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The sequencing of the entire mitochondrial DNA belonging to haplogroup U2d reveals that this clade is defined by four coding-region mutations at positions 1700, 4025, 11893, and 14926. Phylogenetic analysis suggests that western Eurasian haplogroup U2d appears to be a sister clade with the Indo-Pakistani haplogroup U2c. Results of a phylogeographic analysis of published population data on the distribution of haplogroup U2d indicate that the presence of such mtDNA lineages in Europe may be mostly a consequence of medieval migrations of nomadic tribes from the Caucasus and eastern Europe to central Europe.

We studied 53 cutaneous lymphoproliferative disorders, all of which manifested hair follicle hyperplasia. There were 42 cases conforming to the description of pseudolymphomatous folliculitis (PLF) and 11 cases of authentic lymphomas including mycosis fungoides, CD30+ anaplastic large cell lymphoma, diffuse large B-cell lymphoma, B-cell small cell lymphoma/leukemia, and peripheral T-cell lymphoma, not otherwise specified. All patients with PLF clinically presented with a solitary nodule preferentially involving the face. Beside hair follicle hyperplasia, the typical features were a dense infiltrate of small well-differentiated lymphocytes, lymphoplasmacytoid cells, plasma cells, and epithelioid histiocytes forming tiny granulomas. Some unusual or worrisome features recognized included eccrine/apocrine duct hyperplasia, subcutis/muscle infiltration, lymphocyte "smudging," single file infiltration, and large atypical cells. Immunohistochemically, T-cell predominant cases dominated in the series. All 34 tested cases revealed a polyclonal pattern of kappa and lambda immunoglobulin (Ig) light chain expression. In 4 cases, scattered CD30+ cells were identified. Monoclonal rearrangements of T-cell receptor (TCR) and IgH genes were detected in 19 and 3 cases respectively, including 1 case with dual T-cell receptor/IgH rearrangement. Three of 30 tested cases proved positive for herpes simplex virus-1, whereas herpes simplex virus-2 always tested negative. Of 31 cases tested for Borrelia burgdorferi, 30 specimens were negative. In 9 cases, fluorescent in situ hybridization for t(11;18) and t(14;18) revealed none of the above translocations. The most common treatment modality was surgical removal. Forty patients with a mean follow-up of 3.7 years included 39 patients with no evidence of disease and 1 individual with local recurrence. The comparison of "clonal cases of PLF" and those with polyclonal population or in which clonality remained undetermined revealed no differences between the 2 groups in the clinical presentation, pathologic, and immunohistochemical features. We conclude that hyperplasia of hair follicles and other adnexa can be seen not only in the condition currently known as PLF, but also in genuine cutaneous lymphomas and may be just a happenstance secondary to a basic pathologic process.

Normal medullary interstitial cells regulate blood flow, water and salt absorption, and ultimately blood pressure through synthesis and secretion of prostanoids in which cycloxygenases play the rate-limiting steps. We found that most renomedullary interstitial cell tumors overexpressed cycloxygenase-2 (COX-2), with concomitant expression of microsomal prostaglandin E synthase-1 and the receptor for prostaglandin E2. Prostaglandin E2 is the major prostaglandin product of COX-2/microsomal prostaglandin E synthase-1 enzymatic pathway in medullary interstitial cells, and concomitant expression of COX-2, microsomal prostaglandin E synthase-1, and prostaglandin E2 receptor on interstitial cell tumors implies the presence of an autocrine growth loop important in pathogenesis of these tumors. Furthermore, overexpression of COX-2 protein was observed in association with homozygosity in several polymorphic sites within COX-2 gene (promoter region sites -1186 T/T and -765 G/G, intron 5 IVS5-275 T/T, and exon 10 Ex10+837 T>C), indicating their role in development of these tumors.

To elucidate the origin of African-specific mtDNA lineages, revealed previously in Slavonic populations (at frequency of about 0.4%), we completely sequenced eight African genomes belonging to haplogroups L1b, L2a, L3b, L3d and M1 gathered from Russians, Czechs, Slovaks and Poles. Results of phylogeographic analysis suggest that at least part of the African mtDNA lineages found in Slavs (such as L1b, L3b1, L3d) appears to be of West African origin, testifying to an opportunity of their occurrence as a result of migrations to Eastern Europe through Iberia. However, a prehistoric introgression of African mtDNA lineages into Eastern Europe (approximately 10 000 years ago) seems to be probable only for European-specific subclade L2a1a, defined by coding region mutations at positions 6722 and 12903 and detected in Czechs and Slovaks. Further studies of the nature of African admixture in gene pools of Europeans require the essential enlargement of databases of African complete mitochondrial genomes.

We attempted to investigate the clinicopathological correlation of renal oncocytoma (RO) with renal vein extension. We identified seven ROs with extension into the branches of renal vein. The age of seven patients ranged from 61 to 82 years. Five cases were identified; incidentally, two patients had gross hematuria. After surgery, all patients were alive and free of tumors with follow-up of 1 to 5 years (mean=3.6). Oncocytomas measured from 2.2 to 7.5 cm. Renal vein extension was grossly suspected in 5/7 cases and histologically confirmed in all seven cases. Tumor cells were positive for cytokeratins, mitochondrial antigen, epithelial membrane antigen, and parvalbumin; 5/7 tumors were focally positive for cluster of differentiation 117. Ultrastructurally, the cytoplasm was packed by mitochondria. Molecular genetic analysis did not detect abnormal numbers of chromosomes 1, 2, 6, 7, 10, 17, and XY by fluorescence in situ hybridization, loss of heterozygosity on 3p, and mutation of Von Hippel-Lindau gene in all cases. Array comparative genomic hybridization analysis of two cases did not show any major genetic changes. Conclusions are: (1) renal oncocytomas may have intravascular extension to the branches of the renal vein; (2) renal oncocytomas with intravascular extension to the branches of the renal vein have the same morphological, immunohistochemical, and cytogenetic findings as have their counterparts without evidence of intravascular invasion; (3) the absence of metastases suggests an overall benign behavior of this tumor, but this has to be substantiated by further studies with a long-term follow-up; (4) in a renal tumor with granular cytoplasm showing renal vein extension, it is necessary to carefully exclude renal cell carcinomas (RCC) such as chromophobe RCC, oncocytic variant of papillary RCC, and granular variant of clear cell RCC.

To elucidate the human colonization process of northern Asia and human dispersals to the Americas, a diverse subset of 71 mitochondrial DNA (mtDNA) lineages was chosen for complete genome sequencing from the collection of 1,432 control-region sequences sampled from 18 autochthonous populations of northern, central, eastern, and southwestern Asia. On the basis of complete mtDNA sequencing, we have revised the classification of haplogroups A, D2, G1, M7, and I; identified six new subhaplogroups (I4, N1e, G1c, M7d, M7e, and J1b2a); and fully characterized haplogroups N1a and G1b, which were previously described only by the first hypervariable segment (HVS1) sequencing and coding-region restriction-fragment-length polymorphism analysis. Our findings indicate that the southern Siberian mtDNA pool harbors several lineages associated with the Late Upper Paleolithic and/or early Neolithic dispersals from both eastern Asia and southwestern Asia/southern Caucasus. Moreover, the phylogeography of the D2 lineages suggests that southern Siberia is likely to be a geographical source for the last postglacial maximum spread of this subhaplogroup to northern Siberia and that the expansion of the D2b branch occurred in Beringia ~7,000 years ago. In general, a detailed analysis of mtDNA gene pools of northern Asians provides the additional evidence to rule out the existence of a northern Asian route for the initial human colonization of Asia.

Gastrointestinal stromal tumor (GIST) is the most frequent mesenchymal tumor of the alimentary tract, presently being defined as a tumor composed of spindle and/or epithelioid cells presumably differentiating towards interstitial cells of Cajal. The most frequent location of gastrointestinal stromal tumor is the stomach, followed by other sites of gastrointestinal tract. Occasional sites of occurrence are mesenterium, omentum, retroperitoneum, gall bladder, urinary bladder, pancreas, prostate and the vagina. Most of these tumors are KIT-immunoreactive and almost all carry mutated KIT or PDGFRA genes encoding two transmembrane class III tyrosine kinases. These mutations not only shed light on molecular oncogenesis of GISTs, but can also serve as diagnostic markers of this type of tumor, and, last but not least, the function of the proteins encoded by the mutated genes may be influenced by small molecule tyrosine kinase inhibitors. Nevertheless, negative results of immunohistochemistry and mutational analysis do not exclude histologically proven diagnosis of GIST, and although the response to tyrosine kinase inhibitors is correlated with the presence and type of KIT and PDGFRA mutations, the molecular genetic analysis of these genes is presently not required for imatinib therapy of GISTs.

Skin adnexal type tumors situated in the parenchyma of the breast are very rare. We report herein a case of solid-cystic hidradenoma of the breast. The tumor was situated in the parenchyma of the breast of a 55-year-old female and showed no connection to the overlying skin on ultrasound and radiology investigations, grossly and microscopically. Histologically, the tumor was identical to its cutaneous counterpart and was surrounded by breast tissue. The neoplasm was composed of solid and cystic areas. The cystic component, which predominated in the lesion, was filled with homogeneous eosinophilic material. The solid component consisted of several nodules with vague lobulated architecture protruding into the cystic spaces. The nodules were composed of cuboidal monomorphous cells that were continuous with larger polygonal cells and rare, large mucinous cells with basophilic granular cytoplasm. Several mammary ducts in close proximity to the tumor showed features of columnar cell hyperplasia. A 120-bp METC1/MAML2 fusion transcript was identified by RT-PCR and subsequent sequencing technique. This t(11;19) translocation has been reported in approximately 50% of hidradenomas of the skin.

The authors describe 2 tumors that, to the best of their knowledge, are hitherto undescribed. The predominant cell type was small round to fusiform dark blue cells. The dark blue cells formed distinct epithelial cords with gland-like formations with mucicarmine-positive mucus. Another distinctive component of the tumors was a mesenchymal one. The mesenchymal areas appeared benign and could be likened to a fibroma having a densely collagenous stroma, or they had spindle cells set in the myxoid background, rendering a myxoma-like appearance. Another distinctive feature was ganglion cell differentiation. Mitotic figures, including atypical forms, were found only in the small cell component. All cells were immunohistochemically negative for actin, calponin, desmin, HMB45, neurofilament protein, CD99/MIC2, Melan A, tyrosinase, serotonin, CD56, Melan A, GFAP, and S-100 protein. Cytokeratin, synaptophysin, FLI1 protein, and chromogranin antibodies reacted only in the primitive small round cells, while all the other components were cytokeratin negative. Fluorescence in situ hybridization showed that the tumors are without the EWSR1 gene translocation and gain 12p. Ultrastructurally, the cells were endowed with well-formed intercellular desmosomes membrane-bound secretory in the cytoplasm. Granules were found in the cytoplasm. We suggest the name "primitive small cell tumor with epithelial, gangliocytic, neuroendocrine, and mesenchymal differentiation" for this neoplasm.

The authors report two examples of nodular hyperplasia of the Bartholin gland. Each occurred in the vulva, close to the introitus of women aged 33 and 49 years, who presented with slightly painful lesions that were clinically thought to be cysts. Grossly, both masses exhibited a multilobular architecture, were elastic, were gray in color, and measured 4 cm and 3.2 cm in greatest dimension. On microscopic examination, the lesions looked similar and exhibited an increased number of secretory acini, with maintenance of the normal duct-acinar relationship--features compatible with nodular hyperplasia. Rare dilated ducts were observed, and intraluminal inspissated secretions were occasionally seen. In one case, there were a focal mild inflammatory infiltrate, squamous metaplasia of larger ducts, and rare ruptured ducts with extravasated stromal mucin. Clonality analysis performed in one case revealed a monoclonal pattern, suggesting that the lesion may be a neoplastic process rather than simple reactive hyperplasia.

Objective: The leukemia inhibitory factor (LIF) is one of the most important signaling factors in the embryo-maternal cross talk during the embryo implantation. We investigated the prevalence of the LIF gene mutations in the population of infertile women and their impact on infertility treatment., Design: A cohort study., Setting: Department of Obstetrics and Gynecology, Faculty of Medicine and University Hospital of Charles University, Pilsen., Subjects and Methods: The population to screen consisted of 399 infertile women. The control population was comprised of 202 healthy fertile subjects. For the mutational analysis, the temperature gradient gel electrophoresis (TGGE) followed by subsequent sequencing of the positive samples, had been used. The groups of fertile controls and infertile patients were compared for statistically significant difference using the Fisher's 2 by 2 Exact test., Results: Twelve potentially functional LIF gene mutations, the G to A transversion at the position 3400 leading to the valin to methionin exchange at codon 64 (V64M) were detected in the group of infertile women. No mutations were identified in the control group, which means that the frequency of functionally relevant mutations of the LIF gene in infertile women is significantly enhanced in comparison with controls (P = 0.01, Fisher's 2 by 2 Exact test ). Seven of these patients were successfully treated by in vitro fertilization (IVF)., Conclusion: The results suggest that the LIF gene mutation, the heterozygote G to A transition on the position 3400, affects fertility but the infertility treatment can succeed. Even though LIF gene mutations occur infrequently and can be overcome by infertility treatment, their impact on molecular events during early phases of pregnancy should be further elucidated.

We present a series of 18 atypical apocrine mixed tumors of the skin characterized by architectural and/or cytologic atypia but which nevertheless do not qualify these lesions as carcinomas. There were 15 males and 3 females, and all but 1 presented with solitary nodules ranging in size from 4 to 20 mm; 1 female had a large tumor of 12 cm. The tumors were preferentially located on the head area, especially the face (13 cases). Other locations included the lower extremities (3) and inguinal area (2). In all patients, surgical excision of the tumors was performed. Clinical follow-up was available in 11 cases and ranged from 1 to 24 years (mean 9.6 y; median 5 y). No recurrences or metastases were documented. Overall, the lesions manifested a rather benign architecture, usually with good circumscription, lack of capsular breach or hypercellularity; however, some asymmetry, focally irregular infiltrationlike or pushing tumorous borders were seen. Microscopically, 17 cases conformed to the so-called hyaline cell-rich variant and showed multinucleated, bizarre, hyperchromatic cells in hyaline cell areas that had a myoepithelial immunophenotype; in 1 case, atypical mitotic figures were noted. One case showed mild nuclear pleomorphism in the ductal component. Tumors were negative for p53, including bizarre giant cells that did not label with Ki-67. Ultrastructurally, hyaline cells exhibited features consistent with myoepithelial differentiation. Seven cases studied by immunohistochemistry proved negative for HER-2/neu (c-erbB-2) protein expression, and the HER-2/neu gene was not amplified by fluorescence in situ hybridization analysis in 5 cases tested. As controls, 4 authentic malignant mixed tumors were studied, but these likewise tested negative for HER-2/neu protein expression and showed no gene amplification; 1 malignant mixed tumor had polysomy 17. We conclude that some atypical cytoarchitectural features in apocrine mixed tumors, albeit worrisome, do not indicate a malignant change.

In this study, 60 gastrointestinal stromal tumors of the stomach were analyzed to elucidate the possible relation of their morphology to the mutation status of KIT and PDGFRA genes. The patients included 27 men and 33 women with a mean age of 63.8 years (range, 12-92 years). Only 1 tumor occurred before the age of 21 years. KIT mutations were detected in 31 cases (51.7%), PDGFRA mutations in 22 cases (36.7%), and 7 cases (11.7%) were KIT and PDGFRA wild type. When the mutation status was correlated with histologic features of the tumors, epithelioid or mixed epithelioid/spindle cell pattern and mast cell infiltration were found as the most reliable signs of PDGFRA mutation. Neoplastic rhabdoid cells and multinucleated giant cells, also previously reported as features of PDGFRA-mutated gastrointestinal stromal tumors, seemed to be less specific but still helpful markers in our study. Finally, tumor-infiltrating lymphocytes and myxoid stroma do not seem to be valuable histologic signs.

To characterize the impact of the potentially functional mutation--the G to A transition at the position 3400 of the leukemia inhibitory factor (LIF; a pluripotent cytokine that plays a central role in the control of the embryo implantation) gene that leads to the exchange of valine with methionine at codon 64 we evaluated the association of the LIF gene mutation and the levels of antiphospolipid antibodies (aPLs) in the peripheral blood of infertile women (the aPLs examination was part of our routine immunological test during the infertility check-up). Eight infertile mutation-positive women were diagnosed with idiopathic infertility (n=5) and endometriosis (n=3) and their levels of aPLs in serum were compared with 115 infertile women without any LIF gene mutation. Enzyme-linked immunosorbent assay was used for the detection of seven antiphospholipid antibodies; the results were statistically assessed by the Fisher's 2 by 2 exact test to evaluate the association of the LIF gene mutations and aPLs in serum of infertile patients. The presence of aPLs was significantly higher in our study group (100%) than in 30% of aPLs-positives in control infertile patients (p = 0.0035) which indicates that the aPLs are elevated in women with LIF gene mutations.

Mitochondrial DNA (mtDNA) variability was studied in a sample of 179 individuals representing the Czech population of Western Bohemia. Sequencing of two hypervariable segments, HVS I and HVS II, in combination with screening of coding-region haplogroup-specific RFLP markers revealed that most Czech mtDNAs belong to the common West Eurasian mitochondrial haplogroups (H, pre-V HV*, J, T, U, N1, W, and X). However, about 3% of Czech mtDNAs encompass East Eurasian lineages (A, N9a, D4, M*). A comparative analysis with published data showed that different Slavonic populations in Central and Eastern Europe contain small but marked amounts of East Eurasian mtDNAs. We suggest that the presence of East Eurasian mtDNA haplotypes is not an original feature of the gene pool of the proto-Slavs but rather may be mostly a consequence of admixture with Central Asian nomadic tribes, who migrated into Central and Eastern Europe in the early Middle Ages.

Imatinib, a tyrosine kinase inhibitor, is currently the therapy of choice for gastrointestinal stromal tumor (GIST). The toxic effects of imatinib treatment are usually mild, and serious adverse events are rare. We report here the case of a patient with peritoneal metastases of GIST involving the pelvis treated by imatinib. Abdominal pain deteriorated early in the course of the therapy along with the enlargement of the tumors. The patient died suddenly, and the autopsy revealed pulmonary embolism originating from the deep vein thrombosis caused by the compression of common iliac vein by the tumor. The possibility of deep vein thrombosis caused by the compression of the veins by necrotic tumor should be considered in patients with abdominal or pelvic metastases of GIST, including patients treated with imatinib.

We present a series of 15 cases of cutaneous lymphoma and pseudolymphoma with dual lineage rearrangement identified among approximately 1200 cases of cutaneous lymphoproliferative disorders assessed in our 4 institutions during the last 8 years in which the results of both T-cell receptor and immunoglobulin heavy chain rearrangement investigations were available. On the basis of the clinicopathologic information, the cases were retrospectively subdivided into 2 categories: (1) cases with definite features of cutaneous lymphoma or pseudolymphoma (n = 11) and (2) cases with unclassifiable disease (n = 4). The detection of dual genotype in the first group did not influence the final diagnosis; 7 cases represented cutaneous B-cell lymphomas, 3 pseudolymphomas, and 1 case lymphomatoid papulosis. The presence of monoclonal T-cell receptor-gene rearrangements in these cases may be explained either by monoclonal or oligoclonal expansion of exuberant T cells (or B cells in case of lymphomatoid papulosis) or by lineage infidelity. Three patients with unclassifiable disease had several clinical and histopathologic features in common. They were elderly, presented with solitary lesions, were in good general health and histopathologically demonstrated a dense multinodular infiltrate containing approximately an equal number of T and B cells and a high number of histiocytes forming granulomas, with prominent granulomatous features in 2 cases. B cells were either scattered with the infiltrate or formed collections vaguely resembling follicles; Reed-Sternberg-like cells were seen in 2 cases. B cells showed expression neither of immunoglobulin light chain. The T-cell component was represented mainly by small, well-differentiated lymphocytes or slightly pleomorphic cells, with some medium-sized convoluted cells. Epstein-Barr virus was not detected by polymerase chain reaction. The exact classification of these cases is unknown; they differ histopathologically from previously published cases of bigenotypic cutaneous lymphomas. They may merely represent a growth or reactive pattern, but, on the other hand, may be low-grade lymphomas. If so, they may be histopathologically related to cutaneous Hodgkin disease, T-cell/histiocyte-rich large B-cell lymphoma, or composite lymphomas. Further reports are needed to identify these lesions to clarify their nature and biologic potential.

Objective: Leukemia inhibitory factor (LIF) is one of the key cytokines in the embryo implantation regulation. We investigated the prevalence of the LIF gene mutations in the population of infertile women that consisted of nulligravid and secondary infertile patients., Study Design: We designed a LIF gene mutation screening method that is based on the Temperature Gradient Gel Electrophoresis (TGGE). The population to screen consisted of 176 infertile women including group A of 147 nulligravid women and group B of 29 women with secondary infertility that had a history of either miscarriage or an ectopic pregnancy but no live births. The control population was comprised of 75 healthy fertile subjects. The groups of fertile controls and infertile patients were compared for statistically significant differences using the t-test., Results: Six potentially functional LIF gene mutations, the G to A transitions at the position 3400 leading to the valin to methionin exchange at codon 64 (V64M) in the AB loop region of the LIF protein, were detected. All of the six positive women were infertile. Four of them were nulligravid and two of them had history of spontaneous conception followed by early miscarriage. No positive TGGE samples were identified in the control group, which means that the frequency of functionally relevant mutations of the LIF gene in infertile women is significantly enhanced in comparison with controls (P<0.05, t-test)., Conclusion: The results suggest that the LIF gene mutations affect fertility. Even though they occur infrequently, their impact on molecular events during early phases of pregnancy should be further established.

Background: Cutaneous lymphomas co-expressing CD56 and CD30 are very rare. They share a clinicopathological overlap with natural killer- (NK)/T-cell lymphomas and anaplastic large-cell lymphomas (ALCLs), two entities with widely disparate clinical behavior., Methods: We present a case of an immunocompetent 57-year-old Caucasian woman with a rapidly growing, angiodestructive and neuroinvasive primary cutaneous ALCL (PCALCL). The neoplastic population of large anaplastic CD30+ and CD56+ T cells was masked by a massive admixture of histiocytes and neutrophils. The partially ulcerated and pus-secreting tumor involved the forehead and scalp and was assessed as clinical stage IAE., Results: After chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone), the patient achieved a complete remission. Additionally, high-dose chemotherapy with autologous peripheral blood stem-cell transplantation was administered as a consolidation of complete remission, in which she has remained for 6 years., Conclusions: This is the first CD30+ and CD56+ primary skin lymphoma to be reported on the head. The presented case carries a remarkable combination of clinicopathological features of PCALCL and NK-/T-cell lymphoma.

Sclerosing polycystic adenosis (SPA) is a recently described, rare lesion of the salivary glands that bears a resemblance to epithelial proliferative lesions of the breast. The true nature of the lesion is unknown, but up to now it has been generally believed to represent a pseudoneoplastic sclerosing and inflammatory process. However, local recurrence developed in about one-third of the cases. Superimposed dysplastic changes ranging from low-grade dysplasia to carcinoma in situ were described in SPA. Although no metastases-related and/or disease-related patient deaths were documented, these clinical and histopathologic features raise the possibility that SPA might represent a neoplastic lesion. Polymorphism of the human androgen receptor locus is most frequently used to assess whether the pattern of X-chromosome inactivation is random or nonrandom, the latter strongly indicating clonality. In this study, the assay was applied to tissue from 12 examples of SPA. Three cases (males) were noninformative and 3 cases (females) could not be analyzed owing to poor quality of DNA, but all the remaining 6 lesions satisfied the criteria for monoclonality. We therefore conclude that the findings in the present study are further supporting evidence that SPA is a neoplasm, and not just a reactive process.

We present the morphological, immunohistochemical, and molecular genetic features of three cases of testicular and four cases of ovarian mixed germ cell sex cord-stromal tumors (MGSCT). The germ cells in the testicular MGSCTs morphologically differed from those in classical seminomas by lacking the typical "square off" quality of the nuclei. In contrast to the nuclei in classical seminomas, their size in testicular MGSCTs was smaller and nucleoli were inconspicuous and the cytoplasm was Periodic Acid-Schiff (PAS) negative. Quite on the contrary, the variability in the size of the nuclei of the germ cells in the testicular MGSCTs was more similar to that seen in the germ cells of spermatocytic seminomas. Immunohistochemically, the germ cells of MGSCTs in one case reacted positively with antibody to AE1-AE3 by paranuclear dot-like or rodlike positivity. All three testicular MGSCTs had a negative reaction with the rest of antibodies, including placental alkaline phosphatase (PLAP), OCT4, and c-kit protein. Ovarian MGSCT in our series differed from the testicular lesions in both the germ cell component and the sex cord component. The germ cells in all four ovarian cases had cytomorphological and immunohistochemical features identical to those in classical seminomas/dysgerminomas. They possessed the typical "square off" quality of the nuclei, which were much more blastic, with more mitoses compared with the testicular tumors in our series, and they were PLAP (4/4), OCT4 (4/4) and c-kit protein (3/4) positive immunohistochemically. The cytoplasm of the germ cells in ovarian neoplasms contained PAS positive glycogen. Germ cells in one ovarian MGSCTs showed amplification of 12p. All other germ cells were negative for amplification of 12p. All five successfully analyzed cases showed no mutation in all studied exons and exon-intron junctions in c-kit and PDFGRA genes.

Anogenital mammary-like glands, although known to exist (as ectopic breast tissue) as early as 1872, have only recently been thoroughly studied and suggested to be the possible origin for various neoplastic (benign and malignant) and reactive conditions that show a striking homology with lesions in the breast. Reported herein is an unusual benign lesion involving anogenital mammary-like glands in the perineal area of a 41-year-old woman. The lesion is unique in that it does not fully fit into any of the previously recognized conditions affecting anogenital mammary-like glands nor has it an apparent well-defined mammary counterpart. Microscopically, at first glance the lesion appeared as a cluster of extended anogenital mammary-like glands of variable complexity and a lobular architecture, which probably resulted from a compact proliferation of closely situated ducts with small, round lumens (when cut transversally). When cut longitudinally, some of these tiny ducts appeared to bud from larger ductal structures, resembling so-called satellitosis in the breast and this gave a fibroadenomatous appearance to the areas. In addition, there were adenosis-like areas. This lesion extends the spectrum of changes seen in anogenital mammary-like glands.

Laboratories dealing with human genome, both inherited and acquired changes, dispose with similar methods and technology. The spectrum of genetic tests is relatively broad and the number of mutations or variants tested differs substantially. Also the number of examinations carried out in individual laboratories varies. Data presented in the tables come from the year 2004 and indicate the number of examinations requested and number of positive results. Many laboratories mentioned in the registry CZDDNAL (http://www.uhkt.cz/lab&#95;a&#95;vysetreni/nr lab&#95;dna&#95;diag/dna&#95;lab&#95;db) perform the same tests but there is also a great number of tests carried out by only one laboratory. Reasons of the request, cost-effectiveness and clinical utility of genetic testing is being discussed.

Gastrointestinal stromal tumor (GIST) is a rare neoplasm exhibiting, in most cases, mutations of c-kit. Recently it has been demonstrated that a majority of GIST patients with c-kit mutations respond to therapy with imatinib, a c-kit tyrosine kinase inhibitor. Although the response rate in patients treated with imatinib in prospective clinical studies is above 50%, complete response is rare, and the data on the use of imatinib as neoaduvant therapy facilitating radical surgery is still scanty. Here, we report on a patient with metastatic gastric GIST who underwent surgery after 6 months of imatinib therapy. No tumor cells were detected on pathological examination of resection specimen. This case report indicates that a pathological complete response could be achieved with imatinib therapy in patients with GIST, but a wider experience and longer follow-up is necessary to appreciate the prognostic significance of pathological complete response in GIST.

This study characterizes the clinicopathological spectrum of lymphoproliferations involving the breast nipple and/or areola. Morphologic, immunohistochemical, molecular-genetic, and clinical features of 58 specimens from 56 patients were analyzed. They were re-diagnosed as cutaneous lymphoid hyperplasia (CLH, n = 44); other benign lymphoid infiltrates (OBLI, n = 8); peripheral T-cell lymphoma, not otherwise specified (n = 1); cases with overlapping features of CLH and B-cell lymphoma (n = 3), one of them composed of spindle cells. Cutaneous lymphoid hyperplasia infiltrates were dense, composed mainly of B cells forming follicles with germinal centers (GC). Cutaneous lymphoid hyperplasia frequently showed features suggesting a malignancy as coalescing follicles with non-polarized germinal centers lacking mantle zones, and smudged infiltrates of lymphoid cells spreading into collagen (often as "Indian files"), smooth muscle, vessel walls, and nerve sheaths. Only two cutaneous lymphoid hyperplasias recurred; otherwise all patients are without disease (mean follow-up 62 months). Monoclonal rearrangement of immunoglobulin heavy chain gene was detected in five, and of T-cell receptor gamma gene in two cutaneous lymphoid hyperplasias using polymerase chain reaction (PCR), but the patients fared well too. In 47% of cases Borrelia burgdorferi was detected by polymerase chain reaction and/or serology, of which one was monoclonal. We conclude that cutaneous lymphoid hyperplasia is the most common lymphoproliferation of the breast nipple, rarely recognized clinically, and often overdiagnosed histologically as lymphoma.

Dendritic cell neurofibroma with pseudorosettes (DCNWPR) is a recently proposed variant of neurofibroma with a distinctive microscopic appearance that is produced by a pseudorosette pattern formed by small, dark, lymphocyte-like cells (Type I cells) arranged concentrically around larger cells, with pale-staining vesicular nuclei and copious faintly eosinophilic cytoplasm (Type II cells). Although DCNWPR appears not to be associated with neurofibromatosis (NF), 1 patient with DCNWPR has been described and suggested to have a form of NF because of multiple skin lesions, with 2 of them being DCNWPR as confirmed histologically. The aim of this study was to find out whether the neurofibromatosis type 2 (NF2) gene is mutated in DCNWPR. Seven histologically proven cases of DCNWPR, from which a substantial amount of archival paraffin-embedded material was available, were selected for this study. Three cases have been previously reported, including the intraneural lesion, and 4 cases were newly identified. There were 3 female and 4 male patients, ranging in age from 30 to 61 years (median, 48 yrs). All patients clinically presented with a small solitary lesion that was clinically diagnosed as fibroma or neurofibroma, and none of the patients had signs of NF. Follow-up was known for 6 patients (range, 1-5 yrs; median, 2.5 yrs) and was uneventful in each case. Microscopically, all lesions fulfilled the criteria for DCNWPR. Exons 1 to 15 of the NF2 gene were amplified by PCR using primers previously published. The amplified fragments were purified and sequenced. The obtained sequences were computer analyzed and compared with the data of the GenBank database. No mutation was identified in 5 analyzed samples from which suitable DNA had been extracted. DCNWPR appears to have no mutation in exons 1-15 of the NF2 gene. Given the relatively small number of cases studied, it seems premature to declare that a mutation of the NF2 gene is not involved in DCNWPR, as the possibility cannot be excluded that mutations were present but remained undetected because they occurred in exons that were not examined.

We present the largest series of mucinous carcinoma involving the skin, describing the histopathologic, immunohistochemical, electron microscopic, and cytogenetic findings. Our aim was fully to characterize the clinicopathologic spectrum and compare it with that seen in the breast. In addition, we wished to reevaluate the differential diagnostic criteria for distinguishing primary mucinous carcinomas from histologically similar neoplasms involving the skin secondarily, and study some aspects of their pathogenesis. We demonstrate that primary cutaneous mucinous carcinomas span a morphologic spectrum compatible to their mammary counterparts. Both pure and mixed types can be delineated morphologically, and some lesions have mucocele-like configurations. Most lesions seem to originate from in situ lesions that may represent, using mammary pathology terminology, ductal hyperplasia, atypical ductal hyperplasia, or ductal carcinoma in situ or a combination of the three. Inverse cell polarity appears to facilitate the progression of the changes similar to lesions in the breast. The presence of an in situ component defines the neoplasm as primary cutaneous, but its absence does not exclude the diagnosis; although for such neoplasms, full clinical assessment is essential. Mammary mucinous carcinoma involving the skin: all patients presented with lesions on chest wall, breast, axilla, and these locations can serve as clue to the breast origin. Microscopically, cutaneous lesions were of both pure and mixed type, and this correlated with the primary in the breast. Dirty necrosis was a constant histologic finding in intestine mucinous carcinomas involving the skin, and this feature may serve as a clue to an intestinal origin.

A hitherto unrecognized variant of solid-pseudopapillary neoplasm of the pancreas is reported. The tumor presented in the pancreatic head of a 57-year-old female patient. It was a well-circumscribed, encapsulated nodule measuring 27 mm in diameter, with variegated yellow to brown and gray cut surface. Histologically, the neoplasm was composed of uniform polyhedral cells arranged around delicate fibrovascular cores retaining their solid pattern in the periphery, whereas central parts of the tumor were characterized by the formation of papillae and smaller pseudocysts. Neither mitotic activity nor invasive growth were found. Immunohistochemically, tumor cells were positive for vimentin, neuron-specific enolase, and CD56, whereas they were negative in reactions with antibodies directed against other neuroendocrine markers, cytokeratins, melanocytic markers, and pancreatic amylase. In addition to these typical findings, intracellular pigmented granules were found in the darker brown zones of the tumor. They were positively stained in periodic acid-Schiff reaction after diastase digestion, sudan black B, and in Schmorl stain. In contrast, they were not stained with Fontana-Masson, Ziehl-Neelsen, and Perls stains. Ultrastructurally, the pigment consisted of dense granules with lipid droplets resembling modified lysosomes. These results exclude the possibility of a melanogenic nature of the pigment and instead determine it as lipofuscin.

A unique and never-before-published example of clear cell renal cell carcinoma (CRCC) found among 9000 primary renal cell tumors is presented. The tumor contained such a dense concentration of glassy hyaline globules (GHG) in the cytoplasm of the neoplastic cells that it overshadowed the morphology of the neoplasm. The resulting appearance of the tumor was quite misleading and different from the conventional CRCC. The GHG were 7-30 microm in diameter. They were glassy and pale to slightly eosinophilic in color in hematoxylin-eosin. The GHG stained positively with periodic acid-Schiff and negatively with silver and Hale's colloidal iron. Immunohistochemically, they were also negative for anti Mycobacterium bovis antigen. At the ultrastructural level, the GHG were formed by an amorphous mass of stellate shape. The GHG were localized within rough endoplasmic reticulum. Molecular genetically, mutation of the distal part of exon 3 of the VHL gene causing elongation of the VHL protein was found in the tumor, thus confirming the diagnosis of CRCC.

Objective: To describe tumors occurring in two cases of testicular feminization syndrome., Subject: Case report., Setting: Dpt. of Special Diagnostics SPAU, University Hospital Plzen., Subject and Method: Two cases of testicular feminization syndrome were selected from four cases in our registry. Patients were 45 and 84-year-old Caucasian "females". Resected material was fixed in formaldehyde, routinely processed and stained with hematoxiline-eosin, inhibin, cytokeratines 20, placentar alkaline phosphatase, CD 99, Melan A, hCG. Sertoli cell adenoma was diagnosed in both patients. Older patient had in addition unclassified sex cord tumor of Leydig cell type. The number of sex chromosomes was examined using FISH analysis in both patients., Conclusion: Patients with testicular feminization syndrome are frequently affected by benign or malignant tumors in the cryptorchid testes. We documented two benign Sertoli cell adenomas and one sex cord tumor of uncertain biological behavior in our patients. The testes should be removed after puberty with subsequent estrogen therapy in patients with testicular feminization syndrome.

We present three cases of subcutaneous tumors with hybrid features of schwannoma-perineurioma (one case) and neurofibroma-perineurioma (two cases), which occurred in two women aged 50 and 52 years and one man aged 52. Locations included the scapular area, skin overlying breast and knee area. The tumors were 1.5, 4 and 5 cm in largest diameter. None of the patients had signs of neurofibromatosis. All tumors were surgically removed, and patients remained disease-free for 1 to 4 years. The classification of the lesion into schwannoma-perineurioma and neurofibroma-perineurioma rested on histopathological and immunohistochemical findings. An ultrastructural study was performed in one case of neurofibroma-perineurioma. All cases were studied for mutation of the NF2 gene, and in one case (neurofibroma-perineurioma) a point mutation was detected in exon 15 of the gene.

Eight cases of reactive nodular fibrous pseudotumor of the gastrointestinal tract are presented. The patients included 6 males and 2 females between the ages of 1 and 68 years (mean age 41.5 years). Three tumors involved the small intestine, and 5 of the investigated lesions were located in the large bowel. Of these, 2 originated in the sigmoid colon, 1 in the cecum, 1 in the appendix, and 1 in the large bowel not otherwise specified. The tumors' size varied from 3 to 10 cm in the greatest diameter (mean 6.2 cm). Histologically they were composed of stellate or spindle shaped cells resembling fibroblasts arranged haphazardly or in intersecting fascicles, embedded in a collagen-rich stroma, with sparse intralesional mononuclear cells frequently arranged in lymphoid aggregates. Immunohistochemically, the lesions were positive for vimentin (7/7), smooth muscle actin (8/8), muscle-specific actin (5/7), cytokeratins AE1/AE3 (6/7), and CAM 5.2 (1/7), and antigen CD68 (1/7). No case (0/8) reacted positively with antibody to CD117 (c-kit). Genetically no substitutions, deletions, or insertions occurred in exon 11 in all analyzed samples. Likewise, no deletions or insertions in part of exon 9 were observed. Ultrastructurally the tumor cells revealed features typical of myofibroblasts. According to the morphologic, immunohistochemical, and ultrastructural features mentioned above, especially to the positivity of low-molecular-weight cytokeratins, we propose this lesion to be related to a proliferation of multipotential subserosal cells rather than ordinary myofibroblasts or fibroblasts.

A case of capillary hemangioblastoma located in the peripheral soft tissue of the inner ankle in a 74-year-old woman is presented. The tumor was an unencapsulated but sharply circumscribed nodule 2.5 cm in size, of a yellow-white color. It showed reddish-brown spots with small cysts up to 2 mm filled with blood. Grossly the tumor was not attached to any peripheral nerve. Signs of von Hippel-Lindau's disease were excluded by thorough clinical evaluation. No additional tumor or erythrocytosis was found in the patient clinically. Immunohistochemically, the tumor stromal cell reacted strongly with antibodies to S-100 protein, NSE, and calponin and they were negative with antibodies to GFAP, CD34, CD31, cytokeratins, actin, desmin, EMA, and HMB-45. Endothelium of the capillaries reacted positively with antibodies to CD31, CD34, and Factor VIII-related protein. Capillary pericytes were actin-positive. All cells of the tumor stained positively with antibody to vimentin. MIB1 antibody reacted only in very few cells (<1%). Ultrastructurally, the stromal cells contained electron-lucent cytoplasm with lipid droplets, a small amount of rough endoplasmic reticulum, and glycogen particles. No electron-dense structures typical of secretory granules were seen in the stromal cells. No mutation of coding sequence of VHL gene was found.

Eighteen cases of Vanek's tumors are presented. The patients included nine men and nine women between the ages of 45 and 93 years (mean, 66.2 years). Nine cases were clinically diagnosed as polyps of the gastric antrum, five cases as polyps of the stomach (not otherwise specified), one polyp was located in the ileum and the three remaining polyps in the small intestine (not otherwise specified). The thirteen polyps with available size information measured from 0.4 to 5 cm in the greatest diameter (mean, 2.2 cm). Immunohistochemically, the affections were positive for vimentin (18/18) and CD34 (15/18). All the cases negative for CD34 also lacked concentric onion skin-like formations of the spindle cells around glands and vessels. The different immunophenotype and absence of concentric formations could be explained by the existence of two different lesions commonly designated as Vanek's tumor (inflammatory fibroid polyp) or by the hypothesis of various evolutional stages. In the differential diagnosis, it is important to distinguish namely eosinophilic gastroenteritis, gastrointestinal stromal tumor, inflammatory pseudotumor, hemangioendothelioma, and hemangiopericytoma. In contrast to gastrointestinal stromal tumors, genetically no substitution, deletion, or insertion occurred in c-kit exon 11 in all analyzed samples. Likewise, no deletion or insertion in part of c-kit exon 9 was observed.

In our study we have examined 198 patients admitted to hospital for shortness of breath at rest due to left ventricle failure. We have divided the patients into two groups according to the presence of diabetes mellitus. We have excluded the patients with noncardiac cause of pulmonary congestion, with valvular or congenital heart disease and with acute coronary syndromes. We have evaluated the presence of hypertension, value of blood sugar on admission, systolic and diastolic blood pressure, heart rate and medication given for heart insufficiency. We have also compared two dimensional transthoracal echocardiogaphic examination in diabetics to nondiabetics. Finally we compared hospital mortality in both groups. Diabetes mellitus (all the patients were type 2 diabetics) was present in 94 patients (47,5 %), in the group of diabetics there were 50 women, in nondiabetics 52 women (n.s.). The average age of diabetics was 75,5 +/- 8 years and 76,6 +/- 10,1 years in nondiabetics (n.s.). History of hypertension had 45 nondiabetics (43 %) and 69 diabetics (73,5 %), p < 0.05. Systolic blood pressure was significantly higher in diabetics 151 +/- 20,8 mm Hg to 140,5 +/- 18,4 mm Hg in nondiabetics, p < 0.05. The values of diastolic pressure and heart rate were comparable in both groups. We have not noticed any significant difference in the application of ACE inhibitors, beta blockers and diuretics for heart failure in both groups. Echocardiographic examination revealed the significantly higher ejection fraction of left ventricle in diabetics as well as the thicker septum and posterior wall of left ventricle. These findings support the role of the diastolic dysfunction in pathogenesis of left ventricle failure. In hospital mortality rate was 8,5 % in diabetics and 7,6 % in nondiabetics (n.s.). Our results confirmed that in pathogenesis of left ventricle failure hypertension and elevated systolic blood pressure play the important part. Apart from the complex secondary prevention of ischemic heart disease the correct treatment of hypertension represents the very important part of the prevention of left ventricle failure. The role of the proper compensation of diabetes mellitus in the prevention of left ventricle failure is also discussed.