Total endoscopic thyroidectomy after open neck biopsy of the follicular lymphoma of the thyroid gland.

Remote-access total endoscopic thyroidectomy (TET) is a recently established approach that can avoid producing scars in the neck. There are no clear surgical indications for TET for benign nodules or for malignant tumors at present. We report a successful TET in a 50-year-old Japanese woman with follicular lymphoma of the thyroid gland after an open neck biopsy. She had been referred to us with a neck tumor noted 2 months earlier. Because of adhesion, we performed a combined resection of the thyroid and partial right sternohyoid muscle. To the best of our knowledge, there is no other report of a TET performed after open neck surgery. Our patient's case demonstrates that (a) the cosmetic outcome of TET is clearly superior to that of conventional open neck surgery, and (b) a TET can be suitable even for reoperation if carefully selected.

A novel mutation of the FAT2 gene in spinal meningioma.

Meningiomas may be classified as neurofibromin 2 (NF2)-associated and non-NF2 meningiomas depending on the presence or absence of molecular alterations in the NF2 gene. One of the characteristic histological features of meningiomas is the whorl formation of neoplastic arachnoid cells. NF2 is a human homolog of the Drosophila gene, Merlin (Mer). In humans, NF2 is the gene responsible for the disease neurofibromatosis type II, which results in the development of brain tumors, including acoustic neurinoma and meningioma. The present study aimed to investigate the molecular pathogenesis of spinal meningioma. It was hypothesized that the whorl formation of meningiomas may occur as a result of a disturbance in the planar cell polarity (PCP) of arachnoid cells, thus, genes understood to govern PCP signaling were analyzed for alterations. Whole exome sequencing followed by Sanger sequencing validation was performed for the analysis of spinal meningioma tissue obtained from a 42-year-old Japanese female. The sequencing identified a nonsynonymous mutation of c.3597G>C, resulting in p.Q1199H, in the FAT atypical cadherin 2 (FAT2) gene. FAT2 is homologous to the Drosophila Fat (Ft) gene, which belongs to the cadherin superfamily. Drosophila Fat is involved in PCP, tumor suppression and Hippo (Hpo) signaling, which is associated with Mer. Taken together, the results of the present study concluded that human FAT2 may function as a key molecule that governs not only PCP, but also NF2-Hpo signaling in arachnoid cells; thus, a mutation in this gene may result in spinal meningioma.

Biallelic alterations of the large tumor suppressor 1 (LATS1) gene in infiltrative, but not superficial, basal cell carcinomas in a Japanese patient with nevoid basal cell carcinoma syndrome.

The present study was conducted to address the molecular pathogenesis underlying the progression of basal cell carcinoma (BCC) in a nevoid basal cell carcinoma syndrome (NBCCS) patient. We analyzed infiltrative BCCs that invaded the subcutaneous tissue of the scalp and penetrated the skull in a 61-year-old Japanese female. Whole-exome sequencing validated by Sanger sequencing was applied to assess the subcutaneously infiltrative BCCs. Differences in genetic alterations between the superficial and infiltrative BCCs were also examined. Of particular note, the infiltrative BCCs showed a nonsense mutation, c.943C>T, resulting in p.Q315X in the large tumor suppressor 1 (LATS1) gene, as well as the loss of the wild-type allele of LATS1 (6q25.1), thus indicating that the LATS1 gene was biallelically disrupted. In contrast, no alterations in the LATS1 gene were observed in the superficial BCCs. Additionally, a loss of heterozygosity analysis revealed that the distal region of chromosome 6q where LATS1 locates was deleted in a heterozygous manner. The present results imply that the biallelic disruption of LATS1 is a progressive factor of the infiltrative BCCs observed in this NBCCS patient and suggest that the Hippo pathway is a potential therapeutic target in cases of infiltrative BCC.

A novel mutation of the axonemal dynein heavy chain gene 5 (DNAH5) in a Japanese neonate with asplenia syndrome.

Asplenia syndrome (Ivemark syndrome) is a complex disorder composed of asplenia, malpositioning of the visceral organs and congenital heart defects. To elucidate the underlying molecular mechanism of asplenia syndrome, we herein analyzed the fatal case of a male neonate who exhibited three lobes of the left lung, asplenia and complex heart anomalies and died 6 hours after delivery. A whole-exome sequence (WES) analysis followed by Sanger sequence identified a heterozygous single nucleotide change (c.7829A>G) in exon 47 of the axonemal dynein heavy chain gene 5 (DNAH5), which results in the missense mutation of p.Glu2610Gly. This mutation was found only in the neonate, but not in his parents, implying de novo mutation of DNAH5 that codes dynein heavy chain, a component of outer dynein arm. The WES analysis also identified a heterozygous single nucleotide substitution (c.3697C>T) in the axonemal dynein heavy chain gene 7 (DNAH7), resulting in p.Arg1233Cys, and a rare SNP (c.2029G>A, p.Gly677Ser) of the axonemal dynein intermediate chain gene 1 (DNAI1) in the patient and his mother, but not in his father. The mutation of p.Glu2610Gly in DNAH5 is novel and we here present a first Japanese case of asplenia syndrome who exhibited a DNAH5 mutation.

Biallelic disruption of the PTCH1 gene in multiple basal cell carcinomas in Japanese patients with nevoid basal cell carcinoma syndrome.

The aim of the present study is to address whether the molecular pathogenesis is identical among multiple basal cell carcinomas (BCCs) present in the same nevoid basal cell carcinoma syndrome (NBCCS) patient. Patient 1 is a 61-year-old (yo) Japanese female whose clinical characteristics and findings of a genetic analysis of PTCH1 have been previously described. Patient 2 is patient 1's 64-yo sister who also suffered from NBCCS with a single base deletion at nucleotide 2613 in exon 16 (c.2613delC) in one PTCH1 allele. Thirteen and 3 independent specimens of BCC were applied for a molecular analysis of loss of heterozygosity (LOH) in PTCH1 in patients 1 and 2, respectively. Of particular note is that all BCC specimens examined showed a loss of the wild-type allele of exon 16 in PTCH1, thus indicating that LOH results in the biallelic disruption of PTCH1 in multiple BCCs that develop in an age- and location-independent manner in the same patient. These results indicate that the germline single base deletion of PTCH1 (c.2613 delC) is a first hit and the LOH of the wild-type allele is a second hit, implying that all 16 BCCs detected in these NBCCS sisters fit the standard two-hit model.

Neuroendocrine carcinoma arising in a hepatitis C virus-infected liver: mechanism of the tumor development may be similar to that of development of pancreatic neuroendocrine cells.

We experienced a case of neuroendocrine carcinoma (NC). The tumor developed in the cirrhotic liver of a 62-year-old Japanese man who had been infected with hepatitis C virus. The tumor cells showed high N/C ratio, formed many rosettes, and expressed CD56, synaptophysin, HepPar1 and pancreatic and duodenal homeobox 1. MIB1 expression was 65%. Because both liver and pancreas are derived from a common endodermal layer during fetal development, we speculated that the tumor may have formed via the interaction of neurogenin 3, insulinoma-associated 1 gene and NeuroD/beta2, which are involved in the stage at which some pancreatic cells commit to becoming endocrine cells. Molecular analysis revealed that the NC had higher relative expression levels of mRNA of the three molecules than did the nontumorous liver. The results indicate that the NC in this patient may have formed via the same mechanism that acts in the development of pancreatic neuroendocrine cells.

Heterozygous loss of NF2 is an early molecular alteration in well-differentiated papillary mesothelioma of the peritoneum.

Well-differentiated papillary mesothelioma of the peritoneum (WDPMP) is a rare disease, and many cases are either benign neoplasms or low-graded malignancies; however, a few cases show rapid progressive clinical courses. No effective therapy has yet been established for WDPMP, and the molecular basis of WDPMP tumorigenesis has never been reported. This study shows the malignant transformation of WDPMP in a Japanese female patient, who was alive for 54 months after the initial diagnosis by a laparoscopic biopsy. A molecular analysis of single nucleotide polymorphisms (SNPs), which were located in the neurofibromatosis type 2 (NF2) gene, a tumor suppressor gene assigned to chromosome 22q12.3, revealed the loss of heterozygosity (LOH) of the NF2 gene. Furthermore, SNP analyses determined that LOH was observed in the IL17RA (22q11.1), CHECK2 (22q12.1), and SHANK3 (22q13.3) genes, thus suggesting that NF2 loss occurred through 22q deletions or monosomy 22. The LOH of the NF2 gene was observed in an early stage of WDPMP, thus indicating that LOH of the NF2 gene is an early molecular alteration, and NF2 loss is a molecular mechanism associated not only with malignant pleural mesothelioma, but also with WDPMP.

Diagnostic challenge: intraductal neoplasms of the pancreatobiliary system.

To help pathologists avoid misdiagnosis of intraductal neoplasms arising from the pancreatobiliary system, we report two cases that illustrate diagnostic pitfalls. The first is of a 66-year-old man who complained of appetite loss. An early examination led to a diagnosis of intraductal papillary mucinous neoplasm. Macroscopically, a multilocular cyst without visible mucin was identified. Histologically, the compartments consisted of complex fusion of tubular glands surrounded by dilated pancreatic duct. The neoplasm resembled an acinar cell cystadenocarcinoma. However, the neoplastic cells were negative for trypsin. Thus, the final histopathologic diagnosis was an unusual cystic variant of intraductal tubulopapillary neoplasm (ITPN) of the pancreas. The second case is of a 71-year-old man who complained of right upper quadrant pain. Although bile duct stone was suspected, a polypoid nodule was extracted. Histologically, the nodule was composed of tubular glands, with some complex fusion and focal dysplasia, consistent with carcinoma. In addition, lack of MUC-5AC expression led to an initial impression of ITPN of the bile duct. However, the neoplasm showed dysplastic cells based on the columnar cells resembling pyloric glands, indicating the sequential progression. Thus, the final histopathological diagnosis was intraductal papillary neoplasm of the bile duct with high-grade intraepithelial neoplasia. Because phenotypic variants of intraductal neoplasms of the pancreatobiliary system exist, ITPN and ITPN-mimicking tumor must be carefully differentiated from other intraductal neoplasms.

A case of pulmonary papillary adenoma: possible relationship between tumor histogenesis/tumorigenesis and fibroblast growth factor receptor 2 IIIb.

Pulmonary papillary adenoma is a rare tumor. We analyzed a tumor which appeared in a 16-year-old Japanese woman. The tumor histologically showed papillary proliferation of one-layered tumor cells coating inflammatory fibrovascular cores. At the periphery of the tumor, the tumor cells grew in a lepidic fashion. The tumor cells were confirmed as type-II pneumocytes with electron-microscope. In this study, using immunohistochemistry, in situ hybridization and real-time reverse transcription polymerase chain reaction, we examined the expressions and quantities of fibroblast growth factor 10 (FGF10), keratinocyte growth factor (KGF) and fibroblast growth factor receptor 2 (FGFR2) IIIb, based on the extent of their abilities of proliferation and differentiation of type II pneumocytes. The tumor cells expressed FGFR 2 and produced 350 times more FGFR2IIIb messenger RNA (mRNA) than did the nontumorous lung. The quantity of KGF mRNA in the tumor tissue was twice that of the nontumorous lung. Moreover, there was dysregulation of FGFR2IIIb transcription in the tumor. According to these findings, we expect overexpression of FGFR2IIIb to play an important role in causing tumor. Because FGFR is suspected to be connected with lung carcinoma, we also treat similar tumorigenesis via FGFR as carcinoma; complete resection of adenoma might be indicated.

Autopsy cases of fulminant bacterial infection in adults: clinical onset depends on the virulence of bacteria and patient immune status.

To assist physicians in recognizing the potentially fatal onset of symptoms in cases of fulminant bacterial infection, we analyzed 11 autopsy cases of such infection (four caused by Streptococcus pneumoniae, four by S. pyogenes, one by S. dysgalactiae subsp. equisimilis, one by Staphylococcus aureus, and one by Vibrio vulnificus). Clinicohistopathologic features were evaluated. All patients experienced sudden onset of hypotension and multiple organ failure, leading to unexpected death. Blood culture confirmed bacteremia. The main chief complaints were gastrointestinal symptoms (45%) and limb pain (36%). All had an underlying chronic illness (82%), e.g., a hematologic disorder (36.3%) or liver cirrhosis (27.2%). Necrotizing fasciitis occurred in only 55% of cases, with none involving pneumococcal infection. Laboratory tests typically showed C-reactive protein elevation but without leukocytosis, indicating a high-level inflammatory state. In ten cases, death was attributed to circulatory collapse due to sepsis; severe pulmonary congestion and hemorrhage were present in these cases. The onset of fulminant bacterial infection depends on both virulence of the bacterium and status of the host defense system.

Autopsy cases of miliary tuberculosis: clinicopathologic features including background factors.

To assist physicians, especially young physicians, in identifying tuberculosis (TB) infection before the terminal stage, we analyzed 7 cases of numerous tuberculous granulomas in multiple organs and compared clinical and autopsy findings between cases. Patients ranged in age from 41 to 86 years at the time of death. The main chief complaint was fever of unknown origin (3 of 7 cases [43%]). The main underlying conditions were liver cirrhosis (2 of 7 cases [29%]) and chronic renal failure (2 of 7 cases [29%]). Two patients (29%) had been given methylprednisolone pulse therapy for various lung disorders. Active TB was not diagnosed before autopsy in 4 of 7 (57%) patients. Calcified lesions indicative of old TB were present in 4 of 7 (57%) patients. Thus, miliary tuberculosis may represent a re-emergence of latent TB infection in these cases. Various histologic features of nonreactive exudative inflammation were seen, along with granulomas containing Langhans giant cells with or without caseous necrosis in hypervascular organs, such as the lung, liver, and bone marrow. Physicians should be mindful of the possibility of miliary TB when older patients with hepatorenal disease and a history of TB infection have undergone immunosuppressive treatment. Active tuberculous infection can depend on the presence of an underlying disease and immunocompromise.

Comparison of immunocytochemical sensitivity between formalin-fixed and alcohol-fixed specimens reveals the diagnostic value of alcohol-fixed cytocentrifuged preparations in malignant effusion cytology.

The most commonly used fixative in effusion cytology is formalin. In the present study, the immunocytochemical properties of formalin-fixed and alcohol-fixed specimens were compared to evaluate the usefulness of alcohol-fixed cytocentrifuged preparations for routine cytologic diagnosis. A total of 269 effusion samples and 17 primary antibodies were used. The sensitivity of immunocytochemical studies in alcohol-fixed specimens was similar and correlated to that of formalin-fixed specimens, suggesting that alcohol-fixed cytocentrifuged preparations are useful in effusion cytology. Pretreatment with or without heat-induced antigen retrieval revealed that antigen retrieval was unnecessary for immunocytochemical studies with most primary antibodies in alcohol-fixed cytocentrifuged preparations. The present study describes the use of immunocytochemical studies with alcohol-fixed cytocentrifuged preparations for diagnosis in routine effusion cytology.

Diagnostic usefulness of EMA, IMP3, and GLUT-1 for the immunocytochemical distinction of malignant cells from reactive mesothelial cells in effusion cytology using cytospin preparations.

To differentiate reactive mesothelial cells (RMs) from metastatic carcinoma and malignant mesothelioma (MM) in effusion cytology is crucial for the cytologic diagnosis and the management of the patients. In the present study, the immunocytochemical staining profile of the epithelial membrane antigen (EMA), the insulin-like growth factor-II mRNA-binding protein 3 (IMP3), and the glucose transporter-1 (GLUT-1) was examined to distinguish RMs from malignant cells. A total of 171 pleural (n = 87) and peritoneal (n = 84) effusion specimens, including 50 benign effusions with RMs, 11 MM effusions, and 110 metastatic malignant effusions, were evaluated for immunocytochemistry. EMA, IMP3, monoclonal GLUT-1, and polyclonal GLUT-1 immunoreactivity were observed in 26.0%, 6.0%, 20.0%, and 18.0% of RMs, respectively. In contrast to RMs, the immunoreactivity in MM was 100%, 36.4%, 100%, and 90.9%; adenocarcinoma (AC) was 100%, 80.8%, 81.7%, and 72.1%; squamous-cell carcinoma was 83.3%, 83.3%, 83.3%, and 66.7%. EMA, IMP3, mGLUT-1, and pGLUT-1 expressions were observed in 98.4%, 65.6%, 88.5%, and 75.4% in the pleural effusion with malignant cells, and 100%, 88.3%, 78.3%, and 71.7% in ascites containing malignant cells, respectively. The findings of the present study indicate that the immunocytochemical staining for EMA, IMP3, and GLUT-1 is a useful diagnostic tool for distinguishing effusions containing malignant cells from those that contain benign cells, and in particular, we suggest that the combination of mGLUT-1 and EMA, and IMP3 and EMA are extremely useful in pleural effusion and in ascites, respectively.

A case of granulocyte colony-stimulating factor and interleukin 6 receptor-producing mediastinal mature cystic teratoma with somatic-type malignancy.

Mediastinal germ cell tumor with somatic-type malignancy is a rare neoplasm. We describe one such case in a 49-year-old Japanese man who had shown an elevated serum concentration of granulocyte colony-stimulating factor (GCSF) and leukocytosis without a shift to the left. Histologically, the tumor formed a teratomatous cyst whose wall contained benign epithelial components, well-differentiated tubular and mucinous adenocarcinoma, and poorly-differentiated pleomorphic carcinoma. Immunohistochemically, both the well differentiated adenocarcinoma and poorly differentiated pleomorphic carcinoma expressed GCSF. Immunohistochemistry and molecular analysis revealed that both components also produced interleukin 6 receptor (IL6R). We diagnosed this tumor as a GCSF- and IL6R-producing mediastinal mature cystic teratoma with somatic-type malignancy. The tumor showed immunohistochemical expression of activated signal transducer and activator of transcription 3. The patient died 6 months after developing systemic symptoms. For a GCSF-producing tumor, complete resection appears to offer the best outcome at present. For any patient presenting with leukocytosis without a shift to the left, a thorough analysis should be conducted, and the tumor diagnosed as early as possible.

Multiple immunoenzyme labeling using heat treatment combined with the polymer method: an analysis of the appropriate inactivation conditions of primary antibodies.

Multiple immunoenzyme labeling is of considerable value to detect several antigens in the same specimen, although this technique is limited when the primary antibodies have been raised in the same animal species. Multiple immunoenzyme labeling using heat treatment is a simple, reliable and straightforward technique wherein the heat treatment prevents mixed labeling and cross-reaction. The present study determined the inactivation time for primary antibodies by heat treatment in order to apply this procedure to routine histopathological diagnosis and research, and found that the inactivation time differed among the primary antibodies. The secondary antibodies and the labeling enzyme were completely inactivated by heating for 10 min. Therefore, the inactivation of the primary antibodies is crucial to perform multiple immunoenzyme labeling using heat treatment. The sequential combination of the primary antibodies is also important; in the study presented here, an anti-thyroid transcription factor-1 (TTF-1) antibody should be used first and anti-cytokeratin AE1/AE3 antibody second, but not in the opposite sequence, to avoid a mixed-colour-labeling reaction. The present data provided the optimum combination of primary antibodies for multiple immunoenzyme labeling using heat treatment.

Involvement of IL-17F via the induction of IL-6 in psoriasis.

Recently, the important role of T helper 17 (Th17) cells in psoriasis has been clarified; however, the role of IL-17F produced by Th17 cells is still not fully understood. IL-6 exhibits multiple biologic functions, such as regulation of immunological responses including those in psoriatic reactions. Therefore, we examined the production of IL-6 protein in normal human epidermal keratinocytes (NHEKs) stimulated by IL-17F, TNF-alpha, IL-17A, and IL-17A in combination with TNF-alpha, and PBS control. We then examined the expression of IL-6 mRNA in mouse skin after intradermal injection of IL-17F. Finally, IL-17F expression in skin biopsy specimens from psoriasis patients was examined by immunohistochemistry. The results showed that IL-17F induced production of IL-6 in NHEKs in a time-dependent manner. This could be attenuated by chimeric inhibitor blocking the IL-17 receptor. The amounts of IL-6 stimulated by IL-17F were much higher than those stimulated by TNF-alpha or IL-17A. IL-6 was also significantly upregulated via synergistic stimulation with IL-17A plus TNF-alpha. The expression of IL-6 mRNA 24 h after IL-17F injection in the mouse skin was 3.2-fold higher than that in the control group. Immunohistochemistry of inflammatory cells in the dermis demonstrated a large number of CD4(+) T cells showing IL-17F positivity in psoriatic skin lesions, but few or none in non-lesional psoriatic skin. Our results indicate that IL-17F produced by CD4(+) T cells causes the inflammation in psoriasis partly through induction of IL-6 in keratinocytes.

Intraductal oncocytic papillary carcinoma of the pancreas showing numerous hyaline globules in the lumen.

Two cases of intraductal oncocytic papillary carcinoma (IOPC) treated surgically were analyzed on light microscopy and immunohistochemistry: that of a 61-year-old man and that of a 55-year-old man. There were no clinical symptoms in either case. Pancreatic abnormalities were discovered incidentally on CT. Various clinical examinations were carried out, and the preoperative diagnosis was intraductal papillary mucinous carcinoma (IPMC) in both cases. Surgery was performed. Macroscopic observation of tissue cross-sections indicated multilocular cystic mass containing polypoid lesions encapsulated by the dilated pancreatic duct. Histologically, the cyst walls were lined by columnar epithelial cells with complex papillary projections associated with oxyphilic cytoplasm, and they were strongly immunoreactive with anti-mitochondrial antibody in the cytoplasm. Electron microscopy showed numerous mitochondria in the cytoplasm. IOPC was diagnosed. Interestingly, amorphous hyaline globules were produced from the oxyphilic cells, which exhibited a bud-like appearance. The hyaline globules were not positive for mucin staining. No case of IPMC with hyaline globules has been reported to date. The production of hyaline globules may be related to oncocytic differentiation. It is suggested that hyaline globules should be regarded as a characteristic of IOPC.

IMP3/L523S, a novel immunocytochemical marker that distinguishes benign and malignant cells: the expression profiles of IMP3/L523S in effusion cytology.

Differentiating reactive mesothelial cells from metastatic carcinoma and malignant mesothelioma is critical in effusion cytology. Numerous immunohistochemical/cytochemical reports use various antibodies in effusion samples, and most antibodies differentiate metastatic adenocarcinoma from malignant mesothelioma, but no antibodies help distinguish malignant mesothelioma from reactive mesothelial cells. A mouse monoclonal antibody (IMP3/L523S) against KOC is a 580-amino acid oncofetal RNA-binding protein containing 4 K homology domains. IMP3/L523S has been identified in several human malignant tumors. The immunocytochemical staining profile of IMP3 was determined in 95% alcohol-fixed cytologic effusion specimens. A total of 229 cases of pleural and peritoneal effusion cytospecimens were evaluated for the study, including 39 benign effusions with reactive mesothelial cells and 190 metastatic malignant effusions. IMP3 immunoreactivity was observed in 2 (5.1%) of 39 cases of reactive mesothelial cells, 138 (72.6%) of 190 cases of malignant effusion, 4 (36.4%) of 11 cases of malignant mesothelioma, 106 (75.7%) of 140 cases of metastatic adenocarcinoma, and 8 (100%) of 8 cases of squamous cell carcinoma. The overall specificity for the diagnosis of malignancy was 94.9%, whereas the sensitivity was 72.6%. In the peritoneal effusions, the sensitivity for the diagnosis of metastatic adenocarcinoma to distinguish reactive mesothelial cells was 92.3%. In conclusion, IMP3 staining is present in many carcinomas and is not a useful marker for distinguishing between carcinomas arising in different organs. However, the IMP3 antibody is a highly specific marker for malignant lesions, and thus, IMP3 staining is useful for distinguishing neoplastic cells from reactive mesothelial cells in effusion samples.

Cytologic features and frequency of plasmacytoid dendritic cells in the lymph nodes of patients with histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease).

Histiocytic necrotizing lymphadenitis (HNL), also known as Kikuchi-Fujimoto disease, is a benign and self-limiting disease. It is histologically characterized by nodal lesions that show the infiltration of histiocytes, lymphoid cells, myeloid dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs), along with either apoptotic or karyorrhexic nuclear debris. pDCs have been proposed to be lymphoid early-committed immature DCs which are positive for CD123, CD303, CD68, and HLA-DR but negative for fascin, a mature DC marker, as well as CD13 and CD33,which are mDC markers. In the present study, we analyzed the cytomorphologic features and frequency of pDCs in the lymph nodes of HNL patients. Because the cytologic apprearance of pDCs with Papanicolau staining was quite similar to that of large lymphocytes, immunocytochemistry against CD123 was necessary for the distinction of pDCs. Counting the number of CD123-positive pDCs in the HNL lymph nodes revealed that pDCs more frequently infiltrated the lymph nodes in the setting of HNL than in either reactive lymphadenitis or T and B cell lymphoma. In addition, interestingly, the numberof pDCs did not depend on the age of the HNL lesion, thus suggesting that pDCs are excellent indicators for the cytologic diagnosis of HNL.

Allelic loss of the PTEN gene and mutation of the TP53 gene in choriocarcinoma arising from gastric adenocarcinoma: analysis of loss of heterozygosity in two male patients with extragonadal choriocarcinoma.

A tumor suppressor gene at 10q23.3, designated PTEN, encoding a dual-specificity phosphatase with lipid and protein phosphatase activity, has been shown to play an essential role in the pathogenesis of a variety of human cancers. Frequent mutations and deletions of PTEN genes are found in cancer. Little is known, however, about the role that PTEN plays in the pathogenesis of a primary choriocarcinoma derived from gastric adenocarcinoma, an extremely rare choriocarcinoma, or in extragonadal retroperitoneal choriocarcinoma. In this study, genetic alterations occurring in extragonadal choriocarcinoma in two Japanese male patients were examined. Loss of heterozygosity (LOH) analysis using a polymorphic marker of the PTEN gene, IVS4+109ins/delTCTTA, revealed a hemizygous deletion of PTEN not only in the primary gastric choriocarcinoma, but also in the gastric adenocarcinoma. Microsatellite marker D12S1051 likewise showed LOH in both the primary gastric choriocarcinoma and the gastric adenocarcinoma. Mutational analysis of the TP53 gene revealed a point mutation in exon 5 (A536G), which resulted in H179R in the gastric choriocarcinoma but not in the gastric adenocarcinoma. No LOH was found for PTEN in an extragonadal retroperitoneal choriocarcinoma. Microsatellite marker D9S162 showed LOH in the extragonadal retroperitoneal choriocarcinoma, but not in the primary gastric choriocarcinoma. These results indicate that LOH of the PTEN gene and of D12S1051 is the molecular pathogenesis of the gastric adenocarcinoma, and the mutation of the TP53 gene is an additional hit for the oncogenesis of choriocarcinoma arising from gastric adenocarcinoma. However, LOH of the PTEN gene is not a common molecular event for pathogenesis of extragonadal choriocarcinoma. In addition, it was found that expression of PTEN is significantly decreased in the nuclei of syncytiotrophoblast-like cancer cells, compared with those of cytotrophoblast-like cancer cells in choriocarcinoma.