C-C Chemokine 21-Expressing T-cell Zone Fibroblastic Reticular Cells, Abundant in Lymph Nodes, Are Absent in Cancer Lymphoid Stroma.

Cancer tissue generally possesses an immunosuppressive microenvironment. However, some cancers are associated with lymphoid stroma (i.e., a widely developed tertiary lymphoid structure). The T-cell zone (paracortex) of secondary lymphoid organs, particularly lymph nodes, is characterized by an abundance of T-cell zone fibroblastic reticular cells (TCZ-FRCs) that express C-C motif chemokine ligand 21 (CCL21) and smooth muscle actin (SMA). We analyzed the presence of TCZ-FRCs in 30 cases of carcinomas with lymphoid stroma of the breast, stomach, colon, tongue, and skin. Immunohistochemistry corroborated the abundance of CCL21+ SMA+ TCZ-FRCs in the normal lymph nodes. In sharp contrast, all 30 carcinomas with lymphoid stroma displayed no CCL21+ SMA+ TCZ-FRCs despite the affluence of T cells. Real-time reverse transcription polymerase chain reaction confirmed a marked decrease in the messenger ribonucleic acid expression of CCL21 and its receptor C-C motif chemokine receptor 7 in cancer lymphoid stroma compared to that in lymph nodes. Next, we analyzed the T cell phenotypes. The cancer lymphoid stroma demonstrated an abundance of CD3+ CD62L- memory-type T cells, in contrast to the presence of CD3+ CD62L+ naïve- and central memory T cells in the T cell zone of lymphoid tissues. Our data demonstrated the following: 1) Cancer lymphoid stroma lacked TCZ-FRCs with abundance of more activated T cells than in lymph nodes and 2) these were common phenomena in cancer lymphoid stroma irrespective of the histological types and organs involved.

Non-papillary serous cystadenoma of the epididymis associated with infected hydrocele of the testis: A case report.

A 50-year-old Japanese man with enlargement of the right scrotum was presented to our hospital. Preoperative examination confirmed a multilocular cyst with septa attached to the testis. Radical orchiectomy was performed. Pathological examination revealed closely-located two cysts; larger one was infected hydrocele testis, and smaller one was epithelial cyst, which were immunohistochemically positive widely for estrogen receptor (ER) and partly for progesterone receptor (PR). We concluded that the smaller cyst was serous cystadenoma of the epididymis.

Malignant Pleural Mesothelioma (MPM) Presenting as Hydropneumothorax.

An 86-year-old man presented with bilateral lower limb edema and was found to have hydropneumothorax on chest radiography. CT revealed a substantial pleural effusion and plaques. The patient had a history of working in a stone workshop, but the extent of asbestos exposure remained unknown. Thoracic drainage and subsequent thoracoscopic surgery confirmed the presence of biphasic malignant mesothelioma through pathological examination. Hydropneumothorax as a presentation of malignant pleural mesothelioma (MPM) is rare, with only a few similar cases reported. Remarkably, despite the coexistence of plural effusion and pneumothorax, the patient did not experience dyspnea. The examination also revealed tumor rupture and disruption of the pleura. Considering the possibility of MPM in patients with asymptomatic hydropneumothorax is essential for early diagnosis and appropriate management.

Molecular comparison of concurrent components of high-grade dysplasia, adenocarcinoma, and sarcomatoid carcinoma in a case of sarcomatoid carcinoma of the gallbladder.

Detailed genetic and immunohistochemical features of a sarcomatoid carcinoma of the gallbladder were reported. Studied was a resected gallbladder tumor involving the transverse colon, which was consisted of 3 histopathological neoplastic components, i.e., high-grade dysplasia, adenocarcinoma, and sarcomatoid carcinoma. The targeted amplicon sequencing showed somatic mutations in TP53 (p.S90fs) and ARID1A (c.4993 + 1G > T) in all of the 3 components. Copy numbers of CDKN2A and SMAD4 were decreased in the adenocarcinoma and the sarcomatoid component. Immunohistochemistry showed loss of expression of p53 and ARID1A in all components. p16 expression was lost in the adenocarcinoma and the sarcomatoid component, while SMAD4 expression was lost only in the latter. These results suggest that this sarcomatoid carcinoma may have developed by progression from high-grade dysplasia via adenocarcinoma with sequential accumulation of molecular aberrations involving p53, ARID1A, p16, and SMAD4. This information should serve to understand the molecular mechanism of this very intractable tumor.

The Conspicuousness of High Endothelial Venules in Angioimmunoblastic T-cell Lymphoma Is Due to Increased Cross-sectional Area, Not Increased Distribution Density.

Angioimmunoblastic T-cell lymphoma (AITL) is a T-cell lymphoma of follicular helper T-cell origin. Histologically, neoplastic T-cells proliferate to form clusters adjacent to or between arborizing high endothelial venules (HEVs). HEVs in normal lymph nodes express sulfated glycans called peripheral lymph node addressin (PNAd); however, it remains unclear whether PNAd is also expressed on HEVs in AITL. Furthermore, although it is widely accepted that HEVs are conspicuous in AITL due to their proliferation, quantitative histological support for this concept is lacking. To investigate these issues, we employed monoclonal antibodies recognizing PNAd, namely, MECA-79, HECA-452, and 297-11A, and performed quantitative immunohistochemical analysis of HEVs in 36 AITL-affected and 67 normal lymph nodes. Staining with all three antibodies confirmed that AITL HEVs express PNAd. Moreover, AITL HEVs were bound calcium-dependently by L-selectin-IgM fusion proteins, indicating that they function in the recruitment of L-selectin-expressing lymphocytes. Unexpectedly, HEV distribution density was not increased but rather decreased in AITL compared with normal lymph nodes, but HEV cross-sectional area in AITL was significantly greater than that seen in normal lymph nodes. Overall, these results indicate that the prominence of AITL HEVs is likely due to increased cross-sectional area rather than increased distribution density.

Primary Intramuscular Classic Hodgkin Lymphoma: A Rare Case Report.

Hodgkin lymphoma (HL) is a hematologic malignancy that typically presents with lymphadenopathy. We herein report a patient with HL who presented with an intramuscular mass that required differentiation from an inflammatory lesion. A 65-year-old Japanese woman was referred to our hospital with a chief complaint of chronic and expanding tumor in her left thigh. By surgical resection, she was diagnosed with primary intramuscular, Epstein-Barr virus-positive, mixed-cellularity classic HL. She received combined modality therapy, resulting in a complete response. Primary intramuscular classic HL is extremely rare. It should be listed as a differential diagnosis of intramuscular tumors.

Congenital right ventricular diverticulum formed by pulmonary regurgitative jet flow in a fetus with tetralogy of Fallot and absent pulmonary valve.

Congenital ventricular diverticulum is a rare anomaly with an unclear pathology. Here, we report a male fetus at 24 weeks of gestation, diagnosed with right ventricular diverticulum associated with tetralogy of Fallot and absent pulmonary valve. The diverticulum was located at the anterosuperior wall of the right ventricle and faced into the massive pulmonary regurgitation flow jet. Intrauterine fetal death from heart failure resulted at 26 weeks of gestation. An autopsy revealed significant subendocardial fibrosis in the diverticular wall without inflammatory cell infiltration. Clinical and pathologic features suggested that the regurgitative blood flow contributed to the formation of the right ventricular diverticulum.

An autopsy case of acute myocarditis with unique lymph node findings characterized by the proliferation of reactive plasmablasts.

We report an autopsy case of acute myocarditis, in which the mediastinal lymph nodes exhibited unique findings. A 15-year-old Japanese boy was diagnosed with the secondary onset of acute myocarditis. No viruses were identified. Autopsy confirmed acute lymphocytic myocarditis. Lymphadenopathy was observed, especially in pulmonary hilar/mediastinal areas. Microscopically, interfollicular areas were uniformly filled with medium-sized, round cells that resembled lymphocytes. They were immunohistochemically CD3- CD5- CD19+ CD20- CD79a- Pax-5- CD138+ MUM1+ LMP1- EBNA2- cytoplasmic IgG+ IgA- and IgM-. No monotypia was observed for kappa and lambda light chains, and multiplex polymerase chain reaction analyses of immunoglobulin heavy chain variable region diversity demonstrated oligoclonal peaks, suggesting reactive change. IgG+ or VS38c+ cells frequently co-expressed Ki-67 (up to 80%). We considered these cells abundantly present in lymph nodes to be reactive plasmablasts because they were early plasma cells with proliferative activity.

A patient with colitis-associated cancer who developed clinically manifest Crohn's disease only after surgery.

BACKGROUND: Patients with prolonged inflammatory bowel disease have a greater risk of colorectal cancer, known as colitis-associated cancer. Here we describe an unusual case of colitis-associated cancer. CASE PRESENTATION: The subject is a 41-year-old male who has not presented digestive symptoms and has an appreciable medical history. He consulted a nearby doctor with left flank pain. A colonoscopy revealed a lateral spreading tumor (granular-type) in his descending colon. With a clinical diagnosis of cancer, D3 left hemicolectomy was performed and a small intestine stoma was constructed. The pathological diagnosis of the tumor was mucinous adenocarcinoma, pT4a(SE), pN2a, which was associated with dysplasia in the surface area. Post-operative ileus was prolonged and the endoscopic examination revealed longitudinal ulcers in the ileum. These ulcers responded quite well to the administration of infliximab, confirming the final diagnosis of Crohn's disease. Pathological re-examination revealed that the tumor was dysplasia-associated type, and another dysplasia was confirmed near the tumor. Furthermore, mural scars and sporadic lymphoid aggregates were noted in the colon tissues, which suggested pre-existing Crohn's disease. The patient died of peritoneal dissemination of cancer on day 207 after surgery. CONCLUSION: The present case was diagnosed as colitis-associated cancer with clinically latent Crohn's disease, who developed clinically manifest Crohn's disease only after surgery. Our review of literature revealed no cases comparable to ours.

Rapidly progressed large cell neuroendocrine carcinoma of the stomach with an increased serum alpha fetoprotein level: a case report.

An 82-year-old man who had multiple hepatic tumors, a gastric tumor, and ascites was referred to our hospital. On the time of our hospital visit, he had a high serum alpha fetoprotein (AFP) level of 1206 ng/mL. Upper gastrointestinal endoscopy revealed a Borrmann Type II gastric tumor approximately 40 mm in diameter in the lesser curvature of cardia, and forceps biopsy was performed. Endoscopic ultrasound fine-needle aspiration was also performed for hepatic tumor. The biopsy specimens from the gastric and hepatic tumor were diagnosed as large cell neuroendocrine carcinoma (LCNEC), containing AFP-positive cells only sporadically by immunohistochemistry. He was diagnosed with gastric LCNEC with liver metastasis. Retrospective analysis of endoscopic data obtained at 5 months ago revealed a 0-IIc lesion, approximately 10 mm in size, in the lesser curvature of cardia, the same area of the present gastric tumor. This indicated rapid growth rate of the present tumor. The patient developed jaundice 5 days after he visited our hospital. And he died 18 days after hospital admission.

Gastric gastrointestinal stromal tumor with predominant cystic formation diagnosed by endoscopic ultrasound-fine needle aspiration.

A 69-year-old woman who had no symptoms was found to have an intraperitoneal tumor on abdominal ultrasonography in a medical checkup. Thereafter, she was referred to our hospital for a further detailed examination. Contrast-enhanced computed tomography revealed a thin-walled cystic tumor with a diameter of 8 cm and with a hypervascular solid masses in the cystic wall, along with intraperitoneal multiple nodules. The cystic tumor was contiguous with the stomach wall. For solid mass of cystic lesions, endoscopic ultrasound-fine needle aspiration was performed transgastrically with a 25-gauge Franseen needle. Pathologically, the cells in the tumor were spindle shaped with atypical nucleus and were positive for c-kit, CD34, and smooth muscle actin. The tumor was diagnosed as gastrointestinal stromal tumor (GIST). With the diagnosis of gastric GIST with peritoneal dissemination, imatinib chemotherapy was initiated.

Microvascular proliferation of the portal vein branches in the liver of biliary atresia patients at Kasai operation is associated with a better long-term clinical outcome.

AIM OF THE STUDY: We previously showed an increased number of smaller portal vein (PV) branches in the portal areas of liver biopsy specimens of biliary atresia (BA) patients. We evaluated the correlation between this histopathological feature and the prognosis. PATIENTS AND METHODS: Twenty-five consecutive patients with BA encountered between 2000 and 2012 were classified into three prognostic groups based on their postoperative outcomes: Excellent (n = 11) for native-liver survivors with a normal liver function, Good (n = 6) for native-liver survivors with liver dysfunction, and Poor (n = 8) for survivors after liver transplant or on a waiting list. Data from morphometrical analyses, including the fibrotic portal area, numbers of PVs, diameter and total area of PV branches, were statistically compared among the three groups. MAIN RESULTS: The number of PV branches per unit area of the whole-liver specimen in the poor prognostic group was significantly lower than that in the excellent group (3.1 ± 0.6 vs. 5.2 ± 2.0/mm2, p = 0.03). There were no significant differences in the other parameters. CONCLUSIONS: This is the first report on the relationships between morphometrically analyzed PV branches and the postoperative course in BA patients. The portal venous system is involved as the primary lesion in BA.

Histological significance of hepatitis-like findings in biliary atresia: An analysis of 34 Japanese cases.

BACKGROUND: Hepatocellular injury including multinuclear changes are common histological features in biliary atresia (BA), as well as in neonatal hepatitis. To date, however, no reports have examined how those findings correlate with the prognosis of BA. We clarified the clinical implications of hepatitis-related changes in BA on histological analysis. METHODS: We retrospectively reviewed 34 cases of BA treated over the past 30 years at Ibaraki Children's Hospital. Liver biopsy specimens during Kasai procedures were evaluated for hepatocyte multinuclear change, ballooning, and acidophilic body, hereby defined as hepatitis-like findings (HLF). Each finding was semi-quantitatively scored as 0-2, and their sum was defined as the HLF score, ranging from 0 to 6. We examined the correlation between HLF score and total bilirubin (T-Bil), direct bilirubin (D-Bil), and other liver function test results at the Kasai procedure, as well as 1 week, and 1, 3, and 6 months after the Kasai procedure. Subsequently, HLF score was compared between native liver survivors (NLS; n = 16) and non-NLS (n = 18) for long-term analyses. RESULTS: Hepatitis-like findings score except for aspartate aminotransferase (AST), had no correlation with the preoperative data. HLF score was positively correlated, however, with T-Bil, D-Bil, and AST at 1 week and 1 month after the Kasai procedure (1 week: P = 0.009, 0.023, and 0.019; 1 month: 0.022, 0.019, and 0.013, respectively). HLF score was not significantly different between the NLS and non-NLS groups. CONCLUSION: Higher HLF score at Kasai procedure is an indicator of poor liver function at short-term follow up.

Morphometric demonstration of portal vein stenosis and hepatic arterial medial hypertrophy in patients with biliary atresia.

PURPOSE: Portal hypertension in patients with biliary atresia (BA) is generally thought to result from portal vein (PV) narrowing secondary to hepatic fibrosis. To test the hypothesis, we morphometrically analyzed the PVs and hepatic arteries (HAs). METHODS: Morphometrical analyses of 25 BA and 26 non-BA liver biopsy specimens from patients treated from 2000 to 2014. The total specimen area, the fibrotic portal area, vessel diameter and medial thickness of the HAs were measured. RESULTS: The PV diameter in BA patients was significantly smaller than that in non-BA patients. In BA, the numbers of normal-sized PVs and capillaries were decreased and increased, respectively. The PV diameter was not significantly correlated with the degree of fibrosis. We newly found that medial hypertrophy and the HA diameter increased with the number of endothelial cells in BA. The PV diameter was not significantly correlated with the medial thickness and was positively correlated with the HA diameter in BA. CONCLUSIONS: The narrowing of the PV is unlikely to occur secondarily to liver fibrosis. The medial hypertrophy of the HA is not correlated with the decrease in the PV blood flow. These findings seem to be unique to the primary vascular lesions of BA.

Primary meningeal myxoid liposarcoma with aggressive behavior after recurrence: case report.

Although liposarcomas are the most common soft tissue sarcomas, their intracranial variants are extremely rare. Here, we present a case of a primary intracranial myxoid liposarcoma in a 23-year-old Japanese man who presented with generalized seizures and a mass in the left frontal lobe. The tumor was totally removed, and histological analyses pointed to liposarcoma. Thirteen years after his initial treatment, the patient presented with right-side weakness and local recurrence of tumor was discovered. Histology from the second resection confirmed the diagnosis of myxoid liposarcoma. Shortly after the second resection, progressive, new intracranial lesions were observed and despite a third resection, extensive intracerebral invasion by the tumor proved fatal. The histological features of myxoid liposarcoma were essentially similar with each recurrence, but the aggressive tumor behavior after the second operation did not align with expectations based on histological classification.

Immune cell expression of TGFß1 in cancer with lymphoid stroma: dendritic cell and regulatory T cell contact.

Although cancer tissue generally shows limited immune responses, some cancers abound with lymphocytes, which generally show favorable prognosis. These cancers, despite their rarity, are important in analyzing immune responses in cancer tissue. Transforming growth factor ß1 (TFGß1) is a multifunctional cytokine, generally having an immunosuppressive function. The present study analyzes the in situ TGFß1 expression in 23 cases of lymphocyte-rich gastric carcinomas (Ly-rich GCs) using immunohistochemistry and in situ hybridization. Immunohistochemistry revealed that latency-associated peptide (LAP) of TGFß1 was localized in mainly immune cells in all cases, which was more abundant than in control GCs. Expression of LAP by cancer cells was only focal. In situ hybridization also confirmed abundant TGFß1 mRNA expression in the lymphoid stroma. Double immunofluorescent microscopy identified LAP+ cells as macrophages, dendritic cells, and part of T cells. Close cell-to-cell contact was observed between LAP+ dendritic-shaped cells and FoxP3+ regulatory T cells (Treg cells). Mature dendritic cells in Ly-rich GCs expressed LAP more frequently than those in the secondary lymphoid organs. Our data revealed abundant expression of TGFß1 in immune cells with contact to Treg cells in lymphoid stroma, which is consistent with the notion that TGFß1 is one of the immunosuppressive factors in cancer stroma.

Unique manifestations of biliary atresia provide new immunological insight into its etiopathogenesis.

Biliary atresia (BA) is a unique cholestatic disease of newborns with a background of exaggerated immune response in the liver of unknown mechanism. Three hypotheses have been proposed; autoimmune type of cholangiopathy triggered by virus infection, graft-versus-host disease type of immune-mediated disease associated with maternal microchimerism and ductal plate malformation theory. Researchers on virus infection theory have experimentally explored immune process causing cholangiopathy on murine models of this disease, while in maternal microchimerism hypothesis were detected maternal cells in the BA patients' liver, of which roles are yet to be determined. Ductal plate malformation theory is an intriguing hypothesis in the sense that it suggests the onset of this disease is in the first trimester. This theory can be secondary to either one of these two immune-related insults. In this review, four unique points are focused; (1) the timing of onset, (2) hepatitis-like pathological picture, (3) heterogenous atrophy of the liver segments when advanced, and (4) swollen lymph nodes at the porta hepatis. These unique clinicopahtological aspects of this disease should be well explained by these hypotheses.