Liver biopsy in the post-hepatitis C virus era in Japan.

In Japan, liver biopsies were previously crucial in evaluating the severity of hepatitis caused by the hepatitis C virus (HCV) and diagnosing HCV-related hepatocellular carcinoma (HCC). However, due to the development of effective antiviral treatments and advanced imaging, the necessity for biopsies has significantly decreased. This change has resulted in fewer chances for diagnosing liver disease, causing many general pathologists to feel less confident in making liver biopsy diagnoses. This article provides a comprehensive overview of the challenges and potential solutions related to liver biopsies in Japan. First, it highlights the importance of considering steatotic liver diseases as independent conditions that can coexist with other liver diseases due to their increasing prevalence. Second, it emphasizes the need to avoid hasty assumptions of HCC in nodular lesions, because clinically diagnosable HCCs are not targets for biopsy. Third, the importance of diagnosing hepatic immune-related adverse events caused by immune checkpoint inhibitors is increasing due to the anticipated widespread use of these drugs. In conclusion, pathologists should be attuned to the changing landscape of liver diseases and approach liver biopsies with care and attention to detail.

Change in Main Histological Type of Invasive Breast Cancer From Ductal to Lobular Carcinoma by Neoadjuvant Chemotherapy.

We present a case study of breast cancer initially diagnosed as invasive ductal carcinoma (IDC), which subsequently substituted into invasive lobular carcinoma (ILC) following neoadjuvant chemotherapy (NAC). A 61-year-old woman presented with a palpable breast lump, and histological examination through core needle biopsy (CNB) confirmed the presence of IDC. After a 6-month course of NAC, the patient achieved a clinically complete response (cCR) and underwent mastectomy. The surgical specimen showed no detectable tumor upon palpation, but microscopic analysis revealed a highly infiltrative growth of poorly-cohesive small atypical cells in the original tumor area. Immunohistochemical staining demonstrated that the tumor cells were negative for E-cadherin, leading to a diagnosis of ILC. To address the histological discrepancy before and after NAC, we re-evaluated the initial CNB using E-cadherin immunohistochemistry. While most tumor cells were E-cadherin positive, a small area displaying scirrhous subtype-like morphology exhibited E-cadherin negativity. Consequently, we revised the diagnosis to mixed IDC-ILC. The differential chemosensitivity between IDC and ILC may provide insight into this phenomenon.

[A Case Report of Rectal MiNEN Surgical Resection].

A 56-year-old man with diarrhea and bloody stools was found to have a type 2 tumor in the rectosigmoid region. A biopsy revealed well-differentiated tubular adenocarcinoma(tub1), and laparoscopic high anterior resection was performed. The final diagnosis was MiNEN(NEC:adenocarcinoma=6:4), RS, type 2, Ly0, V0, pT3(SS), pN0, M0, and pStage Ⅱa. He has been followed up without postoperative adjuvant chemotherapy and has been alive without recurrence for 1 year and 4 months after surgery. MiNEN is a rare disease, and most of them are mixed with NEC components or high- grade NET G3 and have a poor prognosis. We present an important case of rectal MiNEN.

Limited dorsal myeloschisis without extradural stalk continuity to coexisting congenital dermal sinus.

Limited dorsal myeloschisis (LDM) is characterized by a fibroneural tethering stalk linking the skin lesion to the underlying spinal cord. LDM without an extradural stalk is rare. A full-term boy was noted at birth to have a dimple in the upper back (dorsal skin of the lower thoracic region). Computed tomographic scan showed spina bifida at the T9-12 vertebral level and osteochondral tissue at the T10 level. Magnetic resonance imaging (MRI) demonstrated a tiny dorsal lipoma at the T8 vertebral level, but the intradural tethering tract was not apparent. At 18 days of age, the congenital dermal sinus (CDS) tract started from the dimple and terminated at the osteochondral tissue, without continuity of the dura mater, and the osteochondral tissues were resected. At age 2 years 8 months, he developed spastic paresis of the right foot. On MRI, the tethering tract from the dorsal lipoma became apparent. During the second surgery at age 2 years 11 months, the intradural stalk started from the dorsal lipoma and joined the inner surface of the dura mater was untethering from the cord. Postoperatively, right spastic paresis was improved. Histological examination of the intradural stalk revealed the distribution of S100-immunopositive peripheral nerve fibers, which is one of the histopathological hallmarks of LDM. We speculated that the extradural stalk with coexisting CDS originally linked from the skin lesion subsequently regressed and was replaced by fibroadipose tissue with osteochondral tissue migration. Intradural exploration should always be seriously considered in these disorders of persisting neurocutaneous connection.

A case of esophageal squamous cell carcinoma accompanied by pancreatic and bile duct metastases: Successful treatment starts with an accurate diagnosis.

ABSTRACT: Pancreatic and bile duct metastases from esophageal cancer are extremely rare. We report a case of advanced esophageal cancer successfully treated with chemotherapy, selected on the basis of an accurate pathologic diagnosis. A 69-year-old man with chronic renal dysfunction presented with persistent abdominal pain and anorexia. Upper gastrointestinal endoscopy revealed an irregular-shaped tumor in the lower esophagus. Computed tomography and ultrasonography revealed swollen para-aortic lymph nodes, a pancreatic mass, and distal bile duct stenosis. Histopathological examination showed that all of the lesions were squamous cell carcinoma with unique immunohistochemical characteristics of p40+ and cytokeratin 7+. The final diagnosis was esophageal squamous cell carcinoma accompanied by lymph node, pancreas, and bile duct metastases. Taking his renal dysfunction into consideration, modified FOLFOX was administered as the first-line chemotherapy. The patient survived for 15 months since his first presentation. The favorable outcome was attributed to the accurate diagnosis based on comprehensive tissue sampling.

Feasibility, safety and tolerability of the CREB-binding protein/ß-catenin inhibitor OP-724 in patients with advanced primary biliary cholangitis: an investigator-initiated, open-label, non-randomised, two-centre, phase 1 study.

OBJECTIVE: This study aimed to evaluate the safety and tolerability of OP-724, a CREB-binding protein/ß-catenin inhibitor, in patients with advanced primary biliary cholangitis (PBC). DESIGN: An open-label, non-randomised, phase 1 trial was conducted at two hospitals in Japan. Patients with advanced PBC classified as stage III or higher according to the Scheuer classification by liver biopsy between 4 September 2019 and 21 September 2021 were enrolled. Seven patients received intravenous OP-724 infusions at escalating dosages of 280 and 380 mg/m2/4 hours two times weekly for 12 weeks. The primary endpoint was the incidence of serious adverse events (SAEs). The secondary endpoints were the incidence of AEs and the improvement in the modified Histological Activity Index (mHAI) score. RESULTS: Seven patients (median age, 68 years) were enrolled. Of these seven patients, five completed twelve cycles of treatment, one discontinued prematurely for personal reasons in the 280 mg/m2/4 hours cohort, and one in the 380 mg/m2/4 hours cohort was withdrawn from the study due to drug-induced liver injury (grade 2). Consequently, the recommended dosage was determined to be 280 mg/m2/4 hours. SAEs did not occur. The most common AEs were abdominal discomfort (29%) and abnormal hepatic function (43%). OP-724 treatment was associated with histological improvements in the fibrosis stage (2/5 (40%)) and mHAI score (3/5 (60%)) on histological analysis. CONCLUSION: Administration of intravenous OP-724 infusion at a dosage of 280 mg/m2/4 hours two times weekly for 12 weeks was well tolerated by patients with advanced PBC. However, further evaluation of antifibrotic effects in patients with PBC is warranted. TRIAL REGISTRATION NUMBER: NCT04047160.

Safety, tolerability, and anti-fibrotic efficacy of the CBP/ß-catenin inhibitor PRI-724 in patients with hepatitis C and B virus-induced liver cirrhosis: An investigator-initiated, open-label, non-randomised, multicentre, phase 1/2a study.

BACKGROUND: We conducted an exploratory study to assess the safety tolerability, and anti-fibrotic effects of PRI-724, a CBP/ß-catenin inhibitor, in patients with hepatitis C virus (HCV)- and hepatitis B virus (HBV)-induced cirrhosis. METHODS: This multicentre, open-label, non-randomised, non-placebo-controlled phase 1/2a trial was conducted at three hospitals in Japan. Between July 27, 2018, and July 13, 2021, we enrolled patients with HCV- and HBV-induced cirrhosis classified as Child-Pugh (CP) class A or B. In phase 1, 15 patients received intravenous infusions of PRI-724 at escalating doses of 140, 280, and 380 mg/m2/4 h twice weekly for 12 weeks. In phase 2a, 12 patients received the recommended PRI-724 dose. The primary endpoints of phases 1 and 2a were the frequency and severity of adverse events and efficacy in treating cirrhosis based on liver biopsy. This study was registered at ClinicalTrials.gov (no. NCT03620474). FINDINGS: Three patients from phase 1 who received the recommended PRI-724 dose were evaluated to obtain efficacy and safety data in phase 2a. Serious adverse events occurred in three patients, one of which was possibly related to PRI-724. The most common adverse events were diarrhoea and nausea. PRI-724 did not decrease hepatic fibrosis with any statistical significance, either by ordinal scoring or measurement of collagen proportionate area at 12 weeks; however, we observed statistically significant improvements in liver stiffness, Model for End-stage Liver Disease score, and serum albumin level. INTERPRETATION: Intravenous administration of 280 mg/m2/4 h PRI-724 over 12 weeks was preliminarily assessed to be well tolerated; however, further evaluation of anti-fibrotic effects in patients with cirrhosis is warranted. FUNDING: AMED, Ohara Pharmaceutical.

Cytoglobin attenuates pancreatic cancer growth via scavenging reactive oxygen species.

Pancreatic cancer is a highly challenging malignancy with extremely poor prognosis. Cytoglobin (CYGB), a hemeprotein involved in liver fibrosis and cancer development, is expressed in pericytes of all organs. Here, we examined the role of CYGB in the development of pancreatic cancer. CYGB expression appeared predominately in the area surrounding adenocarcinoma and negatively correlated with tumor size in patients with pancreatic cancer. Directly injecting 7, 12-dimethylbenz[a]anthracene into the pancreatic tail in wild-type mice resulted in time-dependent induction of severe pancreatitis, fibrosis, and oxidative damage, which was rescued by Cygb overexpression in transgenic mice. Pancreatic cancer incidence was 93% in wild-type mice but only 55% in transgenic mice. Enhanced CYGB expression in human pancreatic stellate cells in vitro reduced cellular collagen synthesis, inhibited cell activation, increased expression of antioxidant-related genes, and increased CYGB secretion into the medium. Cygb-overexpressing or recombinant human CYGB (rhCYGB) -treated MIA PaCa-2 cancer cells exhibited dose-dependent cell cycle arrest at the G1 phase, diminished cell migration, and reduction in colony formation. RNA sequencing in rhCYGB-treated MIA PaCa-2 cells revealed downregulation of cell cycle and oxidative phosphorylation pathways. An increase in MIA PaCa-2 cell proliferation and reactive oxygen species production by H2O2 challenge was blocked by rhCYGB treatment or Cygb overexpression. PANC-1, OCUP-A2, and BxPC-3 cancer cells showed similar responses to rhCYGB. Known antioxidants N-acetyl cysteine and glutathione also inhibited cancer cell growth. These results demonstrate that CYGB suppresses pancreatic stellate cell activation, pancreatic fibrosis, and tumor growth, suggesting its potential therapeutic application against pancreatic cancer.

Pulmonary Tumor Thrombotic Microangiopathy Caused by Recurrent Gastric Cancer 26 Years After Total Gastrectomy.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare cancer-related complication that induces pulmonary hypertension (PH). PTTM can be caused by recurrent cancer, with 12 years being the longest reported interval from primary cancer to the development of PTTM. We herein report a 74-year-old woman who presented with dyspnea due to PH. The postmortem diagnosis was PTTM caused by recurrent gastric cancer 26 years after total gastrectomy. An autopsy revealed PTTM-specific histological characteristics. Our findings indicate that PTTM should be considered as a diagnosis for patients with a history of cancer who develop PH, even several decades after treatment.

Jejunal hemorrhage due to hemolymphangioma successfully detected and controlled by double-balloon enteroscopy.

Lymphangiomas are benign, often subclinical, neoplasms, which can develop in the digestive tracts. Hemorrhagic jejunal tumors are relatively rare and diagnostic challenge. We report herein a case of hemorrhagic jejunal hemolymphangioma successfully diagnosed and treated by double-balloon enteroscopy.

Malignant pleural mesothelioma in a patient with pneumothorax: A cumbersome subtype both clinically and pathologically.

Here, we report a case of malignant pleural mesothelioma (MPM) that was very difficult to diagnose. A 62-year-old woman with a surgical history of recurrent bilateral pneumothorax was admitted to our hospital with severe dysphagia. Computed tomography (CT) detected stenosis in the lower esophagus. Immunohistochemical examination of a biopsy sample from the stenotic region was suggestive of MPM. Chemotherapy was initiated, but the patient soon weakened and died. Autopsy revealed atypical cells, identical to those seen in the biopsy sample which had spread into the stenotic esophagus and entire thoracic cavity. Although neither pleural thickening/nodules nor asbestos bodies were observed, we finally diagnosed the tumor as a biphasic-type MPM. We re-examined previous surgical specimens of pneumothorax and acknowledged foci of bland mesothelial cell proliferation which had the same pathological findings as tumor cells at autopsy. The lack of asbestos exposure and pleural thickening, an initial manifestation of pneumothorax, and faint cytological atypia prevented an early diagnosis. In cases of recurrent pneumothorax in elderly patients, MPM should be included in the differential diagnosis.

[Surgical Resection of Gastric MANEC-Two Case Reports].

Case 1 was a 78-year-old woman with a tumor in the stomach on preoperative CT of an inguinal hernia. The patient was diagnosed with advanced gastric cancer at posterior wall of fornix and underwent total gastrectomy and splenectomy. Postoperative pathological diagnosis was gastric mixed adenoneuroendocrine carcinoma(MANEC), T1b2, N1, M0, StageⅠB. She has been alive without recurrence for 3 years without postoperative adjuvant chemotherapy. Case 2 was a 78-year-old man who was admitted to the hospital with acute pancreatitis and had a thickened wall of the lesser curvature of the gastric antrum on CT. He was diagnosed with advanced gastric cancer and underwent distal gastrectomy and D2 dissection. Postoperative pathological diagnosis was gastric MANEC, T1b2, N1, M0, Stage ⅠB. Oral administration of S-1 was started as postoperative adjuvant chemotherapy, but he was very tired and ended in 1 course at his request. Computed tomography 6 months after the operation revealed multiple liver metastases, and he was transferred to best supportive care at his request. He died 1 year after surgery. We experienced 2 valuable cases of gastric MANEC.

Deciduosis of the Appendix During Pregnancy.

Acute appendicitis is an important differential diagnosis in patients with right lower quadrant pain during pregnancy. Endometriosis, a hormone-related pathology, is another possibility. Patients with endometriosis are typically symptomatic before pregnancy. Stromal endometriosis is a variant of endometriosis that presents no symptoms before pregnancy but which occasionally presents with the new onset of symptoms during pregnancy. We report the case of a 35-year-old woman in her 8th month of pregnancy who presented with impending appendiceal rupture due to deciduosis of the appendix, a progesterone-related condition, during pregnancy. This case suggests that deciduosis/stromal endometriosis should be considered as a differential diagnosis of acute abdomen during pregnancy, even if the patient is asymptomatic before pregnancy.

Dextran deposition in reticuloendothelial organs in hemodialysis patients: A forgotten adverse effect of low-molecular weight dextran.

We present two autopsy cases of refractory ascites/hydrothorax associated with systemic deposition of low-molecular weight dextran that had been used in hemodialysis over an extended period. The most striking autopsy findings in both cases were dense accumulation of dextran-laden macrophages in sinusoids of reticuloendothelial organs. These accumulated macrophages seemed to have disturbed blood and lymph flow. Based on these findings, we concluded that the persistent ascites and hydrothorax were attributable to systemic deposition of dextran, especially the accumulation of dextran-laden macrophages in the reticuloendothelial organs. We suggest that dextran solution should immediately be designated as contraindicated for hemodialysis patients.

Optimal treatment strategies for hepatic portal venous gas: A retrospective assessment.

BACKGROUND: Hepatic portal venous gas (HPVG) generally indicates poor prognoses in patients with serious intestinal damage. Although surgical removal of the damaged portion is effective, some patients can recover with conservative treatments. AIM: To establish an optimal treatment strategy for HPVG, we attempted to generate computed tomography (CT)-based criteria for determining surgical indication, and explored reliable prognostic factors in non-surgical cases. METHODS: Thirty-four cases of HPVG (patients aged 34-99 years) were included. Necessity for surgery had been determined mainly by CT findings (i.e. free-air, embolism, lack of contrast enhancement of the intestinal wall, and intestinal pneumatosis). The clinical data, including treatment outcomes, were analyzed separately for the surgical cases and non-surgical cases. RESULTS: Laparotomy was performed in eight cases (surgical cases). Seven patients (87.5%) survived but one (12.5%) died. In each case, severe intestinal damage was confirmed during surgery, and the necrotic portion, if present, was removed. Non-occlusive mesenteric ischemia was the most common cause (n = 4). Twenty-six cases were treated conservatively (non-surgical cases). Surgical treatments had been required for twelve but were abandoned because of the patients' poor general conditions. Surprisingly, however, three (25%) of the twelve inoperable patients survived. The remaining 14 of the 26 cases were diagnosed originally as being sufficiently cured by conservative treatments, and only one patient (7%) died. Comparative analyses of the fatal (n = 10) and recovery (n = 16) cases revealed that ascites, peritoneal irritation signs, and shock were significantly more frequent in the fatal cases. The mortality was 90% if two or all of these three clinical findings were detected. CONCLUSION: HPVG related to intestinal necrosis requires surgery, and our CT-based criteria are probably useful to determine the surgical indication. In non-surgical cases, ascites, peritoneal irritation signs and shock were closely associated with poor prognoses, and are applicable as predictors of patients' prognoses.

Infantile macrocephaly and multiple subcutaneous lipomas diagnosed with PTEN hamartoma tumor syndrome: A case report.

A heterozygous loss-of-function mutation of the PTEN gene, one of the tumor suppressor genes, causes a wide variety of disorders, ranging from macrocephaly/autism syndrome to PTEN hamartoma tumor syndrome, including Cowden disease that causes thyroid and breast cancer mainly in the adolescence and young adult generation. An 8-month-old male infant with simple macrocephaly developed a café-au-lait spot and two subcutaneous tumors at the age of 1 year. One of the tumors developed rapidly was resected at the age of 1 year and 9 months and identified as benign lipoma. From the age of 2 years, the patient often threw a tantrum. At the age of 2 years and 9 months, a pathogenic germline mutation was identified in the PTEN gene (NM_000314.7), c.195C>A, p.Y65* in the form of a heterozygous germline variant. Developmental delay was noted but no tumors were found in the thyroid gland and breasts. Immunohistochemistry for PTEN in the resected lipoma demonstrated that the PTEN expression pattern was similar to that in a subcutaneous adipose tissue from a normal subject, suggesting that two-hit was not likely involved in the rapid growth of this lipoma. At the age of 5 years, the patient was diagnosed with autism spectrum disorders with moderate developmental delay. A long-term follow-up is underway to examine developmental changes in psychomotor disorders and possible tumor formation.

Malignant Lymphoma of the Ovary: A Diagnostic Pitfall of Intraoperative Consultation.

Primary ovarian lymphomas are rare, but can potentially evoke diagnostic problems. We present a case of ovarian lymphoma, in which an ambiguous intraoperative pathologic report led to overtreatment (unnecessary surgery). A 73-yr-old woman with fatigue and low-grade fever was diagnosed as having a left ovarian tumor by imaging modalities. Exploratory laparotomy was carried out to confirm the diagnosis. The frozen tissue sections of the ovarian tumor showed condensed proliferation of atypical round cells accompanied with a few small lymphocytes. The pathologists could not determine whether this tumor was a lymphoma or another malignancy (eg, dysgerminoma). Hence, they reported it to gynecologists who operated as simply a malignant tumor in order to evade misdiagnosis. On the basis of the inconclusive pathologic report, the gynecologists decided to change the planned laparotomy to total hysterectomy with bilateral salpingo-oophorectomy and pelvic lymph node dissection. A postoperative paraffin section-based pathologic diagnosis was diffuse large B-cell lymphoma of the ovary, which basically does not require surgical treatments. Subsequently, chemotherapy for B-cell lymphoma was initiated, and no lymphoma recurrence has been reported to date. A more robust preoperative discussion between the gynecologists and the pathologists might have avoided the overtreatment.

Two cases of aplasia cutis congenita with hair collar signs and macrophage hyperplasia.

We report two cases of aplasia cutis congenita associated with hair collar signs and hemangioma simplex in their parietal regions. A hair collar sign and a hemangioma are known to suggest the possibility of underlying neural tube defects. However, no obvious bone defects or heterotopic neural tissue were observed in the imaging and histopathological examinations. Nevertheless, some pathological observations similar in both cases suggested abnormalities in the process of ectodermal fusion. A flat epidermis and a lack of appendages were recognized. Both cases also exhibited the presence of melanocytes in a portion of the superficial dermal layer. An increase in the number of macrophages was observed in the dermal area with neither elastic fibers nor normal collagen fibers. The peripheral hair follicles grew horizontally.