Pancreatic cancer is one of the deadliest malignancies in humans and it is expected to play a bigger part in cancer burden in the years to come. Pancreatic ductal adenocarcinoma (PDAC) represents 85% of all primary pancreatic malignancies. Recently, much attention has been given to PDAC, with significant advances in the understanding of the mechanisms underpinning disease initiation and progression, along with noticeable improvements in overall survival in both localized and metastatic settings. However, given their rarity, rare histological subtypes of pancreatic cancer have been underappreciated and are frequently treated as PDAC, even though they might present non-overlapping molecular alterations and clinical behavior. While some of these rare histological subtypes are true variants of PDAC that should be treated likewise, others represent separate clinicopathological entities, warranting a different therapeutic approach. In this review, we highlight clinical, pathological, and molecular aspects of rare histological types of pancreatic cancer, along with the currently available data to guide treatment decisions.
Should rare subtypes of pancreatic cancer be treated as its most common variant (ductal adenocarcinoma)? The most common type of pancreatic cancer is ductal adenocarcinoma. While much attention has been given to the molecular aspects and treatment aspects of this disease, rare variants of pancreatic cancer have been underappreciated. Some of them present unique molecular features that suggest different treatment approaches could lead to better outcomes. In this review, we summarize information on the clinical, pathological, and molecular features of rare subtypes of pancreatic cancer, along with subtype-specific data on treatment.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor from parafollicular cells that produce calcitonin (Ct). Despite several existing guidelines for the surgical management of sporadic MTC (sMTC), optimal initial surgical management of the thyroid, the central and the lateral neck remains a matter of debate.
METHODS: A systematic review in PubMed and Scopus for current guidelines addressing the surgical management of sMTC and its referenced citations was conducted as per the PRISMA guidelines.
RESULTS: Two-hundred and one articles were identified, of which 7 met the inclusion criteria. Overall, guidelines vary significantly in their recommendations for the surgical management of sMTC. Only one guideline recommended partial thyroidectomy for limited disease, but the possibility to avoid completion thyroidectomy in selected cases is acknowledged in 42% (3/7) of the remaining guidelines. The majority of guidelines (71.4%; 5/7) recommended prophylactic central neck dissection (CND) for all patients while the remaining two guidelines recommended CND based on Ct level and tumor size. The role of prophylactic lateral neck dissection based on preoperative Ct levels was recommended by 42% (3/7) of guidelines. Overall, these guidelines are based on low-quality evidence, mostly single-center retrospective series, some of which are over 20 years old.
CONCLUSIONS: Current surgical management guidelines of sMTC should be revised, and ought to be based on updated data challenging current recommendations, which are based on historic, low-quality evidence. Partial thyroidectomy may become a viable option for small, limited tumors. Prospective, multi-center studies may be useful to conclude whether prophylactic ND is necessary in all sMTC patients.

Papillary thyroid cancer (PTC) and medullary thyroid cancer (MTC) originate from follicular and neuroendocrine parafollicular C cells, respectively. PTC and MTC simultaneously exist in tumors containing both MTC and PTC features in a rare condition known as mixed medullary-follicular thyroid carcinoma (MMFTC). In the present study, a 60-year-old female presented with a small mass on the left side of the neck. Ultrasonography indicated a hyperechoic nodule measuring ~11.9×9.7 mm2 in the left lobe of the thyroid gland. The preoperative calcitonin serum value was elevated and total thyroidectomy and bilateral central compartment lymph node dissection was performed. Histological and immunohistochemical analysis of the tumor demonstrated MMFTC. No metastasis was observed in lymph nodes isolated from the bilateral central compartment. Given the rarity of MMFTC, enhancing understanding and management of such tumors is crucial.

Non-clear cell renal cell carcinoma (nccRCC) is an entity comprised of a heterogeneous constellation of RCC subtypes. Genomic profiling has broadened our understanding of molecular pathogenic mechanisms unique to individual nccRCC subtypes. To date, clinical trials evaluating the use of immunotherapies and targeted therapies have predominantly been conducted in patients with clear cell histology. A comprehensive review of the literature has been undertaken in order to describe molecular pathogenic mechanisms pertaining to each nccRCC subtype, and concisely summarise findings from therapeutic trials conducted in the nccRCC space.

Sporadic or hereditary medullary thyroid carcinoma (MTC) is an uncommon thyroid malignancy arising from calcitonin secreting parafollicular C cells. Interestingly, MTC and calcitonin were distinct entities that were discovered independently yet concurrently, and their association was unknown.
This review aims to present a historical review of the evolution of our understanding of MTC and its tumor marker calcitonin to highlight the prominent individuals that influenced and shaped our knowledge of this uncommon thyroid cancer type up to the dawn of the 21st century. An overview of all published reports of novel research and work summarizing important findings for MTC and calcitonin was carried out.
Surgery remains the cornerstone of treatment for localized MTC. However, several new treatment options are either available or in development for advanced or metastatic MTC, including several novel small molecules targeting oncogenic RET and peptide receptor radionuclide therapy, immunotherapy, radioimmunotherapy, and radiofrequency ablation. In the near future, these novel treatments hold promise for therapy of this very distinct thyroid cancer type.

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor of parafollicular C cells. The majority of MTCs occur sporadically, but about 30% of the cases are associated with multiple endocrine neoplasia type 2 (MEN2) syndrome or familial MTC. Generally, MTCs have no clinical manifestation, but infrequently the patients develop symptoms of hypercortisolism by secreting adrenocorticotropic hormone (ACTH) or corticotropin-releasing hormone (CRH). Although ectopic Cushing syndrome is only found in 0.7% of MTC patients, it can lead to fatal consequences if left untreated. Over 50 cases of MTC-related Cushing syndrome have been reported, and few autopsy cases exist in the literature. In those cases, the tumor cells are positive for calcitonin, but mostly display negative immunostaining for ACTH or CRH. The authors report an autopsy case of a 22-year-old woman who was found dead with no medical history whose cause of death was diabetic ketoacidosis associated with MTC, which showed poor calcitonin stainability.

Schistosomiasis is a major public health problem in sub-Saharan Africa and, in particular, in Cameroon. It is the second parasitic disease endemic after malaria and it is favoured by the coexistence of bioclimatic zones. We report the case of a 6-years old girl presenting with clinical deficit syndrome and medullary infiltration mimicking tumor on medical imaging. Surgery helped to clarify the diagnosis after histopathological examination of the biopsic specimens. The patient had also received a dose of Praziquantel. Regression of symptoms as well as favorable progression of the operative wound facilitated discharge from hospital. The patient was lost to follow-up for three years. Effective management of neuromeningeal bilharziosis should be multidisciplinary.

Mixed medullary and follicular cell-derived thyroid carcinoma (MMFTC) is a rare primary thyroid carcinoma with morphologic and immunophenotypic evidence of admixed parafollicular and follicular cell-derived tumor populations within the same tumor. We herein present the fine-needle aspiration biopsy (FNAB) cytology of a case of MMFTC that was diagnosed histologically and discuss potential clues to the diagnosis for cytologists. We also provide a literature review of this uncommon primary thyroid tumor. The patient was a 47-year-old man with a history of hypothyroidism who presented with ear and neck pain. Imaging demonstrated thyroid nodules with regional lymphadenopathy. FNAB samples of two thyroid nodules and an involved lymph node were diagnosed as papillary thyroid carcinoma (PTC). The subsequent total thyroidectomy specimen demonstrated classic-type PTC which transitioned to a morphologically and immunophenotypically distinct medullary thyroid carcinoma (MTC) component within the same lesion, indicative of MMFTC. The patient experienced recurrence of the medullary component 20 months later and received chemotherapy with subsequent external beam radiation. As in this case, the cytologic diagnosis of MMFTC is almost never made prospectively. Retrospective review of the preoperative FNAB samples showed subtle cytomorphologic features suggestive of MTC in two of three biopsies, an impression confirmed by calcitonin immunohistochemistry on cell block material. In the broader literature, most MMFTCs on FNAB have been diagnosed as MTC, which is usually the more aggressive component of the mixed neoplasm.

The significant variation in the clinical behaviour of sporadic medullary thyroid carcinoma (sMTC) causes uncertainty when planning the management of these patients. Several tumour genetic and epigenetic markers have been described, but their clinical usefulness remains unclear. The aim of this review was to evaluate the evidence for the use of molecular genetic and epigenetic profiles in the risk stratification and management of sMTC.
MEDLINE and Embase databases were searched using the MeSH terms \"medullary carcinoma\", \"epigenetics\", \"molecular genetics\", \"microRNAs\"; and free text terms \"medullary carcinoma\", \"sporadic medullary thyroid cancer\", \"sMTC\", \"RET\", \"RAS\" and \"miR\". Articles containing less than ten subjects, not focussing on sMTC, or not reporting clinical outcomes were excluded. Risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale.
Twenty-three studies met the inclusion criteria, and key findings were summarized in themes according to the genetic and epigenetic markers studied. There is good evidence that somatic RET mutations predict higher rates of lymph node metastasis and persistent disease, and worse survival. There are also several good quality studies demonstrating associations between certain epigenetic markers such as tumour miR-183 and miR-375 expression and higher rates of lymph node and distant metastasis, and worse survival.
There is a growing body of evidence that tumour genetic and epigenetic profiles can be used to risk stratify patients with sMTC. Further research should focus on the clinical applicability of these findings by investigating the possibility of tailoring management to an individual\'s tumour mutation profile.