[Case of primary retroperitoneal GIST (gastrointestinal stromal tumor) with rapid progression].

A 69-year-old man complaining of left abdominal pain was referred from a private clinic for retroperitoneal masses that were discovered on abdominal ultrasound in November 2010. CT scan showed retroperitoneal masses, located above the left kidney, measuring 10 cm. Para-aortic lymph nodes were swelling. We performed open biopsy to make the diagnosis in December 2010. The diagnosis was primary retroperitoneal GIST (gastrointestinal stromal tumor). We started imatinib 400 mg/day according to the Japan GIST guideline in January 2011. However the tumor pogressed rapidly, after 1 month the patient died.

Comparative analyses of tumour immune microenvironment between collecting duct carcinoma and fumarate hydratase-deficient renal cell carcinoma.

AIMS: Collecting duct carcinoma (CDC) and fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) have similar histological morphologies and both show a poor prognosis. Programmed death ligand 1 (PD-L1) inhibitor has been approved for the treatment of RCC. However, tumour-infiltrating neutrophils stimulated by interleukin-8 (IL-8) interfere with PD-L1 inhibitors. Here, we retrospectively analysed PD-L1 and IL-8 expression, and examined its relationship with infiltrating immune cells. METHODS: Nine cases of CDC and seven cases of FH-deficient RCC were selected. We defined PD-L1 and IL-8 expression by the Tumour Proportion Score and Combined Positive Score (CPS). We counted the numbers of CD8+, CXCR2+, CD11b+, CD66b+ and CD33+ immune cells located in the tumour components. RESULTS: A number of CXCR2+ (p=0.0058), CD11b+ (p=0.0070) and CD66b+ (p=0.0067) immune cells infiltrating into CDC were significantly higher than those infiltrating into FH-deficient RCC. In CDC, PD-L1 expression was correlated with a high density of CD8+ lymphocytes (p=0.0389), but was not in FH-deficient RCC (p=0.6985). IL-8 CPS was significantly higher in CDC than in FH-deficient RCC (p=0.0069). In addition, among the CDC cases, IL-8 CPS showed significant positive correlations with CXCR2+, CD11b+ and CD66b+ immune cell densities (p=0.0250, p=0.0104 and p=0.0374, respectively), whereas FH-deficient RCC showed no significant correlations between IL-8 CPS and immune cell densities. CONCLUSIONS: Our results suggest the difference of each tumour microenvironment between CDC and FH-deficient RCC, and IL-8 is a potential therapeutic target for treating CDC, but not FH-deficient RCC.

Approach for reclassification of collecting duct carcinoma and comparative histopathological analysis with SMARCB1/INI1-deficient renal cell carcinoma and fumarate hydratase-deficient renal cell carcinoma.

Collecting duct carcinoma (CDC) is a rare subset of high-grade renal cell carcinoma (RCC). To diagnose CDC, it is necessary to rule out other renal tumors including renal medullary carcinoma and fumarate hydratase (FH)-deficient RCC. However, there is overlap in the morphology of these three tumors, which all have poor outcomes. There is also still a need to sufficiently examine the therapeutic strategies for each of these tumors. In this study, we retrospectively reclassified invasive/infiltrating high-grade RCC and investigated its pathological features. We reviewed 18 cases previously diagnosed as "CDC," "FH-deficient RCC," and "unclassified RCC," which were reclassified as SMARCB1/INI1-deficient RCC, FH-deficient RCC, and CDC by SMARCB1/INI1, FH, and 2SC immunohistochemistry (IHC) and FH gene mutational status. As the result, 18 cases were reclassified into 2 cases of SMARCB1/INI1-deficient RCC, 7 cases of FH-deficient RCC, and 9 cases of CDC. The morphological features of each group overlapped, and no specific immunohistochemical expression except for SMARCB1/INI1, FH, and 2SC was detected. These results suggest that invasive/infiltrating high-grade RCC should be diagnosed by the combination of immunohistochemistry and molecular biological technique.

[A case of primary pleural angiosarcoma metastasing to the bladder].

The patient was a 79-year-old man who underwent right extrapleural lucite ball plombage for pulmonary tuberculosis at aged 19. He was followed BPH with medication from May 2008 at our hospital. He presented with macrohematuria in January 2010, but cystoscopy and CT scan showed no significant abnormalities. He was admitted to complaining of general fatigue and anemia in February 2010. TURBT was performed 10 days after admission, and showed the bleeding sites with oozing in mucosa at the bilateral and posterior wall of the bladder. Neither CT nor cytological examinations were helpful in diagnosing this disease, although histological observation implied a possibility of malignant vasoformative tumor. He died one month after admission. Autopsy revealed a huge bloody mass at the right upper thoracic wall and same metastatic tumors of both adrenals, the bone, the stomach and the urinary bladder. Microscopic examination revealed that atypical cells had proliferated and formed vascular structures, which were stained positively with CD31, and vimentin. Finally, the diagnosis was made of pleural angiosarcoma and multiple metastasis. Metastatic angiosarcoma of the bladder is very rare and difficult to make definite diagnosis, however we have to keep in mind the presence of this disease.

A new 7-point method facilitates accurate diagnosis of high-grade urothelial carcinoma in routine urinary cytology practice.

INTRODUCTION: This study was designed to identify the minimal and necessary cell morphologies to be considered for high-precision diagnosis of high-grade urothelial carcinoma (HGUC) in a routine urinary cytology practice. MATERIALS AND METHODS: We included 338 urine cytology specimens from 11 medical facilities in Japan. Six experts evaluated these Papanicolaou-stained specimens using their own diagnostic criteria to categorize them within an initial 4-tiered classification system. Of the 338 cases, 70 HGUC and 32 benign cases (with a complete consensus diagnosis of 6 experts) were included for the analysis. Two of the cytologists evaluated the specimens for 20 specific cellular features. The results were analyzed using a contingency table and by discriminant analysis. RESULTS: Of the original 338 cases, 165 were originally diagnosed as HGUC, but only 70 (42.4%) were scored as malignant by all participating cytologists; of the 101 benign cases, only 32 (31.7%) were classified as such in all examinations. These specimens were re-evaluated by 6 experts using a panel of 20 specific cellular features used to distinguish between HGUC and benign diseases; tests of significance and discriminant analyses identified 7 critical features that were most useful for cytological diagnosis. Statistical analysis revealed that a focus on these 7 features led to a diagnosis of HGUC with a probability of over 95%. CONCLUSIONS: The accuracy of our presently used method to evaluate urinary cytology is not consistently high. This novel classification system, which focuses on 7 critical features, facilitates the high accurate diagnosis of HGUC in routine cytology practice.

Morphological, immunohistochemical, and genomic analyses of papillary renal neoplasm with reverse polarity.

Papillary renal neoplasm with reverse polarity (PRNRP) is a recently proposed entity of renal tumor. It shows a far better prognosis than papillary renal cell carcinoma (PRCC) and frequently has KRAS missense mutation. In this study, we compared 14 cases of PRNRP and 10 cases of PRCC type 1 (PRCC1) and type 2 (PRCC2) from clinical, morphological, immunohistochemical, and molecular biological perspectives. We subjected all PRNRP and PRCC cases to immunohistochemical analysis. Whole-exome sequencing using next-generation sequencing (NGS) was performed for six cases of PRNRP, three cases of PRCC1, and four cases of PRCC2. A search for KRAS gene mutation in the remaining eight cases of PRNRP was performed by polymerase chain reaction (PCR) sequencing. The results showed that all cases of PRNRP were pT1N0M0, none of which followed a course of recurrence or tumor-related death. Immunohistochemical analysis revealed diffuse staining of CK7, EMA, PAX8, and GATA3 but weak or negative staining of CD10, CD15, and AMACR in PRNRP. By NGS and PCR, KRAS missense mutation was detected in 11 of 14 PRNRP cases, although pathogenic KRAS mutation was not observed in PRCC1 and PRCC2. NGS analysis revealed less tumor mutation burden in PRNRP than in PRCC. PRNRP also showed no specific chromosomal copy number abnormalities, including gains of 7 and 17. In conclusion, we propose that PRNRP is a distinct condition from PRCC.

Intracytoplasmic Lumen in Urine Cytology Predicts Worse Prognosis in Non-Muscle-Invasive Bladder Cancers.

BACKGROUND: Intracytoplasmic lumina (ICL) are observed in several cancers, including urothelial carcinoma (UC). We have reported that ICL in urine cytology (cICL) is more frequent in high-grade UCs than in low-grade UCs; however, the correlation between the presence of ICL and prognosis is unclear. OBJECTIVES: The aim of this work was to determine the association between cICL and prognosis in bladder cancer. METHOD: We retrospectively investigated 87 patients with bladder cancer who received a histological diagnosis within 3 months of urine cytology at Kanazawa Medical University between 2003 and 2007. The cytological diagnosis and the number of cICL, histological diagnosis, tumor grade or variant, pT stage, ICL in histological specimens, and immunohistochemistry for mucins were evaluated. Data on the treatment type, recurrence, survival, cause of death, and length of follow-up were collected from electronic medical records. RESULTS: Muscle invasion, high-grade UC, lymph node metastasis, distant metastasis, adjuvant therapy, and disease-related mortality were more frequent in patients with cICL-positive bladder cancer than in those without cICL-positive bladder cancer. Immunohistochemistry revealed the expression of Muc-1 and Muc-4 in patients with cICL-positive bladder cancer. Univariate analysis revealed that cytological diagnosis by the Paris system and the 2015 version of the Japanese reporting system, muscle invasion, high-grade UC, lymph node metastasis, distant metastasis, and adjuvant chemotherapy and/or radiotherapy were significant factors associated with prognosis. Furthermore, survival was shorter in patients with cICL-positive non-muscle-invasive bladder cancer than in those with cICL-negative non-muscle-invasive bladder cancer. In the multivariate analysis, only distant metastasis was significantly associated with survival. CONCLUSIONS: cICL predicted shorter survival in patients with non-muscle-invasive bladder cancer, suggesting that ICL is one of the important diagnostic features of high-grade UC with a worse prognosis in urine cytology.

Hepatitis B caused by a hepatitis B surface antigen escape mutant.

Amino acid substitutions within the S gene involving the major antigenic a determinant of the hepatitis B virus (HBV) surface antigen (HBsAg) have been detected in cases of failure of immunization against the virus. Our report showed development of clinical hepatitis in presence of antibody to HBsAg in a healthy individual. A single amino acid substitution (G145R) within the a determinant of the HBsAg was determined by sequencing of the isolated HBV strain. Lamivudine treatment efficiently cleared the peripheral HBV DNA, HBsAg, and hepatitis B e antigen. In conclusion, the immune escape mutant in the S gene can cause hepatitis despite pre-existing naturally acquired immunity.

Haploinsufficiency of 8p22 may influence cancer-specific survival in prostate cancer.

Although Knudson's two-hit hypothesis with functional loss of a tumor suppressor gene has been widely accepted, accumulating evidence suggests that several genes are regulated by the quantity of their product in a dose-dependent manner (gene dosage effect). The study was designed to identify the influence of gene dosage effect of 8p22 on patient prognosis. With a median age of 71 years, 40 patients with prostate cancer (11 organ-confined, 13 capsular penetrating, and 16 nodal and/or distant metastatic) were followed for a median of 68.5 months. A fluorescence in situ hybridization (FISH) technique was applied using a region-specific cosmid probe combined with centromeric probe. Allelic losses of 8p22, 8p21.3, 8p21.1 approximately 2, and 8p12 were found in 23, 22, 14, and 9 patients, respectively. A Cox proportional hazard model revealed that decreased fraction (i.e., the fraction of nuclei with a lesser number of cosmid signals than of centromeric probe signals) of 8p22 proved to be the sole independent prognostic factor predicting cancer-specific death, as well as disease progression--but allelic loss of 8p22 was not predictive. Cytogenetic estimation of 8p22 by FISH can yield quantitative evaluation of relevant gene dosage, which may become a useful biomolecular marker predicting poor patient prognosis.

Thrombotic Microangiopathy Following Chemotherapy with S-1 and Cisplatin in a Patient with Gastric Cancer: A Case Report.

BACKGROUND: Thrombotic microangiopathy (TMA) represents a spectrum of serious disorders characterized by occlusive microvascular thrombosis, thrombocytopenia and end-organ damage. TMA is associated with a broad range of conditions and is also a well-described complication of both cancer and its treatment. CASE REPORT: A 77-year-old Japanese woman underwent S-1 and cisplatin chemotherapy for treatment of advanced gastric cancer with multiple lymph node and liver metastases. She was found with severe anemia and thrombocytopenia during the third course of chemotherapy. She was diagnosed with TMA based on thrombocytopenia, schistocytosis, hemolytic anemia and renal dysfunction. She underwent treatment with plasmapheresis; however, her response to treatment was poor and died on day 16 of hospitalization. The autopsy performed revealed microthrombi in the glomeruli and tubulonecrosis in the kidneys. CONCLUSION: This is the first case report of TMA in association with the use of S-1 and cisplatin. Therapists have to take account of TMA when using S-1 and cisplatin treatment.

Splenic large B-cell lymphoma in patients with hepatitis C virus infection.

Hepatitis virus infection, especially type C (hepatitis C virus [HCV]), has been suggested to be one of the important pathogenetic factors for low- and high-grade B-cell lymphoma, including splenic marginal zone lymphoma (SMZL), in southern Europe. Here, we analyzed the incidences of HCV and hepatitis B virus (HBV) infections, and the clinicopathologic features in 29 cases of splenic diffuse large B-cell lymphoma (DLBCL), 10 SMZL, 3 splenic mantle cell lymphoma, 1 hairy cell leukemia, 13 B-chronic lymphocytic leukemia, and 12 hepatosplenic T-cell and natural killer cell lymphoma. Fifteen (51.7%) splenic DLBCL cases were HCV antibody-positive, and another 6 (20.7%) had the HBsAg. The incidence of each was significantly (P < .01) higher than those of HCV (9.3%) and HBV (1.9%) infections in 54 node-based DLBCL cases. Four examined HCV-positive DLBCL cases showed no type II cryoglobulinemia. HCV RNA was detected in fresh tumor tissues from 6 of 7 examined DLBCL cases, and HBV DNA was present in another 2, as evaluated by real-time polymerase chain reaction. Immunohistologically, tumor cells in 5 of 7 examined DLBCL cases showed intracytoplasmic reactions for HCV NS3 and E2 proteins and the viral receptor CD81. Of 6 cases, 2 showed an intranuclear reaction for the HBV surface protein. By Southern blot analysis, no rearrangement of the Bcl2 gene was detected in the tumor tissue of 7 HCV-positive DLBCL cases. For the other types of malignant lymphoma, 1 case each of SMZL (10%) and hepatosplenic T-cell and natural killer cell lymphoma (8.3%) showed HCV infection. In conclusion, persistent human hepatitis virus infections, especially HCV, may play an important role in the tumorigenesis of splenic DLBCL in Japan.

A rare association of primary biliary cirrhosis and pernicious anemia.

Primary biliary cirrhosis is often associated with autoimmune diseases. However, an association between primary biliary cirrhosis and pernicious anemia has rarely been reported. We report a patient with primary biliary cirrhosis associated with pernicious anemia and autoimmune gastritis. The patient was a 64-year-old Japanese woman who had been diagnosed as having primary biliary cirrhosis 5 years previously. She was readmitted with jaundice and macrocytic anemia. The diagnosis of pernicious anemia was confirmed by the low level of serum vitamin B12 and the presence of anti-parietal cell antibody and anti-intrinsic factor antibody. Pernicious anemia should be regarded as a possible complication of primary biliary cirrhosis.

Poorly differentiated adenocarcinoma with signet-ring cells of the Vater's ampulla, without jaundice but with disseminated carcinomatosis.

A 49-year-old man was hospitalized because of a 2-month history of purpura in his extremities and for back pain. Laboratory findings showed alkaline phosphatase to be greatly elevated, and platelet counts and coagulation factor showed that the patient had disseminated intravascular coagulation (DIC). Compression fractures of the thoracic vertebrae were found on radiological examination. The histological findings from bone marrow showed metastasis of adenocarcinoma with signet-ring cells, although the primary site was unknown. To reduce tumor cells in number and improve DIC, 11 cycles of 5-Fluorouracil and leucovorin therapy were done, and the patient survived for 12 months. Autopsy showed a 0.8 cm diameter, poorly differentiated adenocarcinoma with the signet-ring cell type in the lamina propria of the Vater's ampulla. Many metastatic foci and micro tumor emboli were found in the lung and in bone marrow. The sections of the stomach, the gallbladder, urinary bladder, prostate, and thyroid gland showed no malignant cells. These findings suggest that the origin of the cancer may have been located in the Vater's ampulla. This is a rare case of an ampullary tumor of poorly differentiated adenocarcinoma with the signet-ring cell type, without jaundice but with multiple metastasis. 5-Fluorouracil and leucovorin were effective for increasing survival time and improving quality of life.

Localized biphasic type malignant mesothelioma arising in the peritoneum: Report of a case.

This report describes a rare case of localized malignant biphasic (mixed epithelioid and sarcomatoid) mesothelioma arising in the peritoneum. A 69-year-old male with a history of asbestos exposure, complaining of a painful mass in the left chest wall, was found via computed tomography (CT) to have a tumor in the left peritoneum. The resected tumor was histologically and immunohistochemically consistent with a malignant mesothelioma with mixed epithelioid and sarcomatoid type and no distant metastasis. The diagnosis of localized malignant biphasic mesothelioma arising in the peritoneum was appropriate because there was no evidence of any other primary tumor.

Molecular and immunohistologic analyses cannot reliably solve diagnostic variation of flat intraepithelial lesions of the urinary bladder.

We examined diagnostic variation of flat intraurothelial lesions with comparison with immunohistochemical and fluorescence in situ hybridization (FISH) analyses. Nine uropathologists diagnosed 23 biopsy samples from the urinary bladder. The samples were analyzed by immunohistochemical expression of cytokeratin 20, high-molecular-weight cytokeratin, Ki-67, p53, and p16(INK4a), and multicolor FISH using the UroVysion probe set (Vysis, Abbott, Des Plaines, IL). Diagnostic agreement for each classification and for nonneoplastic or neoplastic lesions was obtained in 8 (35%) and 16 (70%) of 23 lesions, respectively. The preference ratio of neoplasia to nonneoplasia (0.9 to 4.8) or carcinoma in situ to dysplasia (0.2 to 4.0) also varied among the pathologists. In 6 ancillary analyses, the majority of neoplastic lesions with diagnostic agreement indicated more than 2 aberrant results, whereas the majority of lesions without diagnostic agreement showed no or only 1 aberrant result. The molecular and immunohistochemical analyses can discriminate between neoplastic and nonneoplastic lesions; however, they cannot reliably solve diagnostic variation of flat intraepithelial lesions.

Intrathoracic ganglioneuroma in an elderly patient over 70 years of age.

We herein present an exceedingly rare case of intrathoracic ganglioneuroma that was surgically resected in an elderly patient over 70 years of age. A 74-year-old woman was asymptomatic, but a computed tomography (CT) scan of the thorax indicated the presence of a posterior mediastinal mass paravertebrally. A thoracotomy was thus performed under a strongly suggested diagnosis of a neurogenic tumor because of the appearance and position of the mass on the chest CT and magnetic resonance imaging findings, and measuring 6.9 x 5.8 x 1.6 cm. Not only tumors originating from the nerve sheath, but also neurogenic tumors occurring in young patients such as ganglioneuroma, should be included in the different diagnosis of posterior mediastinal tumor occurring in elderly patients.