Franz M. Enzinger: his life and work.
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History, 20th Century↗
Biomedical subjects
Sharon W Weiss
Publications and source records attributed to Sharon W Weiss.
Epstein-Barr virus-associated smooth muscle tumors are distinctive mesenchymal tumors reflecting multiple infection events: a clinicopathologic and molecular analysis of 29 tumors from 19 patients.
Epstein-Barr virus-associated smooth muscle tumors (EBV-SMT) are rare lesions that occur in immunocompromised patients. Because they have not been fully characterized pathologically or at the molecular level, we have studied 29 tumors from 19 patients, the largest series to date. Cases coded as EBV-SMT were identified in 19 patients from consultation files and from the renal transplant database at Singapore General Hospital. EBV-SMT occurred in adults (mean age 39 years; range, 21-57 years) and predominantly affected males (12 male, 7 female). Causes of immunocompromise were renal transplantation (10), AIDS (8), and steroid therapy (1). Tumors were located in soft tissue (5), lung (5), liver (4), and miscellaneous sites (15). In 13 patients (68%), the tumors were multiple. Infection with EBV was confirmed in all cases by in situ hybridization for EBV early RNAs (EBER). EBV-SMT were typically well-differentiated smooth muscle tumors with little atypia and usually a low level of mitotic activity. Unlike classic leiomyosarcomas, they lacked significant pleomorphism but frequently displayed primitive round cell areas and prominent intratumoral T lymphocytes. No consistent relationship between histologic features and clinical outcome was noted. All expressed actin (29 of 29) and less frequently desmin (14 of 26). Multiple tumors in a given patient were clonally distinct as assessed by the long terminal repeat region of the virus, supporting the view that multifocal tumors arise from multiple infection events rather than from metastasis. Strain typing by analysis of the EBNA-3C gene confirmed the presence of EBV type 2. Two of four tumors assessed were positive for a 30-bp deletion in the LMP1 gene. EBV copy number per cell ranged greatly between patients and between tumors from the same patient. Follow-up information was available in 18 of 19 patients (mean, 25 months; range, 1-105 months). Fifteen patients were alive: 11 with disease and 4 without. Three patients died, 1 due to disease. We conclude that EBV-SMT are histologically distinct from classic soft tissue smooth muscle tumors, are not readily evaluated by means of conventional histologic criteria, and in the case of multifocal tumors are the result of multiple infection events rather than metastasis. EBV-2 can transform smooth muscle cells, independent of the presence of the LMP1 deletion associated with greater virulence.
Acquired Immunodeficiency Syndrome↗
Heterotopic mesenteric ossification: a distinctive pseudosarcoma commonly associated with intestinal obstruction.
Heterotopic mesenteric ossification (HMO) is a rare intraabdominal bone-producing pseudosarcoma with fewer than 14 reported cases in the literature. We report our experience with 6 additional cases, all of which were referred to us with a diagnostic consideration of extraskeletal osteosarcoma (EO) or "sarcoma" and emphasize features which distinguish HMO from EO. Six intraabdominal lesions coded as "heterotopic mesenteric ossification," "ossifying pseudotumor," or "reactive myofibroblastic proliferation with ossification" were retrieved from our consultation files. Clinical follow-up information was obtained. Lesions occurred exclusively in males, with a mean patient age of 49 years (range, 22-72 years). The tumors occurred in the mesentery (N = 4), omentum (N = 1), or both (N = 1) and were preceded by significant abdominal surgery (4 cases) or trauma (1 case) in all but 1 case. Five patients presented with bowel obstruction and 1 with abdominal sepsis. Tumors were difficult to precisely measure; the mean size of the resection specimens was 11.8 cm (range, 3.5-20 cm). Grossly, the tumors resembled fat necrosis and often cut with a gritty sensation. Microscopically, all lesions demonstrated an exuberant, reactive (myo)fibroblastic proliferation resembling nodular fasciitis, with extensive hemorrhage and fat necrosis. All tumors produced abundant bone and osteoid, often "lace-like," and 2 contained cartilage. The proliferating (myo)fibroblasts, osteoblasts, and chondroblasts were mitotically active but cytologically bland. Follow-up (4 cases; mean, 47.3 months; range, 5-120 months) showed 3 patients alive without disease and 1 dead of unrelated causes. One case was recent. HMO is a distinct intraabdominal ossifying pseudotumor that typically occurs in males, almost always after surgery or abdominal trauma, and frequently presents with symptoms of intestinal obstruction. This clinical history, presence of clearly reactive zones resembling nodular fasciitis, thick osteoid, and absence of nuclear atypia, necrosis, and atypical mitotic figures allow the distinction of HMO from its most important morphologic mimic, EO.
Adult↗
Pseudosarcomatous myofibroblastic proliferations of the bladder: a clinicopathologic study of 42 cases.
Inflammatory pseudotumor or pseudosarcomatous fibromyxoid tumor and postoperative spindle cell nodule of the bladder are unusual lesions of uncertain pathogenesis which share overlapping, if not identical, histologic features. We present our experience with 42 cases, the largest series to date, to study the etio-pathogenesis, histologic features, biologic behavior and relationship to "inflammatory myofibroblastic tumor" of childhood. Patients ranged in age from 7 to 77 years (mean 47 y) and males predominated (3.2:1). Most patients presented with hematuria (31/42). Common associations were smoking (10/30) and previous instrumentation or surgery (9/42). The clinicopathologic features of patients having or not having prior instrumentation were identical. Grossly the lesions were polypoid or nodular and involved any portion of bladder wall, most commonly the dome (9/27) and measured 1 to 10 cm (mean 4 cm). They were composed of spindled and stellate cells arranged in a myxoid background with numerous inflammatory cells. Myxoid hypocellular areas were more pronounced near the mucosal surface with greater cellularity and a fascicular arrangement in the deep aspect of the lesion. "Atypical" features included mitotic activity (0 to 20/10 HPF; mean 2/10 HPF; median 1/10 HPF; none atypical), necrosis (22/42), and extension into muscularis propria (28/32) or perivesicular fat (3/8). Lesions were positive for cytokeratin (31/33), SMA (23/34), desmin (21/35), and Alk-1 protein (12/26). FISH confirmed the Alk-1 translocation in 4/6 cases. Treatment included transurethral resection (30/42), partial cystectomy (9/42), and total cystectomy (3/42). Initial diagnostic error resulted in radiotherapy and chemotherapy in 3 patients. Follow-up was available in 28 patients. (range 3 to 93 mo; median 25 mo). Three patients developed recurrences, but none had metastases. Because the clinicopathologic features of lesions associated with and without instrumentation were similar and inseparable, we believe they are essentially the same entity, and propose the term pseudosarcomatous myofibroblastic proliferation. The preponderance of evidence which includes the extravesical growth, local recurrence, and Alk-1 gene translocation in some cases suggests perhaps a neoplastic process with limited growth potential. Even in the face of atypical histologic features (muscle invasion and necrosis) the prognosis is excellent. Despite the Alk-1 gene translocation, there continues to be sufficient evidence for regarding these as distinct from the so-called inflammatory myofibroblastic tumor of childhood.
Adolescent↗
Expression of Wilms tumor 1 gene distinguishes vascular malformations from proliferative endothelial lesions.
BACKGROUND: Vascular malformations and hemangiomas, which are endothelial lesions of childhood, may result in considerable morbidity because they can cause discomfort and functional impairment and have a negative affect on the patient's appearance. Although vascular malformations may initially appear very similar to hemangiomas, they have distinct clinical courses. Infantile hemangiomas progress through 3 stages: proliferative, involuting, and involuted. The proliferative phase is characterized by clinical growth. Once hemangiomas reach their maximum size, they begin to regress or involute. Histologically, this stage is characterized by endothelial apoptosis. Finally, the involuted stage of the hemangioma occurs when the original lesion is replaced by a connective tissue remnant. In contrast to hemangiomas, vascular malformations do not involute but continue to enlarge as the patient grows. OBSERVATIONS: The biochemical differences between hemangiomas, which involute, and vascular malformations, which do not involute, are not well understood. We found that the transcription factor encoded by the Wilms tumor 1 (WT1) gene is expressed in the endothelium of hemangiomas but not in vascular malformations. CONCLUSIONS: Defects in WT1 signaling may underlie the inability of malformation endothelial cells to undergo physiologic apoptosis and remodeling. The availability of WT1 staining in hospital laboratories may allow the clinician to distinguish hemangiomas from vascular malformations and thus to give appropriate therapy to the patient.
Apoptosis↗
Intercellular junctions in Ewing sarcoma/primitive neuroectodermal tumor: additional evidence of epithelial differentiation.
Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) has recently been shown to frequently express cytokeratins, suggesting partial epithelial differentiation. Older ultrastructural studies have documented primitive cell-cell junctions in ES/PNET, reportedly resembling poorly formed desmosomes. Recently, paraffin-reactive antibodies have become available to proteins found in a variety of intercellular junctions indicative of epithelial differentiation, including tight junctions, desmosomes and adherens junctions. We examined intercellular junction protein expression in a large number of genetically confirmed ES/PNET. Formalin-fixed, paraffin-embedded sections from 23 primary and seven recurrent or metastatic cases of genetically confirmed ES/PNET were immunostained for claudin-1 and occludin (tight junction structural proteins), zonula occludens-1 (ZO-1, tight junction linker protein), desmoglein 1/2 (desmosomal adherens protein), desmoplakin (desmosomal structural protein) and E-cadherin (epithelial adherens junction protein), using steam heat-induced epitope retrieval and the Dako Envision system. Cases with >5% positive cells were scored as 'positive'. Normal colonic epithelium and skin served as external positive controls. Claudin-1 was expressed by 19 of 30 specimens (63%), ZO-1 was expressed by 15 of 29 specimens (51%), and occludin was expressed by three of 28 specimens (11%). In 28 specimens all three tight junction markers were evaluable. In all, 15 samples (54%) expressed only one tight junction marker, and 10 samples (36%) expressed two tight junction markers. No case expressed all three tight junction markers. Desmoglein was expressed in one of 30 (3%) samples. Desmoplakin was expressed in two of 28 (7%) samples. E-cadherin was negative in all cases. Our data suggest that many of the previously described cell-cell junctions in ES/PNET are poorly formed tight junctions, given the high frequency of claudin-1 and ZO-1 expression. This may underestimate the true frequency of tight junction protein expression in ES/PNET, as there are at least 20 different claudins and other ZO proteins. These tight junctions are almost certainly abnormal, given the absence of occludin expression in most cases. Desmosomal and adherens junction protein expression was rare to absent. Our findings provide additional evidence that ES/PNET frequently show partial epithelial differentiation.
Bone Neoplasms↗
Dual-color, break-apart fluorescence in situ hybridization for EWS gene rearrangement distinguishes clear cell sarcoma of soft tissue from malignant melanoma.
Clear cell sarcoma of soft tissue (malignant melanoma of soft parts) is a soft tissue sarcoma with melanocytic differentiation that typically occurs in the tendons and aponeuroses of young adults. As demonstrated by cytogenetics and reverse-transcriptase polymerase chain reaction, between 70% and over 90% of clear cell sarcomas have a t(12;22) translocation, fusing the EWS and ATF1 genes on chromosomes 22q12 and 12q13, respectively. Identification of this translocation distinguishes clear cell sarcoma from histologic mimics, most importantly conventional malignant melanoma. We report our experience with a commercially available, dual-color, break-apart fluorescence in situ hybridization (FISH) probe, which allows detection of EWS (22q12) gene rearrangement in formalin-fixed, paraffin-embedded tissues. Histologically and immunophenotypically well-characterized cases of clear cell sarcoma (n = 10) and malignant melanoma (n = 32) were evaluated with a 22q12 dual-color, break-apart probe (Vysis, Downer's Grove, IL, USA), which spans the known common breakpoints in the EWS gene on chromosome 22 (introns 7-10). Signals from tumor cell nuclei were counted under a fluorescence microscope and the presence of red-green break-apart signals was recorded. Of the clear cell sarcoma cases, seven of 10 showed evidence of an EWS gene rearrangement with a mean of 81.6% positive cells per sample (range: 60-95%). All cases of malignant melanoma (n = 32) showed virtually absent break-apart signals in the EWS gene (less than 4% cells per case). FISH detects EWS gene rearrangement in a substantial proportion of clear cell sarcomas, with excellent specificity. Importantly, EWS FISH is negative in malignant melanoma, a clinically dissimilar tumor, which may closely mimic clear cell sarcoma histologically and immunohistochemically. As the studied probe can be utilized in routinely processed tissue, FISH provides an excellent alternative to reverse-transcriptase polymerase chain reaction in cases where fresh tissue is unavailable.
Diagnosis, Differential↗
Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin: a clinicopathologic study of 26 cases and review of the literature.
PEComas, occasionally associated with the tuberous sclerosis complex, are defined by the presence of perivascular epithelioid cells that coexpress muscle and melanocytic markers. This family of tumors includes angiomyolipoma (AML), clear cell sugar tumor of the lung (CCST), lymphangioleiomyomatosis (LAM), and very rare tumors in other locations. Because non-AML/non-LAM PEComas are extremely rare and their natural history and prognostic features undefined, we present our experience with 26 PEComas of soft tissue and the gynecologic tract, the largest series to date. We also performed a detailed review of the literature, with special attention to features predictive of clinical behavior. All PEComas exclusive of AML and LAM were retrieved from our consultation files. Immunohistochemistry for pan-cytokeratin (CK), S-100 protein, smooth muscle actins (SMA), desmin, vimentin, HMB45, Melan-A, microphthalmia transcription factor (MiTF), TFE3, CD117, and CD34 was performed. Clinical follow-up information was obtained. Fisher's exact test was performed. The median patient age was 46 years (range, 15-97 years); there was a marked female predominance (22 females, 4 males). Sites of involvement included the omentum or mesentery (6 cases), uterus (4 cases), pelvic soft tissues (3 cases), abdominal wall (2 cases), uterine cervix (2 cases), and vagina, retroperitoneum, thigh, falciform ligament, scalp, broad ligament, forearm, shoulder, and neck (1 case each). The tumors ranged from 1.6 to 29 cm in size (median, 7.8 cm). Tumors were epithelioid (N = 9), spindled (N = 7), or mixed (N = 10). Multinucleated giant cells were present in 18 cases. High nuclear grade was noted in 10 cases, high cellularity in 7 cases, necrosis in 8 cases, and vascular invasion in 3 cases. Mitotic activity was 0 to 50 mitotic figures (MF)/50 high power fields (HPF) (median, 0 MF/50 HPF) with atypical MF in 6 cases. IHC results were: SMA (20/25), desmin (8/22), HMB45 (22/24), Melan-A (13/18), MITF (9/18), S-100 protein (8/24), CK (3/23), vimentin (12/14), TFE3 (5/17), c-kit (1/20), and CD34 (0/7). Clinical follow-up (24 of 26 patients, 92%; median, 30 months; range, 10-84 months) showed 3 local recurrences and 5 distant metastases. At last available clinical follow-up, 2 patients (8%) were dead of disease, 4 patients (17%) were alive with metastatic or unresectable local disease, and 18 patients (75%) were alive with no evidence of disease. No patient in our series had a history of tuberous sclerosis complex. Recurrence and/or metastasis was strongly associated tumor size > median size (8 cm), mitotic activity greater than 1/50 HPF, and necrosis. We conclude that PEComas of soft tissue and gynecologic origin may be classified as "benign," "of uncertain malignant potential," or "malignant." Small PEComas without any worrisome histologic features are most likely benign. PEComas with nuclear pleomorphism alone ("symplastic") and large PEComas without other worrisome features have uncertain malignant potential. PEComas with two or more worrisome histologic features should be considered malignant. Occasional PEComas express unusual markers, such as S-100 protein, desmin, and rarely CK. The role of TFE3 in PEComas should be further studied.
Adolescent↗
Maintenance of certification for pathologists: what we know so far.
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Certification↗
Morphologic and immunophenotypic diversity in Ewing family tumors: a study of 66 genetically confirmed cases.
More than 85% of Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET), or "Ewing family of tumors" (EFTs), have the translocation, t (11;22) (q24;q12), with others having variant translocations. Identification of these by cytogenetic and/or molecular genetic techniques is specific for EFT and is increasingly recognized as the "gold standard" for diagnosis. However, these techniques are not universally available. We therefore studied a large group of genetically confirmed EFTs to more completely understand the morphologic and immunophenotypic spectrum of this rare sarcoma. Sixty-six cytogenetically, FISH or RT-PCR proven-EFTs were retrieved. In 56 cases, immunohistochemistry (IHC) was performed for pan-cytokeratins (PanCK), high molecular weight cytokeratins (HMWCK), desmin (DES), CD99, CD117, and FLI1 protein using heat-induced epitope retrieval and the Dako Envision system. The cases arose chiefly in children and young adults (median 18 years; range, 3-65 years) of both sexes (male, 32; female, 31; unknown, 3) in a variety of bone (N = 39) and soft tissue (N = 27) sites. Histologically, 46 cases (73%) showed only typical features of ES, 9 cases (16%) showed features of PNET, 3 cases (5%) showed "adamantinoma-like" features, 3 cases (5%) corresponded to "atypical Ewing sarcoma," 3 cases (5%) showed principally intersecting fascicles of spindled cells, and 2 cases had abundant hyalinized matrix. IHC results were as follows: PanCK (18 of 56, 32%), HMWCK (3 of 55, 5%), DES (1 of 56, 2%), CD99 (52 of 52, 100%), CD117 (13 of 54, 24%), and FLI1 (44 of 47, 94%). HMWCK was expressed only in "adamantinoma-like" EFTs, none of which expressed DES. In conclusion, most, but not all, EFTs can be accurately diagnosed using time-honored morphologic criteria and ancillary immunohistochemistry. However, genetic confirmation remains essential for the diagnosis of unusual morphologic variants of EFT, including "adamantinoma-like," spindled, sclerosing, and clear cell/anaplastic variants. Therefore, to exclude or confirm the diagnosis of Ewing's sarcoma in round cell sarcomas having a variety of patterns but not specifically conforming to a tumor of known lineage (eg, rhabdomyosarcoma), cytogenetics, and/or molecular analysis is required.
12E7 Antigen↗
Aberrant expression of tight junction-related proteins ZO-1, claudin-1 and occludin in synovial sarcoma: an immunohistochemical study with ultrastructural correlation.
Synovial sarcoma demonstrates epithelial differentiation, either by light microscopy (biphasic synovial sarcoma) or by immunohistochemical/ultrastructural methods only (monophasic) and poorly differentiated synovial sarcoma. Although the glands of synovial sarcoma are known to have tight junction-like structures, far less is known about junction formation in the spindled component of synovial sarcomas. Additionally, it is unknown whether the tight junctions of synovial sarcoma are normally constituted. The tight junction is a multiprotein complex consisting of numerous proteins that include ZO-1, claudin-1 and occludin. A total of 35 cases of synovial sarcoma (13 biphasic, 14 monophasic and eight poorly differentiated) were immunostained for ZO-1, claudin-1 and occludin using commercially available antibodies, heat-induced epitope retrieval and standard avidin-biotin technique. When available, corresponding electron micrographs were reviewed. For five cases, the presence of either an SYT-SSX1 (three cases) or SYT-SSX2 (two cases) gene fusion was known. Positive cases showed particulate membrane staining. The glands of biphasic synovial sarcomas expressed ZO-1 (13/13), claudin-1 (12/13) and occludin (11/13) in a manner identical to normal glandular epithelia, at the apical portion of the lateral membrane. The spindle cells of biphasic synovial sarcomas showed abnormal circumferential membranous expression of ZO-1 (12/13), claudin-1 (6/13) and occludin (3/13). Monophasic synovial sarcomas expressed ZO-1 in a circumferential pattern (13/14) but less often claudin-1 (4/14) or occludin (3/14). Poorly differentiated synovial sarcomas expressed ZO-1 (8/8) and claudin-1 (6/8) but only rarely occludin (2/8). By electron microscopy, recognizable tight junctions were seen only in glands. No correlation was seen between histologic subtype or fusion type and expression of tight junction proteins. We conclude that the glands of biphasic synovial sarcomas show well-organized, true epithelial tight junctions. In contrast, the spindled cells of all synovial sarcomas show significant abnormalities in the expression and localization of tight junction proteins, suggesting partial and/or aberrant epithelial differentiation.
Claudin-1↗
Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature.
Oncogenic osteomalacia (OO) is a rare paraneoplastic syndrome of osteomalacia due to phosphate wasting. The phosphaturic mesenchymal tumor (mixed connective tissue variant) (PMTMCT) is an extremely rare, distinctive tumor that is frequently associated with OO. Despite its association with OO, many PMTMCTs go unrecognized because they are erroneously diagnosed as other mesenchymal tumors. Expression of fibroblast growth factor-23 (FGF-23), a recently described protein putatively implicated in renal tubular phosphate loss, has been shown in a small number of mesenchymal tumors with known OO. The clinicopathological features of 32 mesenchymal tumors either with known OO (29) or with features suggestive of PMTMCT (3) were studied. Immunohistochemistry for cytokeratin, S-100, actin, desmin, CD34, and FGF-23 was performed. The patients (13 male, 19 female) ranged from 9 to 80 years in age (median 53 years). A long history of OO was common. The cases had been originally diagnosed as PMTMCT (15), hemangiopericytoma (HPC) (3), osteosarcoma (3), giant cell tumor (2), and other (9). The tumors occurred in a variety of soft tissue (21) and bone sites (11) and ranged from 1.7 to 14 cm. Twenty-four cases were classic PMTMCT with low cellularity, myxoid change, bland spindled cells, distinctive "grungy" calcified matrix, fat, HPC-like vessels, microcysts, hemorrhage, osteoclasts, and an incomplete rim of membranous ossification. Four of these benign-appearing PMTMCTs contained osteoid-like matrix. Three other PMTMCTs were hypercellular and cytologically atypical and were considered malignant. The 3 cases without known OO were histologically identical to the typical PMTMCT. Four cases did not resemble PMTMCT: 2 sinonasal HPC, 1 conventional HPC, and 1 sclerosing osteosarcoma. Three cases expressed actin; all other markers were negative. Expression of FGF-23 was seen in 17 of 21 cases by immunohistochemistry and in 2 of 2 cases by RT-PCR. Follow-up (25 cases, 6-348 months) indicated the following: 21 alive with no evidence of disease and with normal serum chemistry, 4 alive with disease (1 malignant PMTMCT with lung metastases). We conclude that most cases of mesenchymal tumor-associated OO, both in the present series and in the reported literature, are due to PMTMCT. Improved recognition of their histologic spectrum, including the presence of bone or osteoid-like matrix in otherwise typical cases and the existence of malignant forms, should allow distinction from other mesenchymal tumors. Recognition of PMTMCT is critical, as complete resection cures intractable OO. Immunohistochemistry and RT-PCR for FGF-23 confirm the role of this protein in PMTMCT-associated OO.
Adolescent↗
Kaposiform hemangioendothelioma: a study of 33 cases emphasizing its pathologic, immunophenotypic, and biologic uniqueness from juvenile hemangioma.
Kaposiform hemangioendothelioma (KH) is a rare tumor of childhood often associated with Kasabach-Merritt phenomenon (KMP) and occasionally lymphangiomatosis. Although generally considered distinct from other vascular neoplasms, its rarity has precluded a thorough study of its immunophenotypic profile and long-term behavior. Thirty-three cases of KH were reviewed and immunostained for alpha-smooth muscle actin, various endothelial markers (CD31, CD34, vWf, FLI1), a platelet marker (CD61), and the juvenile hemangioma-associated markers GLUT-1 and Lewis Y antigen (LeY). In addition, the presence of HHV-8 was evaluated by RT-PCR. The patients (20 males and 13 females) ranged in age from 2 weeks to 20 years (mean 3 years 9 months). Tumors developed on the extremities (17 cases), head/neck (8 cases), and other sites (8 cases) and affected both superficial and deep soft tissue. Those in the skin presented as slightly raised blue-red lesions. More than half of the patients presented with KMP (14 of 25). Tumors consisted of irregular, infiltrating nodules of compressed vessels, which modulated between areas resembling a capillary hemangioma and Kaposi sarcoma (KS). Endothelial cells in nodules were CD31, CD34, and FLI1 positive but negative for GLUT1 and LeY. Scattered "epithelioid" or glomeruloid islands featuring endothelium associated with clusters of plump alpha-smooth muscle actin-positive pericytes, stippled hemosiderin, and CD61-positive fibrin thrombi likely represent the morphologic sites of platelet consumption. Small and large lymphatic channels occurred in 22 of 33 cases and were typically seen peripheral or deep to the main tumor mass. HHV-8 transcripts were not identified (0 of 3 cases). Follow-up information was available in 22 patients (range 8 months to 15 years; mean 2 years) and indicated that 3 died of disease, 8 were alive with disease, and 10 were alive without residual disease. Two patients developed regional perinodal soft tissue involvement, but none developed distant metastases. KH is a lesion having both a vascular and lymphatic component. Its common association with KMP probably relates in part to unique architectural features that favor turbulent blood flow and platelet activation. KH can also be reliably separated from JH by GLUT-1 and LeY immunostaining, indicating differences in the morphologic and functional attributes of the endothelium between the two lesions. The absence of HHV-8 in KH underscores a different pathogenesis from Kaposi sarcoma. Our study, the largest to date, emphasizes that mortality is due to KMP and not metastatic disease, which appears limited to regional perinodal soft tissue. Given this behavior, its continued classification as a vascular tumor of intermediate malignancy is warranted.
Adolescent↗
Paraganglioma-like dermal melanocytic tumor: a unique entity distinct from cellular blue nevus, clear cell sarcoma, and cutaneous melanoma.
We are reporting a previously undescribed primary dermal melanocytic tumor identified by reviewing all dermal melanocytic tumors referred in consultation that did not qualify histologically as a previously described entity. From these cases, 8 were remarkably similar. We termed them "paraganglioma-like dermal melanocytic tumor" (PDMT) based on their nested growth pattern. This term is used descriptively and does not imply any histogenetic or biologic similarity to true paraganglioma. PDMT is primarily a tumor of the extremities of adult females (18-53 years, mean 35 years; males 2; females 6) which present as a dermal nodule (range, 0.5-4.2 cm; mean, 1.4 cm) composed of nests of clear to amphophilic oval cells separated by delicate fibrous strands. Nuclear atypia was mild and mitotic activity low (1-4 mitoses/10 HPF). Melanin was not obvious on light microscopy. Tumors expressed S-100 protein (8 of 8), Melan-A (4 of 8), HMB-45 (8 of 8), and microphthalmia transcription factor (8 of 8) and lacked pancytokeratin (8 of 8) and smooth muscle actin (8 of 8). FISH analysis of 5 cases revealed an intact EWS gene locus, supporting absence of the clear cell sarcoma 12;22 translocation. Follow-up information in 8 patients (range, 35-92 months; mean, 54 months) indicated that all were alive without disease. PDMT comprises a clinically and pathologically unique subtype of dermal melanocytic tumors. Our study suggests a benign course, although a lesion of low malignant potential cannot be excluded.
Adolescent↗
Cutaneous angiosarcoma following breast-conserving surgery and radiation: an analysis of 27 cases.
Iatrogenic angiosarcomas (AS), following treatment of breast carcinomas and attributed to chronic lymphedema, were first described by Stewart and Treves. With emphasis on breast-conserving therapy combined with adjuvant radiation, a recently recognized form of cutaneous postradiation angiosarcoma of the breast (CPRASB) has emerged. To more completely characterize CPRASB, 27 cases were analyzed. Histologic features studied included pattern of growth (vasoformative, sieve-like, or solid), nuclear grade, necrosis, and mitotic rate. Clinical and follow-up information was obtained. The patients received relatively standard radiation treatment. The median interval to diagnosis of CPRASB was 59 months; 5 occurred in less than 3 years. Lymphedema was largely absent, and when present was only mild in nature. CPRASB was frequently multifocal at presentation (13 of 27). All tumors had a vasoformative pattern of growth; the majority (16 of 27) had areas with a sieve-like pattern. The solid pattern was less frequent (7 of 27). The majority had high-grade nuclear features (16 grade 3, 8 grade 2, 3 grade1). The mean mitotic rate was 9/10 HPF. Necrosis was rare (2 of 27). All were treated with wide excision or mastectomy. Follow-up was available on 22 of 27 cases (median 44 months). Fourteen experienced local recurrence and 6 had multiple recurrences. Metastasis was documented in 9 of 22 patients and involved lungs (6), contralateral breast (3), skeleton (2), lymph nodes (1), and soft tissue (1). Eight patients died of disease, 2 died with disease, 4 were alive with disease, and 8 are alive without disease. The median interval to death was 33.5 months. All 4 patients with disease have documented metastasis. CPRASB differs from Stewart-Treves AS by its shorter latency period and lack of association with lymphedema.
Aged↗
Pleomorphic hyalinizing angiectatic tumor: analysis of 41 cases supporting evolution from a distinctive precursor lesion.
The pleomorphic hyalinizing angiectatic tumor (PHAT) is a rare, low-grade neoplasm that features atypical stromal cells containing hemosiderin, partially thrombosed ectatic vessels with circumferential hyalinization, and a variable inflammatory infiltrate. Over the years, we have occasionally observed a monomorphic partially myxoid spindle cell component (provisionally termed "early PHAT") co-existing with classic PHAT. In some instances, this monomorphic lesion occurs by itself, suggesting an early stage in the evolution of PHAT. To explore this hypothesis and to better define the long-term behavior of PHAT, we have reviewed our experience with these lesions. Forty-one cases were identified from consultation files. They occurred chiefly in adults (median 51 years, range 10-79 years) of either sex (23 female, 18 male), ranged from 0.3 to 19.7 cm (median 5.6 cm), and involved the subcutis of the ankle/foot (N = 15), leg (N = 10), thigh (N = 6), and other sites. Thirteen tumors had been present for more than 1 year prior to biopsy. Fifteen tumors consisted entirely of typical PHAT. Twelve cases conformed to "early PHAT," lacked fully developed features of PHAT, and showed instead short fascicles of hemosiderin-stippled spindled cells that infiltrated fat and surrounded congeries of small, damaged vessels. With close scrutiny, all contained rare pleomorphic cells with intranuclear pseudo-inclusions, as seen in typical PHAT. Fourteen cases contained both classic and early PHAT, in variable proportions. Follow-up was available in 18 patients (mean 84 months, median 52 months; range 13-420 months). Six of 18 patients developed recurrences, 1 with classic PHAT, 1 with mixed early-classic PHAT, and 4 with early PHAT. Following resection, 16 are disease free and 2 have persistent disease. None has developed metastasis. Based on the histologic overlap between early and classic PHAT, the presence of early PHAT at the periphery of classic PHAT, and the admixture of both patterns within the same tumor, we conclude that early PHAT represents a precursor lesion for PHAT. It appears essentially identical to the lesion termed "hemosiderotic fibrohistiocytic lipomatous lesion," supporting the notion that the latter is a neoplastic rather than a reactive lesion. PHAT should be considered mesenchymal tumors of intermediate malignancy, given their high rate of (sometimes aggressive) local recurrence.
Adolescent↗
Epithelioid sarcoma-like hemangioendothelioma.
We are reporting seven histologically identical cases of a distinctive, low-grade vascular tumor that closely mimics an epithelioid sarcoma because of growth in solid sheets and nests, the eosinophilia of the rounded to slightly spindled neoplastic cells, and the diffuse, strong cytokeratin expression. Termed epithelioid sarcoma-like hemangioendothelioma, all were diagnosed by the submitting pathologist or another expert consultant as epithelioid sarcoma. Although none displayed architectural evidence of vascular differentiation in the form of multicellular vascular channels, some displayed subtle cytologic features of vascular differentiation and all displayed immunohistochemical evidence of endothelial differentiation. The patients (four male; three female) ranged in age from 17 to 54 years (median 23 years). Ranging in size from 1 to 3.5 cm, they occurred in the extremities (n = 5), scalp (n = 1), and chest wall (n = 1), both in deep (n = 3) and superficial (n = 3) soft tissue or both (n = 1). The tumors were characterized by sheets, ill-defined nodules, or fascicles of deeply eosinophilic cells set within a desmoplastic stroma. Multicellular vascular channel formation and/or hemorrhage were absent in all cases. In four cases intracytoplasmic vacuolization suggestive of intracytoplasmic vascular lumen formation was noted. The typical neoplastic cell was large and rounded in shape but modulated in areas to a spindled or multipolar shape. Mitotic activity was low (<5 mitotic figures/50 high power fields), nuclear pleomorphism was mild to moderate, and necrosis was absent. The tumors were positive for cytokeratin (6 of 6), vimentin (6 of 6), CD31 (5 of 6), FLI-1 (6 of 6), but negative for CD34 (0 of 6). Within a follow-up period of 3-72 months (median 39 months), two patients experienced a local recurrence and one patient regional soft tissue metastases, but no distant ones. Two patients presented with multifocal lesions suggestive of regional metastases. Currently, two patients are alive with disease and five are disease free. Epithelioid sarcoma-like hemangioendothelioma appears to be a largely unrecognized epithelioid vascular tumor with an indolent course. Despite its similar clinical and histologic features, it differs from epithelioid sarcoma by the presence of endothelial markers and the absence to date of distant metastases. Its distinction from other epithelioid vascular lesions is discussed. We think this tumor fits best into the family of "hemangioendothelioma" or vascular lesions of intermediate malignancy.
Adolescent↗
Ossifying fibromyxoid tumor of soft parts: a clinicopathologic study of 70 cases with emphasis on atypical and malignant variants.
The ossifying fibromyxoid tumor of soft parts (OFMT) is an uncommon soft tissue neoplasm of uncertain lineage. Approximately 100 cases of OFMT have been reported. Although the majority behave in a benign fashion, very rare tumors with histologic and clinical evidence of malignancy have been reported. Criteria for malignancy in OFMT have not as yet been defined. Seventy cases of OFMT were retrieved from our consultation archives and studied with respect to patient age and sex, tumor site and size, growth pattern, percentage of typical OFMT, cellularity and nuclear grade, mitotic figures (MF)/50 high power fields (HPF), atypical mitoses, necrosis, vascular invasion, and the presence of bone. Immunohistochemistry for pancytokeratin, S-100 protein, smooth muscle actin, desmin, and collagen II was performed on a subset of cases. Follow-up information was obtained from the submitting pathologists and clinicians. The Fisher exact test was used for statistical analysis. Patients (39 male, 31 female) ranged in age from 14 to 83 years (median 49 years). The tumors occurred primarily as subcutaneous or deeply seated masses in the trunk and proximal extremities and ranged from 1 to 14 cm (median 4.0 cm). The percentage of typical OFMT present in each case ranged from 0% to 100% (median 70%), and bone was present in 44 cases (63%). Mitotic activity ranged from 0 to 40 MF/50 HPF (median 2 MF/50 HPF), necrosis was present in 12 cases (17%), and vascular invasion was seen in 8 cases (11%). High cellularity or high nuclear grade was seen in 14 and 13 cases, respectively. Immunohistochemical results were as follows: S-100 protein (33 of 55, 60%), pancytokeratin (5 of 48, 10%), smooth muscle actin (2 of 44, 5%), desmin (5 of 39, 13%), and collagen II (1 of 26, 4%). Follow-up (51 cases, mean 54 months, median 36 months, range 5-151 months) showed local recurrences in nine patients and metastases in eight patients. Currently, 41 patients are disease free, 6 are alive with disease, 4 are dead of disease, and 1 died of other causes. The presence of high cellularity (p = 0.002), high nuclear grade (p = 0.001), or >2 MF/50 HPF (p = 0.004) were significantly associated with the development of metastatic disease and local recurrence. Infiltrative growth was also associated with increased risk of local recurrence (p = 0.03). We conclude that the histologic spectrum of OFMT is broader than previously appreciated, as many clinically benign cases display moderate cellularity, nuclear enlargement, or have identifiable mitotic figures. Our results strongly suggest that OFMT with 1) high nuclear grade or 2) high cellularity and mitotic activity of >2 MF/50 HPF should be regarded as sarcomas with significant potential for metastasis and untoward outcome ("malignant OFMT"). The remainder can be considered within the spectrum of OFMT, recognizing that even these lesions possess a risk, albeit very low, of metastasis. Consequently, OFMT should be considered tumors of intermediate malignancy. Their line of differentiation remains unclear, although we suggest they may belong to the category of translocation-associated sarcomas, not all of which recapitulate a normal line of differentiation.
Adolescent↗