histiocytoma of subcutaneous and deep soft tissue: a clinicopathologic analysis of 21 cases.

Twenty-one cases of benign fibrous histiocytoma arising in noncutaneous soft tissue are reported. These tumors presented most often in young to middle-aged adults with a predominance in males. They originated in deep subcutis (16 cases), skeletal muscle (three cases), and mesentery (two cases). The most common sites of incidence were the lower limb (eight cases) and head and neck region (six cases). Four of 12 cases with follow-up (median 3.0 years) recurred locally; all had originated in the subcutis. None metastasized. These lesions are generally larger and better circumscribed than their cutaneous counterparts. They are also usually more monomorphic and have a more consistent storiform pattern than the latter. A pericytomalike vascular pattern (six cases), xanthoma cells (six cases), and multinucleate giant cells (six cases) may be prominent. Hyaline or myxoid degeneration of the stroma is common. Rare features include small foci of necrosis and intravascular growth. Immunohistochemically, deep benign fibrous histiocytoma shows no evidence of true monocyte/macrophage differentiation and its histogenesis remains uncertain. The differential diagnosis includes malignant fibrous histiocytoma, dermatofibrosarcoma and hemangiopericytoma.

Myxoid leiomyosarcoma of soft tissue, an underrecognized variant.

Myxoid leiomyosarcoma is an uncommon tumor which, although previously well described in the uterus, is recognized to a lesser extent at other sites. We describe 18 cases of soft tissue leiomyosarcoma in which myxoid stroma occupied >50% of the tissue examined. Patients ranged in age from 22 to 84 years old (median, 57.5 yrs) and female patients outnumbered male patients 14 to 4. Tumor locations included the limbs (6 cases), female external genitalia (4 cases), head and neck region (3 cases), chest (2 cases), nipple, paratesticular soft tissue, and perineum (one case each). The tumors had a grossly gelatinous appearance and adopted three major histologic architectures: fascicular, reticular/microcystic, and "myxofibrosarcoma-like." The tumor cells were predominantly spindled in all cases with typical features of smooth muscle differentiation; there was a mixture of spindle and epithelioid cells in one case. No cases with pure epithelioid cytology were seen. All tumors displayed immunoreactivity for smooth muscle markers (smooth muscle actin 16/17, desmin 8/18) and, in addition, four cases were positive for keratin CAM 5.2 and three for epithelial membrane antigen. The tumors had a tendency to be morphologically lower grade (9 tumors were grade I, 8 were grade II, and only 1 was grade III). Follow up was available in 13 patients with a duration of 8 months to 41 years (median, 39 mos), and revealed local recurrences (often repeated) in five cases and metastases in two cases. There were three tumor-related deaths, of which two were the result of uncontrolled local disease. The differential diagnosis of myxoid leiomyosarcoma is broad and encompasses both benign and malignant lesions. Accurate diagnosis is critical because therapies may differ widely for entities in the differential diagnosis of myxoid leiomyosarcoma.

Benign lymphangioendothelioma (acquired progressive lymphangioma): a lesion not to be confused with well-differentiated angiosarcoma and patch stage Kaposi's sarcoma: clinicopathologic analysis of a series.

The clinicopathologic features of 12 cases of benign lymphangioendothelioma (acquired progressive lymphangioma) are reported. There were five male and seven female patients. Age at diagnosis ranged from 17 to 90 years (median age, 54 yrs). Development of a single macular/papular hemangiomatous or pigmented lesion was the main presenting symptom. Symptom duration before diagnosis ranged from 2 months to 20 years (median, 5.5 yrs). Tumor size ranged from 0.3 cm to 10 cm (median. 1.5 cm). Location included skin of the head and neck (n = 5), back (n = 1), breast (n = 1), shoulder (n = 1), forearm (n = 1), plantar aspect of the foot (n = 2), and oral mucosa (n = 1). No patient had any other concomitant vascular anomaly (for example, lymphangiomatosis) or was suspected to have acquired immunodeficiency syndrome. Treatment consisted of excisional biopsy in nine patients, incisional biopsy in two, and wide excision in one. Follow-up information on nine patients (range, 4-40 mos; median, 12 mos) showed two local recurrences in one patient. Microscopically, the lesions consisted of anastomosing, often widely dilated vascular structures developing in the superficial dermis. As the lesion grew within deeper dermis, the vascular spaces collapsed and dissected the dermal collagen in an angiosarcoma-like pattern. The lining endothelium was flat and monolayered, with little or no cytologic atypia and no evident mitoses. Some vascular structures contained stromal papillary projections resembling papillary endothelial hyperplasia, and intravascular red blood cells were present occasionally. Immunohistochemistry performed in eight specimens showed variable endothelial cell reactivity for CD31 (7 of 8), CD34 (7 of 7), and factor VIII-related antigen (4 of 6). A smooth muscle cell layer was observed focally around the vascular spaces in six lesions. Benign lymphangioendothelioma (acquired progressive lymphangioma) is an uncommon benign lesion that, in view of major differences in treatment and prognosis, should be distinguished from well-differentiated angiosarcoma and Kaposi's sarcoma, especially the patch stage and lymphangioma-like variants of the latter.

Malignant mesenchymoma. Clinicopathologic analysis of a series with evidence of low-grade behaviour.

Malignant mesenchymoma is a rare soft tissue neoplasm which, by definition, shows at least two distinct types of frankly malignant mesenchymal differentiation in addition to any "undifferentiated" or "fibrosarcomatous" areas. It is generally regarded as a high-grade tumor. A series of nine new cases is presented in which all patients except one were adults. Four tumors arose in the retroperitoneum, three in the thigh. The only definable constituents were rhabdomyosarcoma (eight cases), liposarcoma (seven cases), and osteo/chondrosarcoma (five cases). On histologic grounds, at least one element in each case would normally be regarded as high grade. Of six cases with a median follow-up of 4.2 years, only one has died from tumor. One further case was an incidental postmortem finding. In contrast to most current opinion, these data suggest that malignant mesenchymoma is not as aggressive as the histology would imply.

Pseudosarcomatous myofibroblastic proliferations of the spermatic cord ("proliferative funiculitis"). Histologic and immunohistochemical analysis of a distinctive entity.

Pseudosarcomatous myofibroblastic proliferations have been recognised at a variety of sites. We describe five lesions of the spermatic cord, four of which were incidental findings at inguinal herniorrhaphy. The patients' age range was 52-76 years. In all cases, sarcoma was suspected histologically, but each lesion showed morphologic features in keeping with fasciitis-like lesions described at other sites. Two cases showed actin positivity, supporting this interpretation. All were marginally or incompletely excised. One recurred locally. We believe that ischemia or torsion is of pathogenetic importance at this site. We propose that the term "proliferative funiculitis" be used to describe this type of reactive process when it presents in the spermatic cord.

Diffuse-type giant cell tumor: clinicopathologic and immunohistochemical analysis of 50 cases with extraarticular disease.

The clinical and pathologic features of 50 cases of diffuse-type tenosynovial giant cell tumor (D-TGCT), also known as extraarticular pigmented villonodular tenosynovitis (PVNTS), are presented. Patients' ages ranged from 4 to 76 years (median, 41 yrs), with a slight female predominance (28 women, 22 men). By definition, all lesions presented as predominant soft tissue masses, with or without an associated articular component. Tumor sites included the wrist (9 cases), knee (8 cases), thigh and foot (6 cases each), finger (5 cases), ankle (3 cases), hand, elbow, toes, buttock, paravertebral region (2 cases each), lower leg, sacrococcygeal area, and retroperitoneum; 27 cases were described as entirely extraarticular. Tumors showed infiltrative margins and, in most cases, a sheet-like growth pattern. Striking variation in the number of osteoclast-like giant cells, foamy cells, amount of hemosiderin, and in the degree of stromal hyalinization were responsible for a wide morphologic spectrum. In addition to the predominant histiocyte-like cells, we identified in most cases a subpopulation of large dendritic, desmin-positive cells showing characteristic, but potentially misleading, cytologic features, including abundant eosinophilic cytoplasm, large vesicular nuclei, paranuclear eosinophilic inclusions, and occasional nuclear inclusions. Follow-up information was available for 24 patients, with a duration ranging from 6 months to 30 years (mean, 55 mos). Local recurrence occurred in eight cases (33%), between 4 months and 6 months after surgery (median, 15 mos) and was repeated in five cases; recurrence did not appear to correlate with morphologic parameters. Six cases showed atypical histologic features and four of these contained areas of sarcomatous change. Among the latter, one of three cases with available follow up developed pulmonary metastases and died after 35 months. In addition, one histologically benign lesion gave rise, after two local recurrences, to inguinal and iliac lymph node metastases. Despite this exceedingly uncommon event, we think most cases of D-TGCT are best regarded as benign but locally aggressive neoplasms with significant recurrent potential and should be treated, when possible, by wide excision. Atypical features such as increased mitotic activity, necrosis, spindling of the mononucleate cells, and cytologic atypia are not indicative of malignancy when present individually. This study also confirms the existence of malignant tenosynovial giant cell tumors, some of which are characterized by aggressive behavior.