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.

Comprehensive genetic features of gastric mixed adenoneuroendocrine carcinomas and pure neuroendocrine carcinomas.

We aimed to determine the pathogenesis of gastric mixed adenoneuroendocrine carcinoma (MANEC) and pure neuroendocrine carcinoma (NEC), which is largely unknown. Targeted DNA sequencing was performed on 34 tumor samples from 21 patients - 13 adenocarcinoma (ADC)/NEC components from MANECs and eight pure NECs - and 21 matched non-neoplastic gastric tissues. Mutational profiles of MANECs/NECs were compared with those of other tumors using public databases. The majority (64.1%; 59/92) of mutations in MANEC were shared by both ADC and NEC components. TP53 was the most commonly mutated gene in MANEC (69.2%, 9/13) and pure NEC (87.5%, 8/9). All TP53 mutations in MANEC were pathogenic mutations and were shared by both ADC and NEC components. A subset of TP53WT MANECs had a microsatellite-unstable phenotype or amplifications in various oncogenes including ERBB2 and NMYC, and the only TP53WT pure NEC harbored MYC amplification. Compared to NEC in other organs, NECs arising from the stomach had unique features including less frequent RB1 mutations. Differentially altered genes of MANEC ADC components were significantly associated with receptor tyrosine kinase signaling pathways, while differentially altered genes of MANEC NEC components were significantly associated with the NOTCH signaling pathway. Our data provide evidence suggesting a possible clonal origin of ADC and NEC components of MANEC, and we found that gastric MANECs and pure NECs are distinct entities with unique mutational profiles and underlying protein networks. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Sarcomatoid Dedifferentiated Melanoma: The Diagnostic Role of Next-Generation Sequencing.

ABSTRACT: Sarcomatoid dedifferentiated melanoma (SDDM) represents a diagnostic challenge as this cutaneous spindle cell melanoma lacks expression of classic melanocytic markers including S100, SOX10, Melan-A, HMB45, and MITF. The expression of the emerging melanoma marker preferentially expressed antigen in melanoma (PRAME) in SDDM is largely unknown. In this article, a case of SDDM arising in association with a nodular melanoma is highlighted. A 65-year-old man presented with a several week history of an ulcerated lesion on the right medial knee. A shave biopsy of the lesion revealed a biphasic neoplasm, which consisted of a centrally located poorly differentiated spindle cell component and an adjacent nodular component consisting of atypical melanocytes arranged in nests and fascicles. While the nodular component stained for S100, SOX10, and Melan-A, the spindle cell component failed to stain for these conventional melanocytic markers, only staining diffusely for CD10 and faintly for CD68. Both components stained for PRAME diffusely albeit less intensely within the spindle cell component. Next-generation DNA sequencing assay of the microdissected biphasic components revealed a shared mutation of NRAS. The results of the PRAME immunohistochemical stain and next-generation DNA sequencing assay facilitated in establishing the diagnosis of SDDM in association with nodular melanoma.

Presentation and outcome of mixed neuroendocrine non-neuroendocrine neoplasms of the pancreas.

BACKGROUND/OBJECTIVES: Mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) of the pancreas and periampullary region are extremely rare and heterogeneous malignancies. Literature is sparse, clinical management is not standardized and little is known about survival outcomes. The aim of this study was to identify pathological and radiological features of MiNEN and assess the outcome of surgical management. METHODS: Patients undergoing surgery for pancreatic and periampullary MiNEN between 2001 and 2019 were retrospectively analysed based on a prospective database. Histological, radiological and clinical features were assessed. Survival was analysed in a nested case-control study and matched-pair analyses with pure neuroendocrine neoplasms (pNEN) and ductal adeno- or acinar cell carcinomas of the pancreas. A literature review with focus on survival after surgical resection was additionally performed. RESULTS: Of 13 patients with MiNEN, 5 had acinar-MiNEN and 8 adeno-MiNEN. Two of 5 (40%) acinar-MiNEN and one adeno-MiNEN patients had liver metastases. All but one adeno-MiNEN (88%) showed preoperative radiological features of pancreatic adenocarcinoma, 3 of 5 (60%) acinar-MiNEN exhibited mainly neuroendocrine features. No surgical mortality was observed. The 5-year overall survival rate in all MiNEN was 40%. Five-year survival rate was 58% in adeno-MiNEN and comparable to that of matched ductal adenocarcinomas (36%) and pNEN (48%). Five-year overall survival rate was 20% in acinar-MiNEN, compared to 39% in acinar carcinoma patients and 59% in matched pNEN patients. CONCLUSIONS: MiNEN are rare and difficult to distinguish from pure adenocarcinoma or neuroendocrine neoplasm preoperatively. Surgical resection would therefore be the treatment of choice in localized tumors.

A collision tumor of solitary fibrous tumor/hemangiopericytoma and meningioma: A case report with literature review.

An intracranial collision tumor is a rare lesion composed of two histologically different neoplasms in the same anatomic location. Even more rare is the collision tumor of a solitary fibrous tumor/hemangiopericytoma (SFT/HPC) and meningioma. The patient was a 46-year-old woman who had a 40 × 35 × 30-mm mass in the vermis of the cerebellum. Histologically, the mass consisted of two different components. One component showed the morphology of meningioma (World Health Organization (WHO) grade I), and the other component exhibited small round cell proliferation with hypercellular density, which was revealed to be SFT/HPC (WHO grade III) based on STAT6 immunohistochemistry. STAT6 showed completely different immunohistochemistry results in these two components (nuclear-negative in meningioma and nuclear-positive in SFT/HPC). Since these two neoplasms are associated with different prognoses, they should be distinguished from each other. When meningioma and an SFT/HPC-like lesion are identified morphologically, it is important to recognize the presence of such a collision tumor composed of meningioma and SFT/HPC, and identify the SFT/HPC component by employing STAT6 immunohistochemistry.

The clinical characteristics and prognostic factors of combined Hepatocellular Carcinoma and Cholangiocarcinoma, Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma after Surgical Resection: A propensity score matching analysis.

Background: Clinical characteristics and prognosis among combined hepatocellular carcinoma (HCC) and cholangiocarcinoma (cHCC-CC) with HCC and intrahepatic cholangiocarcinoma (ICC) were inconsistent in previous studies. The aim of this study was to compare postoperative prognosis among cHCC-CC, HCC and ICC, and investigated the prognostic risk factor of cHCC-CC after surgical resection. Methods: A total of 1041 eligible patients with pathological diagnosis of cHCC-CC (n=135), HCC (n=698) and ICC (n=208) were enrolled in this study. Univariate and multivariate Cox analysis were applied for assessing important risk factors. cHCC-CC were further 1:1 matched with HCC and ICC on important clinical risk factors. Survival curves of matched and unmatched cohorts were depicted by Kaplan-Meier method with log-rank test. Results: Patients with cHCC-CC had similar rate of sex, age and cirrhosis with HCC (p<0.05) and comparable incidence of hepatitis B or C with ICC (p=0.197). Patients of cHCC-CC had intermediate prognosis between HCC and ICC, with median overall survival (OS) time of cHCC-CC, HCC and ICC of 20.5 months, 35.7 months and 11.6 months (p<0.001). In matched cohorts, the OS of cHCC-CC were worse than HCC (p<0.001) but comparable with ICC (p=0.06), while the disease-free survival (DFS) of cHCC-CC was worse than HCC but better than ICC (p<0.05). And lymph node infiltration and postoperative transarterial chemoembolization (TACE) were independent risk factors of cHCC-CC associated with prognosis. Conclusion: The long term survival of cHCC-CC was worse than HCC but comparable with ICC when matched on albumin level, tumor size, lymph node infiltration, tumor stage and margin. Presence of lymph node infiltration and no postoperative TACE were associated with poor prognosis of cHCC-CC.

Clear Cell Hidradenoma-Basal Cell Carcinoma Collision.

ABSTRACT: A 91-year-old man presented with a tumor on the left temporal area, clinically suspicious of basal cell carcinoma. The histopathologic study showed a central solid-cystic tumor composed by 3 different types of cells (clear or finely granular cells, polygonal cells, and squamoid cells). It had a sclerotic stroma. At the periphery, another tumor composed by smaller interconnected nests was evident. Some nests were separated from the stroma by clefts. The stroma of this second tumor was highly cellular. There was a sharp delimitation between both tumors, with no transitional area. Immunochemistry demonstrated they are different tumor. A diagnosis of clear cell hidradenoma-basal cell carcinoma collision was performed. To the best of our knowledge, this is the first description of this challenging association.

Dermal and Intraepidermal Merkel Cell Carcinoma With Squamous Cell Carcinoma: A Report of a Rare Case With Special Reference to the Touch Dome.

ABSTRACT: In skin containing hair follicles, specialized epithelial structures known as "touch domes (TDs)" are located where the Merkel cells are clustered. We explored the histogenetic relationship between intraepidermal and dermal Merkel cell carcinomas (MCCs) and investigated which transformed progenitor cells can develop into intraepidermal MCC. We encountered an association between an extremely rare case of dermal and intraepidermal MCC with squamous cell carcinoma, which was examined using standard immunohistochemical methods with various epithelial, neuroendocrine, and TD markers including several immunohistochemical markers. Differential expression levels of CK20 and CD56 were found between intraepidermal and dermal MCCs, indicating molecularly distinct MCC populations. CK15 and CK17, expressed in TDs, were partially expressed in the intraepidermal neuroendocrine component at the tumor periphery in intraepidermal MCC with squamous cell carcinoma. These differences may suggest that the origin of dermal and intraepidermal MCCs is different under pathological conditions. We hypothesize that intraepidermal MCC is derived from tissue-specific stem cells localized within TDs.

Interobserver variation in the assessment of the sarcomatoid and transitional components in biphasic mesotheliomas.

The percentage of sarcomatoid component has an impact on prognosis in patients with biphasic malignant pleural mesothelioma. Recent study showed that the transitional pattern similar to sarcomatoid component of malignant mesothelioma has negative prognostic significance. Practice guidelines recommend quantification of sarcomatoid component despite poor diagnostic reproducibility of biphasic mesothelioma among thoracic pathologists. The aim of this study was to determine the interobserver agreement in the quantification of sarcomatoid component, and in the diagnosis of a transitional component in the biphasic malignant mesothelioma. Thirteen experts in thoracic pathology reviewed the representative H&E and cytokeratin whole-slide images of the 54 biphasic mesotheliomas, without knowledge of BAP1 or p16 deletion status, and completed the survey of 25 questions. The overall interobserver agreement in the assessment of the percentage of the sarcomatoid component in 25% increments was good (wK = 0.62). Excellent agreement was present in 14 of 54 cases (26%), and 3 cases were unanimously scored. Excellent agreement was reached for the cases with 0-24% and > 75% of the sarcomatoid component.The most commonly used criteria for the diagnosis of sarcomatoid component were malignant spindle cells, frank sarcomatoid features and high N/C ratio. The overall interobserver agreement for transitional pattern was fair (wK = 0.40). Unanimous opinion about the absence of transitional pattern was observed in only one case. At least 70% agreement regarding the presence of transitional pattern was observed in 12 cases, with the rest of the cases showing a wide range of disagreement. Morphologic characteristics that favor transitional pattern over non-transitional include sheet-like growth of cohesive, plump, elongated epithelioid cells with well-defined cell borders and a tendency to transition into spindle cells. Our study defined precise morphologic criteria that may be used in the differential diagnosis between transitional pattern and other mesothelioma subtypes including sarcomatoid and epithelioid.

Chromosomal and molecular pathway alterations in the neuroendocrine carcinoma and adenocarcinoma components of gastric mixed neuroendocrine-nonneuroendocrine neoplasm.

Gastric mixed adenoneuroendocrine carcinoma (MANEC) is a clinically aggressive subtype of mixed neuroendocrine-nonneuroendocrine neoplasm (MiNEN) with unclear clonal origin. In this study, we analyzed high-resolution copy number (CN) profiling data using the OncoScan CNV Assay in the neuroendocrine carcinoma (NEC) and adenocarcinoma components of eight MANECs. Some common CNVs, including the gain of CCNE1 (19q12) and the loss of FAT1 (4q35.2), were frequently detected in both components; these CNVs were verified by FISH, qPCR and immunohistochemistry staining assays in samples with sufficient material. The identification of common CNVs in both components supports the likelihood of single clonal origin of morphologically heterogeneous tumor cells and suggests several novel genetic events potentially involved in the development of gastric MANEC. We also detected and validated some CNVs and alterations specific for the NEC component, such as MAPK1 loss and MAPK signaling pathway alterations, which could contribute to the neuroendocrine differentiation of gastric MANEC. In addition, we found that the NEC component presented more CNVs and greater CN loss than the adenocarcinoma component (P = 0.007 and P = 0.004, respectively); the NEC components from different cases were not clustered in the hierarchical clustering analysis, indicating the marked genetic heterogenicity of the NEC component in gastric MANEC. In summary, this study describes the cytogenetic characteristics of each component of gastric MANEC, providing some clues for further studies on the development and progression of gastric MANEC as well as providing some potential therapeutic targets.

Molecular characterization of uterine and ovarian tumors with mixed epithelial and germ cell features confirms frequent somatic derivation.

Ovarian germ cell tumors, including yolk sac tumors, are most commonly diagnosed in children and young women. Most so-called yolk sac tumors reported in women >35 years old have been associated with an epithelial proliferation (endometriosis or carcinoma). Here, we describe eight cases clinically diagnosed as uterine or ovarian germ cell tumors in women >35 years old. In addition to routine morphologic examination and immunohistochemical evaluation, we present data from targeted next-generation sequencing (NGS) and isochromosome (12p) fluorescence in situ hybridization (FISH). We identified two groups of tumors with mixed germ cell and epithelial features: (1) tumors with background endometriosis and endometrioid carcinoma-like mutations (PTEN, PIK3CA, FGFR2, and CTNNB1), and (2) high-grade morphology, presumptive presence of isochromosome (12p) by FISH, and TP53 or PIK3CA mutations. These findings support the notion that the "germ cell tumor" component of these tumors is often somatically derived. Two tumors in our cohort were from premenopausal women; one showed no detectable mutations by NGS (suggestive of germ cell derivation), whereas the other showed PIK3CA, PTEN, and CTNNB1 mutations (suggestive of somatic derivation). Accurate classification of these tumors is likely important for selection of appropriate chemotherapy.

Looking into digestive mixed neuroendocrine - nonneuroendocrine neoplasms: subtypes, prognosis, and predictive factors.

Mixed neuroendocrine - nonneuroendocrine neoplasms (MiNENs) of the digestive system represent a challenge for both pathologists and clinicians. Their nomenclature has changed several times, and their diagnostic criteria, classification and clinical behaviour have been matter of debate over the years. Although several attempts have been made to elucidate the pathogenesis and biology of MiNENs, some issues remain open. This review will provide: a historical background that helps in understanding the evolution of the concept and nomenclature of mixed neoplasms; a revision of the knowledge on this topic, including molecular aspects, to give the reader a comprehensive and practical overview on this challenging field of pathology; a focus on the diagnostic criteria and on the determination of prognostic and predictive factors; and a description of the different tumour types in the different sites of origin.

Malignant tumours of the uterus and ovaries with Mullerian and germ cell or trophoblastic components have a somatic origin and are characterised by genomic instability.

AIMS: Tumours of the female genital tract with a combination of malignant Mullerian and germ cell or trophoblastic tumour (MMGC/T) components are usually diagnosed in postmenopausal women, and pursue an aggressive clinical course characterised by poor response to therapy and early relapses. These clinical features suggest that MMGC/T are somatic in origin, but objective molecular data to support this interpretation are lacking. This study evaluates the molecular features of nine MMGC/T, including seven tumours containing yolk sac tumour (YST), one tumour containing choriocarcinoma and one tumour containing epithelioid trophoblastic tumour. The objectives were to: (i) investigate whether MMGC/T show a distinct genetic profile and (ii) explore the relationship between the different histological components. METHODS AND RESULTS: Next-generation sequencing of paired samples demonstrated that the mutational profile of the Mullerian and non-Mullerian components of the tumour were almost identical in all cases. Moreover, the driver mutations identified were those expected in the specific subtype of Mullerian component present in each case. In contrast, variants expected in postpubertal germ cell tumours and gestational trophoblastic tumours were not identified, and FISH for i(12p) was negative in all cases tested. In this study, mismatch repair-proficient MMGC/T (eight of nine) were characterised by a complex copy-number variant profile, including numerous focal, regional, arm-level and chromosome-level events. CONCLUSIONS: Comparison of paired samples supports that the YST and trophoblastic tumour components of MMGC/T have a somatic origin and often show numerous copy-number variants, suggestive of underlying genomic instability.

Outcomes of Yttrium-90 Radioembolization for Unresectable Combined Biphenotypic Hepatocellular-Cholangiocarcinoma.

PURPOSE: To evaluate outcomes of yttrium-90 radioembolization in patients with combined biphenotypic hepatocellular-cholangiocarcinoma (cHCC-CC). MATERIALS AND METHODS: A retrospective review of patients with biopsy-confirmed cHCC-CC treated with yttrium-90 radioembolization between 2012 and 2018 was performed. Twenty-two patients with cHCC-CC (mean age 65.6 y, 17 men, 5 women) underwent 29 radioembolization treatments (5 resin, 24 glass microspheres). Survival data were available in 21 patients, and hepatic imaging response data were available in 20 patients. Hepatic imaging response to radioembolization was assessed on follow-up CT or MR imaging using modified Response Evaluation Criteria In Solid Tumours criteria. Univariate stepwise Cox regression analysis was used to evaluate the association between demographic and clinical factors and survival. Logistic regression evaluated associations between clinical factors and response to treatment, overall response, and disease control. RESULTS: Hepatic imaging response was as follows: 15% complete response, 40% partial response, 10% stable disease, and 35% progressive disease (55% response rate, 65% disease control rate). Two patients were downstaged or bridged to transplant, and 1 patient was downstaged to resection. Median overall survival was 9.3 mo (range, 2.5-31.0 mo) from time of radioembolization. Nonreponse to treatment, bilobar disease, presence of multiple tumors, and elevated carbohydrate antigen 19-9 before treatment were associated with reduced survival after radioembolization. CONCLUSIONS: Radioembolization is a viable option for locoregional control of cHCC-CC with good response and disease control rates.

Genomic profiling of combined hepatocellular-cholangiocarcinoma reveals similar genetics to hepatocellular carcinoma.

Combined hepatocellular-cholangiocarcinomas (CHC) are mixed tumours with both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) components. CHC prognosis is similar to intrahepatic CC (ICC) and worse than HCC; staging and treatment generally follow ICC algorithms. However, the molecular biology of CHC remains poorly characterised. We performed capture-based next-generation sequencing of 20 CHC and, for comparison, 10 ICC arising in cirrhosis. Intratumour heterogeneity was assessed by separately sequencing the HCC and CC components of nine CHC. CHC demonstrated molecular profiles similar to HCC, even in the CC component. CHC harboured recurrent alterations in TERT (80%), TP53 (80%), cell cycle genes (40%; CCND1, CCNE1, CDKN2A), receptor tyrosine kinase/Ras/PI3-kinase pathway genes (55%; MET, ERBB2, KRAS, PTEN), chromatin regulators (20%; ARID1A, ARID2) and Wnt pathway genes (20%; CTNNB1, AXIN, APC). No CHC had alterations in IDH1, IDH2, FGFR2 or BAP1, genes typically mutated in ICC. TERT promoter mutations were consistently identified in both HCC and CC components, supporting TERT alteration as an early event in CHC evolution. TP53 mutations were present in both components in slightly over half the TP53-altered cases. By contrast, focal amplifications of CCND1, MET and ERRB2, as well as Wnt pathway alterations, were most often exclusive to one component, suggesting that these are late events in CHC evolution. ICC in cirrhosis demonstrated alterations similar to ICC in non-cirrhotic liver, including in IDH1 or IDH2 (30%), CDKN2A (40%), FGFR2 (20%), PBRM1 (20%), ARID1A (10%) and BAP1 (10%). TERT promoter and TP53 mutation were present in only one ICC each. Our data demonstrate that CHC genetics are distinct from ICC (even in cirrhosis) and similar to HCC, which has diagnostic utility and implications for treatment. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications.

Metaplastic breast carcinoma (MBC) is relatively rare but accounts for a significant proportion of global breast cancer mortality. This group is extremely heterogeneous and by definition exhibits metaplastic change to squamous and/or mesenchymal elements, including spindle, squamous, chondroid, osseous, and rhabdomyoid features. Clinically, patients are more likely to present with large primary tumours (higher stage), distant metastases, and overall, have shorter 5-year survival compared to invasive carcinomas of no special type. The current World Health Organisation (WHO) diagnostic classification for this cancer type is based purely on morphology - the biological basis and clinical relevance of its seven sub-categories are currently unclear. By establishing the Asia-Pacific MBC (AP-MBC) Consortium, we amassed a large series of MBCs (n = 347) and analysed the mutation profile of a subset, expression of 14 breast cancer biomarkers, and clinicopathological correlates, contextualising our findings within the WHO guidelines. The most significant indicators of poor prognosis were large tumour size (T3; p = 0.004), loss of cytokeratin expression (lack of staining with pan-cytokeratin AE1/3 antibody; p = 0.007), EGFR overexpression (p = 0.01), and for 'mixed' MBC, the presence of more than three distinct morphological entities (p = 0.007). Conversely, fewer morphological components and EGFR negativity were favourable indicators. Exome sequencing of 30 cases confirmed enrichment of TP53 and PTEN mutations, and intriguingly, concurrent mutations of TP53, PTEN, and PIK3CA. Mutations in neurofibromatosis-1 (NF1) were also overrepresented [16.7% MBCs compared to ∼5% of breast cancers overall; enrichment p = 0.028; mutation significance p = 0.006 (OncodriveFM)], consistent with published case reports implicating germline NF1 mutations in MBC risk. Taken together, we propose a practically minor but clinically significant modification to the guidelines: all WHO_1 mixed-type tumours should have the number of morphologies present recorded, as a mechanism for refining prognosis, and that EGFR and pan-cytokeratin expression are important prognostic markers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Clinicopathological Features of Gastroesophageal Neuroendocrine Neoplasms.

PURPOSE OF REVIEW: Gastroesophageal neuroendocrine neoplasms (NENs) are a rare entity. Recent 2019 WHO classifications reflect our understanding of tumor biology, namely, that distinct molecular characteristics underline tumor behavior and prognosis. Here, we reviewed the evidence for linking molecular findings with the clinicopathological features and treatment of gastroesophageal NENs. RECENT FINDINGS: Degree of differentiation and Ki-67 proliferation index are required for accurate classification of neuroendocrine tumors and carcinomas but not sufficient to distinguish between the two entities. Resection remains the mainstay treatment for early-stage gastroesophageal neuroendocrine tumors. Additional perioperative therapy may benefit mitotically active tumors. There is a role for somatostatin analogues, especially in the setting of metastatic and symptomatic disease. New radiolabeled somatostatin analogues, immunotherapy, and embolization offer multimodality treatments for distant metastases. We need to understand the specific underlying biology of the various subtypes of gastroesophageal NENs to provide tailored treatment.

Endoscopic Submucosal Dissection of Early Gastric Cancer with Mixed-Type Histology: A Systematic Review.

BACKGROUND: Endoscopic submucosal dissection (ESD) criteria are histologically categorized by early gastric cancer (EGC) with differentiated- and undifferentiated-type histology. However, EGC is histologically heterogenous and there have been no separate criteria for EGC with mixed-type histology [EGC-MH; differentiated-type predominant EGC mixed with an undifferentiated component (EGC-MD) or undifferentiated-type predominant EGC mixed with a differentiated component (EGC-MU)]. Moreover, therapeutic outcomes of ESD for EGC-MH have not been clearly described. AIM: This study aimed to evaluate the feasibility of ESD for EGC-MH. METHODS: We searched core databases for specific inclusion factors: patients with EGC-MH, intervention of ESD, and at least one of the following outcomes: rate of en bloc, complete, curative resection, recurrence, procedure-related adverse event, lymphovascular invasion (LVI), or lymph node metastasis (LNM) that enabled evaluation of feasibility of ESD. RESULTS: A total of eight (systematic review) and four studies (meta-analysis) were included. There was no robustness in age, location, or morphology of EGC-MH. Moderately differentiated adenocarcinoma was frequent in pre-ESD biopsy. EGC-MH showed larger size, deeper invasion, and higher rates of LVI/LNM than pure-type EGC. Total en bloc, complete resection, and curative resection rates were 94.6% (95% confidence interval 86.6-97.9%), 77.8% (57.9-89.9%), and 55.1% (50.4-59.6%), respectively. There was no LNM or extra-gastric recurrence after ESD if the EGC-MD met the curative resection criteria. However, the EGC-MD itself was a risk factor for non-curative resection. (Margin positivity was the most common reason.) CONCLUSIONS: Although ESD seems to be technically feasible, inaccurate prediction of lateral or vertical margin leads to lower curative resection rate. Application of more strict indication is needed for EGC-MH.

Understanding the histogenesis of a HRAS-PIK3R1 co-driven metastatic metaplastic breast carcinoma associated with squamous metaplasia of lactiferous ducts.

Metaplastic breast carcinoma (MBC) represents a heterogeneous group of aggressive primary breast cancers that can show differentiation into carcinomatous and sarcomatous elements. Due to its rapid growth, this malignancy can replace precursor lesions, which remain unknown in most cases. Herein, we describe a MBC presenting as a deceptive post-biopsy hematoma. Histopathological and immunohistochemical evaluation of the primary tumor revealed a squamous cell carcinoma arising in a background of squamous metaplasia of lactiferous ducts (SMOLD). In the absence of ductal carcinoma in situ, we consider SMOLD as a nonobligatory precursor of MBC. The tumor showed 'dedifferentiation' into spindle, mucin-producing, osteoclast-like giant cell and fibromatosis-like carcinoma. Next-generation sequencing revealed the driver mutations HRASQ61R and PIK3R1c.1738_1745+2del in addition to MYH11S638L and amplification of ERCC5 and FGF14, which were potential contributors to tumor phenotype. Tumor dedifferentiation was probably facilitated by epithelial-to-mesenchymal transition (EMT) with aberrant expression of platelet and endothelial adhesion molecule-1, leading to early metastasis via hematogenous route rather than lymphatic. The co-occurrence of phosphoinositide 3-kinase and mitogen-activated protein kinase pathway abnormalities along with EMT could mediate divergent growth in breast cancer.

Merkel cell carcinoma with divergent differentiation.

Merkel cell carcinoma (MCC) is a rare primary neuroendocrine carcinoma of the skin, usually occurring at sun-exposed sites in elderly people. Divergent differentiation in MCC, although rare, has been reported in previous case series. We describe two new cases of MCC with divergent differentiation. Patient 1 was a 96-year-old man with a scalp lesion; on biopsy, the morphology and immunoprofile suggested MCC with divergent squamous differentiation. Patient 2 was an 87-year-old woman with a lesion on her leg, originally reported as squamous cell carcinoma, later showing extensive local recurrence. On review, primary histology showed an MCC with divergent differentiation, most likely trichilemmal carcinoma; the recurrence showed only MCC. These cases illustrate that MCC is capable of divergent differentiation, including squamous and adnexal morphologies. Correct diagnosis is essential for appropriate prognosis and management, as later recurrence or metastases may only show the Merkel cell component.