Advances in genetic research and the development of new modalities, such as tyrosine kinase inhibitors and immune checkpoint inhibitors, have led to a paradigm shift in the management of patients with cutaneous melanoma. Melanoma has one of the highest mutation rates among malignancies, and both available therapies are affected by this. Four subtypes of melanoma genotypes were classified based on significantly mutated genes, and BRAF mutations were the most prevalent drivers in Western countries, whereas the proportion was distinct in Japan. Mutation profiles are strongly associated with tumor behaviors, such as proliferation, metastasis, and drug sensitivity. This review aims to help readers better understand the relationship between mutations and tumor biology in cutaneous melanomas. Moreover, it discusses the significance of genetic research in the clinical management of patients with cutaneous melanoma.
Malignant lymphoma is diagnosed by histopathol-ogical examination. However, sample preparation, including immunostaining, is time-consuming. Touch smear cytology of biopsied lymph node specimens requires only stamping and staining smear preparation, allowing rapid microscopic examination. Therefore, individual cell morphologies of lymphoid tissue can be observed in a short time. As cytological diagnosis is the first step to determine malignancy, sample preparation for touch smear cytology is recommended upon lymphoid tissue biopsy. The present article overviews malignant lymphomas and describes the cytomorphological characteristics of malignant lymphomas that should be differentiated from reactive lymphadenopathy, in comparison with the normal lymph node structure.
Microcirculation of the spleen is highly characteristic and open in the human and rat spleen. The open microcircultaion system in the spleen is closely related to its function. Blood enters the spleen by way of the splenic artery that passes through the splenic hilus. The splenic artery branches into trabeculae as the trabecular artery, which turns out of the trabeculae and enters the white pulp. The arteries are surrounded by periarteriolar lymphatic sheaths (central artery). The central artery sends out branches, which terminate in the marginal zone. In the rat spleen, the marginal sinus, formed by the arterial terminal, envelopes the white pulp and bounds the inner edge of the marginal zone. The central artery itself runs out into the red pulp, called the penicillar artery, and terminates in the cords. Blood flows out of the arterial terminal in the marginal zone and the splenic cords. The hemodynamic condition varies in the marginal zone and the splenic cords. Intraarterial injection of two different sized particles into the rat spleen revealed that large particles appeared mainly in the splenic cords and small particles mostly in the marginal zone. The results suggest that blood cells flow out mainly from the penicillar arteries into the splenic cord. Blood-born antigens are trapped in the marginal zone, which functions as an immunological filter.
Monoclonal antibodies against rat macrophages were produced using stromal elements of rat spleen as immunogen, and designated RSM-1, RSM-2, RSM-3 and RSM-4. By the immunohistochemical method, they were found to be specific for certain macrophage populations in the spleen and other tissues. RSM-1 and RSM-2 were reactive with macrophages in the red pulp, germinal center and marginal zone, and marginal metallophils of the spleen. They were also reactive with macrophages of lymph node, both macrophages and epithelial reticulum cells of thymus, Kupffer cells, alveolar macrophages, peritoneal macrophages and monocytes in peripheral blood. RSM-3 recognized macrophages in the red pulp of the spleen and alveolar macrophages in the lung. RSM-4 was reactive with marginal zone macrophages and marginal metallophils of the spleen. By immunoelectron microscopy, reaction products for all antibodies were found on the cytoplasmic membrane.
These antibodies seem to be different from previously produced antibodies against rat macrophages, and are applicable for investigation of macrophage heterogeneity in the spleen and other tissues.
Cancer progression is induced by cell invasion, which is largely associated with the disruption in intercellular adhesions between cancer cells. Afadin is a cytoplasmic component of the adherens junctions and connects nectin to the actin cytoskeleton. Afadin-expression levels have recently been reported to be associated with progression of breast cancer, colon cancer, pancreatic cancer, and endometrial cancer. In this study, we examined whether afadin-expression levels regulated cell invasion in hepatocellular carcinoma (HCC) cell lines. In addition, the molecular mechanisms associated with cell invasion were analyzed. Afadin-expression levels in HCC cell lines were examined by western blotting, which showed high expression level in HepG2 cells and low expression levels in HLF and HLE cells. Matrigel invasion assays disclosed that the stable overexpression of afadin in HLF and HLE cells inhibited cell invasion. In contrast, the knockdown of afadin expression using RNA interference in HepG2 cells promoted cell invasion. Changes of the afadin-expression levels in HCC cell lines regulated the Src kinase activation levels. In addition, a Src kinase inhibitor was able to inhibit cell invasion after afadin knockdown in HepG2 cells. These results suggested that afadin depletion might accelerate HCC progression.
Acne vulgaris is a common skin disease that results from a multifactorial disorder of the pilosebaceous unit. Although topical treatments for acne vulgaris have led to better outcomes, refractory cases are often encountered. The intense pulsed light (IPL) instrument M22TM acne treatment filter operates within two wavelength ranges of 400-600 nm and 800-1,200 nm. The short wavelength exerts both antibacterial and anti-inflammatory effects against acne, whereas the long wavelength is expected to lead to improvement of seborrhea. The present study was conducted to assess the efficacy of IPL treatment using the M22TM acne treatment filter for improvement of acne vulgaris. High treatment satisfaction was obtained after IPL treatment, with a reduction of inflammatory lesions and reddish acne scars. IPL treatment is therefore considered to be effective for refractory acne vulgaris.
Nonalcoholic steatohepatitis (NASH) is a progressive chronic liver disorder in which oxidative stress plays a major role in development and progression. In this study, we examined whether the derivative of reactive oxygen metabolites test (d-ROMs test) is useful in assessing the degree of oxidative stress in NASH. In addition, biopsied liver tissues were immunostained for 8-hydroxy-2'-deoxyguanosine (8-OHdG) to investigate whether the d-ROMs test reflects the degree of oxidative stress in NASH liver. Compared with healthy individuals, NASH patients had significantly higher serum d-ROM levels and more 8-OHdG-positive hepatocytes in liver tissues, and there was a correlation between d-ROM levels and 8-OHdG-positive rate in patients with NASH. These results suggest that the d-ROMs test is useful for assessing the degree of oxidative stress in patients with NASH.
Extramammary Paget’s disease (EMPD) is an apocrine gland-derived skin neoplasm that is common in the elderly. In many cases, the prognosis is good after extended resection. However, the prognosis of advanced EMPD is poor as no effective chemotherapy has been established. Here we report a 73-year-old male patient with EMPD in the genital region who developed metastases in the inguinal area, pelvis, paraaortic lymph nodes (LNs), bone, and brain. Although treatment with docetaxel (DTX) was effective for the primary skin lesion and LN metastasis, the patient died of meningeal carcinomatosis (MC). In our department, DTX has been administered to seven cases of advanced EMPD, showing a partial response in three and progressive disease in four cases. Although DTX treatment was highly effective for LN metastases, complication of MC occurred in three fatal cases. It is expected that DTX will become the first-line chemotherapeutic regimen for advanced EMPD. Development of an additional treatment strategy for advanced EMPD with MC will be crucial.
Tumor inducing osteomalacia is a rare paraneoplastic syndrome characterized by severe hypophosphatemia and osteomalacia caused by the mesenchymal tumor that secretes fibroblast growth factor 23 (FGF23).
A 41-year-old man presented with back pain and diminishing height over a period of 1 year. He was given a diagnosis of osteomalacia with hypophosphatemia by his personal physician, before visiting our hospital. MIBI scintigraphy showed accumulation in the right thigh. Venous sampling showed high FGF23 in the proximal right thigh. MRI showed a neoplastic lesion, measuring 15 × 10 mm in size, in contact with the femoral artery. Based on these findings, we diagnosed tumor inducing osteomalacia due to soft tissue tumor of the femur and performed surgery. Histopathological diagnosis was phosphaturic mesenchymal tumor. FGF23, calcium and phosphorus before and after resection were monitored over time. FGF23 levels halved in 30 minutes, but blood calcium and phosphorus levels did not show significant fluctuations.
Renal cell carcinoma is a malignant tumor originating from the proximal tubule of the kidney, and clear cell renal cell carcinoma (ccRCC) is the most common histological type. Tyrosine kinase inhibitors and mTOR1 inhibitors are used for unresectable or metastatic cases of ccRCC as first-line treatment, and immune checkpoint inhibitors will be considered for second-line treatment. As this case was ccRCC with multiple metastases, sunitinib was used as the first treatment after nephrectomy. However, chemotherapy was terminated due to side effects, and then the patient received nivolumab, but died as a result of poor therapeutic effect. Immunohistochemical studies of surgical specimens of the left kidney (before treatment) and autopsy specimen (after treatment) revealed that tumor cells lacked PD-L1 expression and few immune cells infiltrated in the tumor stroma, which was thought as the cause of the refractoriness to nivolumab.
A man in his 60s was diagnosed with psoriasis vulgaris 10 years ago and was on phototherapy and topical therapy with glucocorticosteroids. Although he noticed edema of the lower extremities 2 years ago, his condition improved following medication with loop diuretics. However, the edema recurred 2 months ago and he was referred to our hospital with suspected nephrotic syndrome. Laboratory data showed evidence of nephrotic syndrome. Collagen disease was ruled out because antinuclear antibody and rheumatoid factor were not detected, and complements showed normal ranges. There was no infection with hepatitis B virus or C virus. Renal biopsy revealed findings of secondary membranous nephropathy. Autoimmune disease, viral hepatitis, and malignancies are secondary etiologies of membranous glomerulopathy. Examinations using gastrointestinal endoscopy and computed tomography of the region from the thorax to the pelvis showed no neoplastic lesions. In rare cases of membranous nephropathy, an association with psoriasis vulgaris has been suggested. Therefore, the renal disorder in this case was presumed to be secondary to psoriasis vulgaris.