High PDL1/PDL2 gene expression correlates with worse outcome in primary mediastinal large B-cell lymphoma.

Primary mediastinal B-cell lymphoma (PMBL) is an uncommon entity of aggressive B-cell lymphoma with an unusually good prognosis, except for 10-15% of chemotherapy-refractory cases. To identify earlier these higher risk patients, we performed molecular characterization of a retrospective multicenter cohort of patients treated with firstline immunochemotherapy. The traits of the patients with gene-expression profiling data (n = 120) were as follows: median age of 34 years (range, 18-67 years); female sex, 58.3%; elevated lactate dehydrogenase, 82.5%; Eastern Cooperative Oncology Group performance status score of 0 to 1, 85.7%; Ann Arbor stage I/II, 55%; International Prognostic Index score of 1 to 2, 64.4%; and median metabolic tumor volume, 290.4 cm3 (range, 15.7-1147.5 cm3). Among all 137 markers tested for correlation with survival data, only programmed death-ligand (PDL) 1 and PDL2 expression showed a prognostic impact. Overall, both PDL1 and PDL2 genes were highly expressed in 37 patients (30.8%; PDL1high/PDL2high). The baseline clinical characteristics of patients with PDL1high/PDL2high were similar to those of other patients. In univariate analysis, PDL1high/PDL2high status was associated with poor progression-free survival (PFS) (hazard ratio [HR], 4.292) and overall survival (OS; HR, 8.24). In multivariate analysis, PDL1high/PDL2high status was an independent prognostic factor of adverse outcomes (PFS: HR, 5.22; OS: HR, 10.368). We validated these results in an independent cohort of 40 patients and confirmed the significant association between PDL1high/PDL2high status and inferior PFS (HR, 6.11). High PDL1/PDL2 gene expression defines a population with strong immune privilege and poorer outcomes from standard chemotherapy who might benefit from firstline checkpoint inhibitor therapy.

Primary oral mucosa-associated lymphoid tissue (MALT) lymphoma in patient with monoclonale gammopathy: a rare case report.

BACKGROUND: Monoclonal gammopathy is a biological reality encountered in approximately 1% of the general population. In the absence of clinical and biological signs, it is considered of undetermined significance; however, it can be a biological signature of a monoclonal lymphocytic or plasma-cell proliferation. Their localisation to the oral mucosa remains rare and difficult to diagnose, particularly in indolent forms that escape imaging techniques. CASE PRESENTATION: Here, we report the case of a 73-year-old woman with a history of IgM kappa gammopathy followed for 13 years. The patient did not have a chronic infection or an autoimmune disease, and all the biological investigations and radiological explorations were unremarkable during this period. The discovery of a submucosal nodule in the cheek led to the diagnosis of MALT lymphoma and regression of half of the IgM kappa level after resection. The review of the literature shows the dominance of clinical signs (i.e., a mass or swelling) in the diagnosis of primary MALT lymphomas of the oral cavity after surgical resection. CONCLUSIONS: Our case illustrates the role of examination of the oral cavity in the context of a monoclonal gammopathy. The absence of clinical and radiological evidence in favor of lymphoplasmacytic proliferation, does not exclude a primary indolent MALT lymphoma of the oral mucosa.

Long-term progression of non-invasive follicular thyroid neoplasm with papillary-like nuclear features: A single-center retrospective study of the French Marne-Ardennes thyroid cancer registry.

CONTEXT: Non-invasive forms of encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) were reclassified as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in order to reduce overtreatment. A few studies showed neck lymphadenopathy at diagnosis, or even distant metastasis in patients with NIFTP. OBJECTIVE: Our aim was to report the frequency, clinical features and long-term progression of histologically confirmed NIFTP, using data from the French Marne-Ardennes thyroid cancer registry, and to compare findings against FVPTC. METHODS: This was a retrospective study on data for follicular variant of PTC (FVPTC) diagnosed between 1975 and 2015 obtained from the specialized Marne-Ardennes thyroid cancer registry. Pathology reports were used to select appropriate cases from a large series, and FVPTC specimens were reviewed by endocrine pathologists. Strict diagnostic criteria were used for reclassification as NIFTP. RESULTS: In total, 115 cases were reviewed histologically out of 383 cases of FVPTC. Sixty-five met all criteria for NIFTP and were consequently reclassified. Incidence of NIFTP was 16.9% of cases of FVPTC. Fifty patients were women (76.9%); median age was 47 years. Mean NIFTP size was 2.6 cm. There were no significant differences in age, gender or tumor size between NIFTP and FVPTC. Fifty patients underwent total thyroidectomy and 15 lobectomy. There were no lymph node metastases at diagnosis, and none of the patients (N=17) who underwent central and/or lateral neck dissection had positive findings on microscopic examination. 46 patients (70.8%) received radioiodine (RAI). Patients were followed up for 1.9-27.3 years (median 14.6 years) after initial treatment. All patients remained in complete remission during follow-up. CONCLUSION: Consistently with previous studies, our results showed the indolent course of NIFTP and that risk of recurrence after complete resection is very low (zero in our cohort), even when size is ≥4cm and in absence of adjuvant RAI treatment. Prospective studies are needed to confirm those results.

Skeletal involvement of hairy cell leukemia.

Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disorder. Skeletal involvement is an unusual manifestation of HCL, complicating the course of the disease in approximately 3% of patients. We describe a case of skull involvement by HCL, a localization rarely reported in the literature.

Clinicopathological description of 43 oncocytic adrenocortical tumors: importance of Ki-67 in histoprognostic evaluation.

Oncocytic adrenocortical tumors are a rare subtype of adrenal tumors with challenging diagnosis and histoprognostic assessment. It is usually believed that oncocytic adrenocortical tumors have a more indolent clinical behavior than conventional adrenocortical tumors. As the Weiss score overestimates the malignancy of oncocytic adrenocortical tumors owing to intrinsic parameters, alternative scores have been proposed. The Lin-Weiss-Bisceglia score is currently recommended. We performed a large nationwide multicenter retrospective clinicopathologic study of oncocytic adrenocortical tumors. Among the 43 patients in our cohort, 40 patients were alive without disease, 2 patients died of their disease and 1 patient was alive with relapse after a median follow-up of 38 months (20-59). Our data revealed that over 50% of the oncocytic adrenocortical tumor cases were diagnosed as carcinoma whatever the classification systems used, including the Lin-Weiss-Bisceglia score. The exception is the Helsinki score, which incorporates the Ki-67 proliferation index and was the most specific prognostic score for oncocytic adrenocortical tumor malignancy without showing a loss in sensitivity. A comparison of malignant oncocytic adrenocortical tumors with conventional adrenocortical carcinomas matched for age, sex, ENS@T stage and surgical resection status showed significant better overall survival of malignant oncocytic adrenocortical tumors.

Impact of Expert Pathologic Review of Lymphoma Diagnosis: Study of Patients From the French Lymphopath Network.

Purpose To prospectively assess the clinical impact of expert review of lymphoma diagnosis in France. Materials and Methods From January 2010 to December 2013, 42,145 samples from patients with newly diagnosed or suspected lymphomas were reviewed, according to the 2008 WHO classification, in real time by experts through the Lymphopath Network. Changes in diagnosis between referral and expert review were classified as major or minor according to their potential impact on patient care. Results The 42,145 reviewed samples comprised 36,920 newly diagnosed mature lymphomas, 321 precursor lymphoid neoplasms, 314 myeloid disorders, and 200 nonhematopoietic neoplasms, with 4,390 benign lesions. There were 4,352 cutaneous and 32,568 noncutaneous lymphomas. The most common mature noncutaneous lymphomas were diffuse large B-cell lymphomas (32.4%), follicular lymphomas (15.3%), classic Hodgkin lymphomas (13%), peripheral T-cell lymphomas (6.3%) of which angioimmunoblastic T-cell lymphomas (2.3%) were the most frequent, and mucosa-associated lymphoid tissue lymphomas (5.8%). A diagnostic change between referral and expert review occurred in 19.7% of patients, with an estimated impact on patient care for 17.4% of patients. This rate was significantly higher for patients sent with a provisional diagnosis seeking expert second opinion (37.8%) than for patients sent with a formal diagnosis (3.7%). The most frequent discrepancies were misclassifications in lymphoma subtype (41.3%), with 12.3% being misclassifications among small B-cell lymphoma entities. Fewer than 2% of changes were between benign and malignant lymphoid conditions. Minor changes (2.3%) mostly consisted of follicular lymphoma misgrading and diffuse large B-cell lymphoma subtype misclassification. Conclusion To our knowledge, this study provides the largest ever description of the distribution of lymphoma entities in a western country and highlights how expert review significantly contributes to a precise lymphoma diagnosis and optimal clinical management in a proportion of patients.

Incremental Value of 18F-Fluorocholine PET/CT in the Localization of Double Parathyroid Adenomas.

A 73-year-old man displaying primary hyperparathyroidism with severe hypercalcemia (Ca: 4.1 mmol/l, PTH > 600 pmol/l) was referred for preoperative localization of a parathyroid adenoma. Tc-pertechnetate and Tc-sestaMIBI dual tracer scintigraphy displayed a mild focal uptake in the projection of the right thyroid lobe with negative ultrasonography. F-Fluorocholine PET/CT was quickly performed considering this discrepancy and not only confirmed the scintigraphic findings but also revealed a second contralateral focus of increased uptake, both later confirmed by operative consideration (the two other parathyroid glands are considered normal by the surgeon), pathology, and intraoperative parathyroid hormone assessment.

MicroRNA-375/SEC23A as biomarkers of the in vitro efficacy of vandetanib.

In this study, we performed microRNA (miRNA) expression profiling on a large series of sporadic and hereditary forms of medullary thyroid carcinomas (MTC). More than 60 miRNAs were significantly deregulated in tumor vs adjacent non-tumor tissues, partially overlapping with results of previous studies. We focused our attention on the strongest up-regulated miRNA in MTC samples, miR-375, the deregulation of which has been previously observed in a variety of human malignancies including MTC. We identified miR-375 targets by combining gene expression signatures from human MTC (TT) and normal follicular (Nthy-ori 3-1) cell lines transfected with an antagomiR-375 inhibitor or a miR-375 mimic, respectively, and from an in silico analysis of thyroid cell lines of Cancer Cell Line Encyclopedia datasets. This approach identified SEC23A as a bona fide miR-375 target, which we validated by immunoblotting and immunohistochemistry of non-tumor and pathological thyroid tissue. Furthermore, we observed that miR-375 overexpression was associated with decreased cell proliferation and synergistically increased sensitivity to vandetanib, the clinically relevant treatment of metastatic MTC. We found that miR-375 increased PARP cleavage and decreased AKT phosphorylation, affecting both cell proliferation and viability. We confirmed these results through SEC23A direct silencing in combination with vandetanib, highlighting the importance of SEC23A in the miR-375-associated increased sensitivity to vandetanib.Since the combination of increased expression of miR-375 and decreased expression of SEC23A point to sensitivity to vandetanib, we question if the expression levels of miR-375 and SEC23A should be evaluated as an indicator of eligibility for treatment of MTC patients with vandetanib.

Cytopathology of Vitreous Humor Samples in Routine Practice.

OBJECTIVE: To describe findings in vitreous fluid samples in routine cytology practice. STUDY DESIGN: The pathology archives from 1988 to 2008 at our institution were searched for vitreous samples. The slides were reviewed and clinical and follow-up information was obtained. RESULTS: One hundred and eighty-two vitreous fluid samples from 166 patients were analyzed. Most of the samples had been collected for vitreous hemorrhage (75 cases). The second reason for vitreous sample cytological evaluation was an intraocular inflammatory process (55 cases). A specific cause of inflammation was found by combining clinical, microbiological and cytopathological findings in 19 cases, i.e. infection in 7, sarcoidosis in 3, retinal necrosis in 3, lens-induced endophthalmitis in 2, uveitis associated with systemic disease in 2, retrobulbar neuritis in 1 and sympathetic ophthalmia in 1. Among the 19 samples from 16 patients collected to rule out malignancy, 8 had a confirmed intraocular malignancy. Malignant cells were observed in 5 cases (3 lymphomas, 1 melanoma and 1 carcinoma). Undiagnosed malignancies included 2 lymphomas and 1 choroidal melanoma. Other samples were collected during surgery for retinal detachment and cataracts. CONCLUSIONS: In routine practice, cytology of the vitreous fluid is performed in many and varied situations that are most often nonneoplastic. In nonneoplastic cases, cytology is a useful adjunct to vitrectomy, in spite of its limitations.

Tracheobronchial Involvement of Rosai-Dorfman Disease: Case Report and Review of the Literature.

Rosai-Dorfman Disease (RDD) is a rare non-neoplastic entity, also known as sinus histiocytosis with massive lymphadenopathy (SHML), characterized by a benign proliferation of histiocytes in lymph nodes. Localized forms of RDD involving the tracheobronchial tree are very rare. There is no consensus regarding the management of central airway forms and recurrence is frequent. We report the case of an 81-year-old Caucasian woman admitted in 2014 for chronic cough. Her main medical past history included a diagnosis of sinonasal RDD in 1996 with recurrent obstructive rhinosinusitis requiring repeated sinonasal surgery, and a diagnosis of tracheal RDD in 2010 with 2 asymptomatic smooth lesions (5 and 7 mm) on the anterior tracheal wall. Physical examination was normal in 2014. Pulmonary function tests showed an obstructive pattern. Computed tomographic scan revealed a mass arising from the anterior wall of the trachea that projects into the tracheal lumen. Fiberoptic bronchoscopy showed a hypervascular multilobular lesion (2 cm) arising from the anterior tracheal wall and causing 50% obstruction of the tracheal lumen. Mechanical resection with electrocoagulation of the tracheal mass was performed by rigid bronchoscopy with no complication. Histological examination demonstrated tracheal RDD. One year after endotracheal resection, the patient presented no recurrence of cough and the obstructive pattern had resolved. Reports on tracheobronchial involvement are scarce. Symptomatic tracheobronchial obstruction requires mechanical resection by rigid bronchoscopy or surgery. Recurrence is frequent, justifying long-term follow-up.

Long-term results of fractionated stereotactic radiotherapy as third-line treatment in acromegaly.

The treatment of acromegaly is based on surgery, drugs, and radiotherapy as a third-line option. Fractionated stereotactic radiotherapy (FSRT) is a new technique with a need for long-term evaluation. The purpose of the study was to evaluate long-term results of FSRT in acromegaly. Overall, 34 patients [sex ratio 1.12, age 45 (5-65) years] with a pituitary adenoma of 24.5 (9-76) mm including 20 invasive tumors were treated by radiotherapy in fractionated stereotactic conditions delivering 50 gy in 27 sessions. Baseline growth hormone (GH) and IGF1 levels were 18 (±14.5) and 632.6 (±339) µg/L, respectively. Indications of FSRT were failure of surgery and drug treatments (n = 30) or contraindication/refusal of surgery (n = 4). Hormonal control was defined by normal age- and sex-adjusted IGF1. Remission was defined by hormonal control after withdrawal of drugs for a minimum of three consecutive months. Data were analyzed in SPSS software with a significance level at p < 0.05. After a mean follow-up of 152 months, hormonal control was achieved in 33 patients (97 %) with withdrawal of drugs in 13 patients (38.2 %) without any recurrence. Factors found to be significantly associated to remission in a multivariate Cox regression were lower baseline hormone levels (GH and IGF1) and smaller tumor size. Tumor control was achieved in all patients. Acquired hypopituitarism after radiotherapy was the main side effect reported with a rate of 39 %. FSRT seems to be an effective and well tolerated third-line treatment of acromegaly, particularly adapted to macro adenomas treatment.

Parathyroid carcinoma: Diagnostic criteria, classification, evaluation.

Parathyroid carcinoma is a little-known cancer, difficult to diagnose. We focus this short review on the current diagnostic criteria, the classification and the evaluation tools for this cancer based on latest publications.

[A cause of palatal necrosis not to ignore]. / Une cause de nécrose palatine à ne pas méconnaître.

We report a case of pseudotumoral nasal septum and hard palate perforation in a 42-years-old man. The diagnosis retained after differential diagnosis exclusion was necrotic midfacial lesion due to chronic inhalation of cocaine. This condition can mimic vasculitis, primary tumors and granulomatous infections. Differential diagnosis and pathophysiology of this condition will be discussed in this anatomo-clinical case.

Adrenocortical tumors: improving the practice of the Weiss system through virtual microscopy: a National Program of the French Network INCa-COMETE.

The Weiss score is the reference method to distinguish between a benign and a malignant adrenocortical tumor (ACT). A program was initiated to improve the reproducibility of the pathologic diagnosis of ACTs in France through the National INCa-COMETE Network. Twelve pathologists from all Reference Centers of the Network analyzed 50 selected ACTs using a web-based virtual microscopy approach in a blind design, allowing to determine the intraobserver and interobserver reproducibilities of the Weiss system. All ACTs were read twice in random order before and after a coaching meeting organized to harmonize and improve analyses and create an online tutorial. The validity of the virtual approach was first established by comparing the 2 consensuses (virtual and microscopic) obtained for each tumor by 3 pathologists who performed the 2 approaches in a blinded manner. For the "dichotomized Weiss score" (separating malignant ≥3 from benign ≤2 tumors) interobserver reproducibility was "substantial" at the first "virtual" reading (κ = 0.70) and increased at the second "virtual" reading (κ = 0.75). In parallel, 7 of the 9 items of the Weiss system showed improvement. The diagnostic accuracy of the observers as a group, using the modal group score approach, showed an improved sensitivity from 86% to 95% for the diagnosis of malignant ACTs. We show the validity of the virtual microscopy approach and that the program improved the practice of the Weiss system reading and therefore the diagnosis of ACT. This tool can now be extended for other research and/or routine purposes in this rare cancer.

Angiomatoid fibrous histiocytoma: unusual sites and unusual morphology.

Angiomatoid fibrous histiocytoma is a soft tissue neoplasm of low malignant potential, typically occurring in the superficial soft tissues of the extremities in children and young adults. Occurrence outside somatic soft tissues is most uncommon. This report describes eight such cases, involving the lung (three cases), mediastinum (one case), vulva (two cases), retroperitoneum (one case) and ovary (one case), with the latter three locations being hitherto unreported sites of occurrence. Patients had a median age of 48 years, and presented with symptoms related to the mass lesion (five cases) or were incidentally found to harbor a tumor (three cases). Besides the typical histological features such as an outer shell of lymphoid tissue, multinodular aggregates of dendritic-like tumor cells, blood-filled spaces and abundant admixed plasma cells, unusual features were found focally in some cases, including clear cells, rhabdomyoblast-like cells, pulmonary edema-like pattern and tumor cell cords lying in a myxoid stroma. Immunoreactivity for the epithelial membrane antigen, desmin, smooth-muscle actin, CD68 and CD99 was found in 100, 63, 43, 100 and 100% of cases, respectively. Molecular studies provided support for the diagnosis in all seven tested cases-EWS gene translocation in six cases (partner gene being CREB1 in three and ATF1 in two in which information was available) and FUS gene translocation in one case. Comparison of the reported cases of extrasomatic angiomatoid fibrous histiocytoma with their somatic soft tissue counterparts showed a number of differences: higher mean age, slight male predominance (particularly for bone lesions), larger tumors, higher frequency of systemic symptoms, higher recurrence rate, myxoid change being more common and a much higher frequency of EWS/ATF1 gene fusion.

Thyroid gene expression in familial nonautoimmune hyperthyroidism shows common characteristics with hyperfunctioning autonomous adenomas.

CONTEXT: Dominant activating mutations of the TSH receptor are the cause of familial nonautoimmune hyperthyroidism (FNAH) (inherited mutations affecting the whole gland since embryogenesis) and the majority of hyperfunctioning autonomous adenomas (AAs) (somatic mutations affecting only one cell later in the adulthood). OBJECTIVE: The objective of the study was defining the functional and molecular phenotypes of FNAH and comparing them with the ones of AA. DESIGN: Functional phenotypes were determined in vitro and molecular phenotypes by hybridization on microarray slides. PATIENTS: Nine patients with FNAH were investigated, six for functional in vitro study of the tissue and five for gene expression. RESULTS: Iodide metabolism, H(2)O(2), cAMP, and inositol phosphate generation in FNAH slices stimulated or not with TSH were normal. The mitogenic response of cultured FNAH thyrocytes to TSH was normal but more sensitive to the hormone. Gene expression profiles of FNAH and AAs showed that among 474 genes significantly regulated in FNAH, 93% were similarly regulated in AAs. Besides, 783 genes were regulated only in AAs. Bioinformatic analysis pointed out common down-regulations of genes involved in immune response, cell/cell and cell/matrix adhesions, and apoptosis. Pathways up-regulated only in AAs mainly involve diverse biosyntheses. These results are consonant with the larger growth of AAs than FNAH tissues. CONCLUSIONS: Whether hereditary or somatic after birth, activating mutations of the TSH receptor have the same qualitative consequences on the thyroid cell phenotype, but somatic mutations in AAs have a much stronger effect than FNAH mutations. Both are variants of one disease: genetic hyperthyroidism.