Indolent Tumors Research Articles

Abstract 781: DNA methylation patterns between aggressive and indolent prostate tumors from Puerto Rican men

Abstract Background: In 2020, approximately 191,930 new prostate cancer (PCa) cases and 33,330 deaths are estimated in the US only. Hispanic/Latinos (H/L) are the second largest racial/ethnic group in the US. A previous study reported that prostate cancer-specific mortality rate among Puerto Rican men with prostate cancer is higher than ones of non-Hispanic Whites and non-Hispanic Blacks. The aims of this study are to: (1) assess the methylation patterns between aggressive and indolent PCa, (2) to study the methylation status of DNA repair genes between these groups, and (3) to assess the ancestry proportions of the study participants. Variations in methylation patterns will be detected between study groups. Methods: Archived formalin fixed paraffin-embedded (FFPE) prostate tumors (n=24) were collected through the Puerto Rico Biobank. Tumor specimens were classified as aggressive (n=11) and indolent (n=13) cases based on the Gleason scores (6+7(3+4) vs. 7(4+3)+8+9). Tumor areas and adjacent normal tissue were annotated on the H&E slides by a pathologist and extracted by macro-dissection. The Illumina 850K DNA methylation platform was used to measure DNA methylation patterns. The raw data was processed using minfi and normalized. Amount of missing values, histogram of β-values, principal component analysis (PCA) was to assess quality and to detect outliers. Results: A PCA model clearly separated the normal samples from the tumor samples. One of the most significantly differently methylated genes was AOX1. Further comparisons using TCGA PRAD data base revealed the predictable negative correlation between the gene expression and the average β-values. Regarding the PCa aggressiveness, 23 probes were identified as potential candidates using a p<0.001 and a Δβ-value of 0.2 as cut-off. These probes where located in six hypermethylated genes; RREB1, FAM71F2, JMJD1C, COL5A3, RAE1, GABRQ, and eleven hypomethylated; COL9A2, FAM179A, SLC17A2, PDE10A, PLEKHS1, TNNI2, OR51A4, RNF169, SPNS2, ADAMTSL5, and CYP4F12. Of the 179 candidate DNA repair genes. We found two significant differentially methylated DNA repair genes: JMJD1C and RNF169 between groups. The results from the ancestry proportions for African, European, and Indigenous American were: 24.1%, 64.2%, and 9% respectively. Conclusion: The identification of DNA methylation patterns related to PCa in Puerto Rican (PR) H/L men along with specific patterns related to aggressiveness and DNA repair constitutes a pivotal effort on the understanding of PCa disparities in this population. This constitutes a unique effort to provide an overview regarding methylation and ancestry patterns in PR H/L men. Acknowledgements; supported by U54 CA163071 and U54 CA163068-07 Citation Format: Jong Y. Park, Gilberto Ruiz-Deya, Jarline Encarnacion, Juile Dutil, Liang Wang, Carmen Ortiz Sanchez, Ryan Putney, Anders Berglund, Youngchul Kim, Jaime Matta. DNA methylation patterns between aggressive and indolent prostate tumors from Puerto Rican men [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 781.

MANAGEMENT OF ENDOCRINE DISEASE: Papillary thyroid microcarcinoma: toward an active surveillance strategy.

In the last decades, the incidence of thyroid cancer (TC) has more than doubled, but the disease-specific mortality rate was stable. To date, 30-40% of all TC is represented by papillary microcarcinomas (mPTC), an indolent tumor, that probably remained undiagnosed before routine ultrasound use. In 1993, Miyauchi was the first who hypothesized a conservative approach for low-risk mPTC and introduced the concept of active surveillance (AS) in its clinical management. The progression rate of mPTC during AS was low and delaying surgery did not impact the efficacy of treatment or outcome. Since then, several authors from all over the world have reported their experience of AS in mPTCs. As suggested by current guidelines, AS can be considered as an alternative to immediate surgery to avoid overtreatment in low-risk mPTC and may be the strategy to avoid complications from unnecessary surgery. In the last years, AS inclusion criteria have been extended to both bigger tumors and to younger/healthier patients. The adoption of AS should take into consideration not only tumor characteristics but also patient psychological profiles and medical team expertise. Its safety and efficacy have been demonstrated in long-term outcome studies and in other types of tumors; however, skepticism in patients, families and physicians should be overcome by strong recommendations coming from scientific guidelines. This review analyses the several and different experiences of AS and the potential obstacles in implementing it as a routine approach in mPTC patients.

Abstract LB241: Genomic and molecular features of metachronous metastasis in clear cell renal cell carcinoma

Abstract Molecular features associated with risk of metachronous metastases (MM) in clear cell renal cell carcinoma (ccRCC) are poorly defined. Here, we performed systematic genomic and molecular analysis of 192 ccRCC primary tumors with extended clinical follow-up for development of MM. Whole-exome sequencing analysis revealed no association between somatic mutations and development of MM. However, chromosomal deletions at 1p33 were more prevalent in tumors that later progressed with MM. We inferred immune cell infiltrates and found that depletion of regulatory T cells and M1 macrophages were associated with development of MM. Next, we used bulk tumor transcriptome deconvolution to estimate cancer (malignant) and stromal (non-malignant) cell gene expression differences between MM and indolent primary tumors. Downregulation of the Crumbs complex component PATJ (1p31) in cancer cells of MM tumors suggested loss of apicobasal cell polarity as a risk factor in metastatic progression. We also identified downregulation of fatty acid degradation in cancer cells of MM tumors. Overall, our results nominate novel genomic and molecular features underpinning metachronous metastasis in ccRCC. Citation Format: Marjan Mojtabavi Naeini, Neha Rohatgi, Umesh Ghoshdastider, Ari A. Hakimi, Anders Jacobsen Skanderup. Genomic and molecular features of metachronous metastasis in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB241.

Abstract 2867: Laboratory analyses of metastatic ER+/Her2- breast cancer treated with fulvestrant plus enzalutamide

Abstract Background: The clinical implications of the androgen receptor (AR), particularly in the context of aromatase inhibitor (AI) refractory metastatic breast cancer (MBC) are unclear. While AR is associated with more indolent primary tumors, high AR relative to ER in primary breast cancer is associated with endocrine resistance, and in the absence of estradiol or low or blocked ER, AR can exert a pro-survival signal. In a phase II trial of fulvestrant plus enzalutamide in ER+/Her2- MBC we analyzed serial biopsies pre- and post-treatment Methods: Eligible patients were women with ECOG 0-2, ER+/Her2- MBC. Fulvestrant 500 mg IM days 1, 15, 29 and every 4 weeks thereafter and Enzalutamide at 160 mg po daily on a continual basis were administered. Biopsies were required at study entry and at ~4 weeks on therapy. The clinical benefit rate at 24 weeks (CBR24) was the primary endpoint for efficacy. We performed mutational analysis to detect mutations including ESR1 exon 8 mutations.We examined estrogen, progesterone, androgen and glucocorticoid receptors, multiplex analysis of immune cells and PD-L1, and performed reverse phase protein array (RPPA) based protein pathway activation analysis of over 150 proteins/phosphoprotein drug targets from LCM-enriched tumor epithelium in baseline and post-treatment metastatic biopsies. Comparisons of PFS Responders (PFS longer than or equal to 24 weeks) and PFS Non-Responders (PFS shorter than or equal to 5 weeks) were performed using moderated t-tests on log2 transformed data. Results: 32 were eligible and median age was 61 years (46-87); PS 1 (0-1); a median of 2 prior chemotherapy and 2 prior hormonal therapies for metastatic disease (including 7 with prior Fulvestrant) and 90% had visceral disease. ESR1 mutant metastases had higher levels of ER and PR than those with wild type ESR1 (p<0.05). In a paired t test, ER and Ki67 decreased (p<0.05) with treatment. RPPA analysis of the baseline biopsy sample indicated activation of mTOR pathway proteins associated with non-response, while phosphorylated RB, EGFR and IRS1 were associated with response (PFS greater than 24 weeks). ESR1 mutation positive metastases had significantly more T helper cells, T regulatory cells and macrophages than those with wild type ESR1.PD-L1 increased with treatment in all patients by paired t test (p<0.03). Conclusions: Clinical benefit lasting 6-12 months was observed in 23% of patients. Our studies show important differences in hormone receptor expression and immune infiltrates in ESR1 mutated disease. RPPA based pathway activation mapping showed that mTOR pathway activation was associated with shorter PFS (p<0.05). Since PD-L1 expression significantly increased with treatment, we conclude that mTOR and/or PD-L1 directed therapies could be useful with Fulvestrant and Enzalutamide in patients with MBC refractory to current standard of care treatments Citation Format: Jennifer K. Richer, Nicole S. Spoelstra, Alyse Winchester, Julia Wulfkuhle, Sharon B. Sams, Gregory Vidal, Peter Kabos, Jennifer Diamond, Elena Shagisultanova, Anosheh Afghahi, Jose Mayordomo, Tessa McSpadden, Gloria Crawford, Virginia Borges, Dexiang Gao, Emanuel Petricoin, Anthony D. Elias. Laboratory analyses of metastatic ER+/Her2- breast cancer treated with fulvestrant plus enzalutamide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2867.

Diagnostic Value of Galectin-3 in Distinguishing Invasive Encapsulated Carcinoma from Noninvasive Follicular Thyroid Neoplasms with Papillary-Like Nuclear Features (NIFTP).

Simple SummaryThe reclassification of NIFTP raised the need for rebuilding the clinical, histologic, cytological and molecular parameters, including re-evaluation of the previously examined biomarkers, for assisting in the diagnosis of this subset of indolent noninvasive tumors from invasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). In this retrospective study, Galectin-3 (Gal-3) IHC staining on patient’s thyroid tissues showed a statistically significant higher cytoplasmic Gal-3 expression in invasive EFVPTC than in NIFTP and other benign subgroups. Our findings refined the diagnostic value of Gal-3 expression as an ancillary marker in identifying NIFTP among encapsulated follicular variant nodules.Background: non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), which is considered as low-risk cancer, should be distinguished from the malignant invasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). Improved discrimination of NIFTPs from invasive EFVPTCs using a molecular biomarker test could provide useful insights into pre- and post-surgical management of the indeterminate thyroid nodule. Galectin-3 (Gal-3), a β-galactosyl-binding molecule in the lectin group, is involved in different biological functions in well differentiated thyroid carcinomas. The aim of this study was to determine whether Gal-3 expression as a diagnostic marker could distinguish indolent NIFTP from invasive EFVPTC on tissue specimens from surgical thyroid nodules. Methods: immunohistochemical (IHC) analysis of cytoplasmic and nuclear Gal-3 expression was performed in formalin-fixed paraffin-embedded (FFPE) surgical tissues in four specific diagnostic subgroups- benign nodules, NIFTPs, EFVPTCs and lymphocytic/Hashimoto’s thyroiditis (LTs). Results: cytoplasmic Gal-3 expression (mean ± SD) was significantly increased in invasive EFVPTCs (4.80 ± 1.60) compared to NIFTPs (2.75 ± 1.58, p < 0.001) and benign neoplasms (2.09 ± 1.19, p < 0.001) with no significant difference between NIFTPs and benign lesions (p = 0.064). The presence of LT enhanced cytoplasmic Gal-3 expression (3.80 ± 1.32) compared to NIFTPs (p = 0.016) and benign nodules (p < 0.001). Nuclear Gal-3 expression in invasive EFVPTCs (1.84 ± 1.30) was significantly higher than in NIFTPs (1.00 ± 0.72, p = 0.001), but similar to benign nodules (1.44 ± 1.77, p = 0.215), thereby obviating its potential clinical application. Conclusions: our observations have indicated that increased cytoplasmic Gal-3 expression shows diagnostic potential in distinguishing NIFTP among encapsulated follicular variant nodules thereby serving as a possible ancillary test to H&E histopathological diagnostic criteria when LT interference is absent, to assist in the detection of the invasive EFVPTC among such nodules.

It's all in the name: Does nomenclature for indolent prostate cancer impact management and anxiety?

Despite consensus guidelines, many men with low-grade prostate cancer are not managed with active surveillance. Patient perception of the nomenclature used to describe low-grade prostate cancers may partly explain this discrepancy. A randomized online survey was administered to men without a history of prostate cancer, presenting a hypothetical clinical scenario in which they are given a new diagnosis of low-grade prostate cancer. The authors determined whether diagnosis nomenclature was associated with management preference and diagnosis-related anxiety using ratings given on a scale from 1 to 100, adjusting for participant characteristics through multivariable linear regression. The survey was completed by 718 men. Compared with Gleason 6 out of 10 prostate cancer, the term grade group 1 out of 5 prostate cancer was associated with lower preference for immediate treatment versus active surveillance (β = -9.3; 95% CI, -14.4, -4.2; P < .001), lower diagnosis-related anxiety (β = -8.3; 95% CI, -12.8, -3.8; P < .001), and lower perceived disease severity (β = -12.3; 95% CI, -16.5, -8.1; P < .001) at the time of initial diagnosis. Differences decreased as participants received more disease-specific education. Indolent lesion of epithelial origin, a suggested alternative term for indolent tumors, was not associated with differences in anxiety or preference for active surveillance. Within a hypothetical clinical scenario, nomenclature for low-grade prostate cancer affects initial perception of the disease and may alter subsequent decision making, including preference for active surveillance. Disease-specific education reduces the differential impact of nomenclature use, reaffirming the importance of comprehensive counseling and clear communication between the clinician and patient.

Adenoid cystic carcinoma. An indolent but aggressive tumour. Part A: from aetiopathogenesis to diagnosis.

SUMMARYAdenoid cystic carcinoma (ACC) is a relatively rare tumour of the minor and major salivary glands. It is uncommon in the parotid gland while it is much more frequent in the submandibular gland and in minor salivary and mucinous glands (oral cavity, oropharynx, and paranasal sinuses). ACC may also arise in secretory glands located in other tissues, such as in the tracheobronchial tree, oesophagus, breast, lungs, prostate, uterine cervix, lachrymal and Bartholin’s glands, and skin. The natural history of ACC is characterised by an indolent growth rate, a relatively low probability of regional lymph node metastases and a high likelihood of haematogenous dissemination. ACC has been traditionally subdivided into three histological groups (cribriform, tubular, and solid) based on solid components of the tumour. Some studies have shown that tumours with a solid growth component have a rapid fatal course, compared to tumours without a solid growth component, but other studies have failed to correlate growth patterns with clinical course. The purpose of this review is to analyse the very large number of studies (sometimes contradictory) on ACC. In this first part, the aetiology, epidemiology, histopathology, clinical behaviour and diagnostic workup are examined.

Hepatic Epithelioid Hemangioendothelioma: A Review of Three Liver Transplant Recipients

Introduction: Hepatic epithelioid hemangioendothelioma (HEHE) is a discrete vascular tumor with an unpredictable natural course. This rare tumor is commonly found incidentally and not too often is mistaken radiologically and histologically for another tumor. No single treatment strategy has yet been established for it, partly due to its variable clinical course, ranging from an indolent tumor with prolonged survival to an aggressive, fatal disease. Case Presentation: Among 1,029 liver transplantation cases performed at our hospital between January 2001 and November 2019, three were done for HEHE. In this study, we present these three cases and review their clinical and histopathologic characteristics. Conclusions: Epithelioid hemangioendothelioma (EHE) of the liver is a low-grade malignant tumor with different presentations, treatment strategies, and outcomes. The histopathologic characteristics of HEHE can hide its vascular nature, thus leading to its confusion with other lesions. This tumor is unique in that its clinical and histopathologic features do not always correlate with its biologic behavior. There are no reliable criteria in predicting the clinical outcome of HEHE, which needs further research.

Intraductal carcinoma of the salivary gland with NCOA4-RET: expanding the morphologic spectrum and an algorithmic diagnostic approach

After the publication of the 2017 World Health Organization Classification of Head and Neck Tumours, there has been increasing interest in the classification of newly categorized intraductal carcinomas. Intraductal carcinoma (IC) is an indolent tumor, typically arising in the parotid gland, with an intact myoepithelial layer and a cystic, papillary, often cribriform architecture. Early studies of IC identified a heterogeneous group of molecular alterations driving neoplasia, and recent studies have defined three primary morphological/immunohistochemical variants, subsequently linking these morphologic variants with defined molecular signatures. Although studies to date have pointed toward distinct molecular alterations after histological classification, this study used a novel approach, focusing primarily on six cases of IC with NCOA4-RET gene rearrangement as determined by next-generation sequencingand describing the spectrum of clinicopathologic findings within that molecularly-defined group, among them a unique association between the NCOA4-RET fusion and hybrid variant IC and the first case of IC arising in association with a pleomorphic adenoma. RET-rearranged IC show histological and immunohistochemical overlap with the more widely recognized secretory carcinoma, including low-grade morphology, a lumen-forming or microcystic growth pattern, and co-expression of S100, SOX10, and mammaglobin, findings undoubtedly leading to misdiagnosis. Typically regarded to have ETV6-NTRK3 fusions, secretory carcinomas may alternatively arise with RET fusions as well. Adding our cohort of six NCOA4-RET fusion-positive IC compared with four cases of secretory carcinoma with ETV6-RET fusions and a single case of fusion-negative IC with salivary duct carcinoma-like genetics, we propose a diagnostic algorithm that integrates histological elements, including atypia and invasiveness, and the likelihood of specific molecular alterations to increase diagnostic accuracy in what can be a very subtle diagnosis with important clinical implications.

Severe Cyclical Hypercortisolism Due to Metastatic Neuroendocrine Cancer Initially Diagnosed as Colon Cancer

Case Description: A 65 year-old male with initial diagnosis of metastatic colon cancer based on liver biopsy presented for evaluation of severe hypercortisolism with 24-hour urinary free cortisol (UFC) of 1184 mcg/day after presenting to his Oncologist in December 2019 requesting evaluation for muscle weakness and weight gain. On re-evaluation in March, his cortisol had dramatically improved with 24-hr UFC of 120 mcg/day and ACTH of 84 pg/mL and had resolved with 24-hr UFC of 32.6 mcg/day by May.A 2 cm pancreatic lesion was noted during cancer staging; a second opinion was obtained on the liver biopsy which was interpreted as metastatic neuroendocrine tumor, possibly of pancreatic origin. The patient was started on FOLFINIRNOX in December 2019. This was transitioned to carboplatin and etoposide after the revised diagnosis and was continued through May with regression of liver lesions on followup imaging. A 68 Ga-DOTATATE PET CT confirmed uptake in the pancreas, retroperitoneal lymph nodes, and thyroid. A thyroid ultrasound was obtained which did not meet FNA criteria.Given the chronologic association between cortisol levels and chemotherapy response we were suspicious for ectopic Cushing’s syndrome due to metastatic neuroendocrine cancer and the patient was followed for recurrence. In September, the patient endorsed leg weakness and hyperglycemia and was found to have a 24-hr UFC of 4731 mcg/day and an 8 am cortisol of 102 mcg/dL.The patient developed severe hypokalemia requiring admission and was restarted on chemotherapy with moderate improvement in cortisol levels and symptoms. Given the degree of cortisol elevation, we recommended bilateral adrenalectomy, for which the patient established care at a more specialized center.Discussion: Ectopic Cushing’s syndrome is an uncommon variety of ACTH-dependent Cushing’s syndrome caused by CRH or ACTH-producing tumors. The more aggressive form is associated with small-cell lung cancer while the chronic form is associated with indolent tumors.Cyclical Cushing’s syndrome is a rare cause of hypercortisolism characterized by cyclical variations in cortisol levels. The pathophysiology of the cyclical variation is unclear. About half of cases are caused by pituitary corticotrophs but up to 26% can be attributed to ectopic ACTH production, typically due to indolent tumors rather than aggressive malignancies.We present a case of cyclical hypercortisolism with an initial diagnosis of colon cancer. On further review, the cyclical hypercortisolism was likely associated with chemotherapy response. Reevaluation of surgical pathology was consistent with metastatic neuroendocrine cancer, the likely source of ectopic ACTH.Our case highlights the importance of maintaining a broad differential when considering cases of cyclical cortisol elevation, including consideration of concurrent chemotherapy for seemingly unrelated malignancies.

Shared B cell but not T cell intratumoral immune repertoire among patients with low grade appendiceal mucinous neoplasms

Abstract Introduction: Low grade mucinous appendiceal neoplasms (LAMNs) are indolent tumors that present with widespread peritoneal metastases. Despite standard of care cytoreductive surgery and heated intraperitoneal chemotherapy (CRS-HIPEC), patients with LAMNs often recur within 1–3 years and respond poorly to chemotherapy. Methods &amp; Results: Histopathologic review identified clusters of lymphocytes associated with epithelial hypercellularity among larger pools of mucin. Utilizing dimer avoidance multiplex-PCR and next generation sequencing, we explored the adaptive immune response in patients with recurrent LAMNs (n=10). Bulk sequencing of tumor tissue following initial CRS-HIPEC revealed a predominant expression of B cell over T cell receptors (mean expression: 0.5% Vα, 1.4% Vβ, 0.01% Vδ, 12.6% IgH, 47.6% Igκ, 37.8% Igλ). Very interestingly, we observed a heightened IgE fraction (8.4%±1.1) in patients with LAMNs, greater than both healthy donor blood (0.57%±0.36, p&amp;lt;0.0001, n=239) and pretreated high-grade tumors (n=66, 3.3%±2.4, p&amp;lt;0.0001). Although the TCR repertoire was extremely private in patients, the BCR repertoire included several shared public and private clones: 11 IgH private CDR3s shared between 2 patients, 64 Igκ public CDR3s shared among &amp;gt;7 patients, 261 private Igκ CDR3s shared among 3 patients, 20 public Igλ CDR3s shared among &amp;gt;7 patients, and 137 private Igλ CDR3s shared between 2 patients, an intriguing and unexpected finding. Conclusions: This, we believe, is the first report of adaptive immunity in low grade mucinous neoplasms that identifies a skewed but diverse infiltration of T and B cells, that warrants study in additional patients.

Clinical characteristics and long-term outcomes for patients who undergo cytoreductive surgery for thoracic meningiomas: a retrospective analysis.

Primary spinal meningiomas represent a rare indolent neoplasm usually situated in the intradural-extramedullary compartment. They have a predilection for afflicting the thoracic spine and most frequently present with sensory and/or motor symptoms. Resection is the first-line treatment for symptomatic tumors, whereas other clinical factors will determine the need for adjuvant therapy. In this study, the authors aimed to elucidate clinical presentation, functional outcomes, and long-term outcomes in this population in order to better equip clinicians with the tools to counsel their patients. This is a retrospective analysis of patients treated at the authors' institution between 1998 and 2018. All patients with thoracic meningiomas who underwent resection and completed at least one follow-up appointment were included. Multiple preoperative clinical variables, hospitalization details, and long-term outcomes were collected for the cohort. Forty-six patients who underwent resection for thoracic meningiomas were included. The average age of the cohort was 59 years, and the median follow-up was 53 months. Persistent sensory and motor symptoms were present in 29 patients (63%). Fifteen lesions were ventrally positioned. There were 43 WHO grade I tumors, 2 WHO grade II tumors, and 1 WHO grade III tumor; the grade III tumor was the only case of recurrence. The median length of hospitalization was 4 days. Seventeen patients (37%) were discharged to rehabilitation facilities. Thirty patients (65.2%) experienced resolution or improvement of symptoms, and there were no deaths within 30 days of surgery. Only 1 patient developed painful kyphosis and was managed medically. Ventral tumor position, new postoperative deficits, and length of stay did not correlate with disposition to a facility. Age, ventral position, blood loss, and increasing WHO grade did not correlate with length of stay. Outcomes are overall favorable for patients who undergo resection of thoracic meningiomas. Symptomatic patients often experience improvement, and patients generally do not require significant future operations. Tumors located ventrally, while anatomically challenging, do not necessarily herald a significantly worse prognosis or limit the extent of resection.

110P Adenoid cystic carcinoma of the breast: A case series of 17 patients and literature review

Adenoid cystic carcinoma (ACC) of the breast is a rare and indolent tumor associated to good prognosis despites its triple-negative status. Due to its paucity, there are no therapeutic consensus or treatment guidelines. Here, we report on 17 patients with ACC of the breast from the database of the Leon Berard cancer center in Lyon. Clinical, histological and molecular features of these carcinomas were characterized. Therapeutic management of patients has been described. Follow-up was done for all patients. Median age was 59 years [22-77] and median follow-up was 3.2 years [0.5-23.9]. Median tumor size was 16mm [8-60]. Only one patient had axillary node metastases. Only 3 tumors were ER or PR positive. All tumors were HER-2 negative. Five patients had a rearrangement of the MYB gene. All patients had initial surgery followed by radiotherapy. Adjuvant chemotherapy was administered to one patient, and 2 patients received adjuvant endocrine therapy. At last follow-up, none of the patients had died from complications of the disease. If ACC are tumors with good prognosis, the occurrence of local relapse or metastases may happen, which requires to maintain long-term follow up. A better understanding of molecular genetic features may help the development of specific therapeutic strategies.

Inflammatory leiomyosarcoma of the head and neck: Case report

Introduction and importancePrimary sarcomas in the head and neck region are rare. Inflammatory leiomyosarcoma was first described in 1995. The case reported herein is the first reported inflammatory leiomyosarcoma occurring in the head and neck.Presentation of caseA 37-year-old male presented with a long history of an asymptomatic slowly enlarging neck mass. Examination revealed a firm mass in the lower third of the right sternocleidomastoid muscle. Computerized tomography and magnetic resonance imaging showed a lobulated, well-circumscribed tumour with malignant features. A wide local excision was performed and histopathological examination confirmed an inflammatory leiomyosarcoma.DiscussionInflammatory leiomyosarcoma is a recently described peculiar soft tissue tumour with histological features overlapping conventional leiomyosarcoma, and dense lymphocytic inflammation and immunohistochemical reactivity for both smooth and skeletal muscle markers. These are indolent tumours and wide local excision is curative.ConclusionThis case highlights the importance of considering primary sarcomas in the differential diagnosis of asymptomatic head and neck masses.

Better Management for Neuroendocrine Neoplasms: A Complex Task Ahead

Neuroendocrine neoplasms (NENs) are rare and indolent tumors characterized by the ability to synthesize, store, and secrete a variety of neuro-amines and peptides which can result in a secretory syndrome [...].

GOECP/SEOR radiotherapy guidelines for thymic epithelial tumours.

Thymic epithelial tumours (TET) are rare, heterogeneous neoplasms that range from resectable indolent tumours to aggressive thymic carcinomas with a strong tendency to metastasize. The pathological diagnosis is complex, in part due to the existence of several different classification systems. The evidence base for the management of TETs is scant and mainly based on non-randomised studies and retrospective series. Consequently, the clinical management of TETs tends to be highly heterogenous, which makes it difficult to improve the evidence level. The role of technological advances in the field of radiotherapy and new systemic therapies in the treatment of TETs has received little attention to date. In the present clinical guidelines, developed by the GOECP/SEOR, we review recent developments in the diagnosis and classification of TETs. We also present a consensus-based therapeutic strategy for each disease stage that takes into consideration the best available evidence. These guidelines focus primarily on the role of radiotherapy, including recent advances, in the management of TETs. The main aim of this document is to promote the standardisation of clinical practice and lay the foundations for future studies to clarify the main unresolved questions related to the optimal management of TET.

Pan-genomic characterization of high-risk pediatric papillary thyroid carcinoma.

Pediatric papillary thyroid carcinomas (pPTCs) are often indolent tumors with excellent long-term outcome, although subsets of cases are clinically troublesome and recur. Although it is generally thought to exhibit similar molecular aberrancies as their counterpart tumors in adults, the pan-genomic landscape of clinically aggressive pPTCs has not been previously described. In this study, five pairs of primary and synchronously metastatic pPTC from patients with high-risk phenotypes were characterized using parallel whole-genome and -transcriptome sequencing. Primary tumors and their metastatic components displayed an exceedingly low number of coding somatic mutations and gross chromosomal alterations overall, with surprisingly few shared mutational events. Two cases exhibited one established gene fusion event each (SQSTM1-NTRK3 and NCOA4-RET) in both primary and metastatic tissues, and one case each was positive for a BRAF V600E mutation and a germline truncating CHEK2 mutation, respectively. One single case was without apparent driver events and was considered as a genetic orphan. Non-coding mutations in cancer-associated regions were generally not present. By expressional analyses, fusion-driven primary and metastatic pPTC clustered separately from the mutation-driven cases and the sole genetic orphan. We conclude that pPTCs are genetically indolent tumors with exceedingly stable genomes. Several mutations found exclusively in the metastatic samples which may represent novel genetic events that drive the metastatic behavior, and the differences in mutational compositions suggest early clonal divergence between primary tumors and metastases. Moreover, an overrepresentation of mutational and expressional dysregulation of immune regulatory pathways was noted among fusion-positive pPTC metastases, suggesting that these tumors might facilitate spread through immune evasive mechanisms.

Outcomes of prostate cancer screening among men using antidiabetic medication

Diabetic men have decreased risk for prostate cancer (PCa) overall and lower PSA compared to non-diabetics. This may affect the outcomes of PSA-based screening. We investigated the effect of PSA-based screening at 4-year intervals on PCa incidence and mortality separately among users and non-users of antidiabetic medication with the hypothesis that screening would detect less low-grade cancer and more high-grade cancer in diabetic men. A cohort of 80,458 men from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) were linked to national prescription database to obtain information on antidiabetic medication purchases. PCa risk and mortality were compared between the FinRSPC screening arm (SA) and the control arm (CA) separately among users and non-users of antidiabetic medication. Among antidiabetic medication users median PSA was lower than in non-users (0.93 and 1.09 ng/ml, respectively, P for difference = 0.001). Screening increased overall PCa incidence compared to CA after the first screen both among medication users and non-users (HR 1.31, 95% CI 1.08–1.60 and HR 1.55, 95% CI 1.44–1.66, respectively). On the second and third screen the difference between SA and CA attenuated only among medication users. Detection of Gleason 6 tumors was lower among medication users, whereas no difference was observed in detection of Gleason 8–10 cancers. Concordantly, screening affected PCa mortality similarly regardless of antidiabetic medication use (HR 0.38, 95% CI 0.14–1.07 and HR 0.19, 95% CI 0.11–0.33 among users and non-users after three screens, respectively. P for difference = 0.18). Median PSA is lower in men using antidiabetic drugs than among non-users. Systematic PSA screening detects less low-risk tumors among medication users, whereas detection of high-risk tumors and mortality effects are similar regardless of medication use. This suggests that antidiabetic medication users may form a suitable target group for PCa screening, with less screening-related overdiagnosis of indolent tumors.

Detection of novel fusion genes by next-generation sequencing-based targeted RNA sequencing analysis in adenoid cystic carcinoma of head and neck

Adenoid cystic carcinoma (AdCC) is a rare, indolent salivary gland tumor that is reported to be driven by fusion genes. However, MYB/MYBL1-NFIB fusions have been detected in <60% of all AdCC cases and the oncogenic driver mutations in approximately 40% of AdCC remain unknown. Our aim was to identify novel gene fusions in AdCC. We investigated 20 AdCC cases using a targeted RNA sequencing panel to identify gene fusions and performed quantitative real-time reverse transcription polymerase chain reaction to assess MYB, MYBL1, and NFIB expression levels. A total of 36 fusion transcripts in 15 cases were detected and validated by Sanger sequencing. The MYB-NFIB and MYBL1-NFIB fusion genes were detected in 9 and 3 cases, respectively, in a mutually exclusive manner. Furthermore, novel gene fusions, namely, NFIB-EPB41L2, MAP7-NFIB, NFIB-MCMDC2, MYBL1-C8orf34, C8orf34-NFIB, and NFIB-CASC20, were identified. Among them, NFIB-EPB41L2 and NFIB-MCMDC2 are thought to activate MYB and MYBL1 expression, respectively, through the insertion of a genomic segment in proximity to MYB and MYBL1 genes, respectively. Six novel gene fusions other than MYB/MYBL1-NFIB were identified. The detection of novel fusion genes and investigation of the molecular mechanism will contribute to the development of novel molecular targeted therapies for this disease.

A novel risk factor panel predicts early recurrence in resected pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PanNETs) are indolent pancreatic tumors derived from neuroendocrine cells in pancreatic islets. To date, reliable predictors for identifying patients at high risk for recurrence after curative cancer resection are lacking. We aimed to determine independent predictors for high-risk PanNETs and patient outcomes after surgery. We analyzed relevant clinicopathological parameters in 319 consecutive patients of derivation cohort 1 and 106 patients of validation cohort 2 who underwent pancreatectomy and were diagnosed with PanNETs. Association of tumor characteristics with recurrence-free survival (RFS) and overall survival (OS) was evaluated using Cox regression. PanNET grade 3 (G3), pancreatic duct dilatation, and perineural invasion were independent prognostic factors for RFS and were significantly associated with early recurrence (within 1.5years) of PanNETs after curative resection (P = 0.019, P < 0.001, and P < 0.001, respectively). Using these factors, we established a novel risk factor panel (R-panel), which predicted early recurrence (P < 0.001, HR = 15.02, 95% CI 5.76-39.19). Predictive accuracy of this R-panel was favorable, with a C-index of 0.853, higher than AJCC TNM staging (0.713). We further built an integrated staging system combining R-panel scoring and TNM staging, which improved predictive probability of TNM staging. Finally, we showed that adjuvant therapy with long-acting somatostatin analogs (SSAs) significantly reduced postoperative recurrence (P < 0.001) and prolonged long-term survival (P = 0.021) in patients with the above risk factors. We identified a novel risk factor panel, which includes PanNET G3, pancreatic duct dilatation, and perineural invasion; this panel predicted early recurrence of PanNETs after curative resection. Patients with these risk factors can benefit from adjuvant therapy with SSAs.