Kennichi Kakudo

Observer variation in the diagnosis of follicular variant of papillary thyroid carcinoma

The histopathologic diagnosis of follicular variant of papillary thyroid carcinoma (FVPCA) can be difficult. Recent reports have suggested that this neoplasm may be frequently overdiagnosed by pathologists. We examined the observer variation in the diagnosis of FVPCA in 87 tumors by 10 experienced thyroid pathologists. The criteria that the reviewers considered most helpful for making a diagnosis of FVPCA were also assessed. A concordant diagnosis of FVPCA was made by all 10 reviewers with a cumulative frequency of 39%. In this series, 24.1% of the patients had metastatic disease (n = 21). In the cases with metastatic disease, a diagnosis of FVPCA was made by all 10 reviewers with a cumulative frequency of 66.7%, and 7 of the reviewers made a diagnosis of FVPCA with a cumulative frequency of 100%. The most important criteria used to diagnose FVPCA included the presence of cytoplasmic invaginations into the nucleus (pseudo-inclusions), abundant nuclear grooves, and ground glass nuclei. These results suggest that although the diagnosis of FVPCA is variable even among experienced thyroid pathologists, most reviewers agreed on this diagnosis for patients with metastatic disease. The use of well-defined histopathologic features should improve the consistency in diagnosing FVPCA. Since most cases with metastatic disease had obvious invasion, caution should be used in making a diagnosis of FVPCA in the absence of the major histopathologic features or clear-cut invasive growth.

Cribriform-morular variant of Papillary Thyroid Carcinoma: Clue to Early Detection of Familial Adenomatous Polyposis-associated Colon Cancer

The cribriform-morular variant (CMV) of papillary thyroid carcinoma (PTC) is a rare histologic subtype of PTC that shows a combination of growth patterns including cribriform and spindle cell areas. The thyroid cancer with this unique histology was originally reported in patients with familial adenomatous polyposis (FAP), although it was later found in patients without polyposis as well. Because of its rarity, its clinical features are not clear. We reviewed seven patients with CMV-PTC who were found among 4194 patients with PTC in our pathology files between June 1991 and March 2003. The prevalence of CMV was 0.16% among all PTCs. We invited these patients to our hospital so we could obtain a detailed family history and recommend colonoscopic examination and germline APC gene analysis. Two patients without subjective symptoms had polyposis of the colon and colon cancers. Germline APC gene mutations were found in both patients. The father of a patient who refused the invitation was revealed to have undergone surgery for colon polyposis. In the remaining four patients, neither polyposis nor APC gene mutation was found. Common clinical features included a young age (mean 25 years), predominance of females, circumscribed tumors, negative node metastasis, and no recurrence of the thyroid cancer after surgery. Two of the three patients with colon polyposis had bilateral multiple thyroid tumors, whereas the remaining four (without polyposis) had a solitary tumor. The histopathology of CMV in patients with PTC should arouse a suspicion of FAP, especially if there are multiple tumors. This finding can lead to early detection of colon cancer.

Clinicopathological Significance of Vascular Endothelial Growth Factor-C in Breast Carcinoma with Long-Term Follow-Up

Expression of angiogenic and lymphangiogenic factors by tumors may influence the route of metastatic spread. The angiogenic factor vascular growth factor-C (VEGF-C) is implicated in the development of lymphatic vessels and promotion of lymphatic metastasis. The purpose of this study was to determine whether VEGF-C correlates with lymph node metastasis or prognosis. We assessed VEGF-C expression using immunohistochemistry in 123 invasive breast carcinomas with long-term follow-up. The relationship between VEGF-C expression and lymph node status and other established clinicopathological parameters was assessed. Whether VEGF-C expression plays a prognostic role in breast cancer was also investigated. VEGF-C expression was identified in 103 cases (83.7%). Positive VEGF-C was significantly correlated with lymph node metastasis (P = 0.0131). Survival curves determined by the Kaplan-Meier method and univariate analysis demonstrated that positive VEGF-C was associated with both disease-free survival (P = 0.0165) and overall survival (P = 0.0175). On the basis of our findings, VEGF-C plays a crucial role in lymph node metastasis and may be a significant prognostic factor for long-term survival in breast cancer.

p63 expression in normal, hyperplastic and malignant breast tissues.

Backgroundp63 is a homologue of the p53 tumor suppressor gene and its protein is selectively expressed in the basal cells of a variety of epithelial tissues. It has recently been confirmed that p63 is expressed in the basal cells of normal prostate glands but not in prostatic carcinomas. Whether expression of p63 in breast correlates with tumor progression is the focus of this study.MethodsForty cases, which all contained normal breast tissue, ductal hyperplasia, ductal carcinomain situ and invasive ductal carcinoma in the same patient were included in this investigation using an indirect immunohistochemical method and double staining.Resultsp63 was exclusively expressed in the myoepithelial cells of normal breast, partially expressed in ductal hyperplasia, rarely expressed in carcinomain situ and not expressed in invasive carcinomas.ConclusionsThe results suggest an association between loss of p63 expression and progression of breast ductal carcinoma. p63 immunostaining might be of assistance for distinguishing invasive ductal carcinoma from ductal carcinomain situ or rare questionable ductal hyperplastic lesions, leading to correct therapy clinically.

Papillary carcinoma of the thyroid in Japan: subclassification of common type and identification of low risk group

Aims: Papillary thyroid carcinoma (PTC) is classified into two subgroups—common type and other histological variants. Correlations between further subgrouping of the common type and patient prognosis are not well documented. Aims: To introduce two novel histological parameters to characterise PTC—loss of cellular polarity and loss of cellular cohesiveness. To investigate a new subgroup of common type PTC with possible prognostic value. Methods: In total, 213 patients with PTCs larger than 1 cm were studied. Histological characteristics of these PTCs, including tumour growth pattern, encapsulation, extrathyroidal invasion, loss of cellular polarity, and loss of cellular cohesiveness were examined and correlated with disease free survival (DFS). Results: Multivariate analysis revealed that invasive growth of unencapsulated PTC, in addition to sex (male) and tumour size (>4 cm) were significant and independent parameters for poor DFS, whereas loss of cellular polarity and cohesiveness, old age (>60 years), extrathyroid invasion, and completeness of surgery were significant only in univariate analysis. PTCs that showed expansive growth and retained cellular polarity had a favourable course, with no recurrence and no cancer related deaths. In contrast, PTCs exhibiting loss of cellular polarity and/or invasive growth with no tumour capsule had a higher risk of recurrence. Conclusion: Cytological features alone cannot predict patient outcome in PTC. This study indicates for the first time that loss of cellular polarity and the tumour growth pattern are useful parameters for identifying the so called low risk group in common type PTC and in predicting patient outcome in terms of tumour recurrence and cancer related death.

Chromosome 3p and breast cancer

AbstractSolid tumors in humans are now believed to develop through a multistep process that activates oncogenes and inactivates tumor suppressor genes. Loss of heterozygosity at chromosomes 3p25, 3p22–24, 3p21.3, 3p21.2–21.3, 3p14.2, 3p14.3, and 3p12 has been reported in breast cancers. Retinoid acid receptor β2 (3p24), thyroid hormone receptor β1 (3p24.3), Ras association domain family 1A (3p21.3), and the fragile histidine triad gene (3p14.2) have been considered as tumor suppressor genes (TSGs) for breast cancers. Epigenetic change may play an important role for the inactivation of these TSGs. Screens for promoter hypermethylation may be able to identify other TSGs in chromosome 3p. Alternatively, use of an “epigenetic modifier” may enhance the response to another type of agent for breast cancer.

Predictive and prognostic markers for invasive breast cancer

Breast cancer is one of the most serious carcinomas among women worldwide, yet there are now encouraging signs that improvements in the mortality rate may be possible. The use of hormone therapy and chemotherapy has been widely accepted as treatment for breast cancer. Predictive factors can be used to predict response or lack of response to a particular therapy, and prognostic factors can be useful in making decisions about which patients should receive adjuvant therapy. Histopathology remains the universal basis of diagnosis, with the identification of new surrogate markers for potential new treatments. These are aimed at blocking tumor cell proliferation, neutralizing growth factors, stimulating apoptosis and blocking metastasis, and represent an integral part of new approaches for improving clinical management of patients with breast cancer. We review the standard predictive and prognostic factors that are routinely available today, and also describe some of the new, potential markers that are currently under investigation.

Prognostic value of thymidine phosphorylase expression in breast carcinoma.

Thymidine phosphorylase (TP), also known as platelet‐derived endothelial cell growth factor (PD‐ECGF), is an enzyme that catalyzes the reversible dephosphorylation of thymidine, deoxyuridine and their analogs. TP has also angiogenic properties, although the precise mechanism by which it promotes angiogenesis is not known. We examined TP expression using immunohistochemistry (654‐1 Mab) in 182 invasive breast carcinomas (67 N0 and 115 N1/2; median follow‐up 78 months [range, 3–177]; 51 patients treated with adjuvant systemic cyclophosphamide, methotrexate and 5‐fluorouracil [CMF] chemotherapy and 82 with tamoxifen). High TP expression was found in 142 cases (78%) and correlated with lower histologic grade and low p53 expression. No correlation was found between TP expression and vascular density. TP‐positive tumors had a significant increase in both disease‐free survival (DFS; p = 0.0025) and overall survival (OS; p = 0.0070) in the total cohort of patients and in the subgroups of node‐positive patients and patients treated with CMF adjuvant therapy; no significant difference in either DFS or OS was observed in patients without CMF treatment. Our findings suggest that TP has little effect on tumor angiogenesis of breast carcinoma, whereas it could represent an interesting marker that could predict response to CMF chemotherapy.

Morules in cribriform‐morular variant of papillary thyroid carcinoma: Immunohistochemical characteristics and distinction from squamous metaplasia

Morules are a diagnostic clue to the cribriform‐morular variant (C‐MV) of papillary thyroid carcinoma, and are superficially similar to squamous metaplasia. In order to clarify the histogenesis of morules and differentiate them from squamous metaplasia, we immunohistochemically compared the morules in five cases of C‐MV with squamous metaplasia in six cases of diffuse sclerosing variant (DSV) of papillary thyroid carcinoma. The squamous metaplastic cells were immunopositive for low‐ and high‐molecular‐weight cytokeratin, whereas the morular cells were negative or focally positive. Vimentin‐positive cells were observed focally in the morules and squamous metaplasia, except for one case of CMV that showed intense positivity. The morular cells showed weak cytoplasmic positivity for beta‐catenin, and the cell membrane was not highlighted. Some nuclei of the morular cells were also positive for this antibody. Beta‐catenin was intensively positive along the cell membrane of the metaplastic cells, and did not react against the nuclei or cytoplasm. Bcl‐2 was positive in the morular cells, but negative in the metaplastic cells. S‐100 protein‐positive dendritic cells were observed in the metaplastic nests, but not in the morules. We argue that morules appear in connection with nuclear and cytoplasmic aberrant localization of beta‐catenin, and are not an early form of squamous metaplasia.

Angiotensin II AT2 receptor localization in cardiovascular tissues by its antibody developed in AT2 gene-deleted mice

In contrast to well-established physiological roles of the angiotensin II type 1 receptor (AT1), the significance of the type 2 receptor (AT2) remains largely unclear. AT2-knockout (AT2KO) mice have a phenotype associated with mild hypertension. This implies that AT2 has a role for the regulation of blood pressure. To gain insight into the mechanism by which AT2 regulates systemic blood pressure, we have investigated the expression of the AT2 receptor protein in adult rat cardiovascular tissues, using a newly developed polyclonal anti-AT2 antiserum that was successfully obtained in the AT2KO mice by immunizing with a peptide fragment of the receptor protein. In blood vessels, a stronger immunoreactivity was observed in endothelial cells than in the muscular media of resistant arteries. In the thoracic aorta, AT2 was observed only in muscular media. Abundant AT2 immunoreactivity was detected in perivascular nerve fibers. In the heart, positive immunostaining for AT2 was restricted to the coronary blood vessels. These data suggest that AT2 expressed in the vascular endothelial cells and muscular media in resistant arteries may play a pivotal role in systemic blood pressure regulation. AT2 was observed for the first time in the perivascular nerve fibers and may also play a role in neuronal blood pressure regulation.