Menopausal hormone therapy and risk of biliary tract cancers.

BACKGROUND AND AIMS: Gallbladder cancer (GBC) has a female predominance, whereas the other biliary tract cancers (BTCs) have a male predominance, suggesting that sex hormones may be involved in carcinogenesis. We sought to evaluate the association between menopausal hormone therapy (MHT) and the risk of BTC in women. APPROACH AND RESULTS: This nested case-control study was conducted in the UK Clinical Practice Research Datalink. Cases diagnosed between 1990 and 2017 with incident primary cancers of the gallbladder (GBC), cholangiocarcinoma (CCA), ampulla of Vater (AVC), and mixed type were matched to 5 controls on birth year, diagnosis year, and years in the general practice using incidence density sampling. Conditional logistic regression was used to calculate ORs and 95% CIs for associations between MHT use and BTC type. The sample consisted of 1,682 BTC cases (483 GBC, 870 CCA, 105 AVC, and 224 mixed) and 8,419 matched controls with a mean age of 73 (SD, 11) years. Combined formulations (estrogen-progesterone) were associated with an increased GBC risk (OR, 1.97; 95% CI, 1.08, 3.59). Orally administered MHT was associated with an increased GBC risk (OR, 2.28; 95% CI, 1.24, 4.17). Estrogen-only formulations (OR, 0.59; 95% CI, 0.34, 0.93) and cream or suppository administrations (OR, 0.57; 95% CI, 0.34, 0.95) were associated with decreased CCA risk. The number of prescriptions, dose, duration of use, and time since last use were not associated with GBC or CCA risk. MHT use was not associated with risk of AVC or mixed cancer. CONCLUSIONS: Combination MHT formulations and oral administrations were associated with increased GBC risk, whereas estrogen-only formulations were associated with a lower CCA risk. MHT formulation and administration should be carefully considered when prescribing.

Combined hepatocellular-cholangiocarcinoma: An update on epidemiology, classification, diagnosis and management.

BACKGROUND: Combined hepatocellular-cholangiocarcinoma (CHC) is a rare subtype of primary hepatic malignancies, with variably reported incidence between 0.4%-14.2% of primary liver cancer cases. This study aimed to systematically review the epidemiological, clinicopathological, diagnostic and therapeutic data for this rare entity. DATA SOURCES: We reviewed the literature of diagnostic approach of CHC with special reference to its clinical, molecular and histopathological characteristics. Additional analysis of the recent literature in order to evaluate the results of surgical and systemic treatment of this entity has been accomplished. RESULTS: The median age at CHC's diagnosis appears to be between 50 and 75 years. Evaluation of tumor markers [alpha fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA)] along with imaging patterns provides better opportunities for CHC's preoperative diagnosis. Reported clinicopathologic prognostic parameters possibly correlated with increased tumor recurrence and grimmer survival odds include advanced age, tumor size, nodal and distal metastases, vascular and regional organ invasion, multifocality, decreased capsule formation, stem-cell features verification and increased GGT as well as CA19-9 and CEA levels. In case of inoperable or recurrent disease, combinations of cholangiocarcinoma-directed systemic agents display superior results over sorafenib. Liver-directed methods, such as transarterial chemoembolization (TACE), percutaneous ethanol injection (PEI), hepatic arterial infusion chemotherapy (HAIC), radioembolization and ablative therapies, demonstrate inferior efficacy than in cases of hepatocellular carcinoma (HCC) due to CHC's common hypovascularity. CONCLUSIONS: CHC demonstrates an overlapping clinical and biological pattern between its malignant ingredients. Natural history of the disease seems to be determined by the predominant tumor element. Gold standard for diagnosis is histology of surgical specimens. Regarding therapeutic interventions, major hepatectomy is acknowledged as the cornerstone of treatment whereas minor hepatectomy and liver transplantation may be applied in patients with advanced cirrhosis. Despite all therapeutic attempts, prognosis of CHC remains dismal.

Retrospective study on mixed neuroendocrine non-neuroendocrine neoplasms from five European centres.

BACKGROUND: Mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) is a rare diagnosis, mainly encountered in the gastro-entero-pancreatic tract. There is limited knowledge of its epidemiology, prognosis and biology, and the best management for affected patients is still to be defined. AIM: To investigate clinical-pathological characteristics, treatment modalities and survival outcomes of a retrospective cohort of patients with a diagnosis of MiNEN. METHODS: Consecutive patients with a histologically proven diagnosis of MiNEN were identified at 5 European centres. Patient data were retrospectively collected from medical records. Pathological samples were reviewed to ascertain compliance with the 2017 World Health Organisation definition of MiNEN. Tumour responses to systemic treatment were assessed according to the Response Evaluation Criteria in Solid Tumours 1.1. Kaplan-Meier analysis was applied to estimate survival outcomes. Associations between clinical-pathological characteristics and survival outcomes were explored using Log-rank test for equality of survivors functions (univariate) and Cox-regression analysis (multivariable). RESULTS: Sixty-nine consecutive patients identified; Median age at diagnosis: 64 years. Males: 63.8%. Localised disease (curable): 53.6%. Commonest sites of origin: colon-rectum (43.5%) and oesophagus/oesophagogastric junction (15.9%). The neuroendocrine component was; predominant in 58.6%, poorly differentiated in 86.3%, and large cell in 81.25%, of cases analysed. Most distant metastases analysed (73.4%) were occupied only by a poorly differentiated neuroendocrine component. Ninety-four percent of patients with localised disease underwent curative surgery; 53% also received perioperative treatment, most often in line with protocols for adenocarcinomas from the same sites of origin. Chemotherapy was offered to most patients (68.1%) with advanced disease, and followed protocols for pure neuroendocrine carcinomas or adenocarcinomas in equal proportion. In localised cases, median recurrence free survival (RFS); 14.0 mo (95%CI: 9.2-24.4), and median overall survival (OS): 28.6 mo (95%CI: 18.3-41.1). On univariate analysis, receipt of perioperative treatment (vs surgery alone) did not improve RFS (P = 0.375), or OS (P = 0.240). In advanced cases, median progression free survival (PFS); 5.6 mo (95%CI: 4.4-7.4), and median OS; 9.0 mo (95%CI: 5.2-13.4). On univariate analysis, receipt of palliative active treatment (vs best supportive care) prolonged PFS and OS (both, P < 0.001). CONCLUSION: MiNEN is most commonly driven by a poorly differentiated neuroendocrine component, and has poor prognosis. Advances in its biological understanding are needed to identify effective treatments and improve patient outcomes.

Incidence of composite intestinal adenoma-microcarcinoid in 158 surgically resected polyps and its association with squamous morule.

Composite intestinal adenoma-microcarcinoid (CIAM) is a rare colorectal lesion consisting of adenoma and small well-differentiated neuroendocrine cell clusters at its base. Its incidence is unknown. Benign squamous morule may demonstrate a neuroendocrine phenotype by immunohistochemistry. We investigated the incidence and clinicopathologic features of CIAM in endoscopically unresectable, surgically removed colorectal adenomas and evaluated its association with squamous morule. Archived pathology materials from 158 surgically resected colorectal adenomas were reviewed. 139 (88%) polyps were entirely submitted for microscopic examination. All lymph nodes were negative for adenocarcinoma and neuroendocrine tumor. CIAM was identified in 6 (3.8%) cases. The microcarcinoid (MC) was distributed over a mean of 5.8 mm (range < 1 to 12 mm), and was multifocal in 5 cases. The MC component was positive for synaptophysin in 6, CK5/6 in 4, and ß-catenin in 3 cases. Two of 6 (33.3%) CIAM showed concurrent squamous morule, compared to 4.0% (6 of 152) of adenomas without MC (p < 0.05). At the end of the mean follow-up of 53 months, 4 were free of disease and one patient with previous history of pulmonary large cell neuroendocrine carcinoma (NEC) had a recurrence of NEC. One patient died of an unrelated disease. The incidence of CIAM in surgically removed colorectal adenomas is 3.8%, with an indolent clinical course. Frequent co-expression of CK5/6 and ß-catenin in MC combined with common co-existence of squamous morule in the same polyp suggests shared pathogenesis of MC in CIAM and squamous morule, likely representing altered Wnt/ß-catenin signaling pathway.

A Comparative Review of Mixed Mammary Tumors in Mammals.

Mixed tumors are characterized by the histological identification of two or more cell types. Commonly, a mixture of epithelial and myoepithelial cells is included in abundant stroma, which can consist of myxoid, chondroid or bony matrices. Spontaneously arising mixed tumors are rare lesions in the human breast but are common in human salivary glands and canine mammary glands. Subtle histopathological characteristics and overlapping attributes of malignant lesions with other benign lesions can lead to a diagnostic challenge. Mixed tumors can present as benign or malignant. While malignant mixed tumors are quite rare in the human breast they have a poor prognosis. Benign mixed mammary tumors occur more frequently in female dogs than in humans and are usually associated with a good prognosis. This review will provide a comprehensive overview of mixed mammary tumors, across various mammalian species.

Complex non atypical hyperplasia and the subsequent risk of carcinoma, atypia and hysterectomy during the following 9-14 years.

INTRODUCTION: The aim of this study was to evaluate the long-term risk of developing atypical hyperplasia/endometrial cancer or having a hysterectomy after being diagnosed with complex non-atypical hyperplasia (CH). MATERIAL AND METHOD: A historic cohort study of 114 women diagnosed with CH between January 1st 2000 and December 31st 2005. All patient records and pathologic reports were reviewed with complete follow up on all patients in the national pathologic database until September 1st 2014. Kaplan-Meier analysis was used to determine (1) no hysterectomy and (2) no diagnosis of endometrial cancer or atypia after the CH diagnosis. RESULTS: 15% (n = 17) were diagnosed with endometrial cancer and 7% (n = 8) with atypia, most during the first year (10 cancer, 7 atypia). 9% (8/85) of the remaining women at risk developed cancer or atypia in the follow-up period after one year. By Kaplan-Meier the five-year risk for cancer or atypia was 20% (CI; 14-21). The risk of having undergone hysterectomy within five years was 30% (CI; 22-39). CONCLUSION: The long-term risk of being diagnosed with atypia or cancer after a CH diagnose is not insignificant, when disregarding patients having undergone hysterectomy. More than half the women with atypia or cancer are diagnosed or operated during the first year. This could indicate the presence of concomitant but unidentified cancer or atypia at the time of initial sampling. This study reinforces the importance of follow up or treatment of women with CH - especially, but not only during the first year. KEY MESSAGE: The risk of having a hysterectomy or diagnosed with atypical hyperplasia/cancer endometrie is high after a diagnosis of complex hyperplasia without atypia.

Carcinoma In Situ Involving Sclerosing Adenosis: Seeking the Salient Histological Characteristics to Prevent Overdiagnosis.

Ductal or lobular carcinoma in situ (DCIS/LCIS) can rarely arise from sclerosing adenosis (SA). The combination of cytologically malignant cells and the infiltrative growth pattern may make it challenging to distinguish it from an invasive carcinoma. The authors reviewed 50 consecutive cases of CIS involving SA to seek the salient histologic characteristics in order to prevent overdiagnosis. The features commonly seen with CIS were the lobular configuration at low magnification (94%), uninvolved SA in neighboring tissue (84%), at least focally identifiable myoepithelial cells on H&E-stained sections (76%), separate foci of unequivocal CIS (58%), associated microcalcifications (54%), and hyaline basement membrane surrounding tumor cell nests (48%). The group of DCIS with high nuclear grade showed a tendency to occupy the entire lobule of SA, whereas those with non-high grade were more often partially involving the affected lobule. The presence of adjacent separate foci of CIS was more closely related to the DCIS lesions when compared to those of LCIS. The finding of an SA lobule entirely involved by CIS was signifi-cantly correlated with the presence of an invasive carcinoma; this should thus strongly prompt the pathologist to search for other evidence of invasion. Awareness of these features is an additional, useful tool for reaching a proper diagnosis.

Neuroendocrine, goblet cell and mixed adeno-neuroendocrine tumours of the appendix: updates, clinical applications and the future.

INTRODUCTION: Appendiceal neuroendocrine neoplasms are rare, clinically challenging tumours that are typically incidentally diagnosed, have a poorly understood biology and have controversy surrounding their management. Most are adequately treated with appendectomy, and although distant metastases are rare, the threat of disease dissemination remains and current guidelines possess poor accuracy in terms of selecting patients requiring more extensive surgery, i.e. oncological right-hemicolectomy. Areas covered: In this article, we discuss the presentation and diagnostic work-up of patients with appendiceal neuroendocrine neoplasms, and also examine the evidence base for existing management strategies. We highlight controversies within the management of these tumours, and anticipate avenues for further progress. Although no longer classified as neuroendocrine neoplasms, we also discuss two related forms of tumours with neuroendocrine features - goblet cell cancers and mixed adeno-neuroendocrine carcinomas. Expert commentary: Existing guidelines for the treatment of appendiceal neuroendocrine neoplasms are derived from a limited evidence base and are unable to accurately predict which patients require extensive attempts at surgical disease control. Future advances in the field of improved patient selection for more extensive surgery may be possible with multi-factorial tumour assessment integrating morphological and molecular analyses.

Histopathology of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is currently the sixth most common type of cancer with a high mortality rate and an increasing incidence worldwide. Its etiology is usually linked to environmental, dietary or life-style factors. HCC most commonly arises in a cirrhotic liver but interestingly an increasing proportion of HCCs develop in the non-fibrotic or minimal fibrotic liver and a shift in the underlying etiology can be observed. Although this process is yet to be completely understood, this changing scenario also has impact on the material seen by pathologists, presenting them with new diagnostic dilemmas. Histopathologic criteria for diagnosing classical, progressed HCC are well established and known, but with an increase in detection of small and early HCCs due to routine screening programs, the diagnosis of these small lesions in core needle biopsies poses a difficult challenge. These lesions can be far more difficult to distinguish from one another than progressed HCC, which is usually a clear cut hematoxylin and eosin diagnosis. Furthermore lesions thought to derive from progenitor cells have recently been reclassified in the WHO. This review summarizes recent developments and tries to put new HCC biomarkers in context with the WHOs reclassification. Furthermore it also addresses the group of tumors known as combined hepatocellular-cholangiocellular carcinomas.

Metatypical carcinoma of the head: a review of 312 cases.

BACKGROUND: Metatypical cell carcinoma (MTC) is a quite rare malignancy accounting for 5% of all non melanoma skin cancers, with features of basal cell carcinoma and squamous cell carcinoma. It can be described as coexistence of basal cell carcinoma and squamous cell carcinoma with no transition zone between them. AIM: Our review identified a correlation between gender and MTC affected region. MATERIALS AND METHODS: We performed a retrospective study of 312 consecutive patients, diagnosed for MTC localized on face and scalp. Statistical analysis was made to determinate most affected areas, gender prevalence, average age, presence of ulceration and infiltration and peripheral clearance rate. RESULTS: A relevant difference came out between two genders. χ2 test emphasized a relation between males and the presence of carcinoma on the scalp. In addition a strong correlation between mixed subtype and ulceration was evident. A strong relation between intermediate subtype and positive surgical margin was found; this data could identify a more aggressive behavior of intermediate type. CONCLUSIONS: In our findings an important correlation between sun exposition and this tumor was found. Moreover, due to the difficulties that can occur in preserving the aesthetic subunits in the surgical treatment of these regions, the prevention of this pathology has an important role.

Recurrent differentiated thyroid cancer.

OBJECTIVE: To discuss the risk of recurrence in patients with differentiated thyroid cancer and emphasize the importance of risk-group stratification. METHODS: Common risk factors associated with recurrent thyroid cancer are outlined, and appropriate management strategies are reviewed. RESULTS: The overall prognosis in patients with differentiated thyroid cancer is excellent. Factors associated with recurrent thyroid cancer include extrathyroidal extension of the primary tumor, bulky nodal metastatic lesions, macroscopic local invasion, and aggressive histologic subtypes. The locoregional recurrence and mortality are higher in patients with high-risk thyroid cancers. Patients initially presenting with locally aggressive and advanced thyroid cancer have a higher incidence of recurrent disease in the thyroid bed or nodal metastasis. These patients also have a high incidence of distant metastatic lesions. Locally recurrent thyroid cancer may be seen in more than 25% of patients with aggressive differentiated thyroid cancer. Recurrent disease in the thyroid bed can be a difficult problem to manage because of the proximity of the tumor to the recurrent laryngeal nerve, visceral structures in the central compartment, and occasional involvement of the trachea or larynx. External beam radiation therapy after surgical treatment may be important for better local control in the thyroid bed region, especially in patients with poorly differentiated histologic features. The role of additional radioiodine therapy remains undefined at this stage. CONCLUSION: Management of patients with recurrent thyroid cancer necessitates a true multidisciplinary approach. These patients require close follow-up, with cross-sectional imaging and positron emission tomographic scanning in selected individuals.

Miscellaneous uterine malignant neoplasms detected during hysteroscopic surgery.

STUDY OBJECTIVES: To estimate the incidence of incidental miscellaneous uterine malignant neoplasms other than endometrioid adenocarcinoma detected during routine resectoscopic surgery in women with abnormal uterine bleeding (AUB) and to examine the effect of hysteroscopic surgery on long-term clinical outcome. DESIGN: Prospective cohort study (Canadian Task Force classification II-3). SETTING: University-affiliated teaching hospital. PATIENTS: Women with AUB. INTERVENTION: From January 1, 1990, through December 31, 2008, one of the authors (G.A.V.) and several fellows performed primary hysteroscopic surgery at St. Joseph's Health Care in 3892 women with AUB. Of the 7 with malignant disease, one underwent hysteroscopic partial (n = 1) or complete (n = 6) rollerball electrocoagulation or endomyometrial resection. After diagnosis of uterine cancer, the women were counseled about the disease and management in accord with established clinical practice guidelines. Follow-up with office visits and telephone interviews ranged from 2 to 8 years (median, 6 years). MEASUREMENTS AND MAIN RESULTS: Of the 3892 women, 4 had undiagnosed and 3 had suspected miscellaneous uterine malignant neoplasms including 1 endometrial stromal sarcoma, 2 carcinosarcomas, 2 atypical polypoid adenomyomas of the endometrium, 1 minimal deviation adenocarcinoma of the cervix, and 1 smooth-muscle tumor of uncertain malignant potential. At 2 to 8 years of follow-up, 1 patient died accidentally after 1 year, 1 died of carcinomatosis of either coexisting breast cancer or a carcinosarcoma (postmortem examination was declined) after 1 year, and 5 were alive and well. CONCLUSION: Resectoscopic surgery in women with miscellaneous uterine malignant lesions not adversely affect 5-year survival and long-term prognosis.

The changing epidemiology of paediatric brain tumours: a review from the Hospital for Sick Children.

PURPOSE: This study examines the changing epidemiology of paediatric brain tumours over the past three decades (1980-2008) in a single institution, SickKids, Toronto, Canada. METHODS: We classified 1,866 surgical pathology cases of brain tumours in children under the age of 19 according to the World Health Organization 2007 consensus and analysed them by gender, histological tumour type, age distribution and decade. RESULTS: Males showed a slightly higher predominance with 56.8% of cases overall. The main histological tumour types were low-grade (I/II) astrocytomas (26.4%), medulloblastoma (10.6%), anaplastic astrocytoma/glioblastoma multiforme (7.1%) and ependymoma (7.0%). Over three decades, an increasing proportion of certain tumour types, including pilocytic astrocytoma, atypical teratoma/rhabdoid tumours and neuronal/mixed neuronal-glial tumours was seen. CONCLUSIONS: Our results are consistent with those published with similar methodologies in other countries. Any changes in the epidemiology of childhood central nervous system tumours over the past three decades may be attributed in part to changing classification systems, improved imaging technologies and developments in epilepsy surgery; however, continued surveillance remains important.

Mixed epithelial and stromal tumour (MEST) of the kidney: report of 14 cases with male and PEComatous variants and proposed histopathogenesis.

AIMS: This article adds new cases and variants of MEST with discussion of the histopathogenesis. METHODS AND RESULTS: Fourteen MEST were originally diagnosed as cystic nephroma which represents an incidence of 1.6% of renal neoplasms in adults. In females, the stromal component showed areas of müllerian differentiation with positive immunoreactivity for oestrogen (ER) and progesterone receptors (PR) and CD10. Immunoreactivity for HMB45 was identified in a single case having a leiomyomatous appearance. The epithelial component displayed features of müllerian epithelium and reactive renal tubular cells. In two male cases, MEST consisted of fibrous and smooth muscle stroma and cysts lined only by reactive renal tubular cells. Immunoreactivity for ER and PR was focal and weak. CONCLUSIONS: MEST represents a tumour developing from müllerian-like stromal cells in the kidney. The neoplastic stroma encroaches on the renal tubules and has the potential to stimulate the growth of the renal tubules by contact, with development into cysts. Furthermore, the müllerian stroma likely induces the renal tubules to differentiate into müllerian-like epithelium. Melanocytic differentiation of the stroma may occur which represents the PEComatous variant. MESTs in males were histopathologically slightly different from those in females due to the different hormonal milieu.

The evolution of the diagnosis and understanding of primitive and embryonic neoplasms in children: living through an epoch.

Approximately 30% of malignant neoplasms in children are dysontogenetic tumors whose pathologic features resemble or recapitulate those of the developing organ or tissue of origin. Archetypes include classic neuroblastoma, Wilms' tumor, and embryonal rhabdomyosarcoma. This review traces the history of the principal types of dysontogenetic neoplasms and the primitive round cell tumors, Ewing's sarcoma, and peripheral primitive neuroectodermal tumor. Retinoblastoma, neuroblastoma, and Wilms' tumor were first described in the 19th century but with several different appellations than those we use today. Although some progress was made in the surgical management of Wilms' tumor during the 1940s and 1950s, most of these unique solid neoplasms of childhood were seen as essentially untreatable and inevitably fatal; surgery and perhaps irradiation were the principal therapeutic offerings. The folic acid analogue, aminopterin, was reported in 1948 as inducing the first complete but temporary remission in acute childhood leukemia. The chemotherapeutic era began shortly thereafter with effective chemotherapy in the management of Wilms' tumor with the introduction of dactinomycin. Pathologists were no longer restricted to being purveyors of the death sentence; they were now responsible for differentiating one type of primitive and embryonic neoplasm from another by using a variety of ancillary techniques, including tissue culture, electron microscopy, immunohistochemistry, and cytogenetics. Favorable or unfavorable morphologic types and subtypes of tumors were defined and, together with the pathologic staging, became incorporated into the therapeutic plan and prognostic assessment. During the past 40 years, these tumors progressed from being virtually treatment resistant to having an overall 5-year survival of 70% or greater. Through the cooperative efforts of pediatric hematologists/oncologists, pediatric surgeons, radiation therapists, and pathologists, the primitive and embryonic neoplasms of childhood are now viewed as some of the most treatable and curable of cancers.