HEG1, BAP1, and MTAP are useful in cytologic diagnosis of malignant mesothelioma with effusion.

BACKGROUND: The specificity and sensitivity of HEG1 for malignant mesothelioma (MM) is high. The use of BAP1/MTAP immunohistochemistry (IHC) is recommended to separate benign and malignant mesothelial proliferations. We determined how ancillary techniques can be used for the cytological diagnosis of MM with effusion. METHODS: Cell blocks from effusions from cases with MM, reactive mesothelial cells (RMCs), and carcinomas were analyzed by IHC with HEG1, BAP1, and MTAP and with homozygous deletion (HD) of CDKN2A by fluorescence in situ hybridization. Staining scores were calculated for IHC by adding the number of categories for the staining intensity and the staining extension. RESULTS: HEG1 was positive in all (41/41) MMs, but negative in carcinomas, except for ovarian carcinomas. Overall 76.9% (20/26) of RMCs and 28.6% (6/21) of ovarian carcinomas expressed HEG1. BAP1 loss was found in 71.1% of MMs, but none was found in RMCs. MTAP loss was found in 76.2% of MMs, but none was found in RMCs. 73.9% of MMs harbored HD of CDKN2A. There was concordance between loss of MTAP and HD of CDKN2A in 95% of MMs. CONCLUSION: HEG1 is a good marker for mesothelial differentiation in effusion cytology. HD of CDKN2A is frequently observed in cell blocks from effusions of MMs, and MTAP IHC may act as a surrogate for HD of CDKN2A. Cell block analysis is recommended for effusions of unknown origins with the following methods: IHC with HEG1 and claudin 4 to validate the mesothelial origin, followed by BAP1 and MTAP IHC to confirm malignancy.

ALK Rearrangement Adenocarcinoma with Histological Transformation to Squamous Cell Carcinoma Resistant to Alectinib and Ceritinib.

Specific tyrosine-kinase inhibitors (TKIs) are widely used for the treatment of non-small-cell lung cancers with anaplastic lymphoma kinase (ALK) translocations. However, most treated patients eventually develop resistance to the TKIs. The histological transformation into small cell carcinoma is well known to be the underlying mechanism for acquired resistance; however, transformation to squamous cell carcinoma is extremely rare. We, herein, report a case of ALK rearrangement-positive adenocarcinoma that transformed to squamous cell carcinoma after administration of alectinib, and was found to be resistant to ceritinib.

Whole-lung pathology of pleuroparenchymal fibroelastosis (PPFE) in an explanted lung: Significance of elastic fiber-rich, non-specific interstitial pneumonia-like change in chemotherapy-related PPFE.

Pleuroparenchymal fibroelastosis (PPFE) is characterized by upper lobe-predominant subpleural fibroelastosis. Despite its characteristic uneven distribution, detailed whole-lung pathological features of PPFE have rarely been studied. We investigated PPFE in the explanted lungs from a 19-year-old male patient with a history of chemotherapy. Grossly, the explanted lungs showed upper lobe-predominant shrinkage with subpleural and central consolidation. Histologically, fibroelastosis was prominent in the perilobular areas and along the bronchovascular bundles. The other areas of the lung showed diffuse, non-specific interstitial pneumonia (NSIP)-like change with a characteristic increase of septal elastic fibers. In the digital image analysis, the ratio of elastic fibers to whole fibrosis (EF score) was lower in the subpleural areas than in the NSIP-like lesions, but the EF scores of the latter showed no significant difference between upper and middle/lower lobes. In the present case, the diffusely distributed elastic fiber-rich NSIP-like change, probably caused by the earlier chemotherapy, may have been conducive to the development of PPFE. This suggests that some unknown vulnerability of the upper lobe may exist, various primary lesions converging to the upper lobe predominance of PPFE.

Tocilizumab-effective multicentric Castleman's disease with infiltration of eosinophil and IgG4-positive plasma cells: A case report.

A 67-year-old woman with fever and cough was diagnosed with eosinophilic pneumonia because of eosinophilia and increased eosinophil levels in the bronchoalveolar lavage fluid and transbronchial biopsy lung specimens. However, prednisolone therapy at a previous hospital was ineffective. Histological findings from thoracoscopic lung and lymph node biopsies were consistent with multicentric Castleman's disease (MCD). Since specimens also showed prominent eosinophil and IgG4-positive plasma cell infiltration, it was difficult to distinguish IgG4-related disease (IgG4-RD) from MCD. Administration of prednisolone plus tocilizumab improved the symptoms and lung lesions, and prednisolone administration was successfully reduced and then terminated. The present case highlights the difficulty in diagnosing MCD and IgG4-RD, and suggests that combined administration of tocilizumab and prednisolone might be effective in such a case.

Successful diagnosis of an occult fallopian tube carcinoma detected from the diaphragm metastasis.

We herein reported a rare case of an occult fallopian tube carcinoma first detected from the diaphragm metastasis. An 83-year-old woman who had a 30-mm tumor on the right diaphragm underwent radical resection. Pathologically, the tumor was diagnosed as a high-grade serous adenocarcinoma, suggesting metastasis from the pelvic visceral carcinoma. Although the primary site could not be detected by imaging examinations, laparoscopy revealed multiple peritoneal disseminations; therefore, total hysterectomy was performed. Finally, microscopic tumor invasion into the right fimbriae of the fallopian tube was found. A precise and detailed pathological and immunohistochemical examinations of the resected metastatic diaphragm tumor helped us obtain a proper diagnosis of the primary lesion and treat the patient appropriately. Since it is difficult to diagnose diaphragm tumors before surgery based on the anatomy, surgical options have played an important role in their treatment and diagnosis clinically.

Therapeutic Effects of XPO1 Inhibition in Thymic Epithelial Tumors.

Exportin 1 (XPO1) mediates nuclear export of many cellular factors known to play critical roles in malignant processes, and selinexor (KPT-330) is the first XPO1-selective inhibitor of nuclear export compound in advanced clinical development phase for cancer treatment. We demonstrated here that inhibition of XPO1 drives nuclear accumulation of important cargo tumor suppressor proteins, including transcription factor FOXO3a and p53 in thymic epithelial tumor (TET) cells, and induces p53-dependent and -independent antitumor activity in vitro Selinexor suppressed the growth of TET xenograft tumors in athymic nude mice via inhibition of cell proliferation and induction of apoptosis. Loss of p53 activity or amplification of XPO1 may contribute to resistance to XPO1 inhibitor in TET. Using mass spectrometry-based proteomics analysis, we identified a number of proteins whose abundances in the nucleus and cytoplasm shifted significantly following selinexor treatment in the TET cells. Furthermore, we found that XPO1 was highly expressed in aggressive histotypes and advanced stages of human TET, and high XPO1 expression was associated with poorer patient survival. These results underscore an important role of XPO1 in the pathogenesis of TET and support clinical development of the XPO1 inhibitor for the treatment of patients with this type of tumors. Cancer Res; 77(20); 5614-27. ©2017 AACR.

Coronary ostium occlusion by coronary cusp displacement in Williams syndrome.

Williams syndrome is a contiguous gene deletion syndrome resulting from a heterozygous deletion on chromosome 7q11.23, and is characterized by distinctive facial features and supravalvular aortic stenosis (SVAS). This syndrome rarely presents unpredictable cardiac death, and yet, as illustrated in the present case, it is still not possible to predict it, even on close monitoring. We herein describe the case of a 6-year-old Japanese girl with Williams syndrome, who had sudden cardiac collapse due to cardiac infarction after pharyngitis. Cardiac failure followed a critical course that did not respond to catecholamine support or heart rest with extracardiac mechanical support. Although marked coronary stenosis was not present, the left coronary cusp abnormally adhered to the aortic wall, which may synergistically cause coronary ostium occlusion with SVAS. Altered hemodynamic state, even that caused by the common cold, may lead to critical myocardial events in Williams syndrome with SVAS.

A case report of pulmonary tumor thrombotic microangiopathy (PTTM) caused by esophageal squamous cell carcinoma.

A 67-year-old male was referred to our hospital after being diagnosed with esophageal squamous cell carcinoma of the middle thoracic esophagus. The clinical stage was T1b(sm)N4M1 cStage IVb, so he was admitted to our hospital for systemic chemotherapy. He had sustained fever and a dry cough. Chest computed tomography showed the presence of irregular shadows, and unidentified respiratory insufficiency had progressed. A transbronchial lung biopsy revealed a pulmonary artery tumor embolus of esophageal squamous cell carcinoma. He developed DIC and died of respiratory failure on the 19th hospital day. The postmortem autopsy detected pulmonary tumor thrombotic microangiopathy accompanied by esophageal squamous cell carcinoma.

Primary neuroendocrine carcinoma of ocular adnexa.

We present our findings in a case of primary neuroendocrine carcinoma (NEC) of the lacrimal gland and a case of primary Merkel cell carcinoma (MCC) of the eyelid. An 86-year-old man noticed a swelling of the left upper eyelid three months earlier. We performed excision biopsy and histopathological examination indicated that he had a primary NEC of the left lacrimal gland. He underwent chemotherapy followed by excision including the clinically visible margins and 50 Gy radiotherapy of the surgical margins. He had neither recurrence nor metastasis for 6 months since the last radiotherapy. An 80-year-old man noticed a nodule in the right upper eyelid and was referred to our hospital because the size was increasing rapidly. A complete surgical excision of the margins of the tumor was performed with histopathological confirmation of negative margins. The final diagnosis was a primary MCC of the right upper eyelid. After surgery, he underwent 50 Gy radiotherapy on the neck to prevent metastasis. No recurrence or metastasis was found for two years. Although primary NEC of the ocular adnexa is extremely rare, the tumor has high malignancy and readily metastasizes. Thus, combined therapy including surgery, radiotherapy, and/or chemotherapy is needed for complete management of NEC.

Adamantinoma-like Ewing family tumor of soft tissue associated with the vagus nerve: a case report and review of the literature.

Adamantinoma-like Ewing family tumor (EFT) is a rare subset of EFTs showing mixed features of Ewing sarcoma and adamantinoma of the long bones. All currently reported cases of the adamantinoma-like type have been associated with bone. Recently, a unique type of EFT was reported showing complex epithelial differentiation associated with the vagus nerve. Here we describe another unique type of EFT arising in the soft tissue of the neck associated with the vagus nerve. An 11-year-old girl presented to our hospital with a neck tumor on her right side. Surgical resection was performed, and histopathologic examination demonstrated a high-grade malignant neoplasm. The tumor was composed of sheets of small round proliferating cells, basaloid tumor nests with marked squamous differentiation, biphasic growth pattern with epithelioid tumor nests, and spindle cell proliferation. Immunohistochemically, the tumor cells showed diffuse expression of CD99 and FLI-1. In addition, small round cells and basaloid/squamoid components were immunoreactive for AE1/AE3, CAM5.2, cytokeratin 5/6, high-molecular weight keratin, p63, and p40 (ΔNp63). Reverse transcription polymerase chain reaction and direct sequencing analysis revealed that the tumor harbored a t(11;22) translocation, involving EWSR1 and FLI-1, which are characteristic of EFTs. According to these findings, our case has characteristics of both a subset of adamantinoma-like EFT and EFT with complex epithelial differentiation. We suggest that EFT with complex epithelial differentiation is in a common spectrum with the adamantinoma-like type and that adamantinoma-like EFTs can arise in soft tissue, leading to difficulty in differential diagnosis with malignant epithelial tumors.

Risk of acute exacerbation of interstitial pneumonia after pulmonary resection for lung cancer in patients with idiopathic pulmonary fibrosis based on preoperative high-resolution computed tomography.

PURPOSE: In patients with lung cancer accompanied by idiopathic pulmonary fibrosis (IPF), acute exacerbation of the IPF often occurs after pulmonary resection; however, few studies have been done to identify its preexisting risk factors. METHODS: We analyzed the high-resolution computed tomography (HRCT) findings of IPF to identify the radiological characteristics of IPF susceptible to acute exacerbation after lung cancer surgery. We reviewed retrospectively 28 lung cancer patients with IPF who underwent pulmonary resection. Clinical data, respiratory function, HRCT findings, and historical features were compared between the acute exacerbation (n = 9) and nonexacerbation (n = 19) groups. The classification of radiological findings of IPF on HRCT was done using a scoring system of seven factors related to the interstitial shadow, including fibrosis, ground-glass opacity, and low-attenuation area. RESULTS: There were no significant differences in clinical background, respiratory function, composite physiologic index, or pathological features between the groups; however, the degree of fibrosis on preoperative HRCT was significantly higher in the exacerbation group (P < 0.003). The fibrosis score was higher on the opposite side to the lung cancer in the exacerbation group (P < 0.05). CONCLUSION: Although it is difficult to predict postoperative acute IPF exacerbation, the degree and laterality of co-existing fibrosis seem to be predictors.

Primary hepatoid adenocarcinoma of the uterine corpus: A case report with immunohistochemical study for expression of liver-enriched nuclear factors.

We report a case of hepatoid adenocarcinoma of the uterus in an 86-year-old woman. Serum AFP was elevated (7824ng/ml) on admission. The surgical specimen obtained by simple hysterectomy and bilateral salpingo-oophorectomy showed an exophytic tumor, 10.5cm×6.0cm×3.7cm in size, in the uterine corpus. Microscopically, tumor cells proliferated in trabecular or cord-like arrangement, which was considered as "hepatoid appearance". An adenocarcinomatous component was intermingled. The expressions of liver-enriched transcription factors, hepatocyte nuclear factor (HNF)-1ß, HNF-3, HNF-4α, and CCAAT/enhancer binding protein (C/EBP)-ß, were investigated in the present case and in 19 cases of endometrioid adenocarcinoma (11 cases of Grade 2 and 8 cases of Grade 3), because these nuclear factors are involved in embryonal hepatogenesis. HNF-4α was diffusely positive in the present case, but negative in all cases of endometrioid adenocarcinoma. HNF-3 and C/EBP-ß were positive for the present case and control adenocarcinoma cases (HNF-3, 36.8% and C/EBP-ß, 84.2%). HNF-1ß was negative for both the present case and endometrioid adenocarcinomas. This is the first report to demonstrate HNF-4α expression in this rare uterine tumor.

Development and validation of diagnostic prediction model for solitary pulmonary nodules.

BACKGROUND AND OBJECTIVE: The aim of this study was to develop a simple prediction model for the underlying diagnosis of solitary pulmonary nodules (SPN) based on clinical characteristics and thin-section CT findings. METHODS: Retrospective analysis was carried out on 452 patients with SPN (113 benign and 339 malignant) smaller than 30 mm, who underwent thin-section CT followed by surgical resection and histological diagnosis. The clinical characteristics were collected from medical records, and radiographic characteristics from thin-section CT findings. The prediction model was determined using multivariate logistic analysis. The prediction model was validated in 148 consecutive patients with undiagnosed SPN, and the diagnostic accuracy of the model was compared with that of an experienced chest radiologist. RESULTS: The prediction model comprised the level of serum CRP, the level of carcinoembryonic antigen, the presence or absence of calcification, spiculation and CT bronchus sign. The areas under the receiver-operating characteristic curve in training and validation sets were 0.966 and 0.840, respectively. The diagnostic accuracies of the prediction model and the experienced chest radiologist for the validation set were 0.858 and 0.905, respectively. CONCLUSION: The simple prediction model consisted of two biochemical and three radiographic characteristics. The diagnostic accuracy of an experienced chest radiologist was higher compared with the prediction model.