Michihiko Narita

Pyothorax-associated lymphoma : An unusual case with biphenotypic character of T and B cells

Pyothorax-associated lymphoma is known to develop in patients who received an artificial pneumothorax for pulmonary tuberculosis some 30 to 40 years previously. Such patients exhibit large, immunoblastic lymphoma cells and often have a B-cell phenotype. We present a patient with an artificial pneumothorax and such a late developing lymphoma but with the unique finding of aberrant T- and B-cell phenotypes. Southern blot hybridization using immunoglobulin gene JH and T-cell receptor beta chain receptors revealed germline configurations. Lymphomas developing in immunocompromised patients, such as those with acquired immunodeficiency syndrome, may show such unusual phenotypes. The unusual phenotypes found in this patient provide evidence that his pyothorax-associated lymphoma was related to an immunocompromised state.

Rheumatoid arthritis with diffuse pulmonary rheumatoid nodules

Rheumatoid nodules in dermal or subcutaneous tissues, while indicative of rheumatoid arthritis, are very rare. It is even less common to identify these rheumatoid nodules by biopsy as well as in autopsy materials from lung tissue. These nodules may be single or multiple, which seldom cause respiratory symptoms. Here, a patient with diffuse pulmonary rheumatoid nodules and interstitial fibrosis throughout both lungs, is described. The patient, with articular symptoms and seropositivity, exhibited a rapid clinical course and died of respiratory failure 3  months after the appearance of dyspnea. Chest radiography indicated interstitial pneumonitis with bilateral diffuse peripheral shadows. At autopsy, numerous rheumatoid nodules and interstitial fibrosis had destroyed both lungs, such that no residual normal pulmonary tissue remained. It is believed that this was an extremely rare case exhibiting large numbers of rheumatoid nodules throughout the lungs. Findings with this patient indicate that, in patients with rheumatoid arthritis, clinical interstitial pneumonitis confirmed radiologically does not exclude the existence of rheumatoid lung nodules.

Pathobiological Implications of Mucin (MUC) Expression in the Outcome of Small Bowel Cancer

Mucins have been associated with survival in various cancer patients, but there have been no studies of mucins in small bowel carcinoma (SBC). In this study, we investigated the relationships between mucin expression and clinicopathologic factors in 60 SBC cases, in which expression profiles of MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC6 and MUC16 in cancer and normal tissues were examined by immunohistochemistry. MUC1, MUC5AC and MUC16 expression was increased in SBC lesions compared to the normal epithelium, and expression of these mucins was related to clinicopathologic factors, as follows: MUC1 [tumor location (p = 0.019), depth (p = 0.017) and curability (p = 0.007)], MUC5AC [tumor location (p = 0.063) and lymph node metastasis (p = 0.059)], and MUC16 [venous invasion (p = 0.016) and curability (p = 0.016)]. Analysis of 58 cases with survival data revealed five factors associated with a poor prognosis: poorly-differentiated or neuroendocrine histological type (p<0.001), lymph node metastasis (p<0.001), lymphatic invasion (p = 0.026), venous invasion (p<0.001) and curative resection (p<0.001), in addition to expression of MUC1 (p = 0.042), MUC5AC (p = 0.007) and MUC16 (p<0.001). In subsequent multivariate analysis with curability as the covariate, lymph node metastasis, venous invasion, and MUC5AC and/or MUC16 expression were significantly related to the prognosis. Multivariate analysis in curative cases (n = 45) showed that SBC with MUC5AC and/or MUC16 expression had a significantly independent high hazard risk after adjusting for the effects of venous invasion (hazard ratio: 5.6, 95% confidence interval: 1.8–17). In conclusion, the study shows that a MUC5AC-positive and/or MUC16-positive status is useful as a predictor of a poor outcome in patients with SBC.

Hodgkin Disease with Subsequent Transformation to CD30 Positive Non-Hodgkin Lymphoma in Six Patients

Previous studies have indicated that some patients with Hodgkin disease have an aggressive clinical course. However, their characteristics have not been elucidated.

An autopsy case of primary nodal plasmacytoma associated with Sjögren's syndrome.

An 81‐year‐old man with a 1 year history of Sjögren’s syndrome and hypergammaglobulinemic purpura was admitted because of high fever and lymphadenopathy. Primary nodal plasmacytoma was suggested from the microscopic and immunohistochemical findings of an inguinal lymph node biopsy specimen. Although chemotherapy achieved a moderate response, the patient died 2 months later from respiratory and cardiac failure. We herein, is described a rare autopsy case of primary nodal plasmacytoma associated with Sjögren’s syndrome, in which the clinical course was progressive and Epstein‐Barr virus‐encoded RNA 1 was positive in a small number of neoplastic plasma cells, showing some difference from previously reported cases.

Immunohistochemical expression of myoepithelial markers in adenomyoepithelioma of the breast: a unique paradoxical staining pattern of high-molecular weight cytokeratins

To determine which immunohistochemical markers are useful for the identification of neoplastic myoepithelial cells in adenomyoepithelioma of the breast, the expression of seven myoepithelial markers (α-smooth muscle actin (α-SMA), calponin, p63, CD10, cytokeratin 5/6, cytokeratin 14, and S-100) was examined in 19 lesions from 16 patients. The lesion consisted of seven spindle and 12 clear cell lesions. For normal myoepithelial cells, α-SMA, calponin, and p63 were significantly more sensitive than cytokeratin 5/6, cytokeratin 14, and S-100. There was no significant difference in the expression of α-SMA, calponin, p63, and CD10 in neoplastic myoepithelial cells of adenomyoepithelioma regardless of spindle or clear cell types. In spindle cell lesions, high-molecular weight cytokeratins (HMWCK; cytokeratin 5/6 and cytokeratin 14) tended to show higher staining scores and S-100 showed lower staining scores than other markers. In clear cell lesions, HMWCK showed significantly lower staining scores than the other five markers. There was no significant difference in staining scores among the other five markers. HMWCK showed a unique paradoxical staining pattern in clear cell lesions, with diffusely positive inner epithelial cells and completely negative outer myoepithelial cells. Although the sensitivity of HMWCK in clear cell lesions is low, with this unique paradoxical staining pattern and relatively high sensitivity in spindle cell lesions, HMWCK could be useful in diagnosing adenomyoepithelioma. In choosing immunohistochemical markers, any of the seven markers are useful, but combining HMWCK and any one of α-SMA, calponin, and p63 would be a good panel for the diagnosis of adenomyoepithelioma.

A comprehensive expression analysis of mucins in appendiceal carcinoma in a multicenter study: MUC3 is a novel prognostic factor.

Background Mucins are implicated in survival in various cancers, but there have been no report addressed on survival in appendiceal carcinoma, an uncommon disease with different clinical and pathological features from those of other colon cancers. We aimed to investigate the clinical implications of expression of mucins in appendiceal carcinoma. Methods Expression profiles of MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC6, MUC16 and MUC17 in cancer tissue were examined by immunohistochemistry in 108 cases of surgically resected appendiceal carcinoma. Results The following relationships of mucins with clinicopathologic factors were identified: MUC1 with positive lymphatic invasion (p = 0.036); MUC2 with histological type (mucinous carcinoma, p<0.001), superficial invasion depth (p = 0.007), negative venous invasion (p = 0.003), and curative resection (p = 0.019); MUC3 with non-curative resection (p = 0.017); MUC5AC with histological type (mucinous carcinoma, p = 0.002), negative lymphatic invasion (p = 0.021), and negative venous invasion (p = 0.022); and MUC16 with positive lymph node metastasis (p = 0.035), positive venous invasion (p<0.05), and non-curative resection (p = 0.035). A poor prognosis was related to positive lymph node metastasis (p = 0.04), positive lymphatic invasion (p = 0.02), positive venous invasion (p<0.001), non-curative resection (p<0.001), and positive expression of MUC3 (p = 0.004). In multivariate analysis, positive venous invasion (HR: 6.93, 95% CI: 1.93–24.96, p = 0.003), non-curative resection (HR: 10.19, 95% CI: 3.05–34.07, p<0.001) and positive MUC3 expression (HR: 3.37, 95% CI: 1.13–10.03, p = 0.03) were identified as significant independent prognostic factors in patients with appendiceal carcinoma. Conclusions Expression of MUC3 in appendiceal carcinoma is an independent factor for poor prognosis and a useful predictor of outcome in patients with appendiceal carcinoma after surgery.

A 12-mm Carcinoid Tumor of the Minor Duodenal Papilla with Lymph Node Metastases

Carcinoid tumors located in the minor duodenal papilla are extremely rare, with only a few cases reported in the literature. Herein, we report the case of a 71-year-old man with a 12-mm carcinoid tumor at the minor duodenal papilla with lymph node metastases. Multidetector-row computed tomography with contrast enhancement revealed a 12-mm well-enhanced tumor in the duodenum. Upper gastrointestinal endoscopy showed a 12-mm submucosal tumor at the minor papilla of the duodenum. Biopsy specimens revealed a carcinoid tumor, and a subtotal stomach-preserving pancreatoduodenectomy was performed. Carcinoid tumors at the minor duodenal papilla have a high prevalence of nodal disease, even for tumors <2 cm in diameter. Therefore, we believe that radical resection with tumor-free margins (i.e. pancreatoduodenectomy) is the treatment of choice.

Partial restoration of CD20 protein expression and rituximab sensitivity after treatment with azacitidine in CD20-negative transformed diffuse large B cell lymphoma after using rituximab

Dear Editor, Rituximab, a first-generation chimeric monoclonal antiCD20 antibody, is a key molecular targeted therapeutic against CD20-positive B cell lymphoma (BCL); favorable results have been obtained by adding rituximab to combination chemotherapy [1–3]. However, CD20-negative phenotypic changes after treatment with rituximab have become a considerable problem, with rituximab resistance showing clinically aggressive phenotype [4–6]. We previously reported the partial induction of CD20 protein expression after treatment with epigenetic modulators such as DNA methyltransferase inhibitors (DNMTis) and histone deacetylase inhibitors (HDACis) using CD20-negative transformed BCL cells in vitro [4, 5, 7]. However, studies on the effects of epigenetic modulators on CD20 protein expression in CD20-negative transformed BCL in vivo have been limited [8, 9]. A 47-year-old man was admitted to our affiliated hospital 15 years ago (Fig. 1A) with lymph node swelling, which was diagnosed as follicular lymphoma (FL) with CD20-positive phenotype by immunohistochemistry (Fig. 1B, a–c). He was treated with combination chemotherapy including rituximab for a total of 16 cycles. (Fig. 1A). After 14 years from initial diagnosis, therapy-related acute myeloid leukemia/myelodysplastic syndrome (t-AML/tMDS) with complex karyotypes including − 7 was confirmed, and CD20-negative transformed diffuse large B cell lymphoma (DLBCL) was confirmed by inguinal lymph node biopsy (Fig. 1B, d–f). 5-Azacitidine (AZA) was administered to treat t-MDS, and dexamethasone was also used to prevent BCL cell proliferation. Flow cytometry (FCM) showed that the percentage of CD20positive fractions in lymphoid-gated cells gradually increased. (Fig. 1C), and rituximab was utilized again at 13 weeks after AZA treatment. Two days after rituximab, the reduction of CD20-positive tumor cells to 2% was confirmed by FCM. However, systemic lymphadenopathy and elevation of LDH later occurred, and the patient died 101 days after receiving AZA. Previous reports indicated that CD20-negative phenotypic changes after rituximab have become a critical problem, leading to a very aggressive phenotype that results in short-term survival [4, 5, 10]. Partial restoration of CD20 expression in CD20-negative transformed BCL was shown to occur within a few days after treatment with the epigenetic modulators, DNMTi and HDACi, and expression lasted 1 week in vitro; however, the precise effects of those drugs in vivo have not been reported. In this case study, CD20 protein expression increased on day 2 and lasted more than 10 weeks after AZA treatment, and the partial effectiveness of rituximab was confirmed even on day 90. This rapid upregulation of CD20 expression within 2 days suggests that expression was likely stimulated by epigenetic mechanisms and not by clonal selection. A previous study indicated that CD20 expression in CD20-positive DLBCL was partially enhanced by administration of AZA in vivo, suggesting that DNMTi affects the basic mechanisms of CD20 gene expression not only in CD20-negative transformed DLBCL cells. Since bendamustine and corticosteroid were also utilized in this case, the possibility of partial effectiveness of these therapeutics to CD20 protein upregulation has not been * Junji Hiraga j–hiraga@toyota.jaaikosei.or.jp; junji.hiraga@gmail.com

EBV-positive Diffuse Large B-cell Lymphoma as a Secondary Malignancy Arising in a Myelodysplastic Syndrome Patient who Was Treated with Azacitidine

We report a case of secondary diffuse large B-cell lymphoma (DLBCL) after azacitidine (AZA) treatment in a 63-years-old man with myelodysplastic syndrome. The patient suffered from febrile neutropenia after 10 cycles of AZA treatment. Despite the performance of a whole-body CT scan, which showed a multifocal low-density area in the liver and a multifocal nodular shadow in the lung, no malignant neoplasms could be detected. An autopsy was performed 6 months later, and a histopathological examination of the lesions of the liver and lung revealed the infiltration of large round-shaped tumor cells with necrotizing lesions. Immunohistochemically, the tumor cells were positive for CD20 and EBER, indicating EBV-positive DLBCL as a secondary malignancy.