Classification of triple-negative breast cancer subtypes based on heterogeneity and comparison with basal-like carcinoma

Immunohistochemical and fluorescence in situ hybridization（FISH）methods have been implemented to characterize triple negative breast cancer（TNBC）due to the lack of expression of estrogen receptor（ER）and progesterone receptor（PgR）as well as human epidermal growth factor receptor ２（HER２）. TNBC exhibits adverse prognostic features, as both hormone and anti-HER２ therapies are ineffective, and thus chemotherapy is required. Among the intrinsic subtypes identified through gene expression analysis, the expression of ER and HER２cluster was found to be low specifically in the basal-like subtype. The basal-like subtype exhibits mammary myoepithelial cell（or basal cell）-like gene expression pattern. Most of the cells were triple negative in immunohistochemical method, and exhibited a characteristic expression of myoepithelial or basal cell markers, such as cytokeratin（CK）５／６, CK１４, CK１７, p６３, and epidermal growth factor receptor（EGFR）. Basal-like carcinoma is similar to TNBC in terms of histology and clinical features. Here, we have presented some of our study results indicating the characteristics of TNBC and basal-like phenotype. TNBC is a heterogeneous disease, and ongoing research is aimed at developing individualized treatment based on its biological characteristics. However, the effective treatment methods and therapeutic efficacy predictors are yet to be discovered. Recently, targeted therapies for TNBC, including the poly（ADP-ribose）polymerase（PARP）inhibitors for germline BRCA mutation-associated breast cancer and immune checkpoint inhibitors, have been approved. Moreover, the level of programmed death ligand１（PD-L１）in tumor-infiltrating immune cells is determined using the histopathological analysis of specimens to assess the effect of immune checkpoint inhibitors. In this review, the classification of TNBC subtypes and characteristics of basal-like carcinoma has been discussed

Pathological diagnosis to support medical care

Pathological diagnosis is useful for the personalization of cancer treatment including that for breast cancer. Breast cancer is subtyped by hormone receptors, Ki-６７ and human epidermal growth factor receptor ２（HER２）. Immunohistochemistry of tumor specimens is performed to determine the expression of these factors, with different treatments administered for each subtype, such as endocrine therapy, HER２-targeted therapy and chemotherapy. In addition, to ascertain the indications for immune checkpoint inhibitors, the status of programmed death ligand １（PD-L１）on tumor-infiltrating immune cells is also determined by the histopathology of specimens. Pathologists examine the effects of neoadjuvant treatment on patient samples obtained during surgery. Such information is useful for guiding the selection of subsequent appropriate therapeutic strategies. Cancer genomic panels using formalin-fixed, paraffin-embedded（FFPE）blocks of pathological samples enable the examination of many important genes and biomarkers that may indicate if a targeted therapy or a clinical trial is suitable for that patient. Clinicians, pathologists, and laboratory technicians work together to correctly handle such specimens to prevent the deterioration of the nucleic acid contained within the blocks. Pathologists review sections of samples on glass slides to assess the sample quality and enable selection of the optimal FFPE blocks. Evaluating tumor content and indicating tumorous regions within sections are also important tasks for pathologists. Furthermore, the suitability of any potential therapy is discussed with the pathologists based on their findings. Routine pathological diagnosis and cancer genome diagnosis are closely related, and pathologists require knowledge of genomic diagnosis technology. However, the most important aspect for optimal treatment is a quick and accurate pathological diagnosis to support the provision of high-quality medical care

キョウマク チュウヒシュ ノ ソシキ シンダン ニオケル モンダイテン

This minireview discusses diagnostic issues of mesothelioma by immunohistochemical markers．A large number of immunohistochemical markers for distinction between pleural mesothelioma and pulmonary adenocarcinoma has been reported to date．Ordóñez, N.G. described that calretinin, cytokeratin 5/6 and WT-1 are the best positive markers, and carcinoembryonic antigen （CEA）, MOC-31 and Ber-EP 4 are the best negative markers for mesothelioma, and recommended the selection of two positive and two negative markers．We evaluated the significance of calretinin, cytokeratin 5/6, mesothelin，CEA, MOC-31 and new marker D 2-40 in 19 mesotheliomas and 19 lung adenocarcinomas．We concluded that calretinin, cytokeratin 5/6，D 2-40 and CEA are the most stable immunohistochemical markers for diagnosis of mesothelioma

キョウマク チュウヒシュ ノ ソシキ シンダン ニオケル モンダイテン

This minireview discusses diagnostic issues of mesothelioma by immunohistochemical markers．A large number of immunohistochemical markers for distinction between pleural mesothelioma and pulmonary adenocarcinoma has been reported to date．Ordóñez, N.G. described that calretinin, cytokeratin 5/6 and WT-1 are the best positive markers, and carcinoembryonic antigen （CEA）, MOC-31 and Ber-EP 4 are the best negative markers for mesothelioma, and recommended the selection of two positive and two negative markers．We evaluated the significance of calretinin, cytokeratin 5/6, mesothelin，CEA, MOC-31 and new marker D 2-40 in 19 mesotheliomas and 19 lung adenocarcinomas．We concluded that calretinin, cytokeratin 5/6，D 2-40 and CEA are the most stable immunohistochemical markers for diagnosis of mesothelioma

Metastatic tumor to the orbital cavity

Metastatic tumors to the orbit of the eye, especially from primary carcinomas of the uterine cervix are very rare. A 64-year-old woman with a history of carcinoma of the uterine cervix presented with right eye pain and blepharoptosis for 2 weeks. Magnetic resonance imaging revealed a mass at the right orbital apex. Surgical extirpation was performed due to severe pain. Postoperative pathology demonstrated a poorly differentiated squamous cell carcinoma. The origin was ultimately considered to be the carcinoma of the uterine cervix. In conclusion, this report describes a rare case of a metastatic tumor at the orbital apex derived from the cervix of the uterus

Inhibition of EP2/EP4 signaling abrogates IGF-1R-mediated cancer cell growth : Involvement of protein kinase C-θ activation

Associations between growth factor receptor-mediated cell signaling and cancer cell growth have been previously characterized. Receptors for prostaglandin E2, such as EP2, and EP4, play roles in cancer growth, progression and invasion. Thus, we examined the interactions between EP2/EP4- and IGF-1R-mediated cellular signaling in human pancreatic cancer cells. Selective antagonists against EP2 and EP4 abrogated IGF-1-stimulated cell growth and suppressed MEK/ERK phosphorylation. In subsequent experiments, phospho-antibody arrays indicated increased phosphorylation levels of protein kinase C-θ (PKC-θ) at the Thr538 position following the inhibition of EP2/EP4-mediated signaling. Inhibition of PKC-θ activity impaired cell viability compared with EP2/EP4-antagonized IGF-1-stimulated cells. PKC-θ kinase MAP4K3, which plays a pivotal role in PKC-θ activation, also affected growth signaling in the presence of EP2/EP4 antagonists. Administration of EP2 and EP4 antagonists significantly inhibited the growth of an orthotopic xenograft of IGF-1-secreting pancreatic cancer cells, with increased phospho-PKC-θ and decreased phospho-ERK. Clinico-pathological analyses showed that 17.4% of surgical pancreatic cancer specimens were quadruple-positive for IGF-1R, EP2 (or EP4), MAP4K3, and PKC-θ. These results indicate a novel signaling crosstalk between EP2/EP4 and IGF-1R in cancer cells, and suggest that the MAP4K3-PKC-θ axis is central and could be exploited as a molecular target for cancer therapy

Subtype and targeted therapy for TNBC

Triple-negative breast cancer (TNBC) is a heterogenous disease. For personalized medicine, it is essential to identify and classify tumor subtypes to develop effective therapeutic strategies. Although gene expression profiling has identified several TNBC subtypes, classification of these tumors remains complex. Most TNBCs exhibit an aggressive phenotype, but some rare types have a favorable clinical course. In this review, we summarize the classification and characteristics related to the various TNBC subtypes, including the rare types. Therapeutic methods that are suitable for each subtype are also discussed. Of the intrinsic breast cancer subtypes identified by gene expression analysis, the basal-like subtype specifically displayed decreased expression of an estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) cluster. We also present results that characterize the TNBC and basal-like phenotypes. TNBC may be categorized into four major classes : basal-like, immune-enriched, mesenchymal, and luminal androgen receptor. Therapeutic strategies for each subtype have been proposed along with newly approved targeted therapies for TNBC, such as immune checkpoint inhibitors. Understanding the classification of TNBC based on gene expression profiling in association with clinicopathological factors will facilitate accurate pathological diagnosis and effective treatment selection

Twin Rectal Tonsils Mimicking Carcinoid or Mucosa-Associated Lymphoid Tissue Lymphoma

The rectal tonsil is a rare polypoid lesion exclusively found in the rectum and is considered a reactive proliferation of the lymphoid tissue. Although this lesion is benign, we recommend that it should be differentiated from carcinoid or polypoid type of mucosa-associated lymphoid tissue lymphomas, based on gross findings. In this case report, we describe a case of rectal lesions with a unique appearance in a 41-year-old man. Colonoscopy revealed two 5-mm-sized nodules located opposite from each other on the left and right sides of the lower rectum. Endoscopic mucosal resection was conducted. Histopathologically, both lesions were mainly located in the submucosa and consisted of prominent lymphoid follicles with germinal centers of various sizes. No immunoreactivity of Bcl-2 was seen in the germinal centers. Immunohistochemical staining for kappa and lambda light chains revealed a polyclonal pattern. Therefore, these lesions were diagnosed as rectal tonsils