Clinical Significance of Signal Regulatory Protein Alpha (SIRPα) Expression in Hepatocellular Carcinoma.

BACKGROUND: Signal regulatory protein alpha (SIRPα), expressed in the macrophage membrane, inhibits phagocytosis of tumor cells via CD47/SIRPα interaction, which acts as an immune checkpoint factor in cancers. This study aimed to clarify the clinical significance of SIRPα expression in hepatocellular carcinoma (HCC). METHODS: This study analyzed SIRPα expression using RNA sequencing data of 372 HCC tissues from The Cancer Genome Atlas (TCGA) and immunohistochemical staining of our 189 HCC patient cohort. The correlation between SIRPα expression and clinicopathologic factors, patient survival, and intratumor infiltration of immune cells was investigated. RESULTS: Overall survival (OS) was significantly poorer with high SIRPα expression than with low expression in both TCGA and our cohort. High SIRPα expression correlated with lower recurrence-free survival (RFS) in our cohort. High SIRPα expression was associated with higher rates of microvascular invasion and lower serum albumin levels and correlated with greater intratumor infiltration of CD68-positive macrophages and myeloid-derived suppressor cells (MDSCs). Multivariate analysis showed that SIRPα expression and high infiltration of CD8-positive T cells and MDSCs were predictive factors for both RFS and OS. Patients with high SIRPα expression and infiltration of CD8-positive T cells and MDSCs had significantly lower RFS and OS rates. In spatial transcriptomics sequencing, SIRPα expression was significantly correlated with CD163 expression. CONCLUSIONS: High SIRPα expression in HCC indicates poor prognosis, possibly by inhibiting macrophage phagocytosis of tumor cells, promoting MDSC infiltration and inducing antitumor immunity. Treatment alternatives using SIRPα blockage should be considered in HCC as inhibiting macrophage antitumor immunity and MDSCs.

[Usefulness of Metal Artifact-reduced Reconstruction for Image-guided Brachytherapy for Cervical Cancer].

PURPOSE: To evaluate the usefulness of single-energy metal artifact reduction (SEMAR) for target delineation in brachytherapy for cervical cancer patients with metal hip implants. MATERIAL AND METHODS: A series of four definitive brachytherapy sessions in the same patient was analyzed. At each brachytherapy session, the identical set of computed tomography images was subjected with or without SEMAR treatment. For both SEMAR-treated and -untreated sets, five radiation oncologists delineated the high-risk clinical target volume (HR-CTV), bladder, and rectum, for which the volume, Dice coefficient, and the dose volume parameters were compared between SEMAR-treated and -untreated datasets. RESULTS: The bladder volume was significantly greater in the SEMAR-treated datasets compared with the SEMAR-untreated datasets. Importantly, for the bladder, Dice coefficient among five radiation oncologists was significantly higher for the SEMAR-treated datasets compared with the SEMAR-untreated datasets. These effects of SEMAR treatment were not evident for HR-CTV and the rectum. CONCLUSIONS: These data indicate that SEMAR treatment contributes to improve delineation of the bladder in brachytherapy for cervical cancer patients with metal hip implants.

Membranous HEG1 expression is a useful marker in the differential diagnosis of epithelioid and biphasic malignant mesothelioma versus carcinomas.

Sialylated HEG1 has been reported as a highly specific and sensitive mesothelioma marker but a comprehensive evaluation of its expression in carcinomas in different organs, various sarcomas and reactive mesothelial proliferations has not been reported. The aim of this study was to evaluate the clinical applicability of HEG1 as a marker in the diagnosis of mesothelioma. HEG1 immunoreactivity was evaluated in whole sections of 122 mesotheliomas, 75 pulmonary carcinomas, 55 other carcinomas, 16 mesenchymal tumors, and 24 reactive mesothelial proliferations and in tissue microarrays containing 70 epithelioid (EM), 36 biphasic (BM), and 2 sarcomatoid mesotheliomas (SM). In whole sections and tissue microarrays, respectively, membranous HEG1 was expressed in 93.0% and 85.5% of EM, 81.3% and 69.4% of BM, 0% and 0% of SM. HEG1 was not expressed in pulmonary adenocarcinomas. HEG1 was expressed as cytoplasmic immunoreactivity in pulmonary squamous cell carcinomas (21.7%). Membranous HEG1 staining was seen in ovarian carcinomas (66.7%), thyroid carcinomas (100%), reactive conditions (16.7%), and mesenchymal tumors (18.8%). The sensitivity of membranous HEG1 expression to distinguish EM/BM from all carcinomas was 88.8%. The specificity for the differential diagnosis between EM/BM and all carcinomas and pulmonary carcinomas was 92.3% and 98.7%, respectively.

[A Case of Intrahepatic Cholangiocarcinoma Confused with a Recurrent Hepatocellular Carcinoma Treated by RFA at Diagnosis].

Intrahepatic cholangiocarcinoma(ICC)is the second most common malignant liver tumor after hepatocellular carcinoma (HCC). ICC is usually ischemic; however, it has variable findings and may be difficult to differentiate from HCC. We report about a case of ICC that was difficult to distinguish from HCC treated by radiofrequency ablation(RFA). A 79‒year‒old woman underwent RFA for HCC of the caudate lobe. Two years after RFA, a spindle‒shaped tumor was identified near the previous treatment site using contrast‒enhanced MRI. Images showed posterior segment bile duct dilation, posterior segment atrophy of the liver parenchyma, and posterior segmental portal vein disruption. We performed surgery because of the suspicion of a recurrent HCC invading into the bile duct. Intraoperative findings showed posterior segment atrophy. Intraoperative echocardiography could not identify the tumor but revealed a tumor plug and portal vein disruption in the posterior segment. The patient underwent post‒enlargement segmentectomy, caudate lobectomy of the liver, and biliary neoplastic resection. Histopathological findings showed no malignant findings in the hepatocytes. A moderately differentiated adenocarcinoma was found in the expanded bile duct, which was diagnosed as an intrahepatic cholangiocarcinoma. Here, we report about the case along with a discussion and a bibliographical consideration.

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.

Recurrent Neurological Episodes for 10 Years Preceding Skin Lesions in Neuro-Sweet Disease.

An absence of skin lesions at the neurological onset may obscure the diagnosis of neuro-Sweet disease (NSD). We herein report a 32-year-old man with NSD in whom neurological symptoms preceded the development of skin lesions by 10 years. The patient exhibited four distinct neurological episodes: meningoencephalitis, scattered brain lesions, ocular flutter, and isolated seizures. Acute relapses responded to corticosteroid therapy, and the patient was successfully maintained on corticosteroid and dapsone combination therapy. NSD should be considered in the differential diagnosis of patients with recurrent neurological manifestations, especially with both meningeal and brain parenchymal involvement, even if no skin lesions are observed.

[Occult Breast Carcinoma and Recurrent Tumor in the Breast 14 Years after Axillary Dissection-A Case Report].

We report a patient with occult breast cancer who underwent axillary dissection as primary surgery. The patient, a 68-yearold woman, noticed a tumor measuring approximately 3 cm in diameter, in her left axilla. Biopsy of the axillary tumor revealed adenocarcinoma. Imaging studies did not detect primary lesions in the mammary gland or other organs. The patient was diagnosed with occult breast cancer and underwent axillary dissection but did not desire mastectomy or radiation therapy. The patient was closely observed thereafter. Tamoxifen was prescribed for 5 years but left breast cancer was detected 14 years after the operation. A simple mastectomy was performed. She died of respiratory failure 1 year later. Occult breast cancer may require axillary lymph node dissection and systemic therapy. Breast preservation could be an alternative treatment if followed by adequate systemic therapy and close observation.

[A Rare Case of Gastric Metastasis from Cholangio Carcinoma].

An 80-year-old man was referred to our hospital because of jaundice and fatigue. Abdominal computed tomography(CT) scan revealed an extrahepatic bile duct tumor, and biliary cytology detected adenocarcinoma; therefore, subtotal stomachpreserving pancreaticoduodenectomy was performed. Histological analysis showed that the tumor was a well-differentiated adenocarcinoma without lymph node metastasis. Two years after the initial surgery, blood examination detected an elevated serum CA19-9 level and submucosal tumor which is 2.5 cm diameter with an ulcer at the gastrojejunostomy anastomosis. Tumor biopsy was performed, and histological analysis revealed a recurrent cholangiocarcinoma. The tumor directly invaded the transverse colon mesentery; therefore, distal gastrectomy and right hemicolectomy were performed. The patient survived 12 months postoperatively without recurrence. Gastric metastasis from cholangiocarcinoma rarely occurs. Intraoperative exposure of bile juice may have caused gastric metastasis in this case.

[A Case of Pancreatic Mixed Acinar-Neuroendocrine Carcinoma with Main Pancreatic Duct Development].

A 78-year-old man was referred to our hospital owing to a pancreatic tumor detected on ultrasonography. He showed weight loss, and his diabetes mellitus had worsened over 3 months. Abdominal contrast-enhanced computed tomography revealed a 3 cm diameter pancreatic head tumor with peripheral enhancement and a dilated pancreatic duct. He underwent subtotal stomach-preserving pancreaticoduodenectomy. Examination of intraoperative frozen sections did not indicate cancer involvement at the edge of the resected pancreatic duct. The tumor was histologically diagnosed as mixed acinar-neuroendocrine carcinoma(MANEC). It was mainly detected in the pancreatic head and was accompanied by intra-ductal growth in the pancreatic duct. The patient has survived for 21 months without recurrence. MANEC is a rare disease associated with intraductal growth. Intraoperative diagnosis of tumor involvement at the edge of the pancreatic duct may be useful for R0 resection in surgery for MANEC.

[Surgical Resection of a Solitary Pulmonary Nodule in a Patient with Breast Cancer-A Case Report].

Solitary lung tumors after radical surgery for breast cancer often present difficulty in diagnosis and treatment. This report describes the case of a patient with a previous history of radicalsurgery for breast cancer who underwent lung surgery. Solitary pulmonary nodules should be diagnosed in patients with breast cancer, because treatments and prognoses differ between metastatic and primary tumors. At the age of 43 years, this patient underwent surgicaltreatment for breast cancer. Eighteen years later, a solitary mass was observed in the middle lobe of the right lung. Right middle lobectomy was performed using video-assisted thoracic surgery. The diagnosis was primary lung carcinoma. In case of primary lung carcinoma, radical treatment is possible through surgical resection. On the contrary, breast cancer metastasis has been known to have subtypes with characteristics that may often be different from those of the originall esions; therefore, surgicalresection helps in the reevaluation of receptor expression. Thus, early pathological diagnosis using surgical resection is useful for early diagnosis and treatment.

[Dose Distribution Optimization in Combined Intracavitary and Interstitial Brachytherapy for Cervical Cancer].

PURPOSE: Hybrid inverse treatment planning optimization (HIPO) is a new optimization tool for brachytherapy. We verified its utility using treatment plans for combined intracavitary and interstitial brachytherapy in cervical cancer. MATERIALS & METHODS: We compared the manually optimized plan and the plan optimized using HIPO. The plan using HIPO was optimized with three different methods: needle only, tandem and needle, and all applicators. The dose volume histogram (DVH) parameters such as D90 of high risk clinical target volume (HR-CTV) and D2cc of OAR (rectum, sigmoid colon and bladder) were used to evaluate each treatment plan. RESULTS: The D90 of HR-CTV in most plans was received more than 600 cGy. In addition, the D2cc of OAR also was less than the tolerance dose on the average of all plans. However, the D2cc of the rectum and bladder treatment plans optimized only with needles was significantly higher than other plans. CONCLUSIONS: The treatment plans used in clinical practice and obtained by HIPO have similar dose distributions and DVH parameters. Moreover, the time needed to create treatment plan was reducing by HIPO. We suggest that HIPO will be an effective tool in treatment planning.

Usefulness of p16/CDKN2A fluorescence in situ hybridization and BAP1 immunohistochemistry for the diagnosis of biphasic mesothelioma.

Malignant mesothelioma is a highly aggressive neoplasm, and the histologic subtype is one of the most reliable prognostic factors. Some biphasic mesotheliomas are difficult to distinguish from epithelioid mesotheliomas with atypical fibrous stroma. The aim of this study was to analyze p16/CDKN2A deletions in mesotheliomas by fluorescence in situ hybridization (FISH) and BAP1 immunohistochemistry to evaluate their potential role in the diagnosis of biphasic mesothelioma. We collected 38 cases of pleural mesotheliomas. The results of this study clearly distinguished 29 cases of biphasic mesothelioma from 9 cases of epithelioid mesothelioma. The proportion of biphasic mesotheliomas with homozygous deletions of p16/CDKN2A in total was 96.6% (28/29). Homozygous deletion of p16/CDKN2A was observed in 18 (94.7%) of 19 biphasic mesotheliomas with 100% concordance of the p16/CDKN2A deletion status between the epithelioid and sarcomatoid components in each case. Homozygous deletion of the p16/CDKN2A was observed in 7 (77.8%) of 9 epithelioid mesotheliomas but not in fibrous stroma. BAP1 loss was observed in 5 (38.5%) of 13 biphasic mesotheliomas and in both epithelioid and sarcomatoid components. BAP1 loss was observed in 5 (62.5%) of 8 epithelioid mesotheliomas but not in fibrous stroma. Homozygous deletion of p16/CDKN2A is common in biphasic mesotheliomas, and the analysis of only one component of mesothelioma is sufficient to show that the tumor is malignant. However, compared with histology alone, FISH analysis of the p16/CDKN2A status and BAP1 immunohistochemistry in the spindled mesothelium provide a more objective means to differentiate between biphasic mesothelioma and epithelioid mesothelioma with atypical stromal cells.

Cytologic Differential Diagnosis of Malignant Mesothelioma and Reactive Mesothelial Cells With FISH Analysis of p16.

BACKGROUND: Mesothelioma patients often present with serosal effusions, which are ideal for cytopathological diagnoses. However, the morphological overlap between malignant and benign mesothelial proliferation can make a conclusive cytological diagnosis of mesothelioma elusive because immunohistochemical staining does not discriminate definitively between the two in this setting. p16 is deleted in up to 80% of pleural mesotheliomas. The aim of this study was to establish the correlation between the p16 deletion status of the cell block with that of its corresponding tumor using fluorescence in situ hybridization (FISH) analysis for individual patient tumors. METHODS: Twenty-two biopsies and 24 corresponding cell blocks, containing serosal effusions with atypical mesothelial cells from 22 patients with histologically confirmed pleural mesotheliomas, were analyzed with p16 FISH. Seventeen cell blocks consisting of serosal effusions with reactive mesothelial cells from nonmesothelioma cases were also analyzed. Combined immunofluorescence and FISH were also performed. RESULTS: Seventeen of the 22 mesothelioma patients (77.3%) showed homozygous deletions of p16 in the tumor tissue and in the atypical mesothelial cells from the cell blocks. p16 FISH followed by immunofluorescence with EMA was helpful towards identifying the mesothelioma cells in the cell blocks. CONCLUSION: We confirmed that the p16 FISH results obtained from the cell blocks are as reliable as those from the tissue sections. Cell block analysis is recommended for patients with serosal effusions of unknown origins with the following methods: immunohistochemistry should be performed to validate the mesothelial origin, and p16 FISH should be performed to confirm malignancy. Diagn. Cytopathol. 2016;44:591-598. © 2016 Wiley Periodicals, Inc.

[Predictors of Overall Survival after Locoregional Breast Cancer Recurrence].

We evaluated prognostic factors of locoregional breast cancer recurrence in 35 patients. The average age at the time of surgery was 58.4 years(range: 32-87 years). Of the 35 patients, 7, 17, and 11 had Stage I , II and III disease, respectively. Immunohistochemically, 25 tumors were ER+, and 10 were ER-, while 6 were HER2+, 27 were HER2-, and 2 had uncertain HER2 statuses. Their median disease-free interval(DFI), which is the intervalbetween initialsurgery and locoregional recurrence, was 29.4 months(range: 1-133 months). After locoregional relapse, 13 patients underwent surgical tumor removal, and 34 received systemic treatment. The median time-to-progression(TTP)after first-line therapy for recurrent breast cancer was 12.7 months(range: 1-185 months), and the median overall survival(OS)was 70.0 months(range: 3-313 months). Univariate analysis showed that disease stage at initial surgery, triple-negative disease, DFI, and TTP significantly affected OS, whereas ER and HER2 status, surgical margin at primary surgery, lymphovascular invasion, irradiation after initial surgery, and resection of the recurrent tumor were not significant factors. Patients with factors that predict worse prognosis after locoregional recurrence should be treated carefully.

[Lung Metastasis of Breast Cancer Five Years after Mastectomy - A Case Report].

The presence of a solitary lung tumor after radical surgery for breast cancer often causes difficulty in the diagnosis and treatment. We report a patient who had previously undergone radical surgery for breast cancer, and who underwent lung surgery. When the patient was 57 years old, she underwent surgical treatment for breast cancer. Six years later, a chest radiograph revealed a solitary mass on the upper lobe of her left lung. A left upper lobectomy was performed, utilizing videoassisted thoracic surgery. The pathological diagnosis, based on hematoxylin and eosin staining, was lung metastasis from breast cancer. The immunohistological findings revealed that the tumor was positive for estrogen receptor, progesterone receptor, and GCDFP-15, and negative for TTF-1 and Napsin A. Although the original breast cancer lesion was positive for the HER2 receptor, the metastatic lung lesion was negative. It has already been reported that the subtypes can change from 1 subtype in the original lesion to another in the metastatic lesion. Adjuvant therapy was administered based on the subtype of the metastatic lesion after the surgery. Therefore, surgical resection is useful for the purpose of reevaluating HER2 receptor status, the results ofwhich can influence the postoperative adjuvant treatment. The patient is now doing well, without any evidence ofrecurrence or metastasis 15 months after surgery.

Diagnostic usefulness of p16/CDKN2A FISH in distinguishing between sarcomatoid mesothelioma and fibrous pleuritis.

The distinction between sarcomatoid mesothelioma and fibrous pleuritis is difficult based on histology, especially when the amount of tumor tissue examined via biopsy is small and immunohistochemical examination is inconclusive. We studied the usefulness of deletion of p16 with fluorescence in situ hybridization (FISH) and p16 hypermethylation with polymerase chain reaction for the diagnosis and prognosis of malignant pleural mesothelioma (MPM). We analyzed 50 MPMs, including 22 sarcomatoid mesothelioma cases and 10 fibrous pleuritis cases. We set the cutoff value of homozygous deletion pattern as 14.4% based on FISH signaling patterns using samples of fibrous pleuritis. The percentage of homozygous deletion pattern was higher than 14.4% in 55.6% of the epithelioid mesotheliomas (10/18) and in all of the sarcomatoid mesotheliomas (22/22). Methylation of p16 was observed in 7 (20.6%) of 34 informative cases. p16 FISH analysis can be a reliable test for distinguishing between sarcomatoid mesothelioma and fibrous pleuritis and a prognostic factor for MPM.

Status epilepticus as the initial presentation of intravascular lymphoma.

Intravascular lymphoma (IVL) is a rare disease form of malignant lymphoma, and it is characterised by the selective growth of lymphoma cells within the lumina of vessels. Identification of this disease at an early stage is difficult because of non-specific clinical symptoms and neuroradiological findings. Most reported IVL cases are diagnosed at post-mortem following autopsy. We report the case of a patient who presented with status epilepticus (SE) as the initial manifestation of IVL. Despite the administration of anti-convulsant agents and general care the patient's condition deteriorated rapidly after admission, culminating in death due to respiratory failure and heart failure 21 days after the onset of symptoms. Post-mortem examination revealed IVL in the brain and multiple organs. Epileptic seizures often appear during the clinical course of IVL; however, they occur most frequently at advanced stages. Diagnosis of IVL that first presents with SE is of clinical importance because the treatment and prognosis of acute SE arising from IVL are different from those of SE originating from other causes.

Malignant pleural mesothelioma: clinicopathology of 16 extrapleural pneumonectomy patients with special reference to early stage features.

The earliest pathological events in the development of malignant pleural mesothelioma (MPM) are not understood. The aim of the present study was to elucidate the early histopathological features of MPM. A total of 16 extrapleural MPM pneumonectomy patients were investigated. Early stage mesothelioma was arbitrarily defined as a tumor < or =5 mm in thickness regardless of the nodal status or other organ involvement. Eight of these patients (six with epithelioid, two with biphasic) had early stage mesothelioma by this definition. Macroscopically there was no visible tumor, but the parietal and visceral pleura were thickened and there was focal adhesion between them. Microscopically, the mesothelioma lesions were multifocal and discontinuous on the pleura. In extremely early cases of epithelioid mesothelioma, tumor cells were generally arrayed in a single layer, but papillary proliferation was observed elsewhere. In sarcomatoid mesothelioma, mesothelioma cells proliferated, forming multiple small polypoid nodules on the pleura. Epithelial membrane antigen was helpful to distinguish reactive from neoplastic mesothelium, but glucose transporter-1 was not. Mesothelioma cells disseminate diffusely throughout the parietal and visceral pleura and mediastinal fat tissue before becoming visible. Stage Ia mesothelioma (neoplasm limited to the parietal pleura) would not be observed in daily practice.