[A Case of Breast Carcinoma That Changed Subtype to Squamous Cell Carcinoma after Chemotherapy].

Metaplastic carcinoma is a rare histological malignancy, often triple-negative, and has a poor prognosis. Here, we report a case of breast cancer in which the primary lesion degenerated into squamous cell carcinoma(triple negative)after drug treatment for invasive ductal carcinoma(Luminal type). The patient was a 41-year-old woman who was diagnosed with Stage Ⅳ left breast cancer T2N2bM1(HEP)(ER 90%, PR 70%, HER2 2+, FISH-)at another hospital and participated in the PATHWAY study(tamoxifen plus goserelin plus palbociclib/placebo). Since the primary lesion and liver metastasis increased in size, the study was discontinued after 8 weeks. She was treated at our hospital thereafter, with capecitabine plus cyclophosphamide, palbociclib plus fulvestrant plus leuprorelin, paclitaxel plus bevacizumab, eribulin, EC therapy, and docetaxel. However, both the primary lesion and liver metastasis increased. In particular, the increase in primary lesion size was remarkable, and the QOL significantly reduced due to bleeding and exudation. Biopsy performed during docetaxel treatment revealed metaplastic/squamous cell carcinoma(ER-, PR-, HER2 0, Ki-67 90-100%)histopathological findings. BRCA and microsatellite instability tests were negative, and PDL1 expression was less than 1%. Although Mohs ointment was used, tumor bleeding, exudate, and stink were poorly controlled, and the patient experienced painful symptoms due to the weight of the tumor. Therefore, left mastectomy plus pectoralis major muscle resection was performed. The patient died one month after the operation.

Elucidation of Melanogenesis Cascade for Identifying Pathophysiology and Therapeutic Approach of Pigmentary Disorders and Melanoma.

Melanogenesis is the biological and biochemical process of melanin and melanosome biosynthesis. Melanin is formed by enzymic reactions of tyrosinase family proteins that convert tyrosine to form brown-black eumelanin and yellow-red pheomelanin within melanosomal compartments in melanocytes, following the cascades of events interacting with a series of autocrine and paracrine signals. Fully melanized melanosomes are delivered to keratinocytes of the skin and hair. The symbiotic relation of a melanocyte and an associated pool of keratinocytes is called epidermal melanin unit (EMU). Microphthalmia-associated transcription factor (MITF) plays a vital role in melanocyte development and differentiation. MITF regulates expression of numerous pigmentation genes for promoting melanocyte differentiation, as well as fundamental genes for maintaining cell homeostasis. Diseases involving alterations of EMU show various forms of pigmentation phenotypes. This review introduces four major topics of melanogenesis cascade that include (1) melanocyte development and differentiation, (2) melanogenesis and intracellular trafficking for melanosome biosynthesis, (3) melanin pigmentation and pigment-type switching, and (4) development of a novel therapeutic approach for malignant melanoma by elucidation of melanogenesis cascade.

Rhabdoid glioblastoma: an aggressive variaty of astrocytic tumor.

Rhabdoid glioblastoma (RGBM) is rare, but the most malignant among astrocytic tumors. Accumulating evidence indicates its highly aggressive nature and distinct histopathological features. Here, we report a new case of RGBM and review previously reported cases of astrocytic tumors with rhabdoid components. We describe a 58-year-old man who presented with aphasia and right-sided weakness. Magnetic resonance imaging revealed a well-delineated intramedullary tumor in the left cerebral hemisphere. Partial resection of the tumor was performed. The tumor was histologically found to contain two distinct areas: a typical glioblastoma, and a rhabdoid component. Immunohistochemical analyses revealed expression of glial fibrillary acidic protein (GFAP) and focal loss of the INI1 protein in rhabdoid cells, although fluorescence in situ hybridization analysis showed no loss of the INI1 gene. Despite subsequent radiochemotherapy for the glioblastoma, the patient died 4.3 months after surgery. Our literature review illustrates the aggressive clinical course and histopathological features of these tumors with GFAP and INI1 expression. INI1 protein dysfunction may be a possible cause of the rhabdoid phenotype. Gross total resection of the tumor and intensive radiochemotherapy may lead to better survival outcomes.

Primary orbital neuroblastoma in a 1-month-old boy.

Neuroblastoma is a malignant tumor predominantly occurring in children and usually arising from the adrenal gland or sympathetic ganglia. We describe a neuroblastoma in a 1-month-old boy arising from his left orbital cavity. This tumor was refractory to chemotherapy or radiotherapy, requiring enucleation of the left eye for complete removal of the intraorbital tumor. Thereafter, he received high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation, and has been in complete remission for 3 years. Unlike neuroblastomas arising from the adrenal gland or sympathetic ganglia, primary orbital neuroblastoma may be refractory even in early infancy.

Rapid on-site evaluation by endosonographer during endoscopic ultrasound-guided fine needle aspiration for pancreatic solid masses.

BACKGROUND AND AIM: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is an established diagnostic method for patients with suspected pancreatic ductal carcinoma. Rapid on-site evaluation (ROSE) has been reported to improve the accuracy. However, an on-site cytopathologist is not routinely available in many institutions. One of the solutions may be ROSE by endosonographer. The aim was to examine whether diagnostic accuracy increases through ROSE by endosonographer using our cytological criteria. METHODS: Patients who underwent EUS-FNA of solid pancreatic masses from January 2006 to August 2009 (n = 53, period 1) and September 2009 to April 2011 (n = 85, period 2) were retrospectively identified. Before initiating ROSE at the start of period 2, two endosonographers underwent training for cytological interpretation, which was focused on four cytological features of pancreatic ductal carcinoma: anisonucleosis, nuclear membrane irregularity, overlapping, and enlargement. During EUS-FNA in period 2, endosonographers classified the Diff-Quik smears under three atypical grades and evaluated the adequacy. All diagnoses were made by one pathologist without knowledge of clinical information. RESULTS: The rate of "inconclusive" diagnoses, interpreted as "suspicious," "atypical," and "inadequate for diagnosis" was reduced from 26.4% in period 1 to 8.2% in period 2 (P = 0.004). Moreover, diagnostic accuracy was increased from 69.2% in period 1 to 91.8% in period 2 (P < 0.001). CONCLUSIONS: This cytological grading system used in ROSE by endosonographers is invaluable for the diagnosis of pancreatic solid masses.

Validity and reproducibility of Ki-67 assessment in gastrointestinal stromal tumors and leiomyosarcomas.

With the aim of standardizing Ki-67 immunohistochemistry, we assessed interobserver and interlaboratory variability of the Ki-67 labeling index and Ki-67 score among eight general pathologists for 24 gastrointestinal stromal tumors (GISTs) and 12 leiomyosarcomas, which were predominantly of the gastrointestinal (GI) tract, mesentery and retroperitoneum, based on a review of a tissue microarrays subjected to immunohistochemistry with antibodies for Ki-67. For Ki-67 immunostaining of mesenchymal tumors of the GI tract, including GISTs, differences were seen in the scores given by regional hospitals. Conversely, for two categories of the Ki-67 labeling index, namely <10% and ≥10%, concordance of the Ki-67 score between microscopic observation and image analysis, and between the observers, was good, but it was not good for the other four categories of the index for <5%, 5-9%, 10-29%, and ≥30%. The concordance of the Ki-67 scores between the observers in two categories was higher using the Ki-67 pre-stained tissue microarrays (TMAs) within each participating institute than that using the Ki-67 stained TMAs between the participating institutes. The reproducibility of a 10% cut-off value for the Ki-67 labeling index to predict the prognosis of GISTs was relatively high, but there is an urgent need to standardize the staining technique.

Detection of specific genetic abnormalities by fluorescence in situ hybridization in soft tissue tumors.

For the detection of chromosome translocations/chimeric genes and specific genetic abnormalities in soft tissue tumors, we conducted fluorescence in situ hybridization (FISH) analysis on 280 cases of soft tissue and other tumors using formalin-fixed paraffin-embedded tissue sections. The detection rate of the FISH split-signal was 84% (129/154 cases) for the translocation-associated soft tissue tumors, such as Ewing's sarcoma/primitive neuroectodermal tumor, synovial sarcoma, alveolar rhabdomyosarcoma, myxoid liposarcoma, clear cell sarcoma and so forth. Positive split-signals from EWSR1, SS18 and FOXO1A probes were detected in 3% (2/64) of various histological types of carcinoma, lymphoma, melanoma, meningioma and soft tissue tumors. In FISH using the INI1/CEP22 probe, the INI1 deletion signal was detected in 100% (9/9) of epithelioid sarcoma. In well-differentiated and dedifferentiated liposarcomas, detection of MDM2 amplification signals in FISH using the MDM2/CEP12 probe were both as high as 85% (11/13) and 100% (13/13), respectively. In other adipocytic and non-adipocytic tumors requiring differentiation from these types, detection was only 13% (5/39), and CEP12 polysomy was frequently detected. As these results demonstrate the high sensitivity and specificity of FISH, we concluded FISH to be a useful pathological diagnostic adjunct for definite and differential diagnosis of soft tissue tumors.

Detection of HEY1-NCOA2 fusion by fluorescence in-situ hybridization in formalin-fixed paraffin-embedded tissues as a possible diagnostic tool for mesenchymal chondrosarcoma.

Mesenchymal chondrosarcoma (MC) is an extremely rare subtype of chondrosarcoma. A tumor specific fusion gene, HEY1-NCOA2 fusion, was recently identified in this tumor. The finding raises the possibility that the diagnosis of MC can be improved by examining the fusion gene. In the present study, we aimed to evaluate the efficacy of fluorescence in situ hybridization (FISH) in detecting HEY1-NCOA2 fusion for the diagnosis of MC. Specimens from 10 patients diagnosed with MC were used for the study. Dual-color FISH was performed using two different probes that specifically hybridize to HEY1 and NCOA2, respectively. Fusion signals were identified in all but two specimens, in which no signal was detected, presumably because of inadequate sample preparation. In accordance with results of a previous study, FISH analysis was highly sensitive in detecting HEY1-NCOA2 fusion in adequately prepared MC samples. The current study adds further support for the use of HEY1-NCOA2 fusion as a valid diagnostic marker for MC.

Use of endoscopic ultrasound-guided fine needle aspiration of the pancreas to diagnose a case of primary linitis plastica of the colon with retroperitoneal dissemination.

A 54-year-old man had previously undergone curative sigmoidectomy for poorly differentiated adenocarcinoma with a signet-ring cell component of the sigmoid colon, which was characterized morphologically by stenosis and inelasticity of the colon (linitis plastica). Six weeks after surgery, the patient developed stenosis of the right ureter. Disseminated sigmoid cancer was suspected, and chemotherapy was started. Nine months after initiation of chemotherapy, obstructive jaundice was observed which was due to stenosis of the distal bile duct (BD). Although computed tomography showed no evident metastatic lesion that could cause the stenosis, swelling of the entire pancreas was evident compared to that of 11 months earlier. Endoscopic ultrasound (EUS) also did not detect any focal masses in the head of the pancreas, although there was a diffuse hypoechoic change in the entire pancreas. Histopathology of the stenotic BD and biopsy specimen from the head of the pancreas showed no malignant cells. Two months after the initial endoscopic bile duct drainage, the patient was admitted again for epigastric pain. A second EUS fine needle aspiration (EUS-FNA) of the head of the pancreas was performed and showed poorly differentiated carcinoma with some signet-ring cells. This finding provided histological confirmation of a disseminated pancreatic lesion of the previously resected linitis plastica of the sigmoid colon. This is a rare case of disseminated pancreatic lesion from primary linitis plastica of the colon diagnosed by EUS-FNA.

Use of tissue microarrays and immunohistochemistry to standardize the diagnosis of gastrointestinal stromal tumors.

We assessed the concordance among seven general pathologists with respect to histologic diagnosis and interpretation of c-kit proto-oncogene (KIT) and platelet-derived growth factor receptor alpha (PDGFRA) immunostaining of 36 cases of primary spindle-cell tumor, predominantly of the gastrointestinal tract, mesentery, and retroperitoneum, based on review of a tissue microarray (TMA) subjected to immunohistochemistry with antibodies to KIT/CD117, PDGFRA, vimentin, desmin, smooth muscle action, CD34, and S-100 protein. Tumors included 20 molecularly analyzed gastrointestinal stromal tumors (GISTs), 4 leiomyosarcomas, 4 schwannomas, 4 desmoid-type fibromatoses, and 4 solitary fibrous tumors. The mean overall concordance with original diagnosis for each histologic type was 91.1%, with a mean kappa value of 0.91. With respect to PDGFRA immunostaining, the four GISTs with PDGFRA mutation were interpreted as cytoplasm positive, but the 16 GISTs with c-kit mutation were interpreted as weak or positive. These results indicate that the overall concordance with original diagnosis in mesenchymal tumors with the use of immunohistochemical panels is high, despite the use of TMAs. To some extent, PDGFRA immunophenotyping may be useful in GISTs with PDGFRA mutation, but it was not highly reproducible or specific. Therefore, in KIT-negative or weakly positive GISTs, mutation analysis will be required.