Comprehensive Molecular and Clinicopathologic Analysis of 200 Pulmonary Invasive Mucinous Adenocarcinomas Identifies Distinct Characteristics of Molecular Subtypes.

PURPOSE: Invasive mucinous adenocarcinoma (IMA) is a unique subtype of lung adenocarcinoma, characterized genomically by frequent KRAS mutations or specific gene fusions, most commonly involving NRG1. Comprehensive analysis of a large series of IMAs using broad DNA- and RNA-sequencing methods is still lacking, and it remains unclear whether molecular subtypes of IMA differ clinicopathologically. EXPERIMENTAL DESIGN: A total of 200 IMAs were analyzed by 410-gene DNA next-generation sequencing (MSK-IMPACT; n = 136) or hotspot 8-oncogene genotyping (n = 64). Driver-negative cases were further analyzed by 62-gene RNA sequencing (MSK-Fusion) and those lacking fusions were further tested by whole-exome sequencing and whole-transcriptome sequencing (WTS). RESULTS: Combined MSK-IMPACT and MSK-Fusion testing identified mutually exclusive driver alterations in 96% of IMAs, including KRAS mutations (76%), NRG1 fusions (7%), ERBB2 alterations (6%), and other less common events. In addition, WTS identified a novel NRG2 fusion (F11R-NRG2). Overall, targetable gene fusions were identified in 51% of KRAS wild-type IMAs, leading to durable responses to targeted therapy in some patients. Compared with KRAS-mutant IMAs, NRG1-rearranged tumors exhibited several more aggressive characteristics, including worse recurrence-free survival (P < 0.0001). CONCLUSIONS: This is the largest molecular study of IMAs to date, where we demonstrate the presence of a major oncogenic driver in nearly all cases. This study is the first to document more aggressive characteristics of NRG1-rearranged IMAs, ERBB2 as the third most common alteration, and a novel NRG2 fusion in these tumors. Comprehensive molecular testing of KRAS wild-type IMAs that includes fusion testing is essential, given the high prevalence of alterations with established and investigational targeted therapies in this subset.

Salivary Mucinous Adenocarcinoma Is a Histologically Diverse Single Entity With Recurrent AKT1 E17K Mutations: Clinicopathologic and Molecular Characterization With Proposal for a Unified Classification.

Mucin-producing salivary adenocarcinomas were historically divided into separate colloid carcinoma, papillary cystadenocarcinoma, and signet ring cell carcinoma diagnoses based on histologic pattern, but have recently been grouped together in the adenocarcinoma not otherwise specified category. It is currently unclear if these tumors represent 1 or more distinct entities and how they are related to well-circumscribed papillary mucinous lesions with recurrent AKT1 E17K mutations that were recently described as salivary intraductal papillary mucinous neoplasm. Here, we sought to evaluate the clinicopathologic and molecular features of salivary mucinous adenocarcinomas to clarify their classification. We identified 17 invasive mucin-producing salivary adenocarcinomas, 10 with a single histologic pattern, and 7 with mixed patterns. While most tumors demonstrated papillary growth (n=15), it was frequently intermixed with colloid (n=6) and signet ring (n=3) architecture with obvious transitions between patterns. All were cytokeratin 7 positive (100%) and cytokeratin 20 negative (0%). Next-generation sequencing performed on a subset demonstrated recurrent AKT1 E17K mutations in 8 cases (100%) and TP53 alterations in 7 cases (88%). Of 12 cases with clinical follow-up (median: 17 mo), 4 developed cervical lymph node metastases, all of which had colloid or signet ring components. Overall, overlapping histologic and immunohistochemical features coupled with recurrent AKT1 E17K mutations across patterns suggests that mucin-producing salivary adenocarcinomas represent a histologically diverse single entity that is closely related to tumors described as salivary intraductal papillary mucinous neoplasm. We propose a unified mucinous adenocarcinoma category subdivided into papillary, colloid, signet ring, and mixed subtypes to facilitate better recognition and classification of these tumors.

Low-Grade Appendiceal Mucinous Neoplasms: A Single Institution Experience of 64 Cases With Clinical Follow-up and Correlation With the Current (Eighth Edition) AJCC Staging.

Background. In this single-institution study, we applied the current (eighth edition) American Joint Committee on Cancer pathologic staging criteria to 64 low-grade mucinous neoplasms of the appendix (LAMNs), examined their histopathologic features, and studied the patients' clinical outcomes. Design. Sixty-four LAMNs, with a median follow-up of 52 months, were reviewed. Results. The distribution of pathologic stages was pTis (n = 39), pT3 (n = 1), pT4a (n = 5), pT4aM1a (n = 8), and pT4aM1b (n = 11). Recurrence was observed in only 2 patients (both with pT4aM1b disease), one of whom died of disease. All remaining patients were disease-free after a median clinical follow-up of 60 months. Conclusions. Our study confirms that pTis LAMNs have an excellent prognosis and suggests that pT4a and pT4aM1a LAMNs may also have a low risk of developing progressive disease.

The correlation between immune subtypes and consensus molecular subtypes in colorectal cancer identifies novel tumour microenvironment profiles, with prognostic and therapeutic implications.

BACKGROUND: Solid tumour growth is the consequence of a complex interplay between cancer cells and their microenvironment. Recently, a new global transcriptomic immune classification of solid tumours has identified six immune subtypes (ISs) (C1-C6). Our aim was to specifically characterise ISs in colorectal cancer (CRC) and assess their interplay with the consensus molecular subtypes (CMSs). METHODS: Clinical and molecular information, including CMSs and ISs, were obtained from The Cancer Genome Atlas (TCGA) (N = 625). Immune cell populations, differential gene expression and gene set enrichment analysis were performed to characterise ISs in the global CRC population by using CMSs. RESULTS: Only 5 ISs were identified in CRC, predominantly C1 wound healing (77%) and C2 IFN-γ dominant (17%). CMS1 showed the highest proportion of C2 (53%), whereas C1 was particularly dominant in CMS2 (91%). CMS3 had the highest representation of C3 inflammatory (7%) and C4 lymphocyte depleted ISs (4%), whereas all C6 TGF-ß dominant cases belonged to CMS4 (2.3%). Prognostic relevance of ISs in CRC substantially differed from that reported for the global TCGA, and ISs had a greater ability to stratify the prognosis of CRC patients than CMS classification. C2 had higher densities of CD8, CD4 activated, follicular helper T cells, regulatory T cells and neutrophils and the highest M1/M2 polarisation. C2 had a heightened activation of pathways related to the immune system, apoptosis and DNA repair, mTOR signalling and oxidative phosphorylation, whereas C1 was more dependent of metabolic pathways. CONCLUSIONS: The correlation of IS and CMS allows a more precise categorisation of patients with relevant clinical and biological implications, which may be valuable tools to improve tailored therapeutic interventions in CRC patients.

Histotype influences emergency presentation and prognosis in colon cancer surgery.

AIM: To investigate whether differences in histotype in colon cancer correlate with clinical presentation and if they might influence oncological outcomes and survival. METHODS: Data regarding colon cancer patients operated both electively or in emergency between 2009 and 2014 were retrospectively collected from a prospectively maintained database and analyzed for the purpose of this study. Rectal cancer was excluded from this analysis. Statistical univariate and multivariate analyses were performed to investigate possible significant variables influencing clinical presentation, as well as oncological outcomes and survival. RESULTS: Data from 219 patients undergoing colorectal resection for cancer of the colon only were retrieved. One hundred seventy-four patients had an elective procedure and forty-five had an emergency colectomy. Emergency presentation was more likely to occur in mucinous (p < 0.05) and signet ring cell (p < 0.01) tumors. No definitive differences in 5-year overall (44.7% vs. 60.6%, p = 0.078) and disease-free (51.2% vs. 64.4%, p = 0.09) survival were found between the two groups as a whole, but the T3 emergency patients showed worse prognosis than the elective (p < 0.03). Lymph node invasion, laparoscopy, histology, and blood transfusions were independent variables found to influence survival. Distribution assessed for pTNM stage showed T3 cancers were more common in emergency (p < 0.01). CONCLUSIONS AND DISCUSSION: Mucinous and signet ring cell tumors are related to emergency presentation, pT3 stage, poorest outcomes, and survival. Disease-free survival in patients who had emergency surgery for T3 colon cancer seems related to the histotype.

The molecular origin and taxonomy of mucinous ovarian carcinoma.

Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across all histological grades, including benign and borderline mucinous ovarian tumors, and compare these to tumors from other potential extra-ovarian sites of origin. Here we show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. Key drivers of progression identified are TP53 mutation and copy number aberrations, including a notable amplicon on 9p13. High copy number aberration burden is associated with worse prognosis in MOC. Our data conclusively demonstrate that MOC arise from benign and borderline precursors at the ovary and are not extra-ovarian metastases.

AJCC 7th edition staging classification is more applicable than AJCC 8th edition staging classification for invasive IPMN.

BACKGROUND: Both the 7th and 8th editions of the American Joint Committee on Cancer (AJCC) staging systems have been introduced for pancreatic adenocarcinoma. However, the applicability of these classifications for invasive intraductal papillary mucinous neoplasms (IPMN) has not been systematically examined. METHODS: Patients with invasive IPMN were retrieved from a cohort of 18 geographical sites (1973-2014 varying) in the Surveillance, Epidemiology, and End Results (SEER) cancer registry. The 7th and 8th editions of the AJCC staging were compared. Survival rates and multivariate analyses were computed. RESULTS: In total, 1216 patients with resected invasive IPMN were included. A major difference between the 7th and 8th systems is the definition of stage IIA (7th, beyond the pancreas without involvement of major arteries; 8th, maximum tumor diameter > 4 cm). The hazard ratio (HR) of stage IIA disease (versus stage IA, HR = 2.33, P < 0.001) was higher than that of stage IB disease (HR = 1.48, P = 0.087) by the 7th edition classification, whereas the HR of stage IIA disease (HR = 1.26, P = 0.232) was even lower than that of stage IB disease (HR = 1.48, P = 0.040) by the 8th edition classification. In addition, for the 8th edition staging system, tumor size was not a predictor of survival in patients with resectable tumor > 2 cm (size > 4 cm versus > 2 ≤ 4 cm, HR = 0.91, P = 0.420). CONCLUSIONS: The AJCC 7th edition staging classification is more applicable than the 8th edition classification for invasive IPMN.

Pancreatobiliary-type intraductal papillary mucinous neoplasm of the pancreas may have 2 subtypes with distinct clinicopathologic and genetic features.

We recently experienced cases of pancreatobiliary-type intraductal papillary mucinous neoplasms (PB-IPMNs) with imaging features resembling pancreatic ductal adenocarcinomas (PDACs), and histologic appearance of purely pancreatobiliary morphology and highly distorted papillary growth, which led to the present study aiming to systematically investigate PB-IPMNs in comparison with PDACs. Surgical cases of PB-IPMNs (n = 31) and PDACs (n = 24) were examined. PB-IPMNs were classified into monotypic tumors (n = 12; 39%) consisting of entirely high-grade pancreatobiliary-type neoplastic cells and polytypic cases (n = 19; 61%) associated with components of low-grade dysplasia and/or other histologic types (eg, gastric, intestinal, or oncocytic types). Clinically, monotypic PB-IPMNs less commonly had dilatation of the ampullary orifice (0% versus 74%) and mucin hypersecretion (17% versus 89%) than did polytypic cases. In most cases of monotypic PB-IPMNs, cystic dilatation of the lesional ducts was less obvious on imaging; therefore, 33% were radiologically diagnosed as PDACs. Histologically, intraductal tumors in monotypic cases showed a highly complex papillary architecture with tubular/cribriform glands and irregular branching, and all these cases were associated with invasive malignancy. GNAS mutations were detected in polytypic PB-IPMNs (6/19; 32%), but there were no GNAS mutations in monotypic cases. The recurrence-free survival of patients with monotypic PB-IPMN or PDAC was similar and significantly worse than that of patients with polytypic PB-IPMN. In conclusion, some cases of monotypic PB-IPMNs lacked the classic characteristics of IPMNs and shared features with PDACs, raising the possibility that these cases may be better classified as a papillary variant of PDACs rather than IPMNs.

Cervical Glandular Neoplasia: Classification and Staging.

Endocervical adenocarcinomas (EAs) account for 25% of all primary cervical carcinomas. Approximately 85% of EAs are driven by high-risk human papillomavirus (HPV) infection, the most common of which is the so-called usual type endocervical adenocarcinomas. Non-HPV-driven subtypes harbor distinct clinicopathologic features and prognosis and have been increasingly recognized in recent years, which has led to efforts to improve classification of EA based on clinically relevant and reproducible criteria. This review discusses a recently proposed classification system, the International Endocervical Adenocarcinoma Criteria and Classification, which uniquely integrates morphology, cause/pathogenesis, and biological behavior of HPV and non-HPV-driven subtypes of EA.

Signet ring cell component predicts aggressive behaviour in colorectal mucinous adenocarcinoma.

Mucinous adenocarcinoma (MAC) is defined by the presence of extracellular mucin covering more than 50% of the tumour area; however, MAC is histologically heterogeneous and some cases exhibit signet ring cell components. The aim of this study was to determine the prognostic impact of such variable morphology. A total of 299 consecutive MAC patients who underwent curative surgery were included. MACs were classified into four categories according to the predominant pattern of floating tumour cells: strips (27.1%), clusters (51.8%), signet ring cells (6.7%), and mixed clusters and signet ring cells (14.4%). In addition, we categorised MACs according to the relative amount of mucin. MACs with signet ring cell component were clearly associated with poor overall and recurrence-free survivals. Moreover, MACs with more than 50% signet ring cell component showed particularly poor clinical outcome just like non-mucinous signet ring cell carcinoma. MACs with a greater amount of extracellular mucin were associated with poor recurrence-free survival, independent of the pathological stage. In addition, lymphovascular and perineural invasion, advanced pathological stage, and old age at diagnosis were also prognostic factors for poor overall survival. MACs with more than 50% signet ring cell component should be classified as signet ring cell carcinoma and the presence of signet ring cells should be included in the pathology report of MACs with 10-50% signet ring cell component.

Should we regard all main duct type intraductal papillary mucinous neoplasms of the pancreas (MD-IPMN) as an indication of surgery? -A retrospective study in 29 patients with MD-IPMN showing mural nodules.

PURPOSE: To elucidate predictive factors for malignant main duct type IPMN (MD-IPMN). METHODS: All 29 subjects had mural nodules (MNs) in the main pancreatic duct (MPD) on preoperative endoscopic ultrasonography and underwent surgery (19, malignant; 10, benign). Possible predictive factors for malignancy such as background, imaging, and histological factors including histological subtype (HS), were evaluated. RESULTS: Multivariate analysis revealed an MPD diameter of ≥12 mm (p = 0.042) and non-gastric type (p = 0.001) to be the statistically significant predictive factors for malignancy. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy to detect malignancy by using "an MPD diameter of ≥12 mm and/or non-gastric type" were 95%, 70%, 86%, 88%, and 86%, respectively. In 7 subjects in whom HS was preoperatively evaluated using pancreatic specimens obtained before surgery, the agreement rate of the preoperative HS with definitive HS evaluated using resected specimens was 86%. CONCLUSIONS: For MD-IPMNs with MNs, "an MPD diameter of ≥12 mm and/or non-gastric type" are indicated for surgery. On the other hand, careful surveillance without immediate pancreatic surgery may be an option for MD-IPMNs showing both an MPD diameter of <12 mm and gastric type.

The Genomic Landscape of Mucinous Breast Cancer.

Mucinous carcinoma of the breast (MCB) is a rare histologic form of estrogen receptor (ER)-positive/HER2-negative breast cancer (BC) characterized by tumor cells floating in lakes of mucin. We assessed the genomic landscape of 32 MCBs by whole-exome sequencing and/or RNA-sequencing. GATA3 (23.8%), KMT2C (19.0%), and MAP3K1 (14.3%) were the most frequently mutated genes in pure MCBs. In addition, two recurrent but not pathognomonic fusion genes, OAZ1-CSNK1G2 and RFC4-LPP, were detected in 3/31 (9.7%) and 2/31 (6.5%) samples, respectively. Compared with ER-positive/HER2-negative common forms of BC, MCBs displayed lower PIK3CA and TP53 mutation rates and fewer concurrent 1q gains and 16q losses. Clonal decomposition analysis of the mucinous and ductal components independently microdissected from five mixed MCBs revealed that they are clonally related and evolve following clonal selection or parallel evolution. Our findings indicate that MCB represents a genetically distinct ER-positive/HER2-negative form of BC.

Adenocarcinoma classification: patterns and prognosis.

Lung cancer is the most frequent human malignancy and the principal cause of cancer-related death worldwide. Adenocarcinoma is now the main histologic type, accounting for almost half of all the cases. The 2015 World Health Organization has adopted the classification recently developed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification has incorporated up-to-date advances in radiological, molecular and oncological knowledge, providing univocal diagnostic criteria and terminology. For resection specimens, new entities have been defined such as adenocarcinoma in situ and minimally invasive adenocarcinoma to designate adenocarcinomas, mostly nonmucinous and ≤ 3 cm in size, with either pure lepidic growth or predominant lepidic growth with ≤ 5 mm invasion, respectively. For invasive adenocarcinoma, the new classification has introduced histological subtyping according to the predominant pattern of growth of the neoplastic cells: lepidic (formerly non mucinous brochioloalveolar adenocarcinoma), acinar, papillary, micropapillary, and solid. Of note, micropapillary pattern is a brand new histologic subtype. In addition, four variants of invasive adenocarcinoma are recognized, namely invasive mucinous (formerly mucinous brochioloalveolar adenocarcinoma), colloid, fetal, and enteric. Importantly, three variants that were considered in the previous classification have been eliminated, specifically mucinous cystadenocarcinoma, signet ring cell, and clear cell adenocarcinoma. This review presents the changes introduced by the current histological classification of lung adenocarcinoma and its prognostic implications.

The pathologic distinction of primary and metastatic mucinous tumors involving the ovary: A re-evaluation of algorithms based on gross features.

The problems associated with the pathologic distinction of primary ovarian mucinous tumors from their metastatic counterparts are well-recognized. Herein, we systematically evaluate a variety of gross parameters to determine the combination of features that most optimally separate primary from secondary mucinous ovarian tumors, and to address the tumor types that are most frequently associated with exceptions. 129 consecutive mucinous tumors involving the ovary formed the study set, including 61 primary mucinous tumors (16 carcinomas, 45 borderline tumors), and 68 metastatic carcinomas (21 colon; 28 appendix; 5 breast; 3 lung; 3 pancreas; 3 cervix; 1 bladder; 4 stomach). Consistent with prior studies, we found that as compared with metastases, primary ovarian mucinous tumors tend to be larger, more frequently unilateral and were more likely to be predominantly cystic and devoid of surface nodules. 41 of the 68 cases in the metastatic group showed intraperitoneal disease, as compared with only 3 of the 61 cases in the primary group (p < 0.0001). In 21% (14/68) of the metastatic group, the ovarian tumor was the first clinical indication of the primary tumor, and 82% of those cases were of gastrointestinal tract primary; this group of cases showed significantly larger tumors than ovarian tumors for patients with an established diagnosis of cancer. Receiver operating curve analyses showed that a tumor size cut off of <13 cm for metastatic disease yielded the maximal area under the curve of 0.877 (sensitivity 80%; specificity 80%); the most frequent exception to the size cut off of <13 cm for metastases was colorectal carcinoma, 30% of which were ≥13 cm. An algorithm whereby a tumor ≥13 cm is considered primary unless it displays surface nodules or bilaterality, and a tumor <13 cm is considered metastatic unless it is unilateral, correctly classified 94% (64/68) of the metastatic tumors and 98% (60/61) of the primary tumors. 3 of the 4 incorrectly classified cases in the metastatic group had intraperitoneal disease. We conclude that gross features are very useful in the distinction of primary from metastatic mucinous tumors in the ovary, and the presence of intraperitoneal disease provides additional diagnostic information. Although algorithms such as the one described herein are imperfect classifiers, they do provide baseline information on which additional findings, including microscopic features, can be added to ultimately provide the most accurate diagnostic classification.

Recent Insights into Mucinous Ovarian Carcinoma.

Ovarian mucinous tumors represent a group of rare neoplasms with a still undefined cell of origin but with an apparent progression from benign to borderline to carcinoma. Even though these tumors are different from the other histological subtypes of epithelial ovarian neoplasms, they are still treated with a similar chemotherapeutic approach. Here, we review its pathogenesis, molecular alterations, (differential) diagnosis, clinical presentation and current treatment, and how recent molecular and biological information on this tumor might lead to better and more specific clinical management of patients with mucinous ovarian carcinoma.

Can low grade PMP be divided into prognostically distinct subgroups based on histological features? A retrospective study and the importance of using the appropriate classification.

INTRODUCTION: The pathological classification of PMP of appendiceal origin has prognostic and treatment implications. Our goals were to • Classify low grade mucinous carcinoma peritonei (LGMCP) into prognostically distinct subgroups based on histological features. • Compare the reproducibility of the WHO and the PSOGI classifications for both PMP and the appendiceal primary tumor. PATIENTS AND METHODS: A retrospective analysis of patients undergoing CRS and HIPEC or debulking surgery was done. All the tumors were re-classified according to the PSOGI classification. LGMCP was further classified into three histological subgroups and the impact on survival was evaluated. RESULTS: From Jun 2011 to June 2016, 101 patients underwent CRS with HIPEC (n = 89) or debulking surgery (n=12). The median PCI was 28 (3-39) and 74.1% patients had CC-0/1 resections. Of the 76.2% patients who had LGMCP, 4 patients (5.1%) were classified as group 1, 54 (70.1%) as group 2 and 19 patients (24.6%) as group 3. At a median follow up of 21 months, the disease free survival was not reached, 30 months and 14 months for groups 1, 2 and 3 respectively (p = 0.09). There was no difference in overall survival. Using the WHO classification, there was a discordance in the grade of the primary tumor and the peritoneal lesions in 19.8% and conflicting terminology was used in 62% of patients. CONCLUSIONS: The subgroups of LGMCP described here are prognostically different though this needs further prospective evaluation in larger series. The PSOGI classification is more uniformly reproducible and should be preferred to the WHO classification.

Acinar-Predominant Pattern Correlates With Poorer Prognosis in Invasive Mucinous Adenocarcinoma of the Lung.

OBJECTIVES: Invasive mucinous adenocarcinoma (IMA) is a variant of lung adenocarcinoma with several growth patterns, such as lepidic acinar and papillary. However, to our knowledge, no study regarding prognostic and clinicopathologic aspects of IMAs with different growth patterns has been reported. METHODS: Of 2,236 patients with primary lung adenocarcinoma, 16 were identified as having lepidic-predominant IMA and 10 as having acinar-predominant IMA. Data regarding the clinicopathologic characteristics, computed tomography (CT) features, and prognosis were collected. RESULTS: No statistically significant difference was noted in sex, age, smoker proportion, and T classification between both groups. The proportion of lymph node metastasis was significantly higher in acinar-predominant IMA (P = .046). Both groups shared many signs in CT findings. Air bronchogram was a relatively specific sign for lepidic-predominant IMA. Survival analysis showed that acinar-predominant IMA had a poorer prognosis (P = .0294). CONCLUSIONS: Lepidic-predominant and acinar-predominant IMA are two different subtypes of IMA. Acinar-predominant IMA is associated with lymph node metastasis and a poorer prognosis.

Mucinous and secondary tumors of the prostate.

Primary mucinous tumors and secondary tumors involving the prostate gland are relatively uncommon, however they have important diagnostic, therapeutic, and prognostic implications. The primary mucinous tumors of the prostate include mucinous (colloid) adenocarcinoma of the prostate, prostatic adenocarcinoma with mucinous features, and mucinous adenocarcinoma of the prostatic urethra (mucin-producing urothelial-type adenocarcinoma of the prostate). Mucinous adenocarcinoma of the prostate is defined as a primary prostatic acinar tumor characterized by the presence of at least 25% of the tumor composed of glands with extraluminal mucin. This diagnosis can only be made in radical prostatectomy specimens. Recent studies have shown that these tumors have a similar or in some cases better prognosis than conventional prostatic adenocarcinoma treated by radical prostatectomy. The preferred terminology for tumors that are composed of <25% extraluminal mucinous component in radical prostatectomy specimens is 'prostatic adenocarcinoma with mucinous features.' All cases of prostatic adenocarcinoma with extraluminal mucinous components in prostate needle core biopsies or transurethral resection of the prostate specimens are also referred to as 'prostatic adenocarcinoma with mucinous features.' Mucinous adenocarcinoma of the prostatic urethra (mucin-producing urothelial-type adenocarcinoma of the prostate) as the name implies, does not arise from prostatic acini or ducts, and is a distinct entity that arises from the prostatic urethra usually from urethritis glandularis or glandular metaplasia with malignant transformation, and is analogous to adenocarcinoma with mucinous differentiation arising from the urinary bladder. This tumor is aggressive and has a relatively poor prognosis. The most common secondary tumors that arise from adjacent organs and spread (direct extension or metastasis) to the prostate gland, include urothelial carcinoma of the bladder and colorectal adenocarcinoma. Other secondary tumors that may involve the prostate include metastatic epithelial tumors from several other sites, malignant melanoma and soft tissue tumors.

Breast cancer subtype discrimination using standardized 4-IHC and digital image analysis.

Breast cancer is a heterogeneous disease. Surrogate classification of intrinsic subtypes of invasive carcinomas by combined immunohistochemistry for estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67 (4-IHC) has increased steadily since the 2011 St Gallen symposium, due to its rapid subtyping of tumors at a reasonable cost. An important step in improving 4-IHC reproducibility and reliability will be to provide reference values from the routine use of standardized 4-IHC followed by image analysis. The aims of the current study were (1) to analyze invasive breast carcinomas using standardized 4-IHC and quantitative image analysis and (2) to compare the results obtained in the classification of biological subtypes using current Ki67 and PR threshold values proposed by different authors to sub-classifying the luminal A-like and the luminal B-like (HER2-negative) subtypes. Five hundred twenty-one tumors were analyzed by standardized immunohistochemistry, with automatic image analysis, and HER2 FISH technique. Positivity for ER was found in 82.7% and for PR in 70.1% of cases. Using the Allred scoring system, hormone receptor results showed a bimodal distribution, particularly for ER. HER2 positivity was found in 15.7% of cases, and the mean Ki67 score was 32.3%. Using the most recently proposed surrogate definitions for the classification of luminal breast cancer subtypes, the percentages of different subtypes that we found were similar to those published with genomic platforms: 40.7% luminal A-like, 32.4% luminal B-like/HER2-negative, 9.8% luminal B-like/HER2-positive, 6.0% HER2-positive, and 11.1% triple negative. Standardized 4-IHC with automatic image analysis constitutes a low-cost method for surrogate definitions of biological subtypes of breast cancer that delivers accurate results in a day.