Metastatic or locally advanced mediastinal neuroendocrine tumours: outcome with 177Lu-DOTATATE-based peptide receptor radionuclide therapy and assessment of prognostic factors.

BACKGROUND: Primary neuroendocrine tumours (NETs) of mediastinum are unusual tumours with aggressive biological behaviour with limited treatment options and guarded prognosis. METHODS: Twenty-seven patients with histopathologically and radiologically proven metastatic or advanced mediastinal NET, who had undergone 177Lu-DOTATATE PRRT, were included in this retrospective analysis. Descriptive statistics was employed to calculate the cumulative overall survival (OS) and progression-free survival (PFS), determining correlation and strength of correlation between different variables with OS and PFS and finally, predictors of outcome (OS and PFS). RESULTS: In all 27 patients enrolled and analyzed, complete symptomatic response was observed in 10 patients (37%), partial response in seven patients (25.9%), symptomatically stable disease in four patients (14.8%), and symptoms progressed or worsened in six patients (22.2%). Metabolic response evaluation demonstrated complete metabolic response in one patient (3.7%), partial metabolic response was seen in nine patients (33.3%), metabolically stable disease was seen in five patients (18.5%), and 12 patients (44.4%) showed metabolic disease progression. None of the patients achieved complete anatomical/morphological response, six (22.2%) showed partial response, seven (25.9%) showed stable disease, and in 14 patients (51.9%), there was morphological disease progression. At the time of analysis, 10 patients (37%) succumbed to the disease. The median PFS was 36 months and the median OS was 66 months. Bivariate analysis showed significant level of association of PFS with surgical intervention, higher cumulative PRRT dose, metabolic response, smaller sized primary lesion, and low lesional FDG uptake. With regard to OS, higher cumulative PRRT dose, low FDG uptake and longer PFS showed significant association. CONCLUSION: Previous surgical intervention (including debulking surgery with R1 resection), higher cumulative dose of PRRT, and low FDG uptake of the tumour are associated with prolonged OS and PFS in patients with metastatic or advanced mediastinal NETs and were independent favourable prognostic markers.

Positron Emission Tomography/Computed Tomography Assessment After Immunochemotherapy and Irradiation Using the Lugano Classification Criteria in the IELSG-26 Study of Primary Mediastinal B-Cell Lymphoma.

PURPOSE: To assess the predictive value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) for disease recurrence after immunochemotherapy (R-CHT) and mediastinal irradiation (RT), using the recently published criteria of the Lugano classification to predict outcomes for patients with primary mediastinal large B-cell lymphoma. METHODS AND MATERIALS: Among 125 patients prospectively enrolled in the IELSG-26 study, 88 were eligible for central review of PET/CT scans after completion of RT. Responses were evaluated using the 5-point Deauville scale at the end of induction R-CHT and after consolidation RT. According to the Lugano classification, a complete metabolic response (CMR) was defined by a Deauville score (DS) ≤3. RESULTS: The CMR (DS1, -2, or -3) rate increased from 74% (65 patients) after R-CHT to 89% (78 patients) after consolidation RT. Among the 10 patients (11%) with persistently positive scans, the residual uptake after RT was slightly higher than the liver uptake in 6 patients (DS4; 7%) and markedly higher in 4 patients (DS5; 4%): these patients had a significantly poorer 5-year progression-free survival and overall survival. At a median follow-up of 60 months (range, 35-107 months), no patients with a CMR after RT have relapsed. Among the 10 patients who did not reach a CMR, 3 of the 4 patients (positive predictive value, 75%) with DS5 after RT had subsequent disease progression (within the RT volume in all cases) and died. All patients with DS4 had good outcomes without recurrence. CONCLUSIONS: All the patients obtaining a CMR defined as DS ≤3 remained progression-free at 5 years, confirming the excellent negative predictive value of the Lugano classification criteria in primary mediastinal large B-cell lymphoma patients. The few patients with DS4 also had an excellent outcome, suggesting that they do not necessarily require additional therapy, because the residual 18F-fluorodeoxyglucose uptake may not reflect persistent lymphoma.

Primary mediastinal seminoma: a comprehensive assessment integrated with histology, immunohistochemistry, and fluorescence in situ hybridization for chromosome 12p abnormalities in 23 cases.

Accurate diagnosis of mediastinal seminoma is critical because of its favorable response to radiation therapy and/or cisplatin-based chemotherapy. Immunohistochemical staining for OCT4 has recently been validated as a powerful tool for detecting gonadal seminoma. However, discrepancies between the genetic alterations and immunoprofiles of mediastinal and testicular seminomas have been reported, raising the question of whether techniques that are useful in the diagnosis of gonadal seminoma are applicable to its mediastinal counterpart. The present study was conducted to evaluate the morphologic and immunohistochemical characteristics and chromosomal abnormalities of 12p in 23 primary mediastinal seminomas and to compare their applicability as diagnostic tools. Dual-color fluorescence in situ hybridization (FISH) analyses for chromosome 12p and immunostains for OCT4, c-kit, placental-like alkaline phosphatase, CD30, and a panel of cytokeratins, including cytokeratin AE1/AE3 (AE1/3), high molecular weight cytokeratin (34betaE12, HMWCK), CAM5.2, cytokeratin 7 (CK7), cytokeratin 20 (CK20), and epithelial membrane antigen were performed. Lymphocytic infiltration was found in all 23 cases (100%). The incidence of other histologic characteristics were as follows: fibrous septa/stroma (21 cases, 91%), prominent tumor cell nucleoli (21 cases, 91%), clear tumor cell cytoplasm (20 cases, 87%), distinct tumor cell borders (20 cases, 87%), granulomatous inflammation (17 cases, 74%), cellular pleomorphism (10 cases, 43%), necrosis (8 cases, 35%), prominent cystic change (2 cases, 8%), intercellular edema (1 case, 4%), and syncytiotrophoblasts (1 case, 4%). The mean mitotic count was 4.4 (range 0 to 16) per 10 high-power fields. Moderate to strong nuclear OCT4 staining was identified in all 23 cases (100%). Seventeen tumors (74%) showed membranous expression of c-kit, with variable staining intensity and percentages. Weakly to moderately intense immunostaining for placental-like alkaline phosphatase was identified in 10 cases (43%) with occasional background staining artifact. The incidences of positive staining were 43% for AE1/3, 39% for HMWCK, 48% for CAM5.2, 39% for CK7, and 9% for epithelial membrane antigen, respectively. In most cases, these epithelial markers highlighted only a small proportion of tumor cells with variable intensities. Immunostaining for CD30 and CK20 was completely negative in all seminomas. Twenty-two seminomas (96%) revealed chromosome 12p abnormalities, including 12p amplification in 20 cases (87%) or i(12p) in 15 cases (65%). Lymphocytic infiltration is the most common histologic feature observed in primary mediastinal seminoma and both OCT4 immunostain and FISH for 12p abnormalities can be very helpful in diagnosing mediastinal seminoma. The intense staining pattern of OCT4 and the high sensitivity of FISH make them superior to other auxiliary diagnostic utilities for detecting seminoma. In addition, the incidences of cytokeratin expression of primary mediastinal seminoma are similar to those of its gonadal counterpart and pathologists must exercise caution in the interpretation of epithelial markers in mediastinal neoplasms.

Expression of hMLH1 and hMSH2 and assessment of microsatellite instability in testicular and mediastinal germ cell tumours.

The aim of this study was to investigate DNA mismatch repair deficiency in male germ cell tumours. We analysed the expression of two mismatch repair proteins, human mutL homologue 1 (hMLH1) and human mutS homologue 2 (hMSH2), and evaluated the frequency of microsatellite instability with 10 mononucleotide and two dinucleotide repeat sequences, in 39 paired tumour/normal DNA samples obtained from 17 testicular and two mediastinal germ cell tumours. In all 19 cases, hMLH1 and hMSH2 both showed nuclear immunolocalization in invasive and testicular in-situ tumours. In non-neoplastic seminiferous tubules, hMLH1 was expressed only in premeiotic germ cells, while hMSH2 was seen in all stages of spermatogenesis. Genetic analysis of dinucleotide markers revealed loss of heterozygosity in one of two testicular yolk sac tumours at D18S58 and an allelic shift at D2S123 in two of three testicular embryonal carcinomas, while none of the 12 seminomas exhibited a genetic abnormality at these loci. No abnormalities were demonstrated with the 10 mononucleotide markers. The two mediastinal germ cell tumours showed no genetic instability or allelic loss with all 12 markers. We suggest that genetic alterations as assessed by microsatellite analysis in germ cell tumours may reflect tissue maturation and phenotypic differentiation rather than tumour progression. In addition, we suggest that hMLH1 and hMSH2 genes may not be implicated in the genesis of germ cell tumours.