PD-L1 Expression in Neoplastic and Immune Cells of Thymic Epithelial Tumors: Correlations with Disease Characteristics and HDAC Expression.

BACKGROUND: Programmed death-ligand 1 (PD-L1) expression in neoplastic and immune cells of the tumor microenvironment determines the efficacy of antitumor immunity, while it can be regulated at the epigenetic level by various factors, including HDACs. In this study, we aim to evaluate the expression patterns of PD-L1 in thymic epithelial tumors (TETs), while we attempt the first correlation analysis between PD-L1 and histone deacetylases (HDACs) expression. METHODS: Immunohistochemistry was used to evaluate the expression of PD-L1 in tumor and immune cells of 91 TETs with SP263 and SP142 antibody clones, as well as the expressions of HDCA1, -2, -3, -4, -5, and -6. RESULTS: The PD-L1 tumor proportion score (TPS) was higher, while the immune cell score (IC-score) was lower in the more aggressive TET subtypes and in more advanced Masaoka-Koga stages. A positive correlation between PD-L1 and HDAC-3, -4, and -5 cytoplasmic expression was identified. CONCLUSIONS: Higher PD-L1 expression in neoplastic cells and lower PD-L1 expression in immune cells of TETs characterizes more aggressive and advanced neoplasms. Correlations between PD-L1 and HDAC expression unravel the impact of epigenetic regulation on the expression of immune checkpoint molecules in TETs, with possible future applications in combined therapeutic targeting.

Searching for Novel Biomarkers in Thymic Epithelial Tumors: Immunohistochemical Evaluation of Hippo Pathway Components in a Cohort of Thymic Epithelial Tumors.

Given the pivotal role of the Hippo pathway in different facets of tumorigenesis, which has been vigorously established in multiple heterogenous malignancies, we attempted to evaluate its potential utility as a prognostic-predictive biomarker in thymic epithelial tumors (TETs). For this purpose, we performed a comprehensive immunohistochemical analysis of four Hippo cascade components (YAP, TAZ, TEAD4 and LATS1) in a sizeable cohort of TETs and attempted to identify possible correlations of their H-score with various clinicopathological parameters. TAZ and TEAD4 displayed both cytoplasmic and nuclear immunoreactivity in almost equal frequency, with their cytoplasmic H-score being strongly associated with more aggressive high-grade tumors (type B3, thymic carcinoma) and more advanced pathological stages. On the other hand, a primarily nuclear staining pattern was encountered in both YAP and LATS1, with the YAP nuclear H-score being higher in more indolent (type A) and earlier stage tumors. Interestingly, none of the four examined factors displayed any statistically significant correlation with patient overall (OS) or disease-free survival (DFS). In summary, our results provide some initial insight into the expression profile of these core Hippo pathway components in thymic neoplasms and point towards some clear associations with tumor characteristics, which are of paramount translational-clinical research with profound implications in therapeutic targeting of this pathway in the context of precision medicine.

Histone Deacetylases (HDACs): Promising Biomarkers and Potential Therapeutic Targets in Thymic Epithelial Tumors.

Histone deacetylases (HDACs) are core epigenetic factors, with pivotal roles in the regulation of various cellular procedures, and their deregulation is a major trait in the acquisition of malignancy properties. In this study we attempt the first comprehensive evaluation of six class I (HDAC1, HDAC2, HDAC3) and II HDACs (HDAC4, HDAC5, HDAC6) expression patterns in thymic epithelial tumors (TETs), with the aim of identifying their possible association with a number of clinicopathological parameters. Our study revealed higher positivity rates and expression levels of class I enzymes compared to class II. Sub-cellular localization and level of staining varied among the six isoforms. HDAC1 was almost exclusively restricted to the nucleus, while HDAC3 demonstrated both nuclear and cytoplasmic reactivity in the majority of examined specimens. HDAC2 expression was higher in more advanced Masaoka-Koga stages, and displayed a positive correlation with dismal prognoses. The three class II HDACs (HDAC4, HDAC5, HDAC6) exhibited similar expression patterns, with predominantly cytoplasmic staining, that was higher in epithelial rich TETs (B3, C) and more advanced tumor stages, while it was also associated with disease recurrence. Our findings could provide useful insights for the effective implementation of HDACs as biomarkers and therapeutic targets for TETs, in the setting of precision medicine.

Primary Thyroid Diffuse Large B-cell Lymphoma in a Child with Hashimoto's Thyroiditis: A Case Report

Primary thyroid lymphoma (PTL) is a rare thyroid gland cancer, with diffuse large B-cell lymphomas (DLBCL) being extremely rare in children and adolescents. Thus, optimal therapy is debatable. We describe a rare case of thyroid DLBCL in an adolescent girl with a history of Hashimoto thyroiditis (HT), the difficulty in diagnosis and the outcome of treatment. A 12-year-old girl with a nine-year history of HT was admitted with a right-sided painless progressive swelling of the neck. Physical examination and imaging including ultrasound (US), computed tomography (CT) and positron emission tomography/CT revealed an enlarged thyroid gland with right side lymphadenopathy and no metastasis. Two fine needle aspirations were done showing suspected lymphoblastic lesions for non-Hodgkin lymphoma without precise diagnosis. US guided core needle biopsy was finally performed confirming the diagnosis of DLBCL. She was treated according to LMB 96-group B protocol with no surgical removal of thyroid. The patient responded very well to treatment and 14 months later there is no evidence of relapse or metastases. PTL is an extremely rare cause of thyroid malignancy in children. However, it should be considered in the differential diagnosis of a thyroid mass in adolescents presenting with a rapidly enlarging neck mass and a history of HT. It is a treatable condition with a good prognosis, even in aggressive histological subtypes, with no need for thyroidectomy.

Predicting lymphoma in Sjögren's syndrome and the pathogenetic role of parotid microenvironment through precise parotid swelling recording.

OBJECTIVE: Parotid swelling (PSW) is a major predictor of non-Hodgkin's lymphoma (NHL) in primary SS (pSS). However, since detailed information on the time of onset and duration of PSW is scarce, this was investigated to verify whether it may lead to further improved prediction. NHL localization was concomitantly studied to evaluate the role of the parotid gland microenvironment in pSS-related lymphomagenesis. METHODS: A multicentre study was conducted among patients with pSS who developed B cell NHL during follow-up and matched controls that did not develop NHL. The study focused on the history of salivary gland and lachrymal gland swelling, evaluated in detail at different times and for different durations, and on the localization of NHL at onset. RESULTS: PSW was significantly more frequent among the cases: at the time of first referred pSS symptoms before diagnosis, at diagnosis and from pSS diagnosis to NHL. The duration of PSW was evaluated starting from pSS diagnosis, and the NHL risk increased from PSW of 2-12 months to >12 months. NHL was prevalently localized in the parotid glands of the cases. CONCLUSION: A more precise clinical recording of PSW can improve lymphoma prediction in pSS. PSW as a very early symptom is a predictor, and a longer duration of PSW is associated with a higher risk of NHL. Since lymphoma usually localizes in the parotid glands, and not in the other salivary or lachrymal glands, the parotid microenvironment appears to be involved in the whole history of pSS and related lymphomagenesis.

Oxidative imbalance increases the risk for colonic polyp and colorectal cancer development.

BACKGROUND: The role of oxidative stress in the pathogenesis of colorectal carcinoma (CRC) has garnered considerable interest recently. Specific oxidative factors have been implicated in the pathogenesis of adenomatous polyps and ultimately adenocarcinoma. AIM: To evaluate the effect of oxidative imbalance as quantified by specific serological markers in the development of sporadic colon adenocarcinoma. METHODS: A total of 170 patients that underwent endoscopy of the lower gastrointestinal tract in a tertiary center within 3 years were included in the study. They were allocated in three groups; those with sporadic colon adenocarcinoma (n = 56, 32.9%), those with colonic polyps (n = 33, 19.4%) and healthy controls (n = 81, 47.7%). All patients were evaluated for oxidant activity and antioxidant capacity with serum measurements of specific markers such as vitamins A, 25(OH) D3, E, C, B12, folic acid, glutathione, selenium (Se), zinc (Zn), free iron (Fe2+), and malondialdehyde and results were compared between groups. RESULTS: Serum levels of vitamins C, E, D, Se, Zn, vitamin B12 and total antioxidant capacity were significantly lower in the combined neoplasia/polyp group than in the control group (P = 0.002, P = 0.009, P < 0.001, P < 0.001, P < 0.001, P = 0.020 and P < 0.001, correspondingly). Increased levels of vitamin E (P = 0.004), vitamin D (P < 0.001), Se (P < 0.001) and Zn (P < 0.001) seem to bestow a protective effect on the development of CRC. For vitamin D (P < 0.001) and Zn (P = 0.036), this effect seems to extend to the development of colon polyps as well. On the other hand, elevated serum levels of malondialdehyde are associated with a higher risk of CRC (OR = 2.09 compared to controls, P = 0.004). Regarding colonic polyp development, increased concentrations of vitamin Α and Fe2+ are associated with a higher risk, whereas lower levels of malondialdehyde with a lower risk. CONCLUSION: Increased oxidative stress may play an important role in the pathogenesis and progression of CRC. Antioxidants' presence may exert a protective effect in the very early stages of colon carcinogenesis.

Unraveling the Role of Histone Variant CENP-A and Chaperone HJURP Expression in Thymic Epithelial Neoplasms.

Background: Recent advances demonstrate the role of chromatin regulators, including histone variants and histone chaperones, in cancer initiation and progression. Methods: Histone H3K4me3, histone variant centromere protein (CENP-A) and histone chaperones Holliday junction recognition protein (HJURP) as well as DAXX expression were examined immunohistochemically in 95 thymic epithelial tumor (TET) specimens. Our results were compared with the expression profile of DAXX, HJURP and CENP-A in gene expression profiling interactive analysis (GEPIA2). Results: The lymphocyte-poor B3- and C-type TETs were more frequently DAXX negative (p = 0.043). B3 and C-Type TETs showed higher cytoplasmic and nuclear CENP-A (p = 0.007 and p = 0.002) and higher cytoplasmic HJURP H-score (p < 0.001). Higher nuclear CENP-A and cytoplasmic HJURP expression was associated with advanced Masaoka−Koga stage (p = 0.048 and p < 0.001). A positive correlation between HJURP and CENP-A was also observed. The presence of cytoplasmic CENP-A expression was correlated with a favorable overall survival (p = 0.03). CENP-A overexpression in survival analysis of TCGA TETs showed similar results. H3K4me3 expression was not associated with any clinicopathological parameters. Conclusions: Our results suggest a significant interaction between CENP-A and HJURP in TETs. Moreover, we confirmed the presence of a cytoplasmic CENP-A immunolocalization, suggesting also a possible favorable prognostic value of this specific immunostaining pattern.

Ephrin Receptors (Ephs) Expression in Thymic Epithelial Tumors: Prognostic Implications and Future Therapeutic Approaches.

Ephrin receptors (Ephs) are receptor tyrosine kinases (RTKs) implicated in tissue development and homeostasis, and they are aberrantly expressed in tumors. Here, immunohistochemical Eph type-A and -B expression in thymic epithelial tumors (TETs) was assessed and correlated with clinicopathological parameters. Tissue microarrays from 98 TETs were stained for EphA1, -A2, -A4 -A6, -B1, -B2, -B4 and -B6. The relationship between neoplastic and lymphoid cell immunoreactivity score (H-score), histopathological parameters (Pearson's test) and survival of 35 patients (Mantel-Cox model) was explored. Epithelial-rich subtypes showed higher EphA6 cytoplasmic H-score (B2/B3, carcinoma) (p < 0.001) and stronger EphA4 H-score (B3, carcinoma) (p = 0.011). The immature T-cells, especially in subtypes AB/B1, had higher EphB6 H-score than carcinoma-associated mature lymphocytes (p < 0.001); carcinomas had higher lymphocytic EphB1 H-score (p = 0.026). Higher lymphocytic and lower epithelial EphB6 H-score correlated with Masaoka stage ≤II (p = 0.043, p = 0.010, respectively). All cases showed variable epithelial and lymphocytic EphA2 expression, but clinicopathological associations were not reached. Our study confirmed that Eph type-A and -B expression in TETs is associated with established prognostic parameters, i.e., tumor subtype and Masaoka stage, although correlation with patient survival was not reached. Such findings suggest involvement of these RTKs in thymic neoplasia, as well as their potential utility as treatment targets.

Bronchocentric granulomatosis in rheumatoid arthritis: case report and literature review.

Bronchocentric granulomatosis (BcG) is characterized by granulomatous destruction of bronchial or bronchiolar walls and adjacent parenchyma, with debris and exudates filling the airway lumen. Approximately 50% of total cases have been associated with asthma and allergic bronchopulmonary aspergillosis, while it has been rarely reported in the context of rheumatoid arthritis (RA). We describe the case of a 69-year-old female RA patient with BcG presenting as a solitary cavitary pulmonary mass. In addition, we conducted a literature review about the clinical and imaging features of BcG in RA patients. A chronically immunosuppressed 69-year-old female patient with a 16-year history of RA presented with constitutional symptoms (low-grade fever, excessive sweating and malaise) and a sizeable cavitary lung lesion. Open lung biopsy was performed and histopathological findings were consistent with the diagnosis of BcG. Other seven cases of BcG have been previously reported in the context of RA, with clinical and laboratory characteristics described in five of them. Overall, pulmonary nodules or masses were the most frequent imaging finding of BcG, while no clear relationship with disease activity or previous treatment modalities could be established. Surgical resection followed by administration of oral steroids was effective for achieving complete remission of symptoms and radiological stability in most cases.

Genetic Variations of VEGFA Gene Are Associated With Infiltration of Adjacent Tissues and the Clinical Outcome of Patients With Nasopharyngeal Carcinoma.

BACKGROUND/AIM: The aim of the present study was to investigate the clinical significance of 7 single nucleotide polymorphisms (SNPs) of vascular endothelial growth factor A (VEGFA), endothelin receptor type A (EDNRA), nibrin (NBS1) and Fas cell surface death receptor (FAS) genes in patients with nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Genomic DNA was extracted from the peripheral blood specimens of 60 patients. Genotyping of 4 VEGFA polymorphisms, namely VEGFA -1154 G/A (rs1570360), -2578 A/C (rs699947), -1498 C/T (rs833061) and +936 C/T (rs3025039), as well as EDNRA SNP p.His323 (rs5333), NBS1 p.E185Q (rs1805794) and FAS -671 A/G (rs1800682) was performed by using Sanger sequencing. RESULTS: The VEGFA +936 CC genotype was more frequent in tumors with bilateral infiltration of pterygoid plates compared to those with ipsilateral (76.9% vs. 69.6%, p=0.008) and no infiltration of pterygoid plates (76.9% vs. 68.8%, p=0.023). VEGFA -2578, VEGFA -1154 and VEGFA +936 were significantly associated with infiltration to the pterygoid processes (p=0.011, p=0.041 and p=0.032, respectively). EDNRA H323H TT genotype was marginally associated with infiltration to the ipsilateral medial pterygoid muscles (p=0.045). A trend towards longer overall survival was observed for VEGFA -2578 CC as compared to AC (HR=0.24, p=0.060). CONCLUSION: The studied VEGFA SNPs seem to be associated with the local extension of the NPC and maybe with the clinical outcome of this patient group.

Coexistence of Hodgkin and Non-Hodgkin Lymphoma; Composite Lymphoma [CL] in a Patient Presenting with Waxing and Waning Lymphadenopathy.

BACKGROUND: The coexistence of two or more types of lymphoma within the same organ at the same time of diagnosis is defined as composite lymphoma, a rare disease that has recently been identified in the literature. Pointedly, the concurrence may be Hodgkin lymphoma with a Non-Hodgkin lymphoma [NHL], either B or T cells, or two different entities of NHLs. Furthermore, this condition has been described concurrently or sequentially. In order for the diagnosis to be established, two or more distinct clones should be proven by morphological and laboratory tests. CASE PRESENTATION: Herein, we cite a seventy-three-year old female patient with low-grade fever, waxing and waning cervical lymphadenopathy, whose biopsy of an axillary lymph node demonstrated the rare coexistence of Hodgkin and NHL, known as composite lymphoma. CONCLUSION: Composite lymphomas pose a particular diagnostic challenge, and currently, there are no agreed standards for treatment.

An HHV-8 Positive HIV Negative Multicentric Castleman's Disease, who Responded well to Rituximab Alone.

BACKGROUND: Multicentric Castleman Disease (MCD) presents with enlarged lymph nodes in multiple regions and systemic inflammatory symptoms, due to the dysregulation of cytokines, most commonly interleukin-6 (IL-6). Human herpes virus-8 (HHV-8) is strongly related to MCD (HHV-8-associated MCD) and is being implicated in cytokine dysregulation in patients, the majority of whom are HIV positive or immunosuppressed. Preferred treatment of HHV-8- associated MCD depends on the presence or not of concurrent Kaposi sarcoma and on whether the patient has life-threatening organ failure or poor performance status thought to be related to HHV- 8-associated MCD. CASE PRESENTATION: Herein, we describe a female patient with HHV-8 positive, HIV negative MCD, who responded well to the administration of rituximab once weekly for four weeks alone for three cycles. CONCLUSION: HHV-8 positive, HIV negative MCD treatment modalities are only anecdotal due to the rarity of this form of MCD. Administration of rituximab alone seems to be beneficial among patients with good performance status and the absence of life-threatening organ failure in cases of HHV-8 positive, HIV negative MCD.

Autoimmune epithelitis beyond the exocrine glands: an unusual case of anti-Ro/La and Scl-70 lymphocytic interstitial pneumonia.

OBJECTIVES: Interstitial lung disease is a life-threatening complication of many systemic autoimmune diseases with diverse clinical and histopathological features. Among them, lymphocytic interstitial pneumonia (LIP) is mainly associated with primary Sjögren's syndrome (pSS). A case of a middle-aged man with LIP, anti-Ro/La, anti-Scl70 autoantibodies and overlapping histopathological features of pSS and systemic sclerosis (SSc) is presented and discussed. METHODS: A 65-year-old man complaining for easy fatigue and dry cough was evaluated. Physical examination revealed bibasilar crackles on auscultation. Imaging tests showed areas of centrilobular nodules with tree-in-bud sign on the medial lobe of the right lung. Pulmonary function tests demonstrated small airways disease. Laboratory evaluation revealed elevated ESR and CRP, ANA titre >1/320, positive Ro52, Ro60 and La autoantibodies but also, weakly positive anti Scl70 autoantibody. RESULTS: Right lobe lung biopsy showed diffuse fibrosis with altered alveolar architecture and diffuse infiltration of alveolar septa by lymphocytes and mast cells. Ectopic germinal centres were disclosed, adjacent to the small bronchi causing lumen obstruction and validated after the demonstration of CD23 expression, specific for follicular dendritic cells. Biopsy of minor salivary glands revealed intense periductal fibrosis with limited round cell infiltrates, not fulfilling the histopathological criteria for pSS. The diagnosis of LIP was established and the patient received corticosteroids with poor response. Subsequently he was treated with rituximab with satisfactory results. CONCLUSIONS: This case with LIP and disease-specific autoantibodies for pSS and SSc teaches the complexity and overlapping nature of both diseases, extending from autoimmune epithelitis with ectopic germinal centres to fibrosis-related SSc. It points out the significance of the affected tissue biopsy, which may uncover the different disease phenotypes. To this end, treatment with anti-CD20, acting at the crossroads of the pathogenetic mechanisms of both diseases may serve as a first choice therapy.

A Case of a Large Cephalic Vein Aneurysm.

Vein aneurysms represent a rare clinical entity with a wide range of clinical symptoms. We present a case of a 67-year-old male who presented with a large, bluish, easily compressible, soft tissue mass in the lateral side of his forearm, which was mildly tender and it had been worsening during the last year. A color duplex ultrasound revealed local venous dilatation of the cephalic vein, measuring 6.3 × 3.2 cm. The patient was operated under local anesthesia and the lesion was removed. Histology showed thinning of the inner and middle layers of the cephalic vein and incipient replacement of the outer layer by acellular fibrous tissue with progressive decrease of elastic, smooth muscle and collagen fibers of the inner and middle layers, compatible with an aneurysm of the cephalic vein. Large cephalic vein aneurysms might cause nerve compression and require surgical removal before permanent neurological defect occurs.

In situ evidence of cellular senescence in Thymic Epithelial Cells (TECs) during human thymic involution.

Cellular senescence, an age-related process in response to damage and stress, also occurs during normal development and adult life. The thymus is a central lymphoepithelial organ of the immune system that exhibits age-related changes termed thymic involution. Since the mechanisms regulating thymic involution are still not well elucidated, we questioned whether cellular senescence is implicated in this process. We demonstrate, for the first time in situ, that cellular senescence occurs during human thymic involution using SenTraGor™, a novel chemical compound that is applicable in archival tissue material, providing thus further insights in thymus histophysiology.

Angiosarcoma of a Thrombosed Arteriovenous Fistula in a Renal Transplant Recipient.

Angiosarcomas developing in nonfunctioning arteriovenous fistulas in renal transplant recipients are quite rare clinical entities with very poor prognosis. Herein we present a 60-year-old male who developed an angiosarcoma in a thrombosed radiocephalic fistula 6 years after renal transplantation. The patient presented with pain and swelling at the site of a previously asymptomatic fistula. The fistula was excised and diagnosis was made by histology. Despite radical surgery with an above-elbow amputation, the patient died of metastatic disease 6 months later.

Genotyping and mRNA profiling reveal actionable molecular targets in biliary tract cancers.

Biliary tract cancer (BTC) represents a heterogeneous disease with dismal outcome. Herein, we examined genotype and angiogenesis features in BTC. We applied genotyping (Sanger, qPCR, 101-gene panel NGS), mRNA relative quantification methods, and ß-catenin immunohistochemistry in 84 FFPE BTC (55 gallbladder [GBC], 14 intrahepatic [ICC], 15 extrahepatic [ECC] carcinomas). We identified 541 mutations in 68 (81%) tumors. Top mutated genes were CTNNB1 (36%); PTEN (33%); TP53 (31%); PIK3R1 (29%); PIK3CA (13%); BRCA2 and KRAS (12%); BRCA1 (11%). Six GBCs were hypermutated [hm] displaying a distinct mutational pattern. Mutations in TP53 and PI3K, Wnt and RAS components were prevalent among non-hypermutated tumors. All hmGBCs carried mutations in BRCA2 and other homologous recombination repair (HRR) genes, in PD1, but not in CTNNB1 and KRAS. None of the pathogenic BRCA2 p.D2723G and BRCA1 p.Q563* and c.5266dupC was present at frequencies expected for germline mutations. We observed copy gains (>6 copies) in EGFR (9% of informative tumors), PRKAR1A (7%), PIK3CA (6%), ERBB2 (5%) and MET (4%). TP53 mutations were prevalent in GBC (P<0.001) and PRKAR1A copy gains in ICC (P=0.007). PTEN was frequently co-mutated with CTNNB1 (P<0.001). Unrelated to CTNNB1 mutations, nuclear ß-catenin was detected in 45% of tumors, among them in 5/6 hmGBC. We observed strong mRNA expression correlation of the two neuropilins (NRP1 and NRP2) with each other (Spearman's rho 0.59) and with the endothelin receptor (NRP2 rho 0.66; NRP2 rho 0.51), and between VEGFA and its receptors (FLT1 rho 0.49; KDR rho 0.45). All PIK3CA mutated tumors expressed endothelin 1 mRNA (P=0.010). Most tumors expressing nuclear ß-catenin were negative for VEGFC (P=0.009) and FLT4 (P=0.002) mRNA expression. In conclusion, we confirmed the presence of known genomic aberrations in BTC and different genotypes between BTC subsets. Novel findings are the coexistence of PI3K and WNT pathway gene alterations in BTC, their association with angiogenesis, and the hypermutated GBCs with HRR gene mutations, all of which may be considered for new treatment options in this difficult to treat disease.

Prevalent somatic BRCA1 mutations shape clinically relevant genomic patterns of nasopharyngeal carcinoma in Southeast Europe.

Genomic patterns of nasopharyngeal carcinomas (NPCs) have as yet been studied in Southeast Asian (SEA) patients. Here, we investigated genomic patterns of locally advanced NPC Southeast European (SEE) patients treated with chemoradiotherapy. We examined 126 tumors (89% EBV positive) from Greek and Romanian NPC patients with massively parallel sequencing. Paired tumor-cell-rich (TC) and infiltrating-lymphocyte-rich (TILs) samples were available in 19 and paired tumor-germline samples in 68 cases. Top mutated genes were BRCA1 (54% of all tumors); BRCA2 (29%); TP53 (22%); KRAS (18%). Based on the presence and number of mutations and mutated genes, NPC were classified as stable (no mutations, n = 27); unstable (>7 genes with multiple mutations, all BRCA1 positive, n = 21); and of intermediate stability (1-7 singly mutated genes, n = 78). BRCA1 p.Q563* was present in 59 tumors (48%), more frequently from Romanian patients (p < 0.001). No pathogenic germline mutations were identified. NPC exhibited APOBEC3A/B and nucleotide-excision-repair-related mutational signatures. As compared to TC, TILs demonstrated few shared and a higher number of low frequency private mutations (p < 0.001). In multivariate analysis models for progression-free survival, EBV positivity was a favorable prognosticator in stable tumors; BRCA1 mutations were unfavorable only in tumors of intermediate stability. In conclusion, other than described for SEA NPC, somatic BRCA1 mutations were common in SEE NPC; these were shared between TC and TILs, and appeared to affect patient outcome according to tumor genomic stability status. Along with the identified mutational signatures, these novel data may be helpful for designing new treatments for locally advanced NPC.