Programmed Death Ligand 1 Expression in Circulating Tumor Cells as a Predictor and Monitor of Response to Atezolizumab plus Bevacizumab Treatment in Patients with Hepatocellular Carcinoma.

There remains no reliable biomarker of therapeutic efficacy in hepatocellular carcinoma (HCC) for the PD-L1 inhibitor atezolizumab and bevacizumab (Atezo/Bev). Circulating tumor cells (CTCs) enable the serial collection of living tumor cells. Pre-treatment and serial CTC gene expression changes and tumor histology were evaluated to identify predictors of response to Atezo/Bev. Peripheral blood from 22 patients with HCC treated with Atezo/Bev and 24 patients treated with lenvatinib was serially collected. The RNA expression in CTCs was analyzed using qRT-PCR. Higher PD-L1 expression in pre-treatment CTCs was associated with response and improved prognosis with Atezo/Bev treatment, but not with lenvatinib. There was no correlation between PD-L1 expression in CTCs and that in liver tumor biopsy specimens scored using imaging software. Furthermore, PD-L1 RNA expression in CTCs was dynamically altered by Atezo/Bev, decreasing during effective response and increasing upon progression. CTC-derived RNA collected during Atezo/Bev indicates that patients with higher PD-L1 expression in CTCs at baseline were 3.9 times more responsive to treatment. Therefore, PD-L1 RNA levels in CTCs are an accurate response predictor and may be a monitorable biomarker that changes dynamically to reflect the response during Atezo/Bev treatment.

Prevalence and diagnostic significance of non-invasive follicular thyroid neoplasm with papillary-like nuclear features in Japan-A multi-institutional study.

This multi-institutional study investigated non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) frequency and its diagnostic significance in Japan. We reviewed 4008 thyroid nodules resected in six institutions before NIFTP was proposed. Overall, 26 cases diagnosed as non-invasive encapsulated follicular variant of papillary thyroid carcinoma (PTC) and 145 cases of follicular thyroid adenoma (FTA) were included. Of these nodules, 80.8% and 31.0%, respectively, were NIFTPs. In five institutions, NIFTPs were more commonly found in FTA than in PTC nodules. When NIFTP was included with PTC, the overall prevalence was 2.3%, with rates in five institutions below 5.0% (0.8%-4.4%). One NIFTP case with nuclear score 3 revealed nodal metastasis 2.5 years post-resection, and the carcinoma cells were immunohistochemically positive for BRAF. FTAs or NIFTPs with nuclear score 2 did not metastasize. NIFTP was more common among FTA than among PTC nodules, possibly due to underdiagnosis of PTC on nuclear findings. Considering the clinical findings, molecular pathogenesis, and therapeutic strategy in Japan, NIFTP with nuclear score 2 is not different from FTA, and use of this entity terminology is not meaningful. In contrast, NIFTP with nuclear score 3 has potential for metastasis and BRAFV600E mutation. Therefore, in NIFTP cases, nuclear scores 2 and 3 should be separately reported.

Human T-cell Lymphotropic Virus Type-1-associated Bronchioloalveolar Disorder with Non-necrotizing Granulomas: A Case Report and Literature Review.

Human T-cell lymphotropic virus type-1 (HTLV-1)-associated bronchioloalveolar disorder (HABA) is a pulmonary disorder characterized by lymphocytic infiltration of the peribronchiolar space and interstitium in HTLV-1 carriers and in adult T-cell leukemia/lymphoma (ATLL). We herein report an 85-year-old woman carrying HTLV-1 with HABA who presented with a miliary pattern of micronodules in both lungs on high-resolution computed tomography and a lymphocytic infiltrate with non-necrotizing granulomas on pathology. This rare case of HABA should be differentiated from sarcoidosis, hypersensitivity pneumonitis, or miliary tuberculosis.

Improved artificial intelligence discrimination of minor histological populations by supplementing with color-adjusted images.

Despite the dedicated research of artificial intelligence (AI) for pathological images, the construction of AI applicable to histopathological tissue subtypes, is limited by insufficient dataset collection owing to disease infrequency. Here, we present a solution involving the addition of supplemental tissue array (TA) images that are adjusted to the tonality of the main data using a cycle-consistent generative adversarial network (CycleGAN) to the training data for rare tissue types. F1 scores of rare tissue types that constitute < 1.2% of the training data were significantly increased by improving recall values after adding color-adjusted TA images constituting < 0.65% of total training patches. The detector also enabled the equivalent discrimination of clinical images from two distinct hospitals and the capability was more increased following color-correction of test data before AI identification (F1 score from 45.2 ± 27.1 to 77.1 ± 10.3, p < 0.01). These methods also classified intraoperative frozen sections, while excessive supplementation paradoxically decreased F1 scores. These results identify strategies for building an AI that preserves the imbalance between training data with large differences in actual disease frequencies, which is important for constructing AI for practical histopathological classification.

Perivascular epithelioid cell tumors (PEComas) of the bone and soft tissue: a Japanese Musculoskeletal Oncology Group (JMOG) multi-institutional study.

PURPOSE: Perivascular epithelioid cell tumors (PEComas) of the bone and soft tissues are rare mesenchymal neoplasms, some of which are malignant. However, their clinical and pathological characteristics remain unclear. This study was performed to investigate the clinical and pathological characteristics of PEComas in bone and soft tissues by leveraging information from the Japanese Musculoskeletal Oncology Group. METHODS: Nine patients, including four male and five female patients with a median age of 50 years, were retrospectively reviewed. PEComas of the visceral organs, including the uterus and retroperitoneum, were excluded. RESULTS: Eight tumors arose in the soft tissue and one in the bone, with a mean size of 8.8 cm. Four patients showed local recurrence or distant metastasis. The 1-year survival rate was 78%. Pathologically, eight tumors were classified as malignant and one as having uncertain malignancy potential. Half of the tumors showed high MIB-1 index values of > 30%. Immunohistochemically, the melanocyte marker HMB45 was expressed in 89% of the cases, and muscle-specific markers were expressed only in 30-50% of the cases. Transcription factor binding to IGHM enhancer 3 (TFE3) expression was positive in 100% of the patients. Tumors with high expression of TFE3 were classified as PEComas with malignant potential according to Folpe's classification. CONCLUSIONS: Bone and soft tissue PEComas may have a higher malignancy potential than other visceral PEComas and are more likely to develop as TFE3-rearranged PEComas.

Follicular cholangitis mimicking a common bile duct cancer: a case report.

BACKGROUND: Follicular cholangitis (FC) is a benign bile duct disease that was first reported 2003. Pathologically, it is characterized by lymphoplasmacytic infiltration with multiple lymphoid follicle formations under the mucosal layer of the biliary tract. However, as this disease is extremely rare, little is known about its etiology and pathogenesis. CASE PRESENTATION: A 77-year-old woman was diagnosed with middle bile duct stenosis and potential increases in alkaline phosphatase (ALP) and γ-glutamyl transpeptidase levels (γ-GTP). Carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9) and IgG4 levels were all within the normal limits. Contrast-enhanced computed tomography (CE-CT) and magnetic resonance imaging (MRI) revealed bile duct dilation from intrahepatic to upper common bile duct and an irregular mass lesion in distal bile duct. Additionally, multiple overlapping leaf-like folds were detected. 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) did not demonstrate fluorodeoxyglucose uptake. Subtotal stomach-preserving pancreaticoduodenectomy with regional lymph node dissection was performed because common bile duct cancer could not be ruled out. The resected specimen showed diffuse homogeneous middle bile duct wall thickening. Microscopically, the lesion exhibited thick fibrosis with several invaded lymphoplasmacytic cells, and lymphoid follicle formations were detected under the mucosal layer. Immunohistochemical staining (IHC) revealed positive for CD3, CD4, CD20 and CD79a, and these findings led to a final diagnosis of FC. The patient has not experienced recurrence to date (42 months postoperatively). CONCLUSIONS: Currently, accurate preoperative diagnosis of FC is difficult. More cases must be accumulated to generate additional knowledge on its precise diagnosis and proper treatment.

Liquid-based cytology (LBC) with immunocytochemical staining improves fine-needle aspiration cytology (FNA) performance for salivary gland tumors.

BACKGROUND: Liquid-based cytology (LBC), now used globally for the head and neck region, has been used at our hospital since 2011. This study was designed to analyze the efficacy of LBC with immunocytochemical staining on preoperative diagnosis of salivary gland tumors. METHODS: This retrospective analysis of fine-needle aspiration (FNA) performance for salivary gland tumors was conducted at Fukui University Hospital. Salivary gland tumor operations conducted during April 2006 - December 2010 (84 cases) were classified as the Conventional Smear (CS) group, which were diagnosed morphologically by Papanicolaou and Giemsa staining. Those done during January 2012 - April 2017 (112 cases) were classified as the LBC group, which were diagnosed using LBC samples with immunocytochemical staining. The FNA results and pathological diagnosis of both groups were analyzed to calculate the FNA performance. RESULTS: Compared to the CS group, cases of inadequate and indeterminate FNA sample were not reduced significantly by LBC with immunocytochemical staining. As for FNA performance, the accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CS group were, respectively, 88.7%, 53.3%, 100%, 100%, and 87.0%. Those of LBC group were all 100%, representing significant improvement over the CS group. CONCLUSIONS: Analysis results indicated the usefulness of LBC with immunocytochemical staining for preoperative diagnosis of salivary gland tumors.

Hepatocellular carcinoma progression promoted by 5-lipoxygenase activity in CD163(+) tumor-associated macrophages.

Arachidonic acid 5-lipoxygenase (5-LOX), an enzyme that synthesizes leukotrienes (LTs), is involved in cancer development including proliferation, invasion, metastasis and drug resistance. However, the functional role of 5-LOX in hepatocellular carcinoma (HCC) remains to be elucidated. In this study, we analyzed the contribution of 5-LOX in HCC progression and investigated the potential of targeted therapy. Analysis of 86 resected HCC specimens and the clinical data of 362 cases of liver cancer from The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset, showed that 5-LOX expression was associated with postoperative survival. The cancer proliferative and stem cell potential were correlated with the levels of 5-LOX in CD163(+) tumor-associated macrophages (TAMs). In an HCC mouse model, CD163(+) TAMs expressed 5-LOX and produced LTB4 and LTC/D/E4; the 5-LOX inhibitor, zileuton, suppressed HCC progression. LTB4 and LTC/D/E4 promoted cancer proliferation and stem cell capacity via phosphorylation of extracellular signal-regulated kinase 1/2 and stem cell-associated genes. Taken together, we identified a novel mechanism of HCC progression in which CD163(+) TAMs express 5-LOX and produce LTB4 and LTC/D/E4, thereby enhancing the proliferative and stem cell potential of HCC cells. Furthermore, inhibition of 5-LOX activity regulates HCC progression, suggesting it has potential as a new therapeutic target.

Histology and cytokine levels in hepatic injury accompanying a case of non-severe COVID-19.

The pathogenesis of liver dysfunction that complicates coronavirus disease 2019 (COVID-19) remains unclear, especially in mild to moderate severity cases. In this case, a novel coronavirus infection was detected by polymerase chain reaction (PCR) in a 76-year-old woman hospitalized after presenting with fever. No other abnormal physical findings were observed, and oxygen administration was not required. Chest computed tomography (CT) showed a ground-glass-like and an infiltrative shadow in the right lung, and moderate COVID-19 was diagnosed. Initially, the fever resolved, and PCR turned negative; however, the fever reappeared on hospitalization day 14, and CT showed pneumonia exacerbation accompanied by new onset of fatty liver. Biochemical testing revealed marked liver dysfunction, accompanied by elevated serum interleukin (IL)-6, IL-10, and tumor necrosis factor-α levels. Physical findings and all laboratory parameters improved after conservative treatment, and she was discharged on day 22. A liver biopsy performed 44 days post-discharge showed T-cell-dominant inflammatory cell infiltration, mainly in the portal region. Some hepatocytes showed fatty degeneration.We report a case of moderate COVID-19 in which histological hepatitis persisted after a substantial period had passed since the initial infection had cleared and associated transaminase elevations had resolved, with a comparison of serum cytokine dynamics.

A fatal case of hemophagocytic lymphohistiocytosis associated with gestational psittacosis without symptoms of pneumonia.

Psittacosis is a zoonotic infection caused by Chlamydia psittaci. Most patients present with acute respiratory symptoms and systemic illness. When C. psittaci infects pregnant women, it causes severe clinical manifestations called gestational psittacosis. Here we report a case of gestational psittacosis. Our patient lacked respiratory symptoms, and pathological postmortem examinations revealed severe placentitis. Both DNA and immunohistochemical analyses were positive for C. psittaci from formalin-fixed paraffin-embedded tissues. The chlamydial DNA in the placenta was about 100 times more abundant than that in the lungs; therefore, the placenta rather than the lungs was the probable target of the C. psittaci infection during this pregnancy. We could not identify the source of infection. Gestational psittacosis should be considered in the differential diagnosis for fever of unknown origin during pregnancy, even in cases lacking respiratory symptoms.

Primary Ewing's sarcoma/primitive neuroectodermal tumor of the kidney and its clinical features.

Introduction: Ewing sarcoma family tumor is a malignant tumor that is primarily of bone origin; it rarely occurs in the kidney. Case presentation: A 22-year-old woman presented with hematuria. Computed tomography revealed a 6 × 6-cm mass in the lower pole of the right kidney with invasion into the right renal vein. A right laparoscopic radical nephrectomy was performed. The tumor was completely encapsulated. Based on the small-round-cell histology, diffusely CD99-positive tumor cells, and EWS (ex7)-FLi1 (ex6) fusion gene break point transcript, we diagnosed Ewing sarcoma/primitive neuroectodermal tumor of the kidney. After surgery, eight cycles of adjuvant chemotherapy including vincristine, doxorubicin (Adriamycin®), cyclophosphamide, ifosfamide, and etoposide were given. No evidence of recurrence has been observed 13 months from diagnosis. Conclusion: This was a rare Ewing sarcoma family tumor in the kidney of a young female with no remarkable family medical history.

A rare case of eosinophilic gastritis induced by nivolumab therapy for metastatic melanoma.

Cancer immunotherapy using immune checkpoint inhibitors can cause immune reactions at various sites as a side effect called immune-related adverse events (irAEs). The gastrointestinal tract is susceptible to irAEs, however, the degree and presentation vary considerably from case to case. A 76-year-old woman was diagnosed with anal mucosal melanoma. She underwent radical surgery and received postoperative adjuvant therapy. However, because new metastases were also found in bilateral inguinal lymph nodes, immunotherapy with nivolumab was performed. Approximately 10 months after the initiation of nivolumab administration, she presented with epigastric discomfort and nausea, and her laboratory data showed severe eosinophilia (1938/mm3). Computed tomography demonstrated a diffuse thickening of the gastric wall. Esophagogastroduodenoscopy and endoscopic ultrasonography showed mucosal thickening due to edema, and histologic examination revealed severe invasion of eosinophils in the lamina propria. Subsequently, she was diagnosed with eosinophilic gastritis due to irAEs induced by nivolumab. Oral administration of prednisolone rapidly normalized her endoscopic and histologic findings, dramatically reducing her symptoms. This is a very rare and important case report of nivolumab-induced severe eosinophilic gastritis. Although gastric lesions as IrAEs is rare, it is necessary to differentiate eosinophilic gastritis if unexplained nausea occurred during the administration of immune checkpoint inhibitors.

Successful early diagnosis of monomorphic epitheliotropic intestinal T-cell lymphoma manifesting as chronic diarrhea and hypokalemia using video capsule endoscopy and double-balloon enteroscopy.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), formerly known as enteropathy-associated T-cell lymphoma (EATL) type II, is a rare disease with a poor prognosis that is often diagnosed when patients present with intestinal perforation or obstruction. Our patient, a man in his 60 s, had a 5-month history of persistent watery diarrhea. Upper and lower gastrointestinal endoscopy, abdominal computed tomography (CT), and stool culture results were unremarkable. He was admitted to our hospital 8 months later with a weight loss of 20 kg, general fatigue, and hypokalemia. Contrast-enhanced CT of the abdomen revealed mild thickening and contrast enhancement of the small intestinal wall. Video capsule endoscopy and double-balloon enteroscopy were performed to reveal a broad ulcer in the jejunum and multiple erosions throughout the small intestine. Examination of the biopsy specimens showed infiltration of atypical lymphocytes with pale cytoplasm in the glandular epithelium. The atypical lymphocytes were positive for CD3, CD8, CD56, granzyme B, and T-cell intracellular antigen-1 by immunostaining. Early diagnosis of MEITL was made, and the patient survived for 21 months with continuous chemotherapy. Aggressive examination of the small intestine is effective for the early diagnosis of serious diseases, such as MEITL, in patients with chronic diarrhea of unknown origin.

The implicated clinical factors for outcomes in 304 patients with salivary duct carcinoma: Multi-institutional retrospective analysis in Japan.

BACKGROUND: Salivary duct carcinoma (SDC) is a high-grade salivary malignancy that frequently occurs as the carcinomatous component of carcinoma ex pleomorphic adenoma. We herein examined the clinical factors affecting outcomes in a large cohort of SDC. METHODS: We selected 304 SDC cases and investigated clinical characteristics and the factors affecting outcomes. RESULTS: The median age of the cases examined was 68 years, the most common primary site was the parotid gland (238 cases), and there was a male predominance (M/F = 5:1). Outcomes were significantly worse when the primary tumor site was the minor salivary glands (SG) than when it was the major SG. Outcomes were also significantly worse in pN(+) cases (161 cases) than in pN0 cases, particularly those with a metastatic lymph node number ≥11. The cumulative incidence of relapse and distant metastases was significantly higher in stage IV cases than in stage 0-III cases. CONCLUSIONS: The absolute number of lymph node metastases, higher stages, and the minor SG as the primary tumor site were identified as factors affecting the outcome of SDC.

Pathological diagnosis of general rules for the description of thyroid cancer by Japanese Society of Thyroid Pathology and Japan Association of Endocrine Surgery.

The Japanese Society of Thyroid Pathology and the Japan Association of Endocrine Surgeons developed the eighth edition of the General Rules for the Description of Thyroid Cancer (GRDTC) in December 2019. This article describes the pathological diagnosis of the GRDTC, which has been improved through repeated revisions based on the experience of Japanese pathologists and translated into English to introduce the Japanese diagnostic standard to foreign countries. In this edition of the GRDTC, the histopathological classification and descriptions differ in some respects from those of the fourth edition of the World Health Organization (WHO) classification as revised in 2017. For example, the GRDTC does not adopt the concept of borderline lesions (FT-UMP, WDT-UMP, and NIFTP) of the WHO, taking into consideration the popular histological criteria accepted by Japanese pathologists. The cytological reporting system of the GRDTC was partly modified from the Bethesda system in 2015. It has an additional cyst fluid category separated from the unsatisfactory category that has been demonstrated to be useful in Japan. This translated edition makes it easy to submit Japanese clinicopathological studies of thyroid tumors in an international journal. We also wish to contribute to the improvement, standardization, and globalization of the pathological diagnosis of thyroid tumors.

Metastatic invasive lobular breast cancer presenting as linitis plastica of the colon: Tumour characterization using [18 F]FES PET/MRI.

Metastatic invasive lobular breast cancer (ILC) to the colon is rare and usually ER-positive. We present an ER-negative case of metastatic ILC presenting as linitis plastica of the colon where [18 F]FES PET/MRI allowed the evaluation of the ER phenotypic transformation in the colonic metastasis from the ER-positive breast ILC in vivo.

Adenoid cystic carcinoma of the sublingual gland developing lung metastasis 20 years after primary treatment: A case report and literature review.

RATIONALE: Adenoid cystic carcinoma (ACC) is a rare malignant tumor that primarily occurs in the salivary glands. Distant metastases can develop despite favorable local control. Moreover, distant metastasis of ACC can occur after a long time interval without local recurrence. We report the first case of ACC of the sublingual gland that developed lung metastasis 20 years after primary treatment. PATIENT CONCERNS: A 52-year-old man was referred to our department with a 1-year history of painful swelling on the right oral floor. DIAGNOSIS: An incisional biopsy was performed, and histopathological examination revealed malignancy. INTERVENTIONS: Surgical excision of the right oral floor and right supra-omohyoid neck dissection with postoperative chemoradiation therapy were performed, and ACC of the sublingual gland was diagnosed. Left pulmonary metastasis was detected 20 years after the primary treatment. Metastasectomy was performed; however, subsequently, skin and bone metastases developed. OUTCOMES: After receiving palliative care, the patient died of multiple organ failure. LESSONS: As late distant metastasis of salivary ACC can develop, patients who undergo primary treatment need a long-term, strict follow-up plan even if locoregional control is favorable.

Gastrointestinal AA amyloidosis secondary to chronic pyelonephritis presenting with refractory diarrhea and severe hypoalbuminemia.

Secondary amyloidosis is a rare complication of chronic inflammatory diseases, such as collagen diseases, and is often difficult to treat. In addition, the gastrointestinal tract is frequently involved in amyloid deposition that often results in various disorders and symptoms. A 70-year-old woman was admitted to our hospital with refractory diarrhea and hypoalbuminemia. Abdominal computed tomography demonstrated extensive edematous wall thickening of the small intestine and colon. Video capsule endoscopy revealed multiple ulcerations with a white mossy appearance of the ileum. Double-balloon endoscopy showed severe circumferential ulcers in the entire ileum. Histological examination of ileum biopsy samples revealed severe amyloid deposition in the lamina propria and perivascular areas of the submucosa. The patient was diagnosed with gastrointestinal AA amyloidosis. The cause of AA amyloid deposition was presumed to be chronic pyelonephritis due to ureteral stones that had been left untreated for 35 years. After treatment with ureteral drainage and antibiotics, the patient's symptoms and serological abnormalities improved dramatically. Here, we describe a case of severe gastrointestinal AA amyloidosis secondary to chronic pyelonephritis. Clinicians should thoroughly investigate the entire gastrointestinal tract in patients with refractory diarrhea and severe hypoalbuminemia considering the possibility of gastrointestinal amyloidosis.

Pembrolizumab-induced autoimmune side effects of colon and pancreas in a patient with lung cancer.

Immune checkpoint inhibitors have been shown to be effective for treating many carcinomas. However, the activated immune response may lead to the development of multiple immune-related adverse events, including rare immune-mediated inflammation due to autoimmune mechanisms. An 82-year-old man was diagnosed with large cell lung cancer (T1aN3M1 stage IVB) and was treated with inhibitors of the programmed cell death receptor-1, pembrolizumab. Diarrhea and melena occurred after six doses of pembrolizumab, and colonoscopy revealed mucosal inflammation of the rectum and sigmoid colon in a continuous manner, resembling the typical endoscopic findings of ulcerative colitis. Subsequently, fever and hyperamylasemia appeared, and the patient was diagnosed with pancreatitis resembling type 2 autoimmune pancreatitis on imaging tests and cytological examination, which showed infiltration of inflammatory cells, mainly neutrophils. Steroid therapy was administered and both, colitis and pancreatitis markedly improved. Here, we present a patient who developed colitis and pancreatitis after ICI treatment for advanced lung cancer. Both are thought to be due to autoimmune side effects of pembrolizumab. Although pancreatitis is a rare irAE, clinicians should be aware of the development of pancreatitis, especially in the case of irAE colitis resembling ulcerative colitis.