Showing papers in "The American Journal of Surgical Pathology in 2007"

Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship.

Abstract: Proposed origins of pelvic serous carcinoma include the ovary, fallopian tube, and peritoneum. Prophylactic salpingo-oophorectomies in BRCA+ women have recently identified the fimbria as a site of origin for early serous carcinoma (tubal intraepithelial carcinoma or TIC). We explored the relationship of TIC to pelvic serous carcinomas in consecutive cases with complete adnexal exam (SEE-FIM protocol). Cases positive (group A) or negative (group B) for endosalpinx (including fimbria) involvement, were subclassified as tubal, ovarian, or primary peritoneal in origin. Coexisting TIC was recorded in group A when present and p53 mutation status was determined in 5 cases. Of 55 evaluable cases, 41 (75%) were in group A; including tubal (n = 5), peritoneal (n = 6), and ovarian (n = 30) carcinomas. Foci of TIC were identified in 5 of 5, 4 of 6, and 20 of 30, respectively. Ninety-three percent of TICs involved the fimbriae. Five of 5 TICs and concurrent ovarian carcinomas contained identical p53 mutations. Thirteen of 14 cases in group B were classified as primary ovarian carcinomas, 10 with features supporting an origin in the ovary. Overall, 71% and 48% of "ovarian" serous carcinomas had endosalpinx involvement or TIC. TIC coexists with all forms of pelvic serous carcinoma and is a plausible origin for many of these tumors. Further studies are needed to elucidate the etiologic significance of TIC in pelvic serous carcinoma, reevaluate the criteria for tubal, peritoneal, and ovarian serous carcinoma, and define the role of the distal tube in pelvic serous carcinogenesis.

Inflammatory myofibroblastic tumor: comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases.

Abstract: Inflammatory myofibroblastic tumor (IMT) is a neoplasm of intermediate biologic potential. In this study, we report a subset of IMTs with histologic atypia and/or clinical aggressiveness that were analyzed for clinicopathologic features, outcome, and immunohistochemical expression of anaplastic lymphoma kinase (ALK) and other markers to identify potential pathologic prognostic features. Fifty-nine IMTs with classic morphology (5 cases), atypical histologic features (21 cases), local recurrence (27 cases), and/or metastasis (6 cases) were studied. Immunohistochemistry was performed for ALK1 and other markers (Mib-1, c-Myc, cyclin D1, caspase 3, Bcl-2, Mcl-1, survivin, p27, CD56, p53, MDM-2) using standard techniques. The 59 IMTs had an age at diagnosis ranging from 3 weeks to 74 years (mean 13.2 y, median 11 y, 44% in the first decade). The mean tumor size was 7.8 cm. Sites included the abdomen or pelvis in 64%, lung in 22%, head and neck in 8%, and extremities in 5%. The follow-up ranged from 3 months to 11 years, with a mean of 3.6 years and a median of 3 years. Thirty-three patients had local recurrences, including 13 with multiple local recurrences and 6 patients with both local recurrences and distant metastases. Six patients died of disease, 5 with local recurrences, and 1 with distant metastases. Histologic evolution to a more pleomorphic cellular, spindled, polygonal, or round cell morphologic pattern was observed in 7 cases. Abdominal and pelvic IMTs had a recurrence rate of 85%. Recurrent and metastatic IMTs were larger, with mean diameters of 8.7 and 11 cm, respectively. Cytoplasmic ALK reactivity was seen in 56%. ALK-negative IMTs occurred in older patients (mean age 20.1) years and had greater nuclear pleomorphism, atypia, and atypical mitoses. All 6 metastatic IMTs were ALK-negative. Nuclear expression of p53 was detected in 80% of IMTs overall, but in only 25% of the metastatic subset. There were no significant differences among the subgroups for c-Myc, cyclin D1, MDM-2, Mcl-1, Bcl-2, CD56, p27, caspase 3, or survivin expression. In conclusion, among these 59 IMTs, ALK reactivity was associated with local recurrence, but not distant metastasis, which was confined to ALK-negative lesions. Absent ALK expression was associated with a higher age overall, subtle histologic differences, and death from disease or distant metastases (in a younger subset). Other proliferative, apoptotic, and prognostic markers did not correlate well with morphology or outcome. Thus, ALK reactivity may be a favorable prognostic indicator in IMT and abdominopelvic IMTs recur more frequently.

Poorly differentiated thyroid carcinoma: the Turin proposal for the use of uniform diagnostic criteria and an algorithmic diagnostic approach.

Abstract: Poorly differentiated (PD) thyroid carcinomas lie both morphologically and behaviorally between well-differentiated and undifferentiated (anaplastic) carcinomas. Following the original description of this entity, different diagnostic criteria have been employed, resulting in wide discrepancies and c

TMPRSS2-ERG Fusion Prostate Cancer: An Early Molecular Event Associated With Invasion

Abstract: Prostate cancer (PCA) is one of the most prevalent cancers and a major leading cause of morbidity and mortality in the Western world. The TMPRSS2-ERG fusion was recently identified as a common recurrent chromosomal aberration in this malignancy. In our study, we interrogated a broad spectrum of benign, precursor, and malignant prostatic lesions to assess the TMPRSS2-ERG fusion status using a multicolor interphase fluorescence in situ hybridization assay. Samples from hospital-based cohorts consisted of 237 clinically localized PCA, 34 hormone naive metastases, 9 hormone refractory metastases, 26 high grade prostatic intraepithelial neoplasia lesions, 15 samples of benign prostatic hyperplasia, 38 of proliferative inflammatory atrophy, and 47 of benign prostatic tissue. The TMPRSS2-ERG fusion was present in 48.5% of clinically localized PCA, 30% of hormone naive metastases, 33% of hormone refractory metastases, and in 19% of high grade prostatic intraepithelial neoplasia lesions in intermingling to cancer foci. Almost all these fusion positive cases show a homogenous distribution of the fusion pattern. In contrast, none of the other samples harbored this genetic aberration. If we consider the high incidence of PCA and the high frequency of this gene fusion, TMPRSS2-ERG is the most common genetic aberration so far described in human malignancies. Furthermore, its clinical application as a biomarker and ancillary diagnostic test is promising given its high specificity.

Xp11 translocation renal cell carcinoma in adults: expanded clinical, pathologic, and genetic spectrum

Abstract: The recently recognized Xp11 translocation renal cell carcinomas (RCCs), all of which bear gene fusions involving the TFE3 transcription factor gene, comprise at least one-third of pediatric RCC. Only rare adult cases have been reported, without detailed pathologic analysis. We identified and analyzed 28 Xp11 translocation RCC in patients over the age of 20 years. All cases were confirmed by TFE3 immunohistochemistry, a sensitive and specific marker of neoplasms with TFE3 gene fusions, which can be applied to archival material. Three cases were also confirmed genetically. Patients ranged from ages 22 to 78 years, with a strong female predominance (F:M=22:6). These cancers tended to present at advanced stage; 14 of 28 presented at stage 4, whereas lymph nodes were involved by metastatic carcinoma in 11 of 13 cases in which they were resected. Previously not described and distinctive clinical presentations included dense tumor calcifications such that the tumor mimicked renal lithiasis, and obstruction of the renal pelvis promoting extensive obscuring xanthogranulomatous pyelonephritis. Previously unreported morphologic variants included tumor giant cells, fascicles of spindle cells, and a biphasic appearance that simulated the RCC characterized by a t(6;11)(p21;q12) chromosome translocation. One case harbored a novel variant translocation, t(X;3)(p11;q23). Five of 6 patients with 1 or more years of follow-up developed hematogenous metastases, with 2 dying within 1 year of diagnosis. Xp11 translocation RCC can occur in adults, and may be aggressive cancers that require morphologic distinction from clear cell and papillary RCC. Although they may be uncommon on a percentage basis, given the vast predominance of RCC in adults compared with children, adult Xp11 translocation RCC may well outnumber their pediatric counterparts.

The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome.

Abstract: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant familial syndrome characterized by the development of cutaneous and uterine leiomyomas as well as renal tumors. The mutation of this condition has been identified in the fumarate hydratase (FH, 1q42.3-q43) gene. The histology of the renal cancers has not been well described or illustrated because of the newness of the syndrome. We reviewed 40 renal tumors resected from 38 patients belonging to HLRCC families with proven fumarate hydratase germline mutation. Patients ranged in age from 17 to 75 years of age. Tumors were unilateral in all but 2 cases. The size of the tumors varied between 2.3 and 20 cm and there was no laterality preference. Several different architectural patterns were recognized: papillary (25 cases), tubulo-papillary (8 cases), tubular (2 cases), and solid (1 case). Mixed patterns were also present in 4 cases. The most important histologic feature of these neoplasms, which we believe to be the hallmark of the HLRCC tumors, is the presence of a characteristic large nucleus with a very prominent inclusion like orangiophilic or eosinophilic nucleolus, surrounded by a clear halo. Immunohistochemical studies did not provide a specific marker for these tumors, however, loss of heterozygosity at 1q32 and 1q42-44 was frequently found. These tumors are associated with poor prognosis and frequent spread to regional lymph nodes. At the moment, morphology is the best tool to recognize these tumors. Proper diagnosis of this syndrome by the pathologist may assist in early detection of these tumors.

Minute gastric sclerosing stromal tumors (GIST tumorlets) are common in adults and frequently show c-KIT mutations.

Abstract: Multifocal hyperplasia of interstitial cells of Cajal (ICC hyperplasia) is a precursor of hereditary gastrointestinal stromal tumors (GISTs) in patients with germline mutations of c-KIT or PDGFRA, but precursor lesions of sporadic GISTs have not been defined yet. Small hyalinizing stromal tumors of the proximal stomach (referred to in this study as GIST tumorlets) were collected prospectively from 98 consecutive autopsies and additional cases were retrieved from surgical pathology files (total n=57). GIST tumorlets were grossly detectable in 22.5% consecutive autopsies performed in individuals older than 50 years. All lesions were located in the cardia, fundus, or proximal body, and ranged in size from 1 to 10 mm (4 mm). Similar lesions were not detected in the antrum, duodenum, and the remainder of the bowel. Histologically, the spindle cell subtype comprised all cases, with hyalinization and calcification in 57% of cases. The spindle cells were immunohistochemically positive for vimentin, CD117, and CD34. Twenty-four cases yielded sufficient DNA for subsequent molecular analysis, which showed c-KIT mutations in 11 cases (46%) and PDGFRA mutations in 1 case (4%). Sporadic GIST tumorlets of the proximal stomach are common in the general population over the age of 50 years and frequently show somatic c-KIT mutations. GIST tumorlets probably represent the grossly recognizable counterpart of sporadic ICC hyperplasia caused by somatic c-KIT or PDGFRA mutations. Early hyalinization and calcification seems to confer limited growth potential, and complete regression of such lesions is common. GIST tumorlets likely represent preclinical (preneoplastic) lesions that need additional stimuli to evolve into clinical GISTs, raising the possibility of a hyperplasia-neoplasia sequence in the development of sporadic GISTs.

Lymphoma of the ocular adnexa: A study of 353 cases.

Abstract: We studied the cases of 353 patients with lymphoma involving the ocular adnexa diagnosed at the Massachusetts General Hospital between 1974 and 2005. The patients included 153 males and 200 females, aged 7 to 95 years, with a mean age of 64 years. In 277 cases, there was no known history of lymphoma. Seventy-six patients had a history of lymphoma, with the ocular adnexa being involved at relapse or with progression of the previously diagnosed lymphoma. The patients had marginal zone lymphoma (182 cases), follicular lymphoma (80 cases), mantle cell lymphoma (18 cases), small lymphocytic lymphoma/chronic lymphocytic leukemia (13 cases), lymphoplasmacytic lymphoma (4 cases), splenic marginal zone lymphoma (2 cases), low-grade B cell, not subclassified (19 cases), precursor B lymphoblastic lymphoma (3 cases), diffuse large B-cell lymphoma (26 cases), and 1 case each of high-grade B-cell lymphoma, not subclassified, peripheral T-cell lymphoma, unspecified type, extranodal NK/T-cell lymphoma, nasal type, and Hodgkin lymphoma, nodular sclerosis type. Almost all marginal zone lymphoma patients (168 of 182, 92%) had primary ocular adnexal lymphoma. Fourteen marginal zone lymphoma patients (8%) had a prior history of lymphoma, usually arising in another extranodal site. Twenty-five of 80 (31%) follicular lymphoma patients had a prior history of lymphoma, usually arising in lymph nodes. Patients with mantle cell lymphoma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, and splenic marginal zone lymphoma almost always had a prior history of lymphoma or were known to have widespread disease at the time of diagnosis of ocular adnexal lymphoma. A subset of the diffuse large B-cell lymphomas were associated with large destructive masses involving adjacent structures such as paranasal sinuses, raising the possibility that they may have arisen from one of the adjacent structures and involved the ocular adnexa by direct extension. The relatively high proportion of low-grade lymphoma, not subclassified, highlights the difficulty that may arise in distinguishing different types of low-grade lymphoma, particularly when biopsies are small and artifactually distorted. Ocular adnexal lymphoma is primarily a disease of older adults, with a slight female preponderance. Most lymphomas are low-grade B-cell lymphomas, with marginal zone lymphoma being by far the most common type. Marginal zone lymphoma typically involves the ocular adnexa primarily, whereas other types of low-grade B-cell lymphoma often involve the ocular adnexa secondarily. High-grade B-cell lymphomas only occasionally involve the ocular adnexa, and T-cell lymphoma, NK-cell lymphoma, and Hodgkin lymphoma are only rarely encountered in this site.

Gastrointestinal tract pathology in patients with common variable immunodeficiency (CVID): a clinicopathologic study and review.

Abstract: Background Common variable immunodeficiency (CVID) is characterized by a host of gastrointestinal (GI) lesions that can mimic other conditions. Methods We reviewed clinical documentation and samples from 132 separate GI biopsy or resection sites on 20 CVID patients obtained over a 26-year period, including biopsies from the colon (34), esophagus (19), small intestine (38), and stomach (35), a partial gastrectomy, small bowel resection, colectomy, 2 cholecystectomies, and 1 appendectomy. Results There were 13 males and 7 females. Nine patients were children (10 y and younger) and 11 were adults. Age at diagnosis ranged from 6 months to 62 years (median, 35.5 y), and age at biopsy ranged from 10 months to 67 years (median, 38 y). Esophageal samples often showed intraepithelial neutrophils, accompanied by candida. Half of patients' esophageal biopsies had prominent intraepithelial lymphocytosis, one of which also had prominent apoptosis. The stomachs of 67% of patients lacked plasma cells. Most showed lymphoid aggregates. An increase in apoptosis was detected in biopsies from a third. About 20% had a lymphocytic gastritis pattern. Intraepithelial neutrophils were found in a subset, accompanied by various infections [cytomegalovirus (CMV), Helicobacter pylori, and Cryptosporidium]. Granulomas were found in 1 patient. Gastric adenocarcinoma was identified in one patient. There was a paucity of small bowel plasma cells in the majority of patients (68%). The small bowel showed prominent lymphoid aggregates in about half (47%). An increase in apoptosis was detected in specimens from about 20%. Increased intraepithelial lymphocytes (IELs) were found in samples from over half of patients (63%), most of whom (83%) also had villous blunting, mimicking celiac disease. Intraepithelial neutrophils were found in a subset (32%) and correlated with CMV and Cryptosporidium infections. Granulomas were seen in biopsies from 2 patients (11%). One patient had a collagenous enteritis pattern (accompanied by a collagenous colitis pattern). One patient had autoimmune enteritis; biopsies from this patient were initially relatively normal but later displayed prominent crypt apoptosis and loss of goblet cells. In colon samples, a paucity of plasma cells was seen in 10 patients (63%). The colon showed lymphoid aggregates in most patients (81%). Apoptosis was prominent in samples from half of the patients (50%). Biopsies from 6 patients had a lymphocytic colitis pattern (38%) and 2 patients had a collagenous colitis pattern. Intraepithelial neutrophils were found in samples from most patients (88%). Crypt distortion was seen in 6 of these patients (43%), thereby mimicking ulcerative or Crohn colitis. Granulomas were found in 3 patients (19%). CMV was detected in 1 patient. The appendix from 1 patient showed Cryptosporidium and acute serositis with a paucity of plasma cells and an increase in apoptosis. The gallbladder from 1 patient showed acute cholecystitis, and another patient's gallbladder lacked plasma cells. Conclusions GI tract CVID displays a wide spectrum of histologic patterns. Its features can mimic lymphocytic colitis, collagenous enterocolitis, celiac disease, lymphocytic gastritis, granulomatous disease, acute graft-versus-host disease, and inflammatory bowel disease. In fact, in our series, we found patients with a prior diagnosis of celiac disease (25%) and inflammatory bowel disease (35%), including Crohn disease (15%). The diagnosis of CVID may be suspected on the basis of the lack of plasma cells in a GI biopsy, but because this feature is only present in about two-thirds of patients, the diagnosis cannot always be suggested in isolation of other clinical and laboratory findings.

TLE1 as a diagnostic immunohistochemical marker for synovial sarcoma emerging from gene expression profiling studies.

Abstract: Synovial sarcoma is a soft tissue malignancy defined by the SYT-SSX fusion oncogene. Demonstration of the t(X;18) by cytogenetics, fluorescence in situ hybridization or reverse-transcriptase polymerase chain reaction has become the gold standard for diagnosis, but practical considerations limit the availability of these methods. Gene expression profiling studies performed by several independent groups have consistently identified TLE1 as an excellent discriminator of synovial sarcoma from other sarcomas, including histologically similar tumors such as malignant peripheral nerve sheath tumor. TLE proteins (human homologues of Groucho) are transcriptional corepressors that inhibit Wnt signaling and other cell fate determination signals, and so have an established role in repressing differentiation. We examined the expression of TLE proteins in synovial sarcoma and in a broad range of mesenchymal tumors using tissue microarrays to assess the value of anti-TLE antibodies in the immunohistochemical confirmation of synovial sarcoma. We demonstrate that TLE expression is a consistent feature of synovial sarcoma using both a well-characterized monoclonal antibody recognizing the TLE family of proteins and a commercially available polyclonal antibody raised against TLE1. Both antibodies gave intense and/or diffuse nuclear staining in 91/94 molecularly confirmed synovial sarcomas. Moderate staining is occasionally seen in schwannoma and solitary fibrous tumor/hemangiopericytoma. In contrast, TLE staining is detected much less frequently and at lower levels, if at all, in 40 other mesenchymal tumors. Our findings establish TLE as a robust immunohistochemical marker for synovial sarcoma, and may have implications for understanding the biology of synovial sarcoma and for developing experimental therapies for this cancer.

Detection of MDM2-CDK4 amplification by fluorescence in situ hybridization in 200 paraffin-embedded tumor samples: utility in diagnosing adipocytic lesions and comparison with immunohistochemistry and real-time PCR.

Abstract: Atypical lipomatous tumor/well-differentiated liposarcomas and dedifferentiated liposarcomas are characterized by the amplification of MDM2 and CDK4 genes. To evaluate the accuracy of fluorescence in situ hybridization (FISH) analysis in the differential diagnosis of adipose tissue tumors, we invest

Epithelial-Myoepithelial Carcinoma: A Review of the Clinicopathologic Spectrum and Immunophenotypic Characteristics in 61 Tumors of the Salivary Glands and Upper Aerodigestive Tract

Abstract: To further define the clinicopathologic spectrum of epithelial-myoepithelial carcinoma (EMCa), we report the gross, histologic, and immunophenotypic characteristics of 61 tumors seen within a 30-year-period. The mean age at presentation was 60.9 years, with a female predominance (1.5:1). The most co

Translocation-positive low-grade fibromyxoid sarcoma: clinicopathologic and molecular analysis of a series expanding the morphologic spectrum and suggesting potential relationship to sclerosing epithelioid fibrosarcoma: a study from the French Sarcoma Group.

Abstract: Low-grade fibromyxoid sarcomas (LGFMS) bear either the t(7,16) (q32-34;p11) or t(11,16) (p11;p11) translocations, resulting in FUS-CREB3L2 or FUS-CREB3L1 fusions, respectively. Heretofore, fusion transcripts were mainly detected in frozen tissues, using reverse transcription-polymerase chain reaction. In this study, we aimed to develop a reliable method to detect these in paraffin-embedded tissues, and to examine the clinicopathologic characteristics of a series of translocation-positive LGFMS. Sixty-three neoplasms with typical morphologic features of LGFMS and 66 non-LGFMS tumors selected for their resemblance to LGFMS (LGFMS-like tumors) were examined. RNA of sufficient quality could be extracted from 111/129 (86%) cases (59 LGFMS, 52 non-LGFMS). Of all, 48/59 (sensitivity, 81%) LGFMS contained detectable transcripts (45 FUS-CREB3L2, 3 FUS-CREB3L1). Most relevant clinicopathologic features of fusion-positive LGFMS included predominance in lower extremities (22/48; thigh: 13/48), deep situation (46/48), and occasional presence of unusual histologic features, for example, hypercellular areas (16/48), foci of epithelioid cells (13/48), and giant rosettes (6/48). Most tumors expressed EMA (41/45), at least focally, CD99 (38/41) and bcl-2 (36/41) while being essentially negative for CD34 (2/45), mdm2 (1/41), smooth muscle actin (1/45), S100 protein (0/46), desmin (0/44), h-caldesmon (0/42), keratins (0/44), and CD117 (0/40). Eleven presumed LGFMS were fusion negative. Of all, 7/52 non-LGMFS neoplasms contained FUS-CREB3L2 transcripts, of which 4 had been diagnosed as sclerosing epithelioid fibrosarcoma. In conclusion, FUS-CREB3L1/L2 fusion transcripts can be detected in paraffin-embedded LGFMS in a sensitive manner, using reverse transcription-polymerase chain reaction. Most fusion-positive LGFMS are EMA-positive and CD34/S100/smooth muscle actin negative. The presence of epithelioid cells and fusion transcripts in both LGFMS and a subset of sclerosing epithelioid fibrosarcoma suggest that these neoplasms might be related.

High frequency of coexistence of columnar cell lesions, lobular neoplasia, and low grade ductal carcinoma in situ with invasive tubular carcinoma and invasive lobular carcinoma.

Abstract: This study was undertaken to determine the morphologic features and frequency of putative precursor lesions involved in the development of some pure forms of special types and low grade breast carcinoma. We reviewed 147 successive tumor cases, comprising tubular carcinoma (TC); pure type (n=56) and mixed type (n=20), invasive lobular carcinoma (ILC); classic type (n=57), and tubulolobular carcinoma (TLC; n=14). The presence of preinvasive lesions including columnar cell lesions (CCLs), usual epithelial hyperplasia, ductal carcinoma in situ (DCIS), and lobular neoplasia (LN) was determined. Estrogen receptor and E-cadherin immunohistochemistry was performed. Ninety-five percent (95%) of pure TCs had associated CCLs with the majority showing flat epithelial atypia. Atypical ductal hyperplasia (ADH)/DCIS was present in 89% patients. Colocalization of CCL, ADH/DCIS, and TC was seen in 85% patients, all displaying the same cytologic-nuclear morphology in most cases. LN was seen in 16%. In ILC, 91% cases showed LN. CCL and ADH/DCIS were seen in 60% and 42% cases, respectively. E-cadherin was positive in TLC but reduced in TC and completely absent in ILC. In conclusion, our findings support the hypothesis that CCLs are associated with pure and mixed forms of TC, and that LN is involved in ILC development. Our observations suggest that these lesions represent family members of low grade precursor, in situ and invasive neoplastic lesions of the breast. Molecular studies are being performed to substantiate the hypothesis that tubular and lobular carcinomas have direct evolutionary links to CCLs and flat epithelial atypia.

Gastric morphology and immunophenotype predict poor outcome in mucinous adenocarcinoma of the uterine cervix

Abstract: Endocervical-type mucinous adenocarcinoma (ECA) of the uterine cervix is defined as a tumor composed of cells resembling those of the endocervical glands, but recent studies have demonstrated that a minority of ECAs displays a gastric immunophenotype. The aim of this study was to assess the significance of the gastric phenotype. Fifty-three cases of mucinous adenocarcinoma of the uterine cervix (37 FIGO stage IB, 4 stage IIA, and 12 stage IIB) were reviewed and reevaluated using a newly established morphologic criteria for distinguishing gastric type adenocarcinoma, which was defined as a tumor showing clear and/or pale eosinophilic and voluminous cytoplasm, with distinct cell borders. The results were correlated with gastric immunophenotype, determined by HIK1083 and MUC6 immunostaining, and patient outcome. Following the current World Health Organization scheme (2003), 47 tumors (89%) were classified as ECA, 1 (2%) as intestinal type, 1 (2%) as mixed endocervical and intestinal type, and 4 (8%) as minimal deviation adenocarcinoma. Twelve of 47 (26%) ECAs and all 4 minimal deviation adenocarcinomas, reclassified as gastric type using the novel criteria, were frequently positive for HIK1083 with a rate of 75% (12/16), whereas only 11% (4/37) of nongastric tumors were positive. There was no significant difference in MUC6 reactivity between gastric and nongastric type tumors (31%, 5/16 vs. 16%, 6/37; P=0.4). Patients with gastric-type adenocarcinomas had a significantly decreased 5-year disease-specific survival rate (30 vs. 77%; P<0.0001), and the gastric type morphology was related to a significant risk for disease recurrence compared with the nongastric type (P=0.001; HR, 4.5; 95% confidence interval, 1.42-14.2). HIK1083-positivity was also related to decreased 5-year disease-specific survival rate (38% vs. 74%; P<0.005). Mucinous adenocarcinoma of the uterine cervix with gastric immunophenotype can be a distinct morphologic variant showing an aggressive clinical course.

IgVH mutational status and clonality analysis of Richter's transformation: diffuse large B-cell lymphoma and Hodgkin lymphoma in association with B-cell chronic lymphocytic leukemia (B-CLL) represent 2 different pathways of disease evolution.

Abstract: Approximately 5% of B-cell chronic lymphocytic leukemia (B-CLL) patients develop a secondary aggressive lymphoma, usually of diffuse large B-cell type (DLBCL), termed Richter's transformation (RT). Rarely, classic Hodgkin lymphoma (HL) is observed. Published small series suggest that tumor cells in DLBCL and HL can be clonally identical to the B-CLL clone or arise as an independent, secondary lymphoma. We describe the morphology, immunophenotype, and clinical features of 34 classic RT patients with DLBCL, 6 cases of B-CLL with HL, and 8 cases with scattered CD30-positive Hodgkin and Reed-Sternberg (HRS)-like cells. The clonal relationship of the 2 components was analyzed using sequencing analysis of immunoglobulin heavy chain variable region (IgVH) genes. In classic RT, 18/23 B-CLL cases (78%) showed clonal progression to DLBCL with identical IgVH sequences in both lymphoma components, whereas in 5 cases (22%) the DLBCL was clonally unrelated. Among clonally related RT samples, 73% carried unmutated IgVH genes, whereas 4/5 unrelated cases were mutated. Immunophenotypically, most cases of DLBCL irrespective of clonal relatedness showed significant differences in phenotype compared with the B-CLL, with common loss of CD5 and CD23. Using immuno-laser capture microdissection, sequencing of the IgVH CDR3 region of isolated HRS cells showed that 2/2 cases with HL were clonally unrelated, whereas they were clonally identical in 1/2 cases of B-CLL with scattered HRS-like cells. HRS or HRS-like cells in all 3 unrelated cases showed evidence of Epstein-Barr virus infection. Of interest, 5/6 cases of B-CLL with HL, and 5/6 cases of B-CLL with HRS cells showed mutated IgVH genes.

Myoepithelial carcinoma of soft tissue in children: an aggressive neoplasm analyzed in a series of 29 cases.

Abstract: Primary myoepithelial tumors of soft tissue are uncommon, and criteria for malignancy among these neoplasms have only recently been established. Of 51 myoepithelial carcinomas of soft tissue in the literature, 11 occurred in children, 7 of which were included in a previous series of myoepithelial tumors from our group. We have collected an additional 22 cases of myoepithelial carcinoma of soft tissue in the pediatric population, and we describe the detailed clinicopathologic features of all 29 cases herein. There were 15 girls and 14 boys; age at diagnosis ranged from newborn to 17 years (median, 9 y). Sites included extremities (14 cases), trunk (6 cases), viscera (5 cases: 3 mediastinal, 1 retroperitoneal, and 1 intracardiac), and head/neck (4 cases). Histologically, the tumors were heterogeneous, with epithelioid, clear, spindle and/or plasmacytoid cells forming nests, cords or solid sheets in a myxoid or hyalinized stroma. Epithelioid cells predominated in the majority of cases (27 of 29; 93%) and in 10 cases (34%), tumor cells focally had scant cytoplasm with round cell morphology. The mitotic rate ranged from <1 to 68 per 10 high power fields (median, 8), and tumor necrosis was present in 14 cases. At least 1 broad-spectrum cytokeratin was positive in all tumors [CAM5.2 in 17 of 18 (94%), AE1/AE3 in 15 of 20 (75%), and PAN-K in 14 of 21 (67%)], and EMA was positive in 19 of 29 cases (66%). Either S100 or GFAP was positive in all but 4 cases [S100 in 21 of 29 (72%) and GFAP in 15 of 28 (54%)]. Clinical follow-up in 23 cases revealed that 9 patients had local recurrences (53% of the 17 patients who underwent complete excision with negative margins); 12 (52%) developed metastases; and 10 (43%) have died of disease so far, at a median interval of 9 months after diagnosis. Despite the relative rarity of carcinomas in the pediatric population, myoepithelial carcinoma seems to be disproportionately common among children and often has an aggressive clinical course.

Placental S100 (S100P) and GATA3: markers for transitional epithelium and urothelial carcinoma discovered by complementary DNA microarray.

Abstract: The morphologic distinction between prostate and urothelial carcinoma can be difficult. To identify novel diagnostic markers that may aid in the differential diagnosis of prostate versus urothelial carcinoma, we analyzed expression patterns in prostate and bladder cancer tissues using complementary DNA microarrays. Together with our prior studies on renal neoplasms and normal kidney, these studies suggested that the gene for placental S100 (S100P) is specifically expressed in benign and malignant urothelial cells. Using tissue microarrays, a polyclonal antiserum against S100P protein stained 86% of 295 urothelial carcinomas while only 3% of 260 prostatic adenocarcinomas and 1% of 133 renal cell carcinomas stained. A commercially available monoclonal antibody against S100P stained 78% of 300 urothelial carcinomas while only 2% of 256 prostatic adenocarcinomas and none of 137 renal cell carcinomas stained. A second gene, GATA3, also showed high level expression in urothelial tumors by cDNA array. A commercially available monoclonal antibody against GATA3 stained 67% of 308 urothelial carcinomas, but none of the prostate or renal carcinomas. For comparison, staining was also performed for p63 and cytokeratin 5/6. p63 stained 87% of urothelial carcinomas whereas CK5/6 stained 54%. Importantly, when S100P and p63 were combined 95% of urothelial carcinomas were labeled by one or both markers. We conclude that the detection of S100P and GATA3 protein expression may help distinguish urothelial carcinomas from other genitourinary neoplasms that enter into the differential diagnosis.

Adenoid cystic carcinoma with high-grade transformation: a report of 11 cases and a review of the literature.

Abstract: High-grade transformation of adenoid cystic carcinoma (ACC) (previously referred to as dedifferentiation) is a rare phenomenon that does not fit into the traditional ACC grading schemes. The importance and minimal criteria for distinction from solid (grade III) ACC are not well established. We report 11 new cases and review the literature to further define the profile of this tumor. The median age was 61 years (range: 32 to 72 y) with a male predominance (male to female ratio of 1.75:1). The most commonly involved sites were sinonasal (4/11) and submandibular (4/11). Lymph nodes were pathologically positive in 4/7 (57.1%) cases. Distant metastases to the lung (n=2) and soft tissue of the shoulder (n=1) were observed. Five of 9 patients (55.6%) died, all within 5 years with a median overall survival of 12 months. Histologically, ACC with high-grade transformation was distinguished from conventional ACC by nuclear enlargement and irregularity, higher mitotic counts, and the loss of the biphasic ductal-myoepithelial differentiation. Useful supportive criteria were prominent comedonecrosis and fibrocellular desmoplasia. The most common morphologies for the high-grade component were poorly differentiated cribriform adenocarcinoma and solid undifferentiated carcinoma. Micropapillary and squamoid patterns were occasionally present. Ki-67 and p53 labeling indices were elevated in the high-grade components, though c-kit and cyclin-D1 were not. ACC-high-grade transformation is a highly aggressive salivary gland tumor with a variety of histologic patterns. The high propensity for lymph node metastases suggests a role for neck dissection in patients with this rare tumor.

Acute exacerbation (acute lung injury of unknown cause) in UIP and other forms of fibrotic interstitial pneumonias.

Abstract: Acute exacerbation of usual interstitial pneumonia (UIP) is a condition in which patients with UIP, and occasionally other forms of fibrotic interstitial lung disease, develop rapid respiratory failure, accompanied by extensive radiologic infiltrates. The pathologic features of this condition are ill-defined in the literature and the outcome is unclear. We report 12 such patients, 9 with underlying UIP, 2 with underlying fibrotic nonspecific interstitial pneumonia, and 1 with underlying chronic hypersensitivity pneumonitis, who underwent surgical lung biopsy for diagnosis. High-resolution computed tomography data were available in 11 cases and showed the presence of extensive bilateral ground-glass opacities, sometimes accompanied by focal consolidation, superimposed on underlying fibrosis. Three microscopic patterns of acute lung injury were seen: diffuse alveolar damage (DAD), organizing pneumonia (OP), and a pattern of numerous very large fibroblast foci superimposed on underlying fibrosis. After the biopsy, all patients were treated with steroids, in some instances accompanied by cyclophosphamide or azathioprine. Ten patients survived the acute episode and were discharged with survival times of 1 to 11 months; of these cases, 6 showed a pattern of OP or OP plus extensive fibroblast foci; 2 a pattern of extensive fibroblast foci only; and 2 a pattern of DAD. Both patients who died had histologic DAD. We conclude that acute exacerbation of UIP and other fibrotic lung diseases produces a variety of pathologic patterns on biopsy, and that patients with OP or extensive fibroblast foci as the acute pattern seem to do better than those with DAD. Our data also imply that survival (of the acute episode) may be better than the literature suggests.

Immunohistochemical differentiation of high-grade prostate carcinoma from urothelial carcinoma.

Abstract: The histologic distinction between high-grade prostate cancer and infiltrating high-grade urothelial cancer may be difficult, and has significant implications because each disease may be treated very differently (ie, hormone therapy for prostate cancer and chemotherapy for urothelial cancer). Immuno

Neurothekeoma: An Analysis of 178 Tumors With Detailed Immunohistochemical Data and Long-term Patient Follow-up Information

Abstract: This report describes the clinicopathologic findings in 176 patients who presented with 178 tumors currently referred to as neurothekeomas. Our study group included 64 males and 112 females, ranging from 20 months to 85 years old at the time of their first surgical procedure (median age: 17 y). Twen

Pseudotumors due to IgG4 immune-complex tubulointerstitial nephritis associated with autoimmune pancreatocentric disease.

Abstract: Autoimmune pancreatitis (AIP) is a mass-forming chronic fibroinflammatory condition centered on the pancreatobiliary system and characterized by predominant immunoglobulin G4 (IgG4)-positive plasma cells. Recent reports have brought to light the multiorgan involvement of this disease. We describe a series of 5 cases of tubulointerstitial nephritis (TIN) associated with AIP and characterize the clinical, pathologic, ultrastructural, and immunopathologic features of TIN. The specimens consisted of 4 biopsies and 1 nephrectomy. The average patient age was 64 years (range 45 to 78) and the male to female ratio was 4:1. All had histologic and/or clinical and radiographic evidence of AIP, mass-forming sclerosing cholangitis, or both. The clinical impression in 4 patients was a renal mass or vasculitis. Two patients had renal insufficiency. Histologic preparations revealed a dense tubulointerstitial lymphoplasmacytic infiltrate. Eosinophils were often numerous. Tubulitis and tubular injury were present, along with tubular atrophy with focally thickened tubular basement membranes (TBMs). The histologic appearance ranged from a cellular, inflammatory pattern without tubular atrophy to a striking expansive interstitial fibrosis with tubular destruction. The nephrectomy specimen demonstrated a masslike nodular pattern of inflammation with normal renal tissue elsewhere. Glomeruli were uninvolved. By immunohistochemistry or immunofluorescence, numerous plasma cells in the infiltrate were positive for IgG4. TBM granular IgG deposits, predominantly of the IgG4 subclass, were detected in 4 of 5 cases by either immunofluorescence or immunohistochemistry. By electron microscopy, corresponding amorphous electron-dense deposits were present in the TBM in these cases. This type of TIN, typically characterized by a masslike lesion consisting of a lymphoplasmacytic infiltrate with eosinophils and prominent IgG4-positive plasma cells and immune-complex deposits in the TBM, may be part of a systemic IgG4-related disease, which we term "IgG4-associated immune complex Multiorgan Autoimmune Disease" (IMAD).

Chronic sclerosing dacryoadenitis: part of the spectrum of IgG4-related Sclerosing disease?

Abstract: To the Editor: We read with interest the recent study by Kitagawa and colleagues, documenting abundance of IgG4-positive plasma cells in chronic sclerosing sialadenitis of the submandibular gland, suggesting that this form of sialadenitis falls within the spectrum of IgG4-related sclerosing disease, of which the prototypic lesion is lymphoplasmacytic sclerosing (autoimmune) pancreatitis. IgG4-related sclerosing disease is a systemic condition probably autoimmune in nature, often affecting more than one organ system, and usually showing good response to steroid therapy. The reported sites of involvement are the pancreas, biliary tract, gall bladder, liver, salivary gland, retroperitoneum, kidney, breast, lung, thyroid, prostate, and lymph node.1,2,4,7 Lacrimal gland involvement is either not mentioned or only briefly alluded to in reviews on this subject. In this brief communication, we report 6 cases of chronic sclerosing dacryoadenitis of the lacrimal gland with abundant IgG4-positive plasma cells. The patients, including 4 women and 2 men aged 24 to 67 years (mean 45.5 y), presented with lacrimal gland swelling (bilateral except 1 case), accompanied by generalized lymphadenopathy in 2 and submandibular swelling in 1 (Table 1). One patient (case 5) was blind in 1 eye due to entrapment of the optic nerve by the disease process. Orbitotomy was performed in all patients. The histologic changes of the lacrimal glands were similar to those of chronic sclerosing sialadenitis of the submandibular gland, featuring atrophy of acini, lymphoplasmacytic infiltration, lymphoid follicle formation, periductal fibrosis, and sclerosis (Fig. 1). An evolution of morphology from predominantly florid reactive lymphoid follicular hyperplasia to markedly atrophic gland with dense sclerosis and scattered lymphoid aggregates was noted in sequential biopsies of case 2 (Fig. 2). Phlebitis was not found in sections stained with hematoxylineosin or elastic van Gieson. In case 5, lacrimal gland biopsy yielded nondiagnostic sclerotic stromal tissue only, but a nasopharyngeal biopsy showed dense sheets of plasma cells in the subepithelial region, in a background of reactive follicular hyperplasia. On immunostaining, there were numerous aggregates of IgG4-positive plasma cells in all cases (5 lacrimal glands and 1 nasopharyngeal mucosa), which account for 44% to 99% of IgG-positive cells (Fig. 3). This finding was in contrast with the sparse and singly scattered IgG4-positive cells in lymph nodes and nasopharyngeal mucosa showing usual reactive lymphoid hyperplasia. The findings in our study are comparable to those observed in the various lesions that constitute IgG4related sclerosing disease, including frequent involvement of multiple sites. In contrast to previous studies, lacrimal gland involvement is a prominent clinical manifestation apart from salivary gland involvement and lymphadenopathy. Phlebitis, a common histologic feature of IgG4related sclerosing diseases, is not found in our cases, although the possibility of sampling error cannot

Improved Methods of Detection of Lymphovascular Invasion Demonstrate That It Is the Predominant Method of Vascular Invasion in Breast Cancer and Has Important Clinical Consequences

Abstract: The presence of vascular invasion (VI), encompassing both lymphovascular invasion (LVI) and blood vascular invasion (BVI), in breast cancer has been found to be a poor prognostic factor. It is not clear, however, which type of VI plays the major role in metastasis. The aims of this study were to use an endothelial subtype specific immunohistochemical approach to distinguish between LVI and BVI by comparing the differential expression of blood vascular (CD34 and CD31) and lymphatic markers (podoplanin/D2-40) to determine their prognostic role in a well-characterized group of breast cancer patients with known long-term follow-up. Sections from 177 consecutive paraffin-embedded archival specimens of primary invasive breast cancer were stained for expression of podoplanin, D2-40, CD31, and CD34. BVI and LVI were identified and results were correlated with clinicopathologic criteria and patient survival. VI was detected in 56/177 specimens (31.6%); 54 (96.4%) were LVI and 2 (3.5%) were BVI. The presence of LVI was significantly associated with the presence of lymph node metastasis, larger tumor size, development of distant metastasis, regional recurrence and worse disease-free interval and overall survival. In multivariate analysis, LVI retained significance association with decreased disease-free interval and overall survival. In conclusion, VI in breast cancer is predominantly of lymph vessels and is a powerful independent prognostic factor, which is associated with risk of recurrence and death from the disease. The use of immunohistochemical staining with a lymphendothelial specific marker such as podoplanin/D2-40 increases the accuracy of identification of patients with tumor associated LVI.

Translocation and expression of CSF1 in pigmented villonodular synovitis, tenosynovial giant cell tumor, rheumatoid arthritis and other reactive synovitides.

Abstract: We recently demonstrated that CSF1, the ligand of the tyrosine kinase receptor, CSF1R, can be translocated in pigmented villonodular synovitis (PVNS) and tenosynovial giant cell tumor (TGCT). In this study, we evaluated the staining characteristics of PVNS/TGCT and reactive synovitides for CSF1 and CSF1R by in situ hybridization and immunohistochemistry on tissue microarrays and correlated these findings with the recently described translocation. We collected specimens of TGCT/PVNS from 60 patients and of rheumatoid arthritis and other reactive synovitides from 74 patients. We identify 2 groups of PVNS and TGCT cases by the presence of CSF1 translocation and CSF1 expression. The first group (35 of 57 cases; 61%) had both the CSF1 translocation and high expression of CSF1 RNA, confirming our previous findings. Interestingly, a second group (22 of 57 cases; 39%) was identified that showed high expression of CSF1 RNA or CSF1 protein but did not have the translocation. The rheumatoid arthritis and reactive synovitis specimens showed localization of CSF1 RNA and protein to the synovial lining cells, implying a possible role for CSF1 in the pathogenesis of these lesions. As the CSF1 translocation is postulated to play an important role in the biology of PVNS/TGCT, the consistent presence of CSF1 expression in translocation-negative cases implies that other mechanisms can lead to CSF1 up-regulation. The consistent presence of CSF1 overexpression in all cases of PVNS/TGCT and reactive synovitides suggests both an important role for CSF1 in the spectrum of synovial pathologies and the possibility of targeting the CSF1/CSF1R interaction therapeutically.

Cellular neurothekeoma: detailed characterization in a series of 133 cases.

Abstract: Cellular neurothekeomas are distinctive benign cutaneous tumors of uncertain histogenesis. As relatively few cases have been reported, their clinical features and morphologic spectrum remain incompletely defined, and the significance of atypical histologic features is uncertain. This study examined the clinicopathologic and immunohistochemical features of 133 cellular neurothekeomas received between 1987 and 2003. There was a 1.8:1 female predominance, with a mean age of 25 years (84% or =5 per 10 high power fields. Most tumors showed mild cytologic atypia in the form of nuclear variability and small nucleoli; 33 (25%) contained notably pleomorphic cells. All tumors were reactive for NKI-C3, 110/123 (89%) expressed neuron-specific enolase, 73/127 (57%) showed at least focal staining for smooth muscle actin, and only 1 was focally desmin positive. All tumors were negative for S-100 protein. Follow-up ranged from 5 to 146 months (mean 44 mo). Ten tumors recurred locally (7 situated on the face), after a mean of 18 months; tumor had been marginally excised or had involved excision margins in all cases with available information. No other clinical or pathologic features correlated with recurrence. Cellular neurothekeomas have a predilection for the upper limbs and head and neck of pediatric and young adult females and rarely recur following incomplete excision. There is no good evidence that these lesions show nerve sheath differentiation and the nomenclature will likely change when the tumor cell lineage is better defined. Atypical histologic features (including pleomorphism, infiltration of subcutis, and a high mitotic rate) seem to have no clinical significance.

Cystic nephroma and mixed epithelial and stromal tumor of kidney: a detailed clinicopathologic analysis of 34 cases and proposal for renal epithelial and stromal tumor (REST) as a unifying term.

Abstract: Cystic nephroma (CN) and mixed epithelial and stromal tumor (MEST) are rare benign renal neoplasms that have overlapping clinical and morphologic features, including predominance in middle-aged women, variably cystic architecture, eosinophilic cells, and hobnail cells lining the cysts and ovarian-type stroma. The aim of this study was to analyze and compare the histologic features and immunohistochemical profile of these tumors. We studied 34 cases from 5 large academic institutions. Twenty tumors were diagnosed as CNs, 18 in women and 2 in men, their age ranged from 24 to 63 (mean 48; median 50) years. Fourteen tumors were diagnosed as MESTs, all in women, their age ranged from 26 to 84 (mean 52; median 51) years. Histologically, all tumors were well-circumscribed except for one MEST. The stromal/epithelial ratio was approximately 2.3 in MESTs versus 0.3 in CNs; cellular ovarian-type stroma composed 45% of the stroma in MESTs and 12% of the stroma of CNs. Stromal hyalinization was prominent in both. Five MESTs showed stromal luteinization. In the epithelial component, the relative amount of large cysts, medium to small cysts, and phyllodes-type glands was: 65%/25%/10% in CNs versus 25%/40%/35% in MESTs. The epithelial component ranged from flat to cuboidal to hobnail cells in both types of tumors. No significant atypia of either component was seen, although the epithelial cells showed reactive changes. Immunohistochemical stains for estrogen receptors and progesterone receptors showed 62% and 85% positivity in the stromal component of MESTs versus 19% and 40% in CNs. CD10 positivity was seen in 77% of MESTs versus 50% of CNs, calretinin was seen in 69% of MESTs versus 41% of CNs, and inhibin in 42% of MESTs versus 36% of CNs, although the staining was focal. Follow-up in both categories of tumors (mean 3.2 y, median 3 y for CNs and mean 2.5 y, median of 2 y for MESTs) showed no evidence of recurrence or metastases in keeping with their benign nature. This study highlights the remarkable similarity between CN and MEST in sex predilection, age distribution, and morphologic attributes of both the epithelial and stromal components and immunohistochemical profile albeit with variation in individual categories with higher prevalence of stromal to epithelial ratio, prominent ovarian stroma, smaller cysts with phyllodes glands pattern and stromal luteinization being more common in MEST; and large cysts, thin septae and low stromal to epithelial ratio in CN. The presence of ovarian-type stroma and mullerian related immunohistochemical markers raises the possibility that these tumors may originate from mullerian remnants misplaced during embryogenesis. On the basis of detailed morphologic analysis of this series of CN and MEST, we propose a unifying term of "renal epithelial and stromal tumor" (REST) to encompass the spectrum of findings observed in these tumors at least until new molecular studies can prove or disprove this challenging hypothesis.

Histologic evolution of angioimmunoblastic T-cell lymphoma in consecutive biopsies: clinical correlation and insights into natural history and disease progression.

Abstract: Angioimmunoblastic T-cell lymphoma (AITL) is an uncommon, but aggressive nodal peripheral T-cell lymphoma. Little is known of its biology and its natural history has been poorly studied. We report the first comprehensive study on the natural history/histologic progression of AITL by reviewing consecutive biopsies in 31 cases. Immunostaining for CD3, CD20, CD10 and CD21, CD23, CNA-42, CD4, CD8, and Ki 67, in situ hybridization for Epstein-Barr virus (EBV)-encoded RNA and polymerase chain reaction for T-clonality and B-clonality were performed. Histologic progression from AITL with limited nodal involvement and hyperplastic follicles (pattern I) to typical AITL with or without regressed follicles (patterns II and III) was observed in 7 cases, one of which relapsed subsequently as pattern I. Thirteen cases showed typical AITL at presentation and follow-up. Eleven cases where polymerase chain reaction results for T-cell receptor-gamma gene rearrangement were directly compared showed an identical band-size in the initial and follow-up biopsies. Seven cases (23%) developed EBV-associated B-cell lymphomas [5 diffuse large B-cell lymphoma (DLBCL) and 2 classic Hodgkin lymphoma]. In 4 cases, a dominant B-cell clone was observed in biopsies lacking evidence of DLBCL. A single case was complicated by EBV-negative DLBCL, whereas another with large cell transformation had a T-cell phenotype. In conclusion, AITL represents a clonal T-cell proliferation with a stable T-cell clone throughout the disease. Partial nodal involvement with hyperplastic follicles is seen in early AITL and at relapse. When "morphologic high-grade transformation" occurs, it is usually due to a secondary (often EBV-associated) B-cell lymphoma, rather than a T-cell neoplasm.

Embryonic stem cell transcription factor signatures in the diagnosis of primary and metastatic germ cell tumors.

Abstract: The core embryonic stem cell transcription factors (TFs) OCT3/4 (OCT4), NANOG, and SOX2 have shared as well as nonoverlapping roles in stem cell growth and differentiation. These same TFs are also expressed in various types of human germ cell tumors (GCTs), implicating them in regulation of tumor gr