Reduced CC Chemokine Receptor 4 Expression in Tumor Cells after Lenalidomide Treatment for Adult T-Cell Leukemia/Lymphoma: A Case Report.

Introduction: CC chemokine receptor 4 (CCR4), which is involved in leukocyte migration, is expressed in most tumor cells in patients with adult T-cell leukemia/lymphoma (ATLL). Case Presentation: Here we report the case of a 78-year-old man diagnosed with lymphoma-type ATLL expressing CCR4. The patient was administered two cycles of lenalidomide but died because of sepsis 5 months after the initial diagnosis. Autopsy revealed ATLL cells at several sites. Immunohistochemical analysis revealed that these ATLL cells had reduced CCR4 expression. Conclusion: The present case suggests that treatment should be carefully determined in ATLL with reference to a history of lenalidomide use and CCR4 expression.

Bronchogenic cysts in rare sites (retroperitoneum, skin, spinal cord and pericardial cavity): A case series and characterization of epithelial phenotypes.

Bronchogenic cysts are congenital malformations of the bronchial tree, detected as a cystic and/or mass lesion in the thoracic cavity. Although it occurs in distant locations, such as skin and retroperitoneum, to the best of our knowledge, little is known about the components and phenotypes of the epithelium that line a bronchogenic cyst in rare sites. The present study reviewed 34 bronchogenic cysts that were surgically resected at Osaka Medical and Pharmaceutical University Hospital (Osaka, Japan) from January 1998 to December 2020. Bronchogenic cysts in rare sites were detected and diagnosis was confirmed based on the presence of pseudostratified, ciliated and/or columnar epithelium together with at least one of the following: Cartilage, smooth muscle or seromucous glands. The phenotypes of epithelium lining the cyst were characterized using immunohistochemical analysis. A total of six bronchogenic cysts in rare sites (two cases each in the retroperitoneum and skin and one case each in the cervical spinal cord and pericardial cavity) met the criteria for confirmation of the diagnoses. The epithelium lining the cyst stained positive for cytokeratin CK7 and thyroid transcription factor 1 (a marker expressed in thyroid follicles and bronchial epithelium) and negative for CK20, indicating that the phenotypes were similar to those of the respiratory epithelium. The present study demonstrated that a bronchogenic cyst can occur in rare sites, such as the retroperitoneum, skin, spinal cord and pericardial cavity, suggesting that it should be considered as a differential diagnosis before surgical approach to implement relevant management modalities such as follow-up, simple or radical resection.

Ocular and extraocular sebaceous carcinomas: A retrospective study with emphasis on the presence of in situ lesion and discussion and review of the histogenesis of extraocular sebaceous carcinoma.

Sebaceous carcinoma (SC) is a rare carcinoma classified as ocular or extraocular. Ocular SC is believed to arise from the meibomian glands or the glands of Zeis. However, the origin of extraocular SC is controversial because there is no evidence of carcinoma arising from pre-existing sebaceous glands. Several hypotheses about the origin of extraocular SC have been proposed, including one suggesting an origin from intraepidermal neoplastic cells. Although extraocular SCs have been shown to occasionally comprise intraepidermal neoplastic cells, no study has investigated whether intraepidermal neoplastic cells possess sebaceous differentiation. The present study analyzed the clinicopathological features of ocular and extraocular SC, with an emphasis on the presence of in situ (intraepithelial) lesions. It retrospectively reviewed the clinicopathological features of eight patients with ocular and three patients with extraocular SC (eight women and three men; median age, 72 years), respectively. In situ (intraepithelial) lesions were observed in four of the eight ocular SC cases and one of the three extraocular SC cases and an apocrine component was noted in one patient with ocular SC (seboapocrine carcinoma). In addition, immunohistochemical analyses showed that the androgen receptor (AR) was expressed in all ocular SCs and two of the three extraocular SC cases. Adipophilin expression was observed in all ocular and extraocular SC. In situ lesions of extraocular SC showed positive immunoreactivity for both AR and adipophilin. The present study is the first to demonstrate sebaceous differentiation in in situ lesions of extraocular SC. The possible origin of extraocular SC is speculated to be the progenitor cells present in the sebaceous duct or interfollicular epidermis. The results of the present study and reported cases of SC in situ indicate that extraocular SC also arises from intraepidermal neoplastic cells.

Transplantation of Graft Anti-Host Cytotoxic T Lymphocytes Along with Allogeneic Bone Marrow Skips Macrophage-Induced Graft-Versus-Host Disease.

Graft-versus-host disease (GVHD) is a physiological response of the graft to allogeneic hosts. However, the effector cells, affected organ(s), and cytokines in the GVHD remain controversially discussed, without having determined a particular cytotoxic activity of the graft against the host. After i.v. injection of C57BL/6 (H-2b) spleen cells into irradiated BDF1 (H-2b/d) mice, the hosts developed interferon-gamma (IFN-γ)-dependent bone marrow (BM) GVHD on days 5-17. When H-2DdKd transgenic H-2b lymphoma cells were i.p. inoculated into irradiated, H-2b splenocyte-transplanted H-2b/d mice, the infiltration of macrophages cytotoxic against H-2DdKd transgenic H-2b mouse skin epithelia (a GVHD activity) into the peritoneal cavity preceded several days the infiltration of interleukin (IL)-2-dependent cytotoxic T lymphocytes (CTLs) to achieve a graft-versus-leukemia (GVL) effect. In contrast, allogeneic BM transplanted alone into the irradiated mice did not induce GVHD for 44 days, whereas i.v. injection of graft anti-host macrophages or graft anti-host CTLs along with allogeneic BM, respectively, induced GVHD or promoted the GVL effect in the absence of GVHD. These results revealed that macrophage-induced GVHD and the CTL-mediated GVL effect were a set (Th1: IFN-γ/IL-2) response of the graft to allogeneic hosts and leukemia cells, respectively, and that graft T cell activation rather than inhibition skipped GVHD after BM transplantation.

IFN-γ Control of an Effector/Target Combination for Skin Allograft Rejection: Macrophage/Skin Components in Normal Mice or T Cell/Endothelial Cells in IFN-γ-Deficient Mice.

Organ, skin, or cell allografts are acutely rejected from normal mice, whereas vascularized organ allografts, but not allografted Meth A cells, are rejected from interferon-γ (IFN-γ)-deficient mice. Here we explored effector/target combinations for i.p. allografted Meth A (cytotoxic T lymphocyte [CTL]-resistant) or RLmale1 (CTL-susceptible) cells into or for BALB/c skin (skin components: CTL resistant) onto normal or IFN-γ-deficient C57BL/6 mice. After allografting, normal mice showed more infiltration but only a little thrombosis/hemorrhage. Monocyte/macrophage MHC receptor (MMR)+ macrophages (on days 5-10) and T cell receptor (TCR)+ CTLs (on days 7-9) were cytotoxic against Meth A cells or skin components and RLmale1 cells, respectively, and the allografts were rejected. After allografting into IFN-γ-deficient mice, MMR- macrophages and highly activated TCR+ CTLs were induced, and the mice died of hemorrhagic ascites with Meth A cells and more acutely rejected RLmale1 cells. The CTLs on days 4-6 were inactive toward skin components at an in vivo effector/target ratio but injured endothelial cells to cause severe thrombosis/hemorrhage and more acute rejection of skin allografts. These results indicate that IFN-γ-dependent MMR expression was essential for macrophage-mediated cytolysis of allogeneic skin components and that IFN-γ-deficient mice more acutely rejected skin allograft by causing CTL-induced injury to endothelial cells.

Association between the severity of symptomatic knee osteoarthritis and cumulative metabolic factors.

BACKGROUND: The association between cumulative metabolic syndrome (MS) factors and knee osteoarthritis (KOA) has been highlighted over the past two decades. AIMS: To clarify the relationship between cumulative MS factors and symptomatic KOA. METHODS: A cross-sectional survey involving 119 women aged 45-88 years who were scheduled to undergo knee surgery was conducted. They were stratified into tertiles of symptoms as assessed by the Japanese Orthopedic Association score for KOA. Multinomial logistic regressions were performed using the severity of symptomatic KOA as the dependent variable and each MS factor or the cumulative MS factors as the independent variables. RESULTS: Logistic regression analyses were performed with the upper tertile of stratified symptoms of subjects used as the reference group. After adjustment for confounders, KOA patients who had two (p = 0.004) or three or more (p < 0.0001) MS factors were significantly more likely to have severe symptoms compared to those who had no MS factors. MS factors excluding obesity were similarly analyzed. Even after additional adjustment for body mass index (BMI), KOA patients who had two or more (p = 0.005) MS factors were significantly more likely to have severe symptoms. CONCLUSION: Among KOA female patients diagnosed using radiographic definition, the severity of symptomatic KOA was significantly associated with hypertension, dyslipidemia, and the number of MS factors after adjustment for age, BMI, strength of the knee extensor, and Kellgren-Lawrence grade. The severity of radiographic KOA was not associated with any MS factor or cumulative MS factors.

Mucinous Balls Tangled With Mesothelial Cells and MUC2-Positive Cancer Cells in the Ascites of Pseudomyxoma Peritonei.

Pseudomyxoma peritonei (PMP) is characterized by extensive mucinous ascites following rupture of mucinous neoplasms of an intra-abdominal origin, and contain secreted gel-forming mucins such as MUC2 and MUC5AC. We encountered a 66-year-old Japanese man complaining of abdominal distension. Ascites at the site was gelatinous upon gross examination, and needle aspirate smears showed histiocytes and many mucinous balls wrapped in spindle cells, which were positive for vimentin, pan-cytokeratin, and podoplanin. The cell block showed several adenocarcinoma clusters, which were positive for MUC2, MUC5AC, CK20, and CDX-2, and negative for CK7. From these findings, a diagnosis of PMP arising from colon cancer was indicated. Cytoreductive surgery was performed, and the cystic diverticulum was found to be infiltrated by tumor cells in the sigmoid colon that caused PMP. Mucinous balls surrounded by mesothelial cells and MUC2-positive adenocarcinoma cells are useful clues in the diagnosis of PMP. Diagn. Cytopathol. 2016;44:628-631. © 2016 Wiley Periodicals, Inc.

Blood supply--susceptible formation of melanin pigment in hair bulb melanocytes of mice.

BACKGROUND: Allogeneic skin grafts onto C57BL/6 mice are rejected, and the rejected skin is replaced by surrounding skin with black hair. In contrast, syngeneic skin grafts are tolerated, and gray hair grows on the grafts. METHODS: To explore the mechanism of gray hair growing on the tolerated skin grafts, we prepared full-thickness skin (2-cm square) autografts, 2 (2 cm + 2 cm) horizontal or vertical parallel incisions, and U-shaped (2 cm × 2 cm × 2 cm) flaps with or without pedicle vessels. The grafts, incisions, and flaps were fixed by suturing with string and protected by a transparent bandage. On day 14 after the operation, the bandages were removed to observe the color of the hair growing on the skin. RESULTS: Skin autografts from wild-type or hepatocyte growth factor-transgenic (Tg) C57BL/6 mice survived with gray hair, whereas those from steel factor (Kitl)-Tg C57BL/6 mice survived with black hair. In addition, U-shaped flaps lacking both of the 2 main feeding vessels of wild-type mice had gray hair at the tip of the flaps. Light microscopy after staining with hematoxylin and eosin or dihydroxyphenylalanine showed that the formation of melanin pigment in the follicles, but not in the interadnexal skin, was susceptible to the blood supply. CONCLUSIONS: Melanin pigment formation in the hair bulb melanocytes appeared to be susceptible to the blood supply, and melanocytosis was promoted in the follicles and in the epidermis of Kitl-Tg C57BL/6 mice.

Immunohistochemical findings and differential diagnosis of papillary-type cutaneous verrucous carcinoma of the neck: A case report.

Verrucous carcinoma (VC) is a rare subtype of squamous cell carcinoma, with the majority of cases occurring in the oral cavity and genital area. The present study describes a rare case of cutaneous VC of the neck manifesting as a semi-pedunculated multinodular protrusion. Histological analysis revealed thickening of the epidermis and papillary growth. Although cellular atypia was generally mild, a large number of mitoses were observed, of which a small number were abnormal. Additionally, bulbous subepidermal invasion was observed. The lesion was differentiated from papillary squamous cell carcinoma, another rare subtype of squamous cell carcinoma, based on the presence of epidermal verrucous growth and the lack of remarkable nuclear atypia. Benign disorders, including seborrheic keratosis, fibroepithelial polyp, verruca vulgaris and pseudocarcinomatous hyperplasia, were also differentiated from the lesion. Immunohistochemical analysis of cytokeratin (CK)10 expression revealed attenuated staining of the lesion, therefore, anti-CK10 immunohistochemistry may be valuable in the diagnosis of VC.

A case of eccrine porocarcinoma: usefulness of immunostain for s-100 protein in the diagnoses of recurrent and metastatic dedifferentiated lesions.

Eccrine porocarcinoma is a rare malignant tumor. Immunostain for S-100 protein, in addition to epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA), is described to be useful in the diagnosis. Herein, we report a case of eccrine porocarcinoma with immunostain for S-100 protein which was useful in diagnoses of recurrent and metastatic lesions. The primary lesion in the left inguinal region was excised, but it recurred on the same site 14 months after the resection. The recurrent lesion showed epithelioid melanocytic findings. Three months later, metastasis to the lungs was found. Since these recurrent and metastatic lesions were dedifferentiated, typical histologic findings of eccrine porocarcinoma disappeared in biopsied specimens. Nevertheless, scattered immunoreactive cells for S-100 protein were maintained in these dedifferentiated lesions. S-100 protein positive cells could be an aid to diagnose, even if histologic findings of recurrent and metastatic lesions have changed by dedifferentiation.

Collecting duct renal cell carcinoma with the syndrome of inappropriate antidiuresis: an autopsy case report.

A 57-year-old Japanese man visited our hospital with a moist cough. Chest radiographic imaging showed a left hilar shadow. Adenocarcinoma cells were found on cytologic screening of fresh sputum. Although multiple metastases including brain were detected, no tumor was observed in the kidneys. The patient underwent whole-brain irradiation and chemotherapy for advanced-stage lung cancer. One month before his death, carcinomatous meningitis was detected. Hyponatremia, hypo-osmolality, and hypertonic urine suggested the syndrome of inappropriate antidiuresis. Restricting water intake improved the hyponatremia; however, he developed fever and hematuria. Despite systemic administration of an antibacterial drug, he died. Primary tumor in the lung was absent, but adenocarcinoma of the right kidney was evident on autopsy. Lectin histochemical analysis of the carcinoma revealed its distal nephron origin, confirming collecting duct carcinoma. Severe carcinomatous meningitis, which is possibly caused the syndrome of inappropriate antidiuresis, was observed, with no cancer involvement of the pituitary gland and hypothalamus.

Fine-needle aspiration cytology of triple-negative basal-like breast cancer.

Invasive breast cancer is divided into luminal A, luminal B, HER2 overexpression, basal-like (BL) and normal-like subtypes, among which the BL subtype has the worst prognosis. The purpose of this study was to determine the clinicopathological and cytological characteristics of BL breast cancer (BLBC). Fine-needle aspiration cytology samples from 17 patients with consecutive BLBC were investigated, and the findings were compared with those of other subtypes (10 cases each) for the following cytomorphological features: necrosis; lymphocyte infiltration; mitotic index; apoptosis; naked nuclei; nuclear/cytoplasmic ratio; nuclear margin, size and pleomorphism; chromatin granularity and density; and nucleolar appearance. Histologically, the BLBCs were heterogeneous, and included medullary carcinoma and metaplastic carcinoma, in addition to invasive ductal carcinoma. Cytologically, high mitotic index, naked nuclei, and irregular nuclear margin were significantly observed when compared with both the luminal A and B subtypes. Large nuclei with nucleoli and lymphocyte infiltration were frequently seen compared with the luminal A and B subtypes, respectively. Squamous nodules were seen in all metaplastic cases, but not in the HER2 overexpression subtype. Lymphocyte infiltration, squamous metaplasia, and nuclear findings such as a high mitotic index, naked or large nuclei, an irregular nuclear margin and the presence of nucleoli, may be clues indicating BLBC.

Biochemical characteristics among Mycobacterium bovis BCG substrains.

In order to evaluate the biochemical characteristics of 14 substrains of Mycobacterium bovis bacillus Calmette Guérin (BCG) - Russia, Moreau, Japan, Sweden, Birkhaug, Danish, Glaxo, Mexico, Tice, Connaught, Montreal, Phipps, Australia and Pasteur - we performed eight different biochemical tests, including those for nitrate reduction, catalase, niacin accumulation, urease, Tween 80 hydrolysis, pyrazinamidase, p-amino salicylate degradation and resistance to thiophene 2-carboxylic acid hydrazide. Catalase activities of the substrains were all low. Data for nitrate reduction, niacin accumulation, Tween 80 hydrolysis, susceptibility to hydrogen peroxide and nitrate, and optimal pH for growth were all variable among these substrains. These findings suggest that the heterogeneities of biochemical characteristics are relevant to the differences in resistance of BCG substrains to environmental stress. The study also contributes to the re-evaluation of BCG substrains for use as vaccines.

Comparable studies of immunostimulating activities in vitro among Mycobacterium bovis bacillus Calmette-Guérin (BCG) substrains.

During the serial passage of Mycobacterium bovis bacillus Calmette-Guérin (BCG) in different countries after initial seed distribution from the Pasteur Institute, specific insertions and deletions in the genome among BCG substrains were observed and speculated to result in differences in immunological activities. 'Early-shared strains' of BCG (Russia, Moreau, Japan, Sweden, Birkhaug), distributed by the Pasteur Institute, which conserve three types of mycolate (alpha, methoxy, keto) in cell wall, exhibited stronger activities of induction of nitric oxide, interleukin-1beta (IL-1beta), IL-6, IL-8, IL-12 and tumor necrosis factor (TNF)-alpha, from human epithelial cell line A549, human myelomonocytic cell line THP-1 and mouse bone marrow cells in the presence of interferon-gamma (IFN-gamma) than did 'late-shared strains' of BCG (Danish, Glaxo, Mexico, Tice, Connaught, Montreal, Phipps, Australia, Pasteur). The stronger induction of IL-12 and TNF-alpha in the presence of IFN-gamma was also observed by trehalose 6,6'-dimycolate (TDM) extracted from BCG-Japan than by TDM from BCG-Connaught, which lacks the methoxymycolate residue. These results suggest that 'early-shared strains' are more potent immunostimulating agents than 'late-shared strains', which could be attributed partially to methoxymycolate. Our study provides the basic information for immunological characterization of various BCG strains and may contribute to a re-evaluation of them as a reference strain for vaccination against tuberculosis.

Suppressive effect on activation of macrophages by Lactobacillus casei strain Shirota genes determining the synthesis of cell wall-associated polysaccharides.

Although many Lactobacillus strains used as probiotics are believed to modulate host immune responses, the molecular natures of the components of such probiotic microorganisms directly involved in immune modulation process are largely unknown. We aimed to assess the function of polysaccharide moiety of the cell wall of Lactobacillus casei strain Shirota as a possible immune modulator which regulates cytokine production by macrophages. A gene survey of the genome sequence of L. casei Shirota hunted down a unique cluster of 10 genes, most of whose predicted amino acid sequences had similarities to various extents to known proteins involved in biosynthesis of extracellular or capsular polysaccharides from other lactic acid bacteria. Gene knockout mutants of eight genes from this cluster resulted in the loss of reactivity to L. casei Shirota-specific monoclonal antibody and extreme reduction of high-molecular-mass polysaccharides in the cell wall fraction, indicating that at least these genes are involved in biosynthesis of high-molecular-mass cell wall polysaccharides. By adding heat-killed mutant cells to mouse macrophage cell lines or to mouse spleen cells, the production of tumor necrosis factor alpha, interleukin-12 (IL-12), IL-10, and IL-6 was more stimulated than by wild-type cells. In addition, these mutants additively enhanced lipopolysaccharide-induced IL-6 production by RAW 264.7 mouse macrophage-like cells, while wild-type cells significantly suppressed the IL-6 production of RAW 264.7. Collectively, these results indicate that this cluster of genes of L. casei Shirota, which have been named cps1A, cps1B, cps1C, cps1D, cps1E, cps1F, cps1G, and cps1J, determine the synthesis of the high-molecular-mass polysaccharide moiety of the L. casei Shirota cell wall and that this polysaccharide moiety is the relevant immune modulator which may function to reduce excessive immune reactions during the activation of macrophages by L. casei Shirota.

Focal hepatic steatosis surrounding a metastatic insulinoma.

Reported herein is a case of focal hepatic steatosis surrounding a metastatic insulinoma in the liver of a 69-year-old woman. The patient complained of losing consciousness after meals, and hypoglycemia and hyperinsulinemia were confirmed. On CT and abdominal angiography a mass, 1 cm in diameter, was seen in the tail of the pancreas. In the early phase of dynamic CT a mass, 5 mm in diameter, was seen in the liver. In the late phase this mass appeared to be 3 cm in diameter. An arterial calcium stimulation/venous sampling test showed insulin levels after calcium injections in the hepatic artery to be extremely high. Thus, the liver tumor was diagnosed as a metastatic insulinoma, and distal pancreatectomy and partial resection of the liver were performed. The pancreatic tumor cells were immunohistochemically positive for insulin. The liver tumor was pale yellow. A white area surrounded the tumor. Histologically, the liver tumor was an insulinoma and the white area was focal fatty change of the liver. High insulin levels are said to inhibit oxidation of free fatty acids into triglycerides, causing free fatty acids to accumulate in hepatocytes. Focal hepatic steatosis caused by the local effects of insulin can present as a focal rim surrounding a metastatic insulinoma.

Neuroendocrine carcinoma of the liver associated with dermatomyositis: autopsy case and review of the literature.

Reported herein is an autopsy case of primary hepatic neuroendocrine carcinoma associated with dermatomyositis. A 71-year-old Japanese man, who was diagnosed with dermatomyositis 5 months before death, had multiple tumors within a non-cirrhotic liver. Histopathologically, the tumors were composed of small- and medium-sized round cells with clear cytoplasm arranged in nests, sheets or rosettes. Immunohistochemically, the tumor cells were positive for chromogranin A, neuron-specific enolase and CD56 and were negative for synaptophysin. This tumor was diagnosed as a primary hepatic neuroendocrine carcinoma with metastasis to the lung, gallbladder and lymph nodes around the pancreas and aorta; no primary lesions were detected in any other organ. The tumor cells were also positive for cytokeratin 7, cytokeratin 19 and epithelial membrane antigen but were negative for anti-hepatocyte antibody and AFP. These findings suggest that the tumor originated in intrahepatic bile duct epithelium. Various cancers have been reported in patients with dermatomyositis, but only seven cases of dermatomyositis associated with primary liver cancer have been reported. To the best of the authors' knowledge, this is the first report of dermatomyositis associated with primary hepatic neuroendocrine carcinoma.