Endoscopic follow-up of low-grade precancerous bronchial lesions in high-risk patients: long-term results of the SELEPREBB randomised multicentre trial.

BACKGROUND: 3-9% of low-grade preinvasive bronchial lesions progress to cancer. This study assessed the usefulness of an intensive bronchoscopy surveillance strategy in patients with bronchial lesions up to moderate squamous dysplasia. METHODS: SELEPREBB (ClinicalTrials.gov NCT00213603) was a randomised study conducted in 17 French centres. After baseline lung computed tomography (CT) and autofluorescence bronchoscopy (AFB) to exclude lung cancer and bronchial severe squamous dysplasia or carcinoma in situ (CIS), patients were assigned to standard surveillance (arm A) with CT and AFB at 36 months or to intensive surveillance (arm B) with AFB every 6 months. Further long-term data were obtained with a median follow-up of 4.7 years. RESULTS: 364 patients were randomised (A: 180, B: 184). 27 patients developed invasive lung cancer and two developed persistent CIS during the study, with no difference between arms (OR 0.63, 95% CI 0.20-1.96, p=0.42). Mild or moderate dysplasia at baseline bronchoscopy was a significant lung cancer risk factor both at 3 years (8 of 74 patients, OR 6.9, 95% CI 2.5-18.9, p<0.001) and at maximum follow-up (16 of 74 patients, OR 5.9, 95% CI 2.9-12.0, p<0.001). Smoking cessation was significantly associated with clearance of bronchial dysplasia on follow-up (OR 0.12, 95% CI 0.01-0.66, p=0.005) and with a reduced risk of lung cancer at 5 years (OR 0.15, 95% CI 0.003-0.99, p=0.04). CONCLUSION: Patients with mild or moderate dysplasia are at very high risk for lung cancer at 5 years, with smoking cessation significantly reducing the risk. Whereas intensive bronchoscopy surveillance does not improve patient outcomes, the identification of bronchial dysplasia using initial bronchoscopy maybe useful for risk stratification strategies in lung cancer screening programmes.

[Systemic EBV+ T-cell lymphoproliferative disease of childhood]. / Lymphoprolifération systémique T liée à l'EBV chez l'enfant.

Systemic EBV+ T-cell lymphoproliferative disease of childhood is a recent entity described in the 2008 World Health Organisation tumours of haematopoietic system and lymphoid tissues as a clonal T-cell EBV+ systemic proliferation. It occurs after acute or chronic active EBV infection. We report the case of a caucasian, immunocompetent 12-year-old girl, with no particular history, who presented with hemophagocytic lymphohistiocytosis in the aftermath of an infectious mononucleosis. Main symptoms were multiple organ failure, hepatosplenomegaly and pancytopenia. Histopathology of peripheral lymph node and bone marrow revealed a T-cell, CD8+, EBV+ lymphoproliferation. An elevated viral load was detected in blood by PCR. The patient died within 3 weeks. Since most of the cases have been reported in Asia and South America, few cases still have been described in Europe. Unlike B-cell lymphoproliferation in immunocompromised individuals, T-cell EBV+ lymphoproliferation occurs in immunocompetent patients and seems to be the consequence of a proliferative disorder of EBV-infected T-cells, attributed to a cytotoxic T-cell response deficiency. These T-cell proliferations are more frequently immunoreactive for CD8 than CD4. A key feature of the diagnosis might be EBV viral load.

Impact of Lymph Node Dissection on Postoperative Complications of Total Thyroidectomy in Patients with Thyroid Carcinoma.

Background: Lymph node dissection (LND) in primary treatment of differentiated thyroid carcinoma is controversial. The aim of our retrospective study was to analyse the risk factors of post-thyroidectomy complications and to assess the morbidity of lymph node dissection, especially in the central neck compartment, since prophylactic central lymph node dissection has not been proven to bring an overall survival benefit. Methods: We performed a retrospective analysis of postoperative complications from 1547 consecutive patients with differentiated thyroid carcinoma in an academic department of endocrine surgery over a period of 10 years. Results: A total of 535 patients underwent lymph node dissection, whereas the other 1012 did not. The rate of postoperative hypoparathyroidism was higher in patients with LND (17.6% vs. 11.4%, p = 0.001). No significant difference in the rate of permanent hypoparathyroidism (2.4% vs. 1.3%, p = 0.096) was observed between these two groups. A multivariate analysis was performed. Female gender, ipsilateral and bilateral central LND (CLND), parathyroid autotransplantation, and the presence of the parathyroid gland on the resected thyroid were associated with transient hypoparathyroidism. Bilateral CLND and the presence of the parathyroid gland on specimen were associated with permanent hypoparathyroidism. The rate of transient recurrent laryngeal nerve (RLN) injury (15.3% vs. 5.4%, p < 0.001) and permanent RLN injury (6.5% vs. 0.9%, p < 0.001) were higher in the LND group. In multivariate analysis, ipsilateral and bilateral lateral LND (LLND) were the main predictive factors of transient and permanent RLN injury. Bilateral RLN injury (2.6% vs. 0.4%, p < 0.001), chyle leakage (2.4% vs. 0%, p < 0.001), other nerve injuries (2.2% vs. 0%, p < 0.001), and abscess (2.4% vs. 0.5%, p = 0.001) were higher in the patients with LND. Conclusions: The surgical technique and the extent of lymph node dissection during surgery for thyroid carcinoma increase postoperative morbidity. A wider knowledge of lymph-node-dissection-related complications associated with thyroid surgery could help surgeons to carefully evaluate the surgical and medical therapeutic options.

Performance of Endobronchial Ultrasound Elastography in the Differentiation of Malignant and Benign Mediastinal Lymph Nodes: Results in Real-life Practice.

BACKGROUND: Little data exists regarding the performance of elastography in EBUS-TBNA. The aim of the study was to evaluate the elastography score proposed and previously published by Izumo, in particular its capacity to perfectly identify benign lymph node, and to discriminate malignant ones. METHODS: This study included patients undergoing EBUS-TBNA for mediastinal lymph nodes (LN). Before LN needle aspiration, an elastography was performed which allowed a color elastogram to be superimposed on the ultrasound image. Three blinded assessors classified these elastograms into 3 types using the score published by Izumo: type 1 (predominantly not blue), type 2 (partially blue, partially not blue), or type 3 (predominantly blue). These types were then compared with pathology results. RESULTS: A total of 217 LN (114 patients) were analyzed: histologic findings identified 97 benign LN (44.7% of the lymph nodes) and 120 malignant LN (55.3%). There were 44 elastographies (20.2%) that were classified as type 1, 90 elastographies (41.5%) classified as type 2, and 83 elastographies (38.3%) classified as type 3. Considering type 1 as benign and type 3 as malignant, sensitivity, specificity, positive predictive value, and negative predictive value were respectively 87.0%, 68.0% , 80.0% , and 77.0%. Ten (23%) of the 44 lymph nodes with a type 1 elastogram were malignant. CONCLUSION: Elastography does not preclude performing TBNA of the lymph nodes. It does not preclude EBUS-TBNA when a type 1 elastogram pattern is found. All lymph nodes visualized should be sampled by EBUS-TBNA, regardless of elastography pattern.

Large sporadic thyroid medullary carcinomas: predictive factors for lymph node involvement.

Lymph node involvement (LNI) is one of the most important prognostic factors for poor survival in medullary thyroid carcinoma (MTC). At diagnosis, LNI is found in over 50% of sporadic MTCs, and especially in large tumours. Cervical lymph node dissection is therefore mandatory during MTC surgery. However, some large tumours (responsible for high preoperative basal calcitonin levels) are found to lack LNI, and can be cured definitely. Preoperative detection of these particular tumours might spare patients from undergoing extensive cervical dissection. The objective of the present retrospective study of a series of large sporadic MTCs was to identify clinical, biological and pathological factors that were predictive of LNI. Consecutive cases of large, sporadic MTCs (measuring at least 1 cm in diameter) were retrieved and reviewed. The levels of several mature microRNAs (miRs) in paraffin-embedded samples were assessed using qPCR. Of the 54 MTCs, 26 had LNI and 28 were pN0. Relative to pN0 patients, patients with LNI had a significant higher preoperative basal calcitonin level (p = 0.0074) and a greater prevalence of infiltrative margins (p < 0.0001), lymphovascular invasion (p = 0.0004), extrathyroidal extension (p < 0.0001), a higher pT stage (p = 0.0003) and more abundant desmoplastic stroma (p = 0.0006). Tumour expression levels of miR-21 (p = 0.0008) and miR-183 (p = 0.0096) were higher in the LNI group. The abundance of desmoplastic stroma (p = 0.007) and the miR-21 expression level (p = 0.0026) were independent prognostic factors for LNI. The abundance of desmoplastic stroma and high levels of miR-21 expression were strong indicators of LNI, and may thus help the surgeon to choose the extent of cervical lymph node dissection for large, sporadic MTCs with no preoperatively obvious LNI.

Eruption of lymphocyte recovery with atypical lymphocytes mimicking a primary cutaneous T-cell lymphoma: a series of 12 patients.

Eruption of lymphocyte recovery (ELR) may occur during bone marrow aplasia after chemotherapies. We reviewed the clinical and pathologic features of 12 patients (male-female ratio, 7:5; median age, 61 years) with an atypical ELR histologically mimicking a primary cutaneous T-cell lymphoma such as Sézary syndrome or CD30+ T-cell lymphoproliferative disorder. All the patients displayed an erythematous maculopapular eruption on the trunk and the limbs associated with fever. All but one had received a polychemotherapy for an acute myeloid leukemia (n=10) or a urothelial carcinoma (n=1) before the occurrence of the skin eruption. One had an autoimmune lymphoproliferative syndrome causing chronic agranulocytosis requiring granulocyte colony-stimulating factor injection. In all patients, the skin eruption was associated with a slight increase of white blood cell count followed by bone marrow recovery within the next weeks. All skin biopsies showed a dermal perivascular lymphocytic infiltrate containing atypical medium- to large-sized CD3+, CD4+ and CD8+, CD25+, ICOS+, PD1- lymphocytes with a strong CD30 expression in most instances (n=10), suggesting the recruitment of strongly activated T cells in the skin. In 6 patients, a diagnosis of CD30+ lymphoproliferative disorder or Sézary syndrome was proposed or suspected histopathologically, and only the clinical context allowed the diagnosis of ELR with a peculiar presentation with atypical lymphocytes. We describe a series of patients with an unusual form of ELR characterized by the presence of atypical activated T cells in the skin. On a practical ground, pathologists should be aware of this distinctive and misleading presentation.

Coexistence of age-related EBV-associated follicular hyperplasia and large B-cell EBV+ lymphoma of the elderly. Two distinct features of the same T-cell dysfunction related to senescence?

Age-related EBV-associated lymphoproliferative disorders form a new clinicopathological group. Until recently, this group was associated with diffuse large B-cell lymphoma (DLBCL), characterised by an aggressive clinical presentation and a poor prognosis. Recent findings in Western Caucasian patients, however, suggest that this entity covers a wide spectrum of diseases, ranging from reactive follicular hyperplasia (HR) to DLBCL. We report the case of an 85-year-old Caucasian man showing lymphadenopathy and numerous hypodense lesions of the liver. Examination of a lymph node revealed follicular hyperplasia with EBV expression confined to germinal centres. The patient was treated with Rituximab and subsequently, the lesions of the liver were explored. They showed extensive necrosis and a polymorphic large B-cell population with strong EBV expression. This is the first report to describe age-related EBV-associated follicular hyperplasia at one site coexisting with DLBCL at another. This case warrants undertaking further investigations each time a diagnosis of age-related EBV-HR is associated with extranodal lesions.

Type II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations.

Enteropathy-associated T-cell lymphoma (EATL), a rare and aggressive intestinal malignancy of intraepithelial T lymphocytes, comprises two disease variants (EATL-I and EATL-II) differing in clinical characteristics and pathological features. Here we report findings derived from whole-exome sequencing of 15 EATL-II tumour-normal tissue pairs. The tumour suppressor gene SETD2 encoding a non-redundant H3K36-specific trimethyltransferase is altered in 14/15 cases (93%), mainly by loss-of-function mutations and/or loss of the corresponding locus (3p21.31). These alterations consistently correlate with defective H3K36 trimethylation. The JAK/STAT pathway comprises recurrent STAT5B (60%), JAK3 (46%) and SH2B3 (20%) mutations, including a STAT5B V712E activating variant. In addition, frequent mutations in TP53, BRAF and KRAS are observed. Conversely, in EATL-I, no SETD2, STAT5B or JAK3 mutations are found, and H3K36 trimethylation is preserved. This study describes SETD2 inactivation as EATL-II molecular hallmark, supports EATL-I and -II being two distinct entities, and defines potential new targets for therapeutic intervention.

Distinctive Patterns of Transthyretin Amyloid in Salivary Tissue: A Clinicopathologic Study of 92 Patients With Amyloid-containing Minor Salivary Gland Biopsies.

Accurate typing of amyloidosis is still a major issue for pathologists and clinicians. Besides clinical data and immunohistochemistry, the histologic distribution of amyloid could represent a useful tool to prevent typing errors, such as the misdiagnosis of hereditary and senile amyloidosis as light chain-related amyloidosis (AL). Minor salivary gland biopsy (MSGB) is a widely performed procedure for amyloidosis diagnosis and typing. In the largest clinicopathologic series of amyloid-containing MSGB specimens to date, we investigated for the first time whether amyloidosis subtypes can be distinguished according to their pattern of salivary amyloid deposition. The histologic distribution and semiquantification of amyloid within salivary tissue were thoroughly reassessed for each case using Congo red-fluorescence. Clinical data were retrospectively collected. The cohort included 92 patients with amyloid-containing minor salivary gland biopsies. The type of amyloidosis was AL in 51 patients (55.4%), non-V30M mutant ATTR in 10 (10.9%), V30M mutant ATTR in 8 (8.7%), serum amyloid A-derived amyloidosis (AA) in 6 (6.5%), wild-type ATTR in 4 (4.3%), gelsolin in 3 (3.3%), and unclassified in 10 (10.9%). Amyloid was more abundant in AL and AA compared with ATTR amyloidosis, because of more extensive basement membranes and vascular deposits. Conversely, non-V30M mutant ATTR and wt-ATTR were strongly associated with peculiar amyloid nodules located in close contact with salivary excretory ducts, with a specificity of 91.7%. In conclusion, our study suggests for the first time that MSGB, in addition to its high sensitivity for amyloidosis diagnosis, is a simple and effective tool for the recognition of ATTR amyloidosis.

MUC1 expression in papillary thyroid carcinoma is associated with BRAF mutation and lymph node metastasis; the latter is the most important risk factor of relapse.

BACKGROUND: The incidence of papillary thyroid carcinoma (PTC) has increased over the past 30 years in Western countries. PTC is usually associated with a good prognosis, but there is a wide range of aggressiveness, and some patients develop distant metastasis and/or resistance to standard treatment. Early identification of these high-risk tumors is a current challenge for appropriate patient management. MUC1 expression has been studied previously in thyroid cancer, but its prognostic value remains controversial. Here, we correlated MUC1 expression in PTC with clinical and pathological features and with the presence of the BRAF(V600E) mutation. METHODS: We performed a clinical and morphological analysis of 190 thyroid tumors (95 PTCs and 95 adenomas). MUC1 immunohistochemistry was carried out on a tissue microarray using different antibodies. The presence of the BRAF(V600E) mutation was investigated by pyrosequencing. MUC1 mRNA levels were assessed by quantitative reverse transcription polymerase chain reaction on a subset of PTC. RESULTS: MUC1 expression was observed in 49% of PTCs and was found to correlate with the presence of papillary architecture, a stromal lymphoid infiltrate, aggressive histological subtypes, extrathyroidal extension, lymph node metastasis, nuclear pseudoinclusions, lymphovascular invasion, and the presence of the BRAF(V600E) mutation (p<0.0001). MUC1 was abundant in nuclear pseudoinclusions. Multivariate analysis showed a strong association of MUC1 expression with the presence of the BRAF(V600E) mutation and lymph node metastasis (p<0.0001). Lymph node metastasis was the most important risk factor of relapse. CONCLUSIONS: Our study shows an association between MUC1 expression and the presence of the BRAF(V600E) mutation in PTC. Analysis of MUC1 expression could improve the risk stratification of PTCs.

Myocardial involvement in systemic capillary leak syndrome: first demonstration by pathologic findings.

This case vignette relates the unknown association between systemic capillary leak syndrome, namely Clarkson's syndrome, and acute cardiac dysfunction. 'Central extra-corporeal life support (ECLS)' was needed for the management of an intractable cardiogenic shock. The acute cardiac condition completely resolved within few days. Pathology showed diffuse interstitial edema within the myocardium suggestive of cardiac involvement of the disease.

Endoscopic ultrasound guided transbronchial fine needle aspiration: a French Department of Pathology's 4-year experience.

BACKGROUND: Endobronchial ultrasound (EBUS) guided transbronchial needle aspiration (TBNA) is an accurate outpatient procedure used to explore mediastinal lymph nodes for lung cancer staging and unexplained mediastinal masses. AIMS AND METHODS: A retrospective study was conducted over four years on EBUS-TBNA sampled lymph nodes investigated for the staging of lung cancer or unexplained mediastinal lymphadenopathies, first using the conventional method (CM) and then a liquid based cytology (LBC). RESULTS: Of the 628 specimens (355 patients) collected, the overall rate of adequacy was 88% and the diagnosis of malignancy was achieved in 43% of cases. The inadequate rate was 6% with LBC and 21% with CM. A paraffin cytoblock was available in 80% with LBC and 62% with CM. Of the 628 aspirates, 270 (43%) were categorised as negative for malignancy including 26 cases consistent with sarcoidosis, 272 (43%) as malignant, 9 (1.4%) as suspicious for non-small-cell carcinoma and 77 as inadequate samples (12%). Of the 272 cases diagnosed as malignant, 87 (32%) were classified as non-small-cell carcinoma, 106 (39%) as adenocarcinoma, 48 (18%) as squamous cell carcinoma and 20 (7%) as small cell carcinoma. Five lymphomas, four metastatic melanomas and two carcinoids were also diagnosed. CONCLUSIONS: EBUS-TBNA is a reliable method for the staging of lung cancer and for unexplained mediastinal mass exploration. The LBC has a lower rate of inadequate samples, a better yield of cytoblock for immunohistochemistry and a dramatically reduced time requirement for interpretation as compared to CM.

Increased trisomy 12 frequency and a biased IgVH 3-21 gene usage characterize small lymphocytic lymphoma.

Small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL) are considered as similar entity by the WHO classification. We assessed the distribution of the four prognostic cytogenetic markers (deletion 11q23, 13q14, 17p13 and trisomy 12) and VH mutational status in 32 SLL and 119 CLL. Trisomy 12 was most frequent (36% vs 13%, p=0.014) and 13q14 deletion was less frequent (9% vs 44%, p=0.001) in SLL in comparison with CLL. An over representation of VH3-21 gene usage was found in SLL (17% vs 1%, p=0.011). In conclusion, SLL show specific genetic markers that distinguish them from classical CLL.

Results of systematic nodal dissection in typical and atypical carcinoid tumors of the lung.

BACKGROUND: To determine the lymphatic spread frequency and location in patients, who underwent lung resection for carcinoid tumors, associated with systematic nodal dissection. METHODS: From January 1998 to June 2007, 54 patients underwent anatomic lung resection associated with systematic nodal dissection for tumors classified as typical (TC) or atypical carcinoid according to 1999 World Health Organization criteria. The number and location of the resected lymph nodes were specified. All patients were followed up. RESULTS: All patients underwent complete resection (R0) that were anatomic in 32 patients (59.2%), and associated with a bronchoplastic procedure in 22 (40.8%). Low morbidity was related to lymphadenectomy. The mean number of resected lymph nodes was of 18 (range, 7-44) per patient, which pathologic studies demonstrated lymphatic spread in 10 patients (18.5%). In the TC group (n = 42) 2 patients were classified N1 (4.8%) and 4 N2 (9.5%). In the atypical group (n = 12) 2 patients were classified N1 (16.6%) and 2 N2 (16.6%).Five of the 6 N2 patients showed a single skip metastasis not discovered by preoperative evaluation (83.3%).The lymphatic spread was correlated with age < or = 35 years (p = 0.01) and a tumor size > or = 3 cm (p = 0.002).Median follow-up was 57 months. Nine patients with lymphatic spread are disease free and one died from metastatic disease at 52 months. CONCLUSION: Systematic nodal dissection showed a high frequency of unpredictable lymphatic spread, mainly in the TC group. This procedure is mandatory to treat carcinoids in a curative intent.