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Cancer stem‐like cells (CSC) or cancer‐initiating cells are now considered to be an important cell population related to cancer recurrence and the resistance to anti‐cancer therapy. Tumor‐associated macrophages (TAM) are a main component of stromal cells and are related to cancer progression in clear cell renal cell carcinoma (ccRCC). Because the detailed mechanisms allowing the maintenance of CSC in cancer tissues remain unclear, we investigated the relationship between TAM and CD44‐expressing cancer cells in ccRCC. CD44 was used as a marker for CSC, and CD163 and CD204 were used as markers for TAM. CD44‐positive cancer cells were detected in 37 of the 103 cases. Although statistical analysis showed no relationship between CD44‐positive cancer cells and the clinical course, the distribution of CD44‐positive cancer cells was significantly associated with a high density of TAM. Our in vitro study using RCC cell lines and human macrophages demonstrated that CD44 expression was upregulated by direct co‐culture with macrophages. Silencing of TNF‐alpha on macrophages abrogated the upregulation of CD44 expression in cancer cells. Macrophage‐induced CD44 overexpression was also suppressed by NF‐κB inhibitors. These results suggest that TNF‐alpha derived from TAM is linked to CD44 overexpression via NF‐κB signaling in ccRCC. Cancer stem‐like cells (CSCs) or cancer‐initiating cells are now considered to be an important cell population related to cancer recurrence and the resistance to anti‐cancer therapy. Tumor‐associated macrophages (TAMs) are a main component of stromal cells and are related to cancer progression in clear cell renal cell carcinoma (ccRCC). Our findings suggest that TNF‐alpha derived from TAMs is linked to CD44 overexpression via NF‐kB signaling in ccRCC.

T-cell immunoglobulin and mucin domain (TIMD) family genes are related to innate immune responses. TIMD4 is a receptor for phosphatidylserine and is involved in the phagocytosis of apoptotic cells by macrophages. In the present study, we found that TIMD4 is expressed on the cancer cells of patients with clear cell renal cell carcinoma (ccRCC). TIMD4 was immunostained in the resected samples of 89 patients diagnosed as ccRCC. High expression of TIMD4 in cancer cells was closely related to short progression free survival time; however, it was not correlated with other clinicopathological factors. Intracellular expression of TIMD4 was observed in the RCC cell line, 786-O. In vitro studies using 786-O cells and shRNA targeting TIMD4 indicated that TIMD4 expression was associated with resistance to sorafenib but not with cell proliferation. TIMD4 might be useful as a prognostic factor and may also be a new target for therapy of ccRCC.

CD163 is preferentially expressed by monocyte/macrophages; however, recent studies using immunohistochemistry (IHC) have reported that some cancer cells also express CD163. In the present IHC study, we investigated CD163 staining of cancer cells and macrophages in clear cell renal cell carcinoma (ccRCC) tissues and determined the relationship between cancer cell CD163 expression and clinical prognosis in patients with ccRCC. IHC for CD163 was performed in ccRCC tissues from 103 patients. CD163-positive cancer cells were detected in 35% of the patients (36/103); however, the positive signals on cancer cells were significantly lower than those on macrophages. CD163-positive cancer cells were preferentially detected in patients with high T classification, and females, and were significantly associated with shortened progression-free survival and a lower overall survival ratio. Notably, a high intensity of CD163-positive macrophage infiltration was detected in the CD163-positive cancer cell-high tumor areas. Although CD163 mRNA was detected in cultured macrophages, no CD163 mRNA was detected in two cultured RCC cell lines. The detailed mechanism by which a positive signal is detected on cancer cells has not been clarified. Detection of the CD163 antigen on cancer cells might be a useful marker for evaluating the clinical course of patients with ccRCC.

Background The immune escape or tolerance of cancer cells is considered to be closely involved in cancer progression. Programmed death-1 (PD-1) is an inhibitory receptor expressed on activating T cells, and several types of cancer cells were found to express PD-1 ligand 1 (PD-L1) and ligand 2 (PD-L2). Methods In the present study, we investigated PD-L1/2 expression in papillary renal cell carcinoma (pRCC). Result We found PD-L1 expression in 29 of 102 cases, but no PD-L2 expression was seen. PD-L1 expression was not significantly correlated with any clinicopathological factor, including progression-free survival and overall survival. The frequency of PD-L1-positive cases was higher in type 2 (36%) than in type 1 (22%) pRCC; however, there was no significant difference in the percentages of score 0 cases ( p value = 0.084 in Chi-square test). The frequency of high PD-L1 expression cases was higher in type 2 (23%) than in type 1 (11%), and the frequency of high PD-L1 expression cases was higher in grade 3/4 (21%) than in grade 1/2 (13%). However, no significant association was found between PD-L1 expression and all clinicopathological factors in pRCC. Conclusion High expression of PD-L1 in cancer cells was potentially associated to highly histological grade of malignancy in pRCC. The evaluation of the PD-L1 protein might still be useful for predicting the efficacy of anti-cancer immunotherapy using immuno-checkpoint inhibitors, however, not be useful for predicting the clinical prognosis.

Very recently, Requena et al. have demonstrated the detailed clinicopathological features of 9 cases of a benign cutaneous plexiform nerve sheath tumor with hybrid characteristics of perineurioma and cellular neurothekeoma, given the name as a benign cutaneous plexiform hybrid tumor of perineurioma and cellular neurothekeoma, all of which were peculiarly located on the lips. Herein we described the first case of that arising from the nose, but not the lip, representing a histological hybridoma of perineurioma and cellular neurothekeoma after thorough consideration especially with its immunohistochemical profile.

A 78-year-old Japanese male noticed a difficulty in the beginning of standing up, followed by 7a progressive numbness of extremities with pain, Bell’s palsy, dysarthria, and difficulty in swallowing. A clinician had suspected cancer of unknown primary origin, accompanied by the diverse and elusive neurological symptoms, likely presenting as painful mononeuropathy simplex and cranial neuropathy. He developed dysbasia over weeks and died 1 month after the symptom onset. At autopsy, an ill-defined large and soft tumor mass in the right lobe of the liver with direct invasion into the right adrenal gland was observed. The left adrenal gland or right iliopsoas muscle was also involved. Microscopic findings showed a monotonous proliferation of medium-sized to large atypical lymphoid cells, which were diffusely positive for CD20 in immunohistochemistry, consistent with diffuse large B-cell lymphoma (DLBL). Furthermore, the lymphoma cells aggressively infiltrated endoneurial and subperineurial spaces not only in the peripheral nerves and plexuses, but partly in the spinal nerve roots, and intravascular spaces in various tissues. Therefore, systemic lymphoma (DLBL) complicated with neurolymphomatosis (NL) and intravascular lymphoma (IVL) was diagnosed. Very early diagnosis and treatment are necessary for the NL patients with poor prognosis. Virtual slides The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5862472377020448 .

A history of an increase in pulmonary mass was presented in the right upper lobe of a 72-year-old male. The bronchial brushing cytology specimens contained many sheet-like or three-dimensional clusters of malignant cells having small to medium-sized, uniform oval to round, and hyperchromatic nuclei, inconspicuous nucleoli, and scanty cytoplasm, admixed with mitotic figures. A coarsely granular chromatin pattern was predominantly noted. We first interpreted it as suspicious of malignancy, such as atypical carcinoid. A right upper lobectomy was performed, and gross examination revealed a centrally cavity-formed tumor lesion, containing asymmetrically thinned wall and looking grayish to whitish, partly adjacent to the bronchiolar wall. On microscopic examination, the tumor was predominantly composed of a solid proliferation of atypical epithelial cells without apparent glandular or squamous differentiation, often arranged in an alveolar growth pattern with peripheral palisading. Immunohistochemically, these atypical cells are negative for all three neuroendocrine markers and thyroid transcription factor 1, whereas positive for 34βE12, p63 and S-100 protein. Therefore, we finally made a diagnosis of basaloid carcinoma with cavity formation. We should be aware that, owing to its characteristic features, cytopathologists might be able to raise basaloid carcinoma of the lung as one of differential diagnoses, based on careful cytological examination. Virtual slides The virtual slide(s) for this article can be found here: http://www.dianosticpathology.diagnomx.eu/vs/1519986488570234

Cardiac tumours are relatively rare and are difficult to diagnose merely with imaging techniques. We demonstrated an unusual case of left atrial myxoma, displaying the successful detection by positron emission tomography using 2-deoxy-2-[ 18  F] fluoro-D-glucose ( 18  F-FDG PET), correlated closely to more intense and enhanced immunoreactivity with glucose transporter-1 (GLUT-1) in a substantial number of cardiac myxoma cells. Further prospective studies are needed to validate the significance of 18  F-FDG PET findings for cardiac myxoma and the association with immunohistochemical GLUT-1 expression in its tumour cells, after collecting and investigating a larger number of surgical cases examined with both of them. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2991481941253449

A 67-year-old Japanese female was followed up due to prolonged idiopathic thrombocytopenia with non-response to steroid therapy for 4 years, but recent progressive pancytopenia, hypo-albuminemia, and hypo-γ-globulinemia were presented. An abdominal CT scan revealed heterogeneously enhanced splenomegaly without any nodular lesions. A splenectomy was performed, and gross examination showed markedly hyperemic red pulp, weighing 760 g, accompanied by multiple foci of peripheral anemic infarction. Surprisingly, microscopic findings exhibited a diffuse proliferation of medium-sized to large tumor cells having pleomorphic nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm, predominantly within the sinuses and cords of the red pulp, which occasionally displayed conspicuous hemophagocytosis and vascular permeation. In immunohistochemistry, these atypical cells were specifically positive for CD68 (KP-1), CD163, and lysozyme, which was consistent with histiocytic sarcoma (HS) of the spleen. Subsequently, section from the aspiration of bone marrow showed infiltration of the neoplastic cells associated with erythrophagocytosis 2 months after the operation, but never before it. Therefore, primary splenic HS presenting with secondary bone marrow involvement was conclusively diagnosed. Since early diagnosis and treatment are necessary for the HS patients with poor outcomes, splenic HS should be considered as a differential diagnosis in cases with chronic thrombocytopenia and splenomegaly. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1009474924812827

Cancer stem‐like cells (CSC) or cancer‐initiating cells are now considered to be an important cell population related to cancer recurrence and the resistance to anti‐cancer therapy. Tumor‐associated macrophages (TAM) are a main component of stromal cells and are related to cancer progression in clear cell renal cell carcinoma (ccRCC). Because the detailed mechanisms allowing the maintenance of CSC in cancer tissues remain unclear, we investigated the relationship between TAM and CD44‐expressing cancer cells in ccRCC. CD44 was used as a marker for CSC, and CD163 and CD204 were used as markers for TAM. CD44‐positive cancer cells were detected in 37 of the 103 cases. Although statistical analysis showed no relationship between CD44‐positive cancer cells and the clinical course, the distribution of CD44‐positive cancer cells was significantly associated with a high density of TAM. Our in vitro study using RCC cell lines and human macrophages demonstrated that CD44 expression was upregulated by direct co‐culture with macrophages. Silencing of TNF‐alpha on macrophages abrogated the upregulation of CD44 expression in cancer cells. Macrophage‐induced CD44 overexpression was also suppressed by NF‐κB inhibitors. These results suggest that TNF‐alpha derived from TAM is linked to CD44 overexpression via NF‐κB signaling in ccRCC.