Simultaneous development of Graves' disease and type 1 diabetes during anti-programmed cell death-1 therapy: A case report.

We present the first case of simultaneous development of Graves' disease and type 1 diabetes during anti-programmed cell death 1 therapy. A 48-year-old man with parotid gland adenocarcinoma and lung metastasis had received five courses of nivolumab. Fourteen days after administration of the sixth course, his casual plasma glucose and hemoglobin A1c levels were 379 mg/dL and 7.2%, respectively. Furthermore, thyrotoxicosis was detected with a blood test. Serum total ketone body and thyroid-stimulating hormone receptor antibody levels increased, and serum C-peptide level decreased to 0.01 ng/mL thereafter. Thus, we concluded that he simultaneously developed anti-programmed cell death 1 therapy-associated type 1 diabetes and Graves' disease. Among Japanese patients with autoimmune polyglandular syndrome type III, the frequency of human leukocyte antigen-DRB1*04:05 is higher in those with both type 1 diabetes and Graves' disease. Our case had human leukocyte antigen-DRB1*04:05, which might be associated with the simultaneous development of the two diseases.

Evaluation of the diagnostic value of immunoglobulin clonal gene rearrangements in patients with parotid gland MALT lymphoma using BIOMED-2 protocol.

OBJECTIVES: The aim of this study was to evaluate the diagnostic value of immunoglobulin (Ig) clonal gene rearrangements for mucosa-associated lymphoid tissue (MALT) lymphoma of the parotid gland. STUDY DESIGN: We collected and retrospectively analyzed clinical data of 21 patients referred to our institution between 2009 and 2017. Eight patients had been primarily diagnosed MALT lymphoma of the parotid gland and the remaining patients with lymphoepithelial lesion. Paraffin-embedded tissues were chosen for extracting genomic DNA and multiplex primer polymerase chain reaction amplification by using BIOMED-2 primers. Polymerase chain reaction amplification products were analyzed by heteroduplex analysis. RESULTS: Generally, 17 patients were identified to have parotid gland MALT lymphoma; 47.06% of them had Sjögren syndrome. The sensitivity of IGH VH-JH FR1, FR2, FR3, IGK Vκ-Jκ, and IGK (Vκ-Kde and intron-Kde) as targets was 76.47%, 82.35%, 88.24%, 29.41%, and 35.29%, respectively. The sensitivity of combined application of the above-mentioned 3 IGH primers as targets was 100%. The sensitivity of combined application of the above two IGK primers as targets was 58.82%. CONCLUSIONS: Ig clonal gene rearrangements assays using BIOMED-2 protocol can be a highly reliable diagnostic method for parotid gland MALT lymphoma. For patients with Sjögren syndrome along with histologically benign lymphoepithelial lesion, identification of Ig clonal gene rearrangements is important for routine differential diagnosis.

Parotid sclerosing mucoepidermoid carcinoma: a case report and immunohistochemical study.

Here we report the case of a 63-year-old female with a parotid sclerosing mucoepidermoid carcinoma diagnosed and treated at the Department of Oral and Maxillofacial Surgery, Emergency County Hospital of Craiova, Romania. The clinical and imaging investigation revealed a parotid malignant tumor with central fluid-filled cystic formation. Histopathology found an intermediate grade sclerosing mucoepidermoid carcinoma that invaded the adjacent adipose and striated muscle tissues, but without perineural and lymphovascular invasion. The immunohistochemistry investigated mainly biomarkers involved in the induction of a local aggressive behavior. This case report describes a rare parotid sclerosing mucoepidermoid carcinoma with peculiar clinical and morphological characteristic features. The immunohistochemical study sustained its intermediate grade malignancy highlighting the prognostic value of some of the used biomarkers.

Warthin's tumour: Aetiopathogenesis dilemma, ten years of our experience.

Despite the volume of studies written after the initial report by Hildebrand (1895) on Warthin's tumour (WT), its aetiopathogenesis continues to be an unresolved and controversial question. Many different genetic and/or environmental aetiological factors seem to act on heterotopic ductal inclusions and may give rise to WT following an unknown tumorigenic event. Recent studies discussed the importance of immunological reactions during the formation of the tumour. A hypersensitive/allergic reaction may play a role in epithelial proliferation and may stimulate the reactivity of the germinal centres in the lymphoid stroma as showed at histological examination. The aim of this study was to inform readers of the current understanding of possible risk factors with a suggested aetiological role in Warthin's tumorigenesis. From 2001 to 2011, a total of 342 patients with benign salivary neoplasm were admitted in the Department of Maxillofacial Surgery of the University of Naples "Federico II". A histological diagnosis of WT was made in 115 of the patients (33.6%); these were retrospectively investigated in our study. Correlation between the onset of WT and positivity for autoimmune diseases and smoking habits was calculated. The incidence rate of autoimmune thyroiditis in our series (9.5%) was significantly greater than that of the general population (0.58%) (p < 0.001). Analysis of our series and review of the literature support the hypothesis that this tumour is the result of an autoimmune reaction. Further studies and larger series are required to confirm this hypothesis and investigate the role of other aetiological factors in WT genesis.

Parotid gland follicular lymphoma lacking both cytoplasmic and surface light chains: a rare case.

Immunoglobulin light chain (LC) restriction is detected in the majority of B-cell non-Hodgkin lymphoma (B-NHL) by flow cytometric immunophenotyping (FCI) and serves as a surrogate marker of monoclonality. Even though it is known a small percentage of mature B-NHLs lacking surface LC, deficiency of both cytoplasmic and surface LCs has been reported in only three B-NHL cases. We report a primary parotid gland follicular lymphoma in a 63-year-old man and the lymphoma cells were deficient of cytoplasmic/surface LCs. Compared to previous reports, we used a more sensitive FCI method by combining both monoclonal and polyclonal anti-LC antibodies. Lacking LCs poses as a pitfall for the initial diagnosis of B-NHL, as well as for detecting minimal residual disease. It is important to be aware of this rare immunophenotypic aberrancy.

Warthin's tumor associated with IgG4-related disease.

Immunoglobulin G4-related disease (IgG4-RD) is an inflammatory condition associated with elevated serum IgG4 levels and tissue infiltration by IgG4-expressing plasma cells. Several inflammatory conditions associated with IgG4-RD have been reported. Warthin's tumor is a benign parotid gland tumor consisting of oncocytic epithelial cells and lymphoid stroma containing lymphoid follicles with reactive germinal centers. This is the first report describing a case of Warthin's tumor with possible involvement of IgG4-RD. The patient was a 71-year-old man presenting with swollen right parotid and bilateral submandibular glands. He had a history of a Warthin's tumor of the left parotid gland, autoimmune pancreatitis, and an inflammatory abdominal aortic aneurysm. Laboratory tests revealed a high serum IgG4 level. Histological examination of the resected parotid gland showed a Warthin's tumor and a nodule showing severe lymphocytic infiltration containing many IgG4-positive plasma cells. This case shows the possible involvement of Warthin's tumor with IgG4-RD.

[Rituximab therapy for systemic manifestations and MALT lymphomas of the parotid gland in Sjögren's disease: preliminary data].

AIM: To evaluate the efficacy of rituximab (RT) in cryoglobulinemic vasculitis (CGV) and MALT lymphomas of the parotid gland (PG) in patients with Sjögren's disease (SD). SUBJECTS AND METHODS: RT therapy was performed in 13 patients with SD and CGV and in 17 with SD and PC MALT lymphoma. Eleven patients with SD received RT monotherapy and 19 with this disease had combined therapy with RT and cyclophosphan (CP). RT was used intravenously dropwise at a dose of 500 mg weekly or once every two weeks in combination with intravenous dropwise CP 1000 mg the next day with 4-6 per course. For the diagnosis of MALT lymphomas, all the patients with SD underwent incisional PG biopsy under local anesthesia at the Research Institute of Rheumatology, Russian Academy of Medical Sciences. PG biopsy specimens were histologically and immunohistochemically studied at the Russian Cancer Research Center, Russian Academy of Medical Sciences. In 11 cases, B-cell clonality was identified from immunoglobulin (Ig) heavy chain genes rearrangements, by using polymerase chain reaction at the Hematology Research Center, Ministry of Health and Social Development of the Russian Federation. RESULTS: Cutaneous manifestations of vasculitis disappeared in 75% of cases after monotherapy with RT and in 100% of cases after combination therapy with RT and CP. At 6-month follow-up, a complete response to therapy remained in 25% of the patients after a course of monotherapy and in 83% after combined therapy. Serum monoclonal Ig cryoglobulins and their urinary light chains ceased to be detectable in 75% of the patients in both groups at 3 months. At 6 months, a recurrence of mixed monoclonal cryoglobulinemia was seen in 50 and 43% of cases after monotherapy and combined therapy, respectively. The clinical and laboratory response of cryoglobunemic glomerulonephritis to combined therapy with RT and CP was complete in 60% of cases at 6-month follow-up. After RT monotherapy, the patients with SD and PG MALT lymphoma achieved a complete clinical response in 88%, of whom histological and immunohistochemical reexaminations of PG biopsy specimens revealed no signs of MALT lymphoma in 71% of cases. B-cell clonality remained in the PG biopsy specimens following RT monotherapy. After the combination of RT and CP, a complete clinical response to therapy was observed in 100% of the patients, a complete histological response and a complete molecular one were seen in 83 and 60%, respectively. CONCLUSION: RT showed its efficacy in treating SD patients with CGV and PG MALT lymphomas.

Rituximab treatment for Sjogren syndrome-associated non-Hodgkin's lymphoma: case series.

Five per cent of patients with primary Sjogren's syndrome (pSS) develop malignant non-Hodgkin's lymphoma (NHL), usually of the mucosa-associated lymphoid tissue (MALT) and most frequently located in the major salivary glands. Rituximab (RTX), a chimeric monoclonal antibody against the CD20 molecule expressed on the surface of mature B cells that has been approved for the treatment of NHL, has been used to treat pSS-associated lymphoma. We have described two cases: one with MALT lymphoma in the parotid glands and the other with a rare thymus lymphoma accompanied by the rare complication of a bullous pneumopathy. Both were treated with RTX at haematological doses, which was unsuccessful in the patient with a salivary lymphoma; in the case of the patient with a thymus lymphoma, the mediastinum mass disappeared and did not relapse. Both patients experienced an improvement in the subjective symptoms of dryness, and their Schirmer's test and scialoscintigraphy results stabilised. The pulmonary bullae remained unchanged.

Carbohydrate antigen 19-9 in saliva: possible preoperative marker of malignancy in parotid tumors.

OBJECTIVE: Facial nerve preservation and oncological safety are crucial in surgery of parotid tumors. An unexpected histopathologic diagnosis of a malignant parotid tumor, however, may unfavorably require a second, more radical surgery. The aim of this study was to find out whether the assessment of serological tumor markers in parotid saliva might have some diagnostic significance in the preoperative differentiation between benign and malignant parotid lesions. STUDY DESIGN, SETTING, PATIENTS, AND METHODS: In a prospective pilot study performed at a university medical center in 28 patients with a unilateral parotid tumor, 7 serological tumor markers established in the clinical routine were quantitatively assessed in parotid saliva collected simultaneously on both sides after stimulation. The results were correlated with the histopathological diagnosis. RESULTS: Of the 4 investigated tumors that were malignant neoplasms, 3 had a sufficient quantity of saliva available for tumor marker measurements. Carbohydrate antigen 19-9 (CA 19-9) consistently revealed high levels compared with the unaffected side in all malignant tumors, thus allowing malignant tumors to be differentiated from benign lesions. CONCLUSION: The results of this pilot study are encouraging, showing that preoperative tumor marker investigation in saliva from parotid glands is feasible and merits further investigation. CA 19-9 might be a valuable new diagnostic tool in the preoperative differentiation between malignant and benign parotid tumors and should be investigated in a larger number of patients.

Simultaneous occurrence of IgG4-related chronic sclerosing dacryoadenitis and chronic sclerosing sialadenitis associated with lymph node involvement and Warthin's tumor.

Chronic sclerosing dacryoadenitis and chronic sclerosing sialadenitis have been shown to belong to the group of diseases referred to as IgG4-related sclerosing disease. The authors report a case of the simultaneous occurrence of IgG4-related sclerosing disease in both lacrimal and submandibular glands, clinically simulating malignant lymphoma. A cervical lymph node and a Warthin's tumor were also involved. This unique case of multiple organ involvement in IgG4-related sclerosing disease is documented.

T cell lymphoblastic lymphoma in parotidectomy for Warthin's tumor: case report and review of the literature.

Lymphomas associated with Warthin's tumor (WT) are extremely uncommon and the majorities are of B cell type. We report the simultaneous occurrence of T-cell lymphoblastic lymphoma (T-LBL) and WT in an 81-year-old patient, who presented with fever, night sweats and enlargement of the right parotid gland. The parotidectomy specimen showed a WT with extensive replacement of the lymphoid stroma by T-LBL, but preservation of the oncocytic epithelium. Staging investigations revealed mediastinal and abdominal lymphadenopathy, bilateral pleural effusions and bone marrow infiltration, in keeping with stage IVB disease. The patient received combination chemotherapy treatment but responded poorly, and died three months after diagnosis. To our knowledge, this is the first case report of T-LBL involving WT. The present study indicates that the lymphoid stroma in WT belongs to the systemic lymphoid tissue and can be involved in disseminated lymphoma. It highlights the importance of careful examination of WT's lymphoid stroma for the possible presence of any coexistent malignancy.

Osteoclast-like giant-cell tumor of the parotid with salivary duct carcinoma: case report and cytologic, histologic, and immunohistochemical findings.

Primary giant-cell tumor of the salivary gland is a rare lesion with an incompletely characterized histogenesis. To the best of our knowledge, only 16 cases have been previously documented in the English-language literature. We report a new case, which occurred in a 75-year-old man who presented with a parotid mass and cervical lymphadenopathy. The patient underwent a left total parotidectomy and cervical lymph node dissection. As far as we know, ours is the only reported case of a primary giant-cell tumor of the salivary gland in which the patient presented with lymph node metastasis. Because so little is known about giant-cell tumor of the salivary gland, we use the occasion of this case report to describe the cytologic, histologic, and immunohistochemical characteristics that we observed.

Increased expression of cyclooxygenase-2 and Ki-67 are associated with malignant transformation of pleomorphic adenoma.

OBJECTIVES: In the present study, we attempted to identify cyclooxygenase-2 (COX-2) expression and Ki-67 index in carcinoma ex-pleomorphic adenoma (Ca ex-PA) using quantitative immunohistochemical analysis and to compare the benign component of the neoplasia. We also aimed to relate the overexpression of COX-2 with the pathways of malignant transformation of Ca ex-PA as evidenced by distinct morphological features. MATERIALS AND METHODS: Forty Ca ex-PA from patients treated at Department of Otolaryngology, Yokohama City University Medical Center, Yokohama, Japan, from 1999 to 2005, were selected. All Ca ex-PA showed only one malignant histological component: adenocarcinoma (23 cases), adenoid-cystic carcinoma (10), epithelial-myoepithelial carcinoma (7). The tissues were stained with monoclonal antibodies to COX-2 and Ki-67. The results were analyzed using quantitative immunohistochemical analysis. We also analyzed the association of the histological classification of the carcinomatous component. RESULTS: In the immunohistochemical analysis of COX-2 and Ki-67 index, significant increase was observed in Ca ex-PA, especially with adenocarcinoma, compared to pleomorphic adenoma and sialadenitis. Quantitative assessment is more sensitive as a measure of cellular protein content as compared to standard optical density measurement. CONCLUSIONS: The data support the hypothesis that increased COX-2 expression is associated with early events in malignant transformation of pleomorphic adenoma.

Parotid metastasis--an independent prognostic factor for head and neck cutaneous squamous cell carcinoma.

BACKGROUND: Metastatic parotid cutaneous squamous cell carcinoma (SCC) is the most common parotid gland malignancy in New Zealand and Australia. The current AJCC TNM staging system does not account for the extent of nodal metastasis. A staging system that separates parotid (P stage) from neck disease (N stage) has been proposed recently. AIM: To review the outcome of patients with metastatic head and neck cutaneous SCC treated at our multidisciplinary Head and Neck Service using the proposed staging system. METHOD: Consecutive patients were culled from our Head and Neck/Skull Base Database, 1990-2004. These patients were restaged according to the proposed staging system: P stage: P0 = no disease in the parotid (i.e., neck disease only); P1 = metastatic node < or = 3 cm; P2=metastatic node > 3 cm and < or =6 cm, or multiple nodes; and P3 = metastatic node > 6 cm, or disease involving the facial nerve or skull base. N stage: N0=no disease in the neck (i.e., parotid disease only); N1 = single ipsilateral metastatic node < or = 3 cm; and N2 = multiple metastatic nodes, or any node > 3 cm, or contralateral neck involvement. Loco-regional recurrence and disease-specific survival were calculated using the Kaplan-Meier method and comparison of graphs made with the log-rank test. Multivariate analysis using the Cox regression model was carried out to assess the impact of various parameters. RESULTS: Sixty-seven patients with metastatic head and neck cutaneous SCC were identified. Thirty-seven patients had parotid metastasis (of whom 13 also had neck disease) while 21 had neck metastasis alone. Nine patients had dermal or soft tissue metastasis. These nine patients were excluded from this series, and data analysis was carried out on the remaining 58 (46 men, 12 women, mean age 71 years) patients. Sixty-seven percent of the patients underwent post-operative adjuvant radiotherapy. The five-year disease-specific survival rate was 54%. Among 56 patients followed up to disease recurrence or for a minimum period of 18 months, the loco-regional recurrence rate was 52%. The presence of parotid disease was an independent prognostic factor on survival (p < 0.01), and P3 fared significantly worse than P1 and P2. Those patients who had both parotid and neck disease fared worse than those who had parotid or neck disease alone (p = 0.01). N2 had a significantly poorer outcome compared with N1 (p < 0.01). Immunosuppression (p = 0.01) and a positive surgical margin (p < 0.01) were significant adverse prognostic factors for survival. Adjuvant radiotherapy, extracapsular spread, and perineural and vascular invasion did not influence survival. Our study demonstrates that the extent of parotid disease is an independent prognostic factor for metastatic head and neck cutaneous SCC.

Timely DNA vaccine combined with systemic IL-12 prevents parotid carcinomas before a dominant-negative p53 makes their growth independent of HER-2/neu expression.

Double transgenic mice overexpressing the transforming rat HER-2/neu oncogene and the mutated p53, with both dominant-negative and a gain-of-function properties, display early aggressive and metastasizing parotid tumors. Multiple acinar and ductal hyperplasia foci overexpressing the HER-2/neu gene product are evident at wk 5 and progress to poorly differentiated carcinoma by wk 7. Mice die before wk 18 with invasive carcinomas and multiple metastases that no longer express HER-2/neu. A combination of repeated electroporations of plasmids coding for the extracellular and transmembrane domains of the rat HER-2/neu receptor with systemic IL-12 administrations started when the parotids that present diffuse hyperplasia protected all female and 50% of the male mice until the close of the experiment at wk 40. This combined treatment began when multifocal in situ carcinomas that were already present cured 33% of the females and 25% of the males. The most prominent immunologic features associated with the antitumor protection were the production of high titers of anti-HER-2/neu Abs and the nonappearance of cell-mediated cytotoxic reactivity. In conclusion, anti-HER-2/neu vaccination combined with systemic IL-12 control parotid carcinomas as far as p53 mutation makes their growth independent of HER-2/neu expression.

Unusual aggressive course of a giant cell tumor of soft tissue during immunosuppressive therapy.

Giant cell tumor of soft tissue with low malignant potential (GCT-ST) is a low-grade, primary soft tissue sarcoma with histological and clinical features similar to giant cell tumor of the bone. The main tumor localizations are the extremities, but it may also occur in the head and neck region. GCT-ST shows a recurrence rate of approximately 15%, but it very rarely metastasizes. The risk of cancer development, especially of the skin, is up to fivefold increased in immunosuppressed patients after organ transplantation. The association of sarcomas and immunosuppressive therapy is best known for Kaposi sarcomas, whereas other types of sarcomas are rarely found. We report of a GCT-ST of low malignant potential, which developed under long-term immunosuppression in a patient 12 years after heart transplantation. The tumor presented with an unusual aggressive course and metastatic site: the parotid gland. Therefore, we suggest that in patients with immunosuppression, even low malignant cancerous lesions should be carefully observed, as their local behavior may be aggressive with development of metastasis.

Carcinosarcoma of the parotid gland: an unusual case with large-cell neuroendocrine carcinoma and rhabdomyosarcoma.

We report a case of carcinosarcoma of the parotid gland in a 72-year-old Japanese man. The patient noticed a rapidly enlarging hard mass in the right parotid gland. He underwent radical parotidectomy with cervical lymph node dissection. The resected tumor measured 3.5 x 4.5 cm and histopathologically showed carcinomatous and sarcomatous components. The carcinomatous component consisted of large-cell neuroendocrine carcinoma (LCNEC), squamous cell carcinoma and adenocarcinoma not otherwise specified, while the sarcomatous component included spindle cell sarcoma not otherwise specified, so-called myxosarcoma and rhabdomyosarcoma. The LCNEC component was predominant within the whole tumor. The diagnoses of LCNEC and rhabdomyosarcoma were also confirmed immunohistochemically. With regard to histopathogenesis, based on the lack of histopathological evidence and antecedent history of pleomorphic adenoma, we considered the present case to be de novo, not expleomorphic adenoma.

Cyclooxygenase-2 regulates the degree of apoptosis by modulating bcl-2 protein in pleomorphic adenoma and mucoepidermoid carcinoma of the parotid gland.

CONCLUSION: These results suggest that COX-2 and bcl-2 protein were overexpressed and that apoptosis was reduced in MEC compared to PMA, and that COX-2 may regulate the degree of apoptosis by modulating bcl-2 protein in PMA and MEC. OBJECTIVE: Cyclooxygenase (COX)-2 plays a crucial role in tumorigenesis and overexpression of COX-2 in vitro accompanied by overexpression of bcl-2 protein has been shown to reduce apoptosis. The purpose of this study was to verify that COX-2 regulates the degree of apoptosis by modulating bcl-2 protein in benign and malignant parotid gland tumors. : We examined archival formalin-fixed, paraffin-embedded tissue sections of 10 pleomorphic adenomas (PMAs) and 10 mucoepidermoid carcinomas (MECs) by immunostaining with anti-COX-2, anti-bcl-2 and anti-single-stranded DNA (ssDNA) antibodies. Labeling indices of the three antibodies were calculated using computer-assisted image analysis. RESULTS: Labeling indices (mean+/-SD) of anti-COX-2 antibody in PMA and MEC were 2.05+/-1.30 and 11.2+/-2.95, respectively (p < 0.001), those of anti-bcl-2 antibody were 2.00+/-1.28 and 9.68+/-4.05, respectively (p < 0.001) and those of anti-ssDNA antibody were 8.06+/-2.54 and 2.08+/-1.47; respectively (p <0.001). Correlation coefficients between the labeling indices of anti-COX-2 antibody and anti-bcl-2 antibody, anti-bcl-2 antibody and anti-ssDNA antibody and anti-COX-2 antibody and anti-ssDNA antibody were 0.88, -0.75 and -0.76, respectively (p <0.001).

Primary angiosarcoma of the non-irradiated parotid gland: a most uncommon, highly malignant tumor.

This case report discusses the clinical presentation, imaging, surgery and further treatment and course of a primary angiosarcoma of a non-irradiated parotid gland.