Kumiko Nakazawa

Amplification and overexpression of c-erbB-2, epidermal growth factor receptor, and c-met in biliary tract cancers

Carcinomas of the biliary tract have a poor prognosis. It is important to understand the molecular genetic characteristics of these tumours in order to employ newer effective treatments and to improve patient prognosis. There is increasing evidence that overexpression of tyrosine kinase growth factor receptors such as ErbB‐2, epidermal growth factor receptor (EGFR), and Met may play important roles in the development of biliary tract carcinomas. The aim of this study was to assess the potential for novel chemotherapies targeting these receptors. Overexpression of the tyrosine kinase receptor proteins was examined by immunohistochemistry in 221 biliary tract carcinomas, of which 28 were from the intrahepatic bile duct, 78 from the extrahepatic bile duct, 89 from the gall bladder, and 26 from the ampulla of Vater. Positively stained tumours were further examined for gene amplification by fluorescence in situ hybridization. Overexpression of ErbB‐2 was found in 15.7%, 11.5%, and 5.1% of carcinomas of the gall bladder, ampulla of Vater, and extrahepatic bile duct, respectively, and gene amplification was present in 79% of these. Overexpression of EGFR was found in 8.1% of tumours with no predominant location and was also associated with gene amplification with high frequency (77%). Met overexpression, most frequent in intrahepatic bile duct carcinomas (21.4%), was not associated with gene amplification. It is proposed that the new adjuvant chemotherapies could be directed to carcinomas of the biliary tract in which ErbB‐2 and EGFR are overexpressed. Copyright

Expression of the LIM Proteins Paxillin and Hic-5 in Human Tissues

The LIM domain is a protein-protein interaction motif critically involved in a variety of fundamental biological processes, including cytoskeletal organization, cell lineage specification, and organ development. In this study we examined the expression of the LIM proteins paxillin and Hic-5 in adult human tissues by immunohistochemistry and immunoblotting. Paxillin expression was widespread and observed both in non-muscle and muscle tissues. Of the latter, paxillin was mainly expressed in multinuclear striated muscle. In contrast, Hic-5 showed restricted expression and was expressed in muscle tissues, mainly in mononuclear smooth muscle. Taken together with previous findings, it appears likely that the counterbalance between paxillin and Hic-5 may be deeply involved in muscle differentiation.

Estimation of prognoses for cervical intraepithelial neoplasia 2 by p16INK4a immunoexpression and high-risk HPV in situ hybridization signal types

The present study used immunohistochemical staining and in situ hybridization (ISH) to examine whether progression of cervical intraepithelial neoplasia, grade 2 (CIN 2) can be predicted by p16INK4a immunoexpression and high-risk human papilloma virus (HPV) ISH signal types. We studied 52 cases histologically diagnosed with CIN 2: dysplasia regressed in 28 cases; 13 cases progressed to CIN 3; and CIN 2 persisted in 11 cases. Expression of p16INK4a and high-risk HPV signal both related to grade of CIN. Stronger p16INK4a immunoexpression and a higher frequency of expression of a punctate nuclear signal were observed in CIN 2 lesions before progression compared with those before regression. CIN 2 cases in which moderate to strong immunoexpression of p16INK4a and a punctate signal were observed simultaneously progressed to CIN 3 in 10 (91%) of 11 cases. CIN 2 cases with moderate to strong immunoexpression of p16INK4a and a high-risk HPV punctate signal should be treated because of the great risk of progression.

p16INK4a Expression Analysis as an Ancillary Tool for Cytologic Diagnosis of Urothelial Carcinoma

We immunochemically studied p16(INK4a) expression in 116 urine cytologic samples and compared results with 190 histologic samples. The cytologic samples were classified into 4 groups: 1, mild cellular atypia; 2, moderate cellular atypia; 3, severe cellular atypia; and 4, malignancy. Overexpression of p16(INK4a) was detected in none of 32 cases in group 1, 8 (16%) of 50 cases in group 2, 5 (42%) of 12 cases in group 3, and 11 (50%) of 22 cases in group 4. In addition, by histologic analysis, p16(INK4a) overexpression was not detected in nonneoplastic urothelium, except for a few cases of reactive atypia, but it was detected in about 50% of urothelial carcinomas. In particular, a high incidence (16/20 [80%]) of p16(INK4a) overexpression in high-grade carcinomas was noted in cytologic samples. Immunocytologic analysis of p16(INK4a) expression in cytologic samples is a useful ancillary tool for detection of urothelial carcinoma with infiltrating potential.

Fine-needle aspiration biopsy of low-grade cribriform cystadenocarcinoma of the salivary gland

Low‐grade cribriform cystadenocarcinoma (LGCCC) is a rare tumor, defined in the 2005 WHO classification as a primary salivary duct tumor. Previously, the neoplasm had been recognized as a variant of salivary duct carcinomas. A 56‐year‐old Japanese woman noticed a mass in the left subaural region. On radiological examinations, a multicystic tumor was seen in the left parotid gland. Fine‐needle aspiration biopsy was performed. The smears revealed several characteristic cytologic features. The tumor cells were arranged in irregular overlapping and showed inconspicuous nuclear atypia with variable‐sized and irregularly shaped cytoplasmic vacuoles. Based on these findings, a cystic tumor with uncertain malignancy was diagnosed. A parotidectomy was performed, because the tumor was slowly growing and contained solid components on the radiological images. Based on the histologic findings, along with immunohistochemistry, LGCCC was diagnosed based on resemblance to breast low‐grade ductal carcinoma in situ and intraductal proliferation of tumor cells. This is the first report of the cytomorphological findings of LGCCC. Diagn. Cytopathol.2011;39:218–222.

Extranodal NK/T-cell lymphoma, nasal type of the uterine cervix: A case report.

We report a rare case of extranodal NK/T‐cell lymphoma, nasal type of the uterine cervix that showed cytologic features mimicking cervical cancer. A 65‐year‐old woman presented with vaginal bleeding. Gynecological examination revealed a bulky tumor of the cervix. A conventional Papanicolaou‐stained cervical smear showed hypercellularity consisting of numerous variably sized cohesive clusters that mimicked epithelial tumors, with a necrotic and inflammatory background. A small number of individually scattered cells were also identified. These scattered cells showed pleomorphic, often cleaved, or horseshoe‐shaped nuclei and pale cytoplasm. Biopsy specimens revealed a diffuse growth of atypical cells with an angiocentric pattern. Extensive necrosis and infiltration of inflammatory cells were present. There were numerous mitotic figures. The tumor cells were positive for CD45RO, CD3ε, CD56, granzyme B, TIA‐1, CD7, and Epstein–Barr virus (EBV)‐encoded small RNA (EBER) by in situ hybridization, and negative for cytokeratin, chromogranin A, synaptophysin, CD4, CD5, CD8, CD20, and CD30. Based on these findings, this tumor was diagnosed as extranodal NK/T‐cell lymphoma, nasal type of the uterine cervix. Diagn. Cytopathol. 2016;44:430–433.

Pancreatic acinar cells in adult human islets of Langerhans.

Pancreatic acinar cells within the islets of Langerhans in human pancreas were investigated both histopathologically and electron microscopically. Acinar cells inside the islets of Langerhans were observed in all 50 adult cases investigated. Between such acinar cells and endocrine tissues, no reticular fiber was observed; they were encapsulated together instead. The acinar cells were immunostained with antiamylase similar to the “extrainsular” acinar cells and were also connected to the small pancreatic duct. Electron microscopically, intercellular junctions of the desmosomal type were found between the acinar cells and the adjacent endocrine cells. Therefore, the acinar cells within the islets of Langerhans were true acinar cells, based on the incomplete demarcation between the islets and the acinar tissue.

Cytologic features of ovarian granulosa cell tumors in pleural and ascitic fluids.

Adult granulosa cell tumor (AGCT) is an uncommon neoplasm of the ovary with potential for aggressive behavior and late recurrence. The most important prognostic factor for AGCT is tumor stage. Thus, cytological assessment of pleural or ascitic fluids is crucial for initial staging and subsequent patient management. We report herein two cases of ovarian AGCT presenting with exfoliated tumor cells in pleural and ascitic fluid. The first case involved a 61‐year‐old woman who presented with stage Ic (a) AGCT. Seven years after initial diagnosis, pleural effusion and pleural dissemination were identified. The second case involved a 50‐year‐old woman who presented with stage IV AGCT with massive ascites and right pleural effusion. Fluid cytology from both cases showed cohesive or loose clusters of small uniform neoplastic cells with round‐to‐oval nuclei, coffee‐bean‐shaped nuclear grooves, small nucleoli, and scant cytoplasm. Call‐Exner bodies were also observed in these cytologic specimens. In the differential diagnosis of small monomorphic tumor cells in pleural effusion or ascites, coffee‐bean‐shaped nuclear grooves and cell clusters forming Call‐Exner bodies are diagnostic clues of AGCT. Diagn. Cytopathol. 2015;43:581–584.

Unusual thyroid carcinoma with excessive extracellular hyaline globules: a case of "hyalinizing papillary carcinoma".

We present an unusual case of papillary thyroid carcinoma in a 47-year-old Japanese woman. The tumor, 0.8 cm in diameter, was located in the upper left lobe of the thyroid. Histologically, we observed a microfollicular-like and trabecular arrangement of the tumor cells with marked hyalinized stroma and hyaline globules. Immunohistochemically, tumor cells were positive for thyroglobulin and thyroid transcription factor 1. Hyaline stroma and globular bodies were immunopositive for laminin and type IV collagen. MIB-1 index was approximately 1% without membranous immunoreactivity. Under the electron microscope, hyaline stroma and globules showed electron-dense, complex meshwork structures composed of granular and fibrous elements similar to the structure of the lamina densa. Genetic analysis demonstrated a BRAF(V600E) mutation. Based on these findings, we diagnosed the present tumor as a rare morphological variation of papillary thyroid carcinoma with excessive hyaline globules consisting of basal membrane materials.

A case of endocervical minimal deviation adenocarcinoma with varicolored cytopathologic features on Pap smear

We report a case of minimal deviation adenocarcinoma (MDA) of the uterine cervix showing varicolored cytopathologic features on Papanicolaou (Pap) smear, which may indicate features suggestive of lobular endocervical glandular hyperplasia (LEGH)‐adenocarcinoma sequence. A 57‐year‐old woman presented with a profuse amount of watery vaginal discharge. Gynecological examination revealed a cervical mass with involvement of the right parametrium. Conventional Pap smear showed hypercellularity consisting of approximately 4 types of clusters as follows: (1) clusters showing a monolayered honeycomb sheet of endocervical cells with golden‐yellow mucin and bland nuclei, (2) three‐dimensional clusters showing varicolored mucin and irregular nuclear overlapping, (3) irregularly shaped clusters showing distorted chicken‐wire‐mesh appearance with noticeable protrusions of the nuclei and clear or faint varicolored cytoplasm, and (4) crowded clusters showing scarce mucin and nuclear atypia. The surgically resected uterus revealed LEGH‐mimicking lesion with fused papillae and a cribriform pattern in the endocervix and many glands exhibiting gastric differentiation that invaded deeper areas of the stroma with a subtle stromal reaction. Compared with histologic findings, two types of clusters, the crowded cluster with scarce mucin and the cluster with distorted chicken‐wire‐mesh‐type appearance, were considered as adenocarcinoma, and the latter was interpreted as a gastric‐type adenocarcinoma. Three‐dimensional varicolored type clusters showed atypical features, but insufficient atypical features compared with those of adenocarcinoma. Detection of clusters with varicolored mucin on conventional Pap smear may provide a clue for the early recognition of the malignant potential of LEGH on cytology. The chicken‐wire‐mesh type clusters may be a characteristic cytologic finding of MDA.