Masahiro Hoshikawa

Involvement of cell‐mediated killing in apoptosis in histiocytic necrotizing lymphadenitis (Kikuchi‐Fujimoto disease)

Histiocytic necrotizing lymphadenitis, also called Kikuchi‐Fujimoto (KF) disease, is a benign disorder characterized histologically by paracortical necrotic foci surrounded by histiocytic aggregates. We analysed affected lymph node tissues from 34 patients with the disease in an attempt to elucidate its histogenesis. The ‘necrotizing’ cells showed typical apoptotic changes, including cell shrinkage and condensed and fragmented nuclei. Apoptotic bodies with a peculiar ultrastructure were demonstrated, and DNA fragmentation was detected in these cells by in situ end labelling. Immunostaining for the apoptosis‐regulating proteins bcl‐2, bax, c‐myc and p53 failed to show their involvement in KF disease. However, perforin, a killer cell‐specific cytolytic protein essential for provoking apoptosis in target cells, was found to be expressed abundantly by the infiltrating cells, which were thought to be cytotoxic T‐lymphocytes. Perforin‐expressing cells were present in the apoptotic foci of 28 of the 34 patients (82.4%). Virtually no cells containing perforin granules were present in non‐pathological regions, lymph node tissues from control subjects with reactive or tuberculous lymphadenitis or those from patients with KF disease with negligible apoptosis. Therefore, the ‘necrosis’ associated with KF disease appears to be attributable to trans apoptotic death of the killer cell target in the affected nodes. We propose that KF disease should be called apoptotic lymphadenitis.

Absence of Nuclear p16 From Epstein-Barr Virus-Associated Undifferentiated Nasopharyngeal Carcinomas

Objective: Epstein‐Barr virus (EBV) is detected in the majority of undifferentiated nasopharyngeal carcinomas (UNPCs, World Health Organization type III). However, the exact mechanism involved in the carcinogenesis of EBV‐associated UNPCs remains to be elucidated. An important unresolved question is: how is the normal cell cycle deregulated during EBV‐associated UNPC development? The p16CDKN2 gene encodes a nuclear protein, p16, which inhibits the D‐type cyclin/cyclin‐dependent kinase complexes that phosphorylate the retinoblastoma gene product (pRb), thus blocking G1 cell cycle progression. The objective of this study was to determine whether p16 absence is involved in the development of EBV‐associated UNPCs.

A Primary Pulmonary Glomus Tumor: A Case Report and Review of the Literature

A case of a glomus tumor originating from the lung is reported. A 43-year-old female had undergone resection of a right lung tumor following a clinical diagnosis of carcinoid, sclerosing hemangioma, or other sarcoma. Histologically, the tumor comprised uniform small round to oval cells with centrally located nucleus, a clear cytoplasm, and apparent cell borders. The tumor also showed a focally hemangiopericytomatous pattern with irregularly branching or dilated vessels. Electron microscopy revealed smooth muscle differentiation of the tumor cells. Immunostaining further revealed that the tumor cells expressed smooth muscle actin, h-caldesmon, muscle specific actin (HHF-35), but not cytokeratin, epithelial membrane antigen, synaptophysin, or chromogranin A. Based on these findings, a diagnosis of primary pulmonary glomus tumor was established. Glomus tumors of the lung are very rare and only 21 cases have been reported to date. The histological features of the present tumor and the relevant literature are discussed.

Distant metastasis from benign solitary fibrous tumor of the kidney.

Solitary fibrous tumor (SFT) rarely occurs in the kidneys, and only one reported case of renal SFT has shown distant metastasis. We report the second case of renal SFT exhibiting distant metastasis. A 48-year-old man was referred to our hospital because of a right renal mass. An abdominal CT scan detected a large renal tumor, which was suspected to be a renal cell carcinoma. Right radical nephrectomy was performed, and the tumor was found to measure 28 × 18 × 10 cm. The pathological diagnosis was benign solitary fibrous tumor of the kidney. Eight years after the operation, lung and liver metastases developed. Pulmonary segmentectomy and partial hepatectomy were performed. The pathological diagnoses of these resected tissue specimens were compatible with benign SFT.

Gastrointestinal stromal tumor presenting with prominent calcification

We present a rare case of a gastrointestinal stromal tumor (GIST) in the stomach with prominent calcification at presentation. A 61-year-old woman visited our hospital because of epigastric discomfort. A spherical calcified lesion with a diameter of about 30 mm was incidentally shown in the left upper quadrant on an abdominal X-ray. Computed tomography demonstrated that the tumor was growing from the upper gastric body, with calcification in the peripheral ring area. A laparoscopic partial gastrectomy was performed, and the resected specimen revealed a well-circumscribed tumor with exophytic growth from the gastric muscularis propria. Microscopic examination revealed spindle-shaped tumor cells with calcification and hemorrhage. Additionally, positive immunoreactivity of the tumor to KIT and CD34 and a low mitotic index resulted in the diagnosis of very low risk GIST. There are a few case reports of heavily calcified GIST, although solitary or punctate calcification of primary GIST has been reported in several case series. Dystrophic calcification of necrotic or degenerative tissue is the supposed cause of primary calcified GISTs. In contrast, appearance of calcification after administration of imatinib mesylate, which may be one indicator of disease response, is possibly caused by a different mechanism.

A case of age-related EBV-associated B-cell lymphoproliferative disorder metachronously showing two distinct morphologic appearances, one of a polymorphic disease resembling classical Hodgkin lymphoma, and the other of a large-cell lymphoma

We report a case of age-related EBV-associated B-cell lymphoproliferative disorder (age-related EBV+ B-cell LPD) metachronously showing two distinct morphologic appearances: one of a polymorphic disease resembling classical Hodgkin lymphoma (CHL), and the other of a large-cell lymphoma. A 71-year-old man was admitted to the St. Marianna University Hospital because of fever and generalized lymphadenopathy. Right axillary lymph node biopsy revealed mixed cellularity classical Hodgkin lymphoma (MCHL). The patient was referred to the Tokyo Medical Center, where he was treated with chemotherapy and obtained CR. One year later, the patient again developed fever and generalized lymphadenopathy. Biopsy of the right cervical mass revealed a diagnosis of diffuse large B-cell lymphoma. The patient was treated with salvage chemotherapies and obtained the second CR. Two years later, the patient developed acute myeloid leukemia (AML). Although CR was achieved with chemotherapy, AML relapsed 5 months later and proved to be refractory. Two and a half years later, the patient developed right cervical lymph node enlargement. The biopsy again revealed diagnosis of MCHL. The patient died 2 months later. On reviewing all of the biopsy specimens, including the findings of immunohistochemistry and in situ hybridization, possibility of CHL was ruled out, because neoplastic giant cells resembling Hodgkin and Reed-Sternberg (HRS) cells were positive for both Oct2 and BOB.1, which has not been reported in CHL. Both HRS-like cells at the time of diagnosis of Hodgkin lymphoma and lymphoma cells at the time of diagnosis of non-Hodgkin lymphoma were positive for CD20 and EBV-encoded small RNAs. This case was finally diagnosed as having age-related EBV+ B-cell LPD. We report the case here as it underscores the difficulty in diagnosing age-related EBV+ B-cell LPDs and also suggests an important role of EBV in the pathogenesis of lymphoid neoplasms.

Clinicopathological and genomic analysis of double-hit follicular lymphoma: comparison with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements

Most high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements are aggressive B-cell lymphomas. Occasional double-hit follicular lymphomas have been described but the clinicopathological features of these tumors are not well known. To clarify the characteristics of double-hit follicular lymphomas, we analyzed 10 cases of double-hit follicular lymphomas and 15 cases of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements for clinicopathological and genome-wide copy-number alterations and copy-neutral loss-of-heterozygosity profiles. For double-hit follicular lymphomas, the median age was 67.5 years (range: 48–82 years). The female/male ratio was 2.3. Eight patients presented with advanced clinical stage. The median follow-up time was 20 months (range: 1–132 months). At the end of the follow-up, 8 patients were alive, 2 patients were dead including 1 patient with diffuse large B-cell lymphoma transformation. Rearrangements of MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6 were seen in 8, 1, and 1 cases, respectively. The partner of MYC was IGH in 6 cases. There were no cases of histological grade 1, 4 cases of grade 2, 5 cases of grade 3a, and 1 case of grade 3b. Two cases of grade 3a exhibited immunoblast-like morphology. Immunohistochemistry demonstrated 9 cases with ≥50% MYC-positive cells. There was significant difference in MYC intensity (P=0.00004) and MIB-1 positivity (P=0.001) between double-hit follicular lymphomas and high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements. The genome profile of double-hit follicular lymphomas was comparable with conventional follicular lymphomas (GSE67385, n=198) with characteristic gains of 2p25.3-p11.1, 7p22.3-q36.3, 12q11-q24.33, and loss of 18q21.32-q23 (P<0.05). In comparison with high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements, double-hit follicular lymphomas had fewer copy-number alterations and minimal common region of gain at 2p16.1 (70%), locus also significant against conventional follicular lymphomas (P=0.0001). In summary, double-hit follicular lymphomas tended to be high-grade histology, high MYC protein expression, high MYC/IGH fusion, and minimal common region of gain at 2p16.1. Double-hit follicular lymphomas seemed to be a different disease from high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements and have an indolent clinical behavior similar to follicular lymphomas without MYC rearrangement.

Can synaptophysin be used as a marker of breast cancer diagnosed by core‐needle biopsy in epithelial proliferative diseases of the breast?

The differential diagnosis of epithelial proliferative disease using core needle biopsy (CNB) is problematic because it is difficult to differentiate between intraductal papilloma, ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma. Many studies have reported that breast cancer lesions are positive for neuroendocrine (NE) markers, whereas only a small number of studies have reported immunopositivity for NE markers in normal mammary tissues or benign lesions. We asked whether NE factors could be used as markers of breast cancer. We determined the immunopositivity rate of synaptophysin, an NE marker, in 204 lesions excised from the breast using CNB in patients who visited a university‐affiliated comprehensive medical facility and examined whether synaptophysin is a marker of breast cancer. The specimens were classified as synaptophysin‐negative cases (56 benign, 99 malignant); equivocal cases (<1 %: 2 benign, 15 malignant); and synaptophysin‐positive cases (1 benign, 31 malignant). The sensitivity, specificity, positive predictive value, and negative predictive value for malignancy of the lesions classified as synaptophysin positive were 23.3 %, 98.2 %, 96.9 %, and 36.1 %, respectively. The respective values for lesions classified as equivocal were 11.6 %, 96.6 %, 88.2 %, and 36.1 %. Synaptophysin may provide a marker of breast cancer diagnosed by CNB.

Long-term expressed human α-Galactosidase A in tissues of HαG transgenic mice

Background : Human alpha‐galactosidase A (hαG) is an essential lysosomal enzyme in catalyzing the hydrolysis of ceramide trihexoside in humans. Effects have been directed to develop effective gene and replacement therapies for the deficiency of hαG, Fabry disease. In recent years, hαG transgenic mice (TGM) have been established, and the expression of hαG in their general organs has been reported. However, detailed distribution of the cells expressing hαG have not yet been defined.

Post-transplant lymphoproliferative disorders in kidney transplantation: histological and molecular genetic assessment.

Abstract:  We performed histopathological and immunohistochemical studies, in situ hybridization (ISH) for Epstein–Barr virus (EBV) and molecular genetic analysis using the PCR method for the immunoglobulin heavy chain gene in six patients with post‐transplant lymphoproliferative disorders (PTLD) to clarify these problems. In two patients, PTLD developed in the graft, and in the remaining four it developed in systemic lymphoid tissues or organs. In terms of morphological classification, lesions in the graft of two patients were polymorphic with features of rejection in the background. In the other four patients, three of them presented monomorphic lesions and the remaining one presented features of reactive lymphoid hyperplasia. All the patients were positive for EBV as determined by ISH. The molecular genetic study could be performed for four patients, the cells in lesions of two patients were found to be monoclonal and those of the remaining two were polyclonal in IgH as determined by PCR. We conclude that PTLD are of two types, namely, intragraft PTLD and extra‐graft PTLD. In the cases of intragraft PTLD their diagnosis is relatively difficult, because lesions are mixed with features of rejection. Molecular genetic analysis and detection of EBV by ISH are useful for diagnosis. In contrast, the diagnosis of extra‐graft PTLD is easier than that of intragraft PTLD, by basing of the latest classification of malignant lymphoma. Grading of severity of PTLD should be carried out according to the newest system and protocols for treatment based on the grade of the lesion should be established as soon as possible.