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The entity known as pituitary carcinoma has been traditionally defined as a tumor of adenohypophysial cells that metastasizes systemically or craniospinally independent of the histological appearance of the lesion. Reported cases of pituitary carcinoma have clinically and histologically resembled their non-metastatic counterparts that were classified as adenomas; the majority of cases were initially diagnosed as adenomas, and with tumor progression and spread, the diagnosis was changed to carcinoma. This classification has been challenged since the definition of malignancy in most organs is not based only on metastatic spread. The extent of local invasion resulting in an inability to completely resect an adenohypophysial tumor can have serious consequences that can cause harm and are therefore not benign. To address this dilemma, it was proposed that pituitary tumors be classified as neuroendocrine tumors. This change in nomenclature is totally appropriate since these tumors are composed of classical neuroendocrine cells; as with other neuroendocrine tumors, they have variable behavior that can be indolent but can involve metastasis. With the new nomenclature, there is no requirement for a distinction between adenomas and carcinomas. Moreover, the WHO/IARC has provided an overarching classification for neuroendocrine neoplasms at all body sites; in this new classification, the term ‘neuroendocrine carcinoma’ is reserved for poorly differentiated high-grade malignancies that are clinically, morphologically and genetically distinct from well-differentiated neuroendocrine tumors. It remains to be determined if there are true pituitary neuroendocrine carcinomas.
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Lipids, Nutrition and Cardiovascular Prevention Clinic of the Montreal Clinical Research Institute, Montreal, Québec, Canada
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Background
This study examined the magnitude of changes and the time required to observe maximal changes in LDL-c, HDL-c, triglycerides (Tg) and non-HDL-c after the introduction of mitotane.
Methods
Retrospective study of 45 patients with adrenocortical carcinoma who were treated at the Centre hospitalier de l’Université de Montréal. Clinical and biochemical data were collected, including lipid profiles before and during the first year of treatment with mitotane.
Results
Among the 45 studied patients, 26 (58%) had a complete lipid profile before the introduction of mitotane and at least 1 lipid profile during the first year of treatment, and 19 patients (42%) had a lipid profile following initiation of the treatment. Among the 26 patients who had lipid profiles before and after the introduction of mitotane, the increase of LDL-c was 2.19 mmol/L (76%) (P< 0.0001), HDL-c was 0.54 mmol/L (35%) (P= 0.0002), Tg was 1.80 mmol/L (129%) (P< 0.0001) and non-HDL-c was 2.73 mmol/L (79%) (P< 0.0001). Between the first and the sixth month of mitotane treatment, peak values (n = 45) of LDL-c and non-HDL-c were reached in 42 patients (93%) and 37 patients (82%), respectively, whereas peak values of HDL-c were reached after 6 months of mitotane treatment in 29 patients (66%). The peak value of Tg was almost equal throughout the first year. The mean peak values of HDL-c, Tg and non-HDL-c showed significant associations with their respective mitotane concentrations (β = 0.352, P= 0.03; β = 0.406, P= 0.02 and β = 0.339, P= 0.05).
Conclusion
The introduction of mitotane produces a clinically significant elevation of lipid parameters (LDL-c, HDL-c, Tg and non-HDL-c) during the first year of treatment.
Medical Oncology, Hematology and Immunotherapy, Cantonal Hospital Baselland, Medical University Clinic, Liestal, Switzerland
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IBCSG, International Breast Cancer Study Group, Bern, Switzerland
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Objective
CR1447, a novel transdermal formulation of 4-hydroxytestosterone, has aromatase-inhibiting and androgen receptor (AR)-modulating properties (IC504.4 nM) with antitumor effects against AR-positive tumor cells in vitro. This trial investigated the efficacy and safety of CR1447 for patients with metastatic estrogen receptor-positive (A) and AR-positive triple-negative breast cancers (B).
Design and methods
(A) included patients with at most one prior endocrine therapy line without progression ≥6 months, whereas (B) included patients with ≤2 prior chemotherapy lines, all displaying advanced signs of disease. The primary endpoint was disease control at week 24 (DC24). The null hypothesis was DC24 ≤30% (A) and ≤15% (B). Thirty-seven patients were recruited (29 in (A) and 8 in (B)); accrual was stopped following an interim analysis demonstrating futility in (A) and slow accrual in (B).
Results
DC24 was attained in 5/21 (95% CI: 8.2–47.2) patients in (A) and none in (B). The median progression-free survival was 5.1 months (95% CI: 2.5–5.6) in (A) and 2.5 months (95% CI: 0.7–2.6) in (B). The median overall survival was 24.6 months (95% CI: 22.9–not applicable) in (A) and 10.8 months (95% CI: 3.3–10.9) in (B). CR1447 had a favorable safety profile without treatment-related grade 3–5 toxicities in (A). Especially no side effects linked to androgenic effects were observed.
Conclusions
Despite this trial being negative, the 24% DC24 rate in a second-line setting, and the prolonged partial response experienced by a patient, indicate activity. Further evaluation of CR1447 in endocrine-sensitive patients or combination trials appears warranted.
Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Center Belgrade, Belgrade, Serbia
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Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Center Belgrade, Belgrade, Serbia
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Pituitary adenomas are benign neoplasms of the pituitary. The most prevalent are prolactinomas and non-functioning pituitary adenomas, followed by growth hormone- and ACTH-secreting adenomas. Most pituitary adenomas seem to be sporadic and their persistent growth is very atypical. No molecular markers predict their behavior. The occurrence of pituitary adenomas and malignancies in the same patient can be either pure coincidence or caused by shared underlying genetic susceptibility involved in tumorigenesis. Detailed family history on cancers/tumors in the first, second and third generation of family members on each side of the family has been reported in a few studies. They found an association of pituitary tumors with positive family history for breast, lung and colorectal cancer. We have reported that in about 50% of patients with pituitary adenomas, an association with positive family history for cancer has been found independent of secretory phenotype (acromegaly, prolactinoma, Cushingʼs disease or non-functioning pituitary adenomas). We also found earlier onset of pituitary tumors (younger age at diagnosis of pituitary tumors) in patients with a strong family history of cancer. In our recent unpublished series of 1300 patients with pituitary adenomas, 6.8% of patients were diagnosed with malignancy. The latency period between the diagnosis of pituitary adenoma and cancer was variable, and in 33% of patients, it was longer than 5 years. Besides the inherited trophic mechanisms (shared underlying genetic variants), the potential influence of shared complex epigenetic influences (environmental and behavioral factors – obesity, smoking, alcohol intake and insulin resistance) is discussed. Further studies are needed to better understand if patients with pituitary adenomas are at increased risk for cancer.
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Summary
Needle tract seeding is a potential, albeit rare, complication following transcutaneous biopsies, leading to the seeding of tumor cells along the path of the needle. Biopsies of adrenal masses are not routinely recommended and are only indicated, after exclusion of pheochromocytoma, when an adrenal metastasis of a primary extra-adrenal cancer is suspected or when pathological confirmation of inoperable adrenocortical cancer (ACC) may impact treatment. Despite guideline recommendations to avoid primary adrenal biopsy, very few needle tract seeding cases have been reported and none were in the context of an ACC. We report the occurrence of needle tract seeding in a patient following adrenal transcutaneous biopsy leading to ACC abdominal wall recurrence.
Learning points
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Needle tract seeding is a rare complication of transcutaneous biopsy. It may increase morbidity and impact overall survival. It has yet to be documented in adrenocortical carcinoma (ACC).
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Adrenal masses can be accurately evaluated for malignancy using a combination of conventional and metabolic imaging, such as CT and fluorodeoxyglucose-PET, obviating the need for biopsies.
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Adrenal mass biopsy is not indicated in ACC unless advanced ACC is diagnosed, and a pathological confirmation would impact management.
Search for other papers by Eleanor Fewings in
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East Anglian Medical Genetics Service, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
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Department of Endocrinology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
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Background
Malignant oncocytic adrenocortical neoplasms (OANs) are rare tumours with a distinctive biological behaviour compared to conventional adrenocortical carcinoma (ACC). The current prognostic systems overestimate the malignant potential of these tumours, and guidance for surveillance and treatment strategies are lacking.
Aim
To evaluate the utility of clinical, pathological and molecular markers in predicting the biological behaviour and outcomes of malignant OANs.
Methods
A retrospective clinicopathological review of 10 histologically confirmed OANs was carried out. Whole exome sequencing (WES) of germline and paired tumour samples was performed for four of the ten OAN cases and compared to WES data from five cases of conventional ACC and data from The Cancer Genome Atlas. We reviewed all the cases of malignant OAN reported in the literature and compared to our case series.
Results
Eight (80%) tumours were classified as malignant, one borderline and one benign (Lin–Weiss–Bisceglia criteria, LWB). The malignant OAN were larger tumours and had higher MIB index and Helsinki scores. Molecular profiling identified a pathogenic germline variant in MSH6 in an individual in the OAN group. The OAN samples had a lower mutation burden compared to the ACC samples. Somatic driver variants were identified in OAN and ACC samples including a pathogenic missense variant in CTNNB1.
Conclusion
In this study, the LWB classification demonstrated sensitivity for the differentiation of benign from malignant OAN. Molecular profiling identified dysregulation in DNA repair and Wnt signalling pathways in both OAN and ACC samples, suggesting a molecular overlap between OAN and conventional ACC.
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Hypoxia, a primary stimulus for angiogenesis, is important for tumour proliferation and survival. The effects of hypoxia on parathyroid tumour cells, which may also be important for parathyroid autotransplantation in patients, are, however, unknown. We, therefore, assessed the effects of hypoxia on gene expression in parathyroid adenoma (PA) cells from patients with primary hyperparathyroidism. Cell suspensions from human PAs were cultured under normoxic or hypoxic conditions and then subjected to cDNA expression analysis. In total, 549 genes were significantly upregulated and 873 significantly downregulated. The most highly upregulated genes (carbonic anhydrase 9 (CA9), Solute carrier family 2A1 (SLC2A1) and hypoxia-inducible lipid droplet-associated protein (HIG2)) had known involvement in hypoxia responses. Dysregulation of oxidative phosphorylation and glycolysis pathway genes were also observed, consistent with data indicating that cells shift metabolic strategy of ATP production in hypoxic conditions and that tumour cells predominantly utilise anaerobic glycolysis for energy production. Proliferation- and angiogenesis-associated genes linked with growth factor signalling, such as mitogen-activated protein kinase kinase 1 (MAP2K1), Jun proto-oncogene (JUN) and ETS proto-oncogene 1 (ETS1), were increased, however, Ras association domain family member 1 (RASSF1), an inhibitor of proliferation was also upregulated, indicating these pathways are unlikely to be biased towards proliferation. Overall, there appeared to be a shift in growth factor signalling pathways from Jak-Stat and Ras signaling to extracellular signal-regulated kinases (ERKs) and hypoxia-inducible factor (HIF)-1α signalling. Thus, our data demonstrate that PAs, under hypoxic conditions, promote the expression of genes known to stimulate angiogenesis, as well as undergoing a metabolic switch.
European NeuroEndocrine Tumours Society (ENETS) Lyon Center of Excellence, Lyon, France
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Institut Multi-Site de Pathologie et Biologie Moléculaire, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
Université de Lyon, Université Claude Bernard Lyon 1, Villeurbanne Cedex, France
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Institut Multi-Site de Pathologie et Biologie Moléculaire, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
Université de Lyon, Université Claude Bernard Lyon 1, Villeurbanne Cedex, France
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Université de Lyon, Université Claude Bernard Lyon 1, Villeurbanne Cedex, France
Fédération d’Endocrinologie, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron Cedex, France
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Université de Lyon, Université Claude Bernard Lyon 1, Villeurbanne Cedex, France
INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, Lyon Cedex 08, France
Fédération d’Endocrinologie, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron Cedex, France
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Université de Lyon, Université Claude Bernard Lyon 1, Villeurbanne Cedex, France
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European NeuroEndocrine Tumours Society (ENETS) Lyon Center of Excellence, Lyon, France
Université de Lyon, Université Claude Bernard Lyon 1, Villeurbanne Cedex, France
INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, Lyon Cedex 08, France
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Summary
We report a case of metastatic pancreatic neuroendocrine carcinoma associated with paraneoplastic Cushing’s syndrome, successively treated with five lines of treatment (platin-etoposide, LV5FU2-dacarbazine, FOLFIRINOX, pembrolizumab, and paclitaxel) and anti-secretory treatment. Circulating-free DNA (cfDNA) was analysed at each morphological evaluation starting from the second-line treatment. cfDNA changes were well correlated with the disease course, and cfDNA may be used as a predictive marker and/or as an early marker of response. In addition, the absolute count of atypical cells was elevated upon disease progression.
Learning points
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cfDNA changes were well correlated with the Cushing’s syndrome course and with the tumour burden changes assessed by laboratory markers and by RECIST criteria.
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cfDNA analysis was used to determine the pharmacogenetic patterns of the present patient.
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An elevated number of atypical circulating cells was noticed upon disease progression.
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Objective
Thyroid cancer can be detected in 5–10% of patients with thyroid nodules. Management may be a challenge if fine-needle aspiration biopsy yields Bethesda III findings. Most of these cases undergo surgery and are ultimately found benign. Our aim was to evaluate whether serum osteopontin can accurately estimate thyroid cancer risk in cases with cytologically Bethesda III thyroid nodules and, thereby, decrease the number of unnecessary surgical interventions.
Design and Methods
We obtained blood samples of cases with repeated cytologically Bethesda III thyroid nodules before surgery, and followed up the pathology results after thyroidectomy. We evaluated serum osteopontin from 36 patients with papillary thyroid cancer and compared them with 40 benign cases.
Results
Serum osteopontin levels in patients with papillary thyroid cancer are significantly higher than in benign cases (mean serum osteopontin: 10.48 ± 3.51 ng/mL vs6.14 ± 2.29 ng/mL, P < 0.001). The area under the receiver operating characteristics curve was 0.851, suggesting that serum osteopontin could have considerable discriminative performance.
Conclusions
In our preliminary study, high serum osteopontin levels can predict the risk of papillary thyroid cancer in thyroid nodules with Bethesda III cytology. Further studies are necessary to confirm these findings.
