Article

Medullary Colorectal Carcinoma Revisited: A Clinical and Pathological Study of 102 Cases

January 2015
Annals of Surgical Oncology 22(9)

Authors:

Redcliffe Hospital

Aim Medullary carcinoma is a recently described subtype of mismatch repair deficient (MMRd) colorectal carcinoma (CRC) which, despite being poorly differentiated by traditional morphological criteria, has been reported to have a good prognosis. We investigated the pathological and clinical features of medullary CRC in an unselected cohort of CRCs undergoing surgical resection. Methods All CRCs resected within a single health district database from 1998 to 2012 were categorized prospectively and underwent retrospective review to identify 91 medullary CRCs, with 11 additional cases from 2013 to 2014. Strict criteria were employed to diagnose medullary carcinoma requiring both MMRd and greater than 90 % of the tumor to demonstrate typical morphology, including solid growth. The demographic and pathological features, as well as all-cause survival, were compared with other CRCs, and specifically to other MMRd CRCs. Results From 1998 to 2012, 91 of 3,295 CRCs (2.8 %) were of the medullary type. Medullary CRC was more likely to arise in females than males (3.3:1; p

Emerging and under-recognised patterns of colorectal carcinoma morphologies: a comprehensive review

Article

Mar 2024

While the overwhelming majority of colorectal carcinomas (CRC) are diagnosed as adenocarcinoma not otherwise specified, there are numerous under-recognised morphologic patterns of CRC. These patterns are recognised by the WHO, appear in reporting manuals for the American Joint Committee of Cancer, and/or are listed on synoptic reports, while many other variants have either fallen out of favour or are emerging as future bona fide patterns. Herein, we discuss 13 variants: serrated adenocarcinoma, micropapillary adenocarcinoma, medullary carcinoma, neuroendocrine carcinoma, mucinous adenocarcinoma, signet-ring cell carcinoma, adenosquamous carcinoma, adenoma-like adenocarcinoma, lymphoglandular complex-like CRC, carcinoma with sarcomatoid components, cribriform-comedo-type adenocarcinoma, undifferentiated carcinoma and low-grade tubuloglandular adenocarcinoma. The purpose of this review is to scrutinise these variants by assessing their clinical characteristics, morphologic cues, as well as pitfalls, and address their prognostic significance. Our analysis aims to bring clarity and updated understanding to these variants, offering valuable insights for pathologists. This contributes to more nuanced CRC diagnosis and treatment strategies, highlighting the importance of recognising a broad spectrum of morphologic patterns in CRC.

Clinicopathological features and survival outcomes of colorectal medullary carcinoma: a retrospective study based on the SEER database

Preprint

Full-text available

Dec 2022

Object: To investigate the relationship between clinicopathological characteristics and survival prognosis of patients with colorectal medullary carcinoma (MC), and to compare the prognostic differences between MC, colorectal neuroendocrine carcinoma (CRC-NEC) and colorectal neuroendocrine tumor (CRC-NET), in order to provide a more targeted treatment plan for colorectal cancer (CRC) and provide an evidence-based basis for evaluating the prognosis of patients. To provide a more targeted treatment plan for colorectal cancer (CRC) and an evidence-based basis for evaluating patient prognosis. Methods: From 2010 to 2019, 495 patients with pathological diagnosis of MC, 2440 patients with CRC-NEC and 9626 patients with CRC-NET were collected from the SEER database. The differences in clinicopathological characteristics between the groups were compared and the corresponding survival curves were plotted. 1:1 Propensity Score Matching (PSM) was used to eliminate the differences in baseline information between the groups, and the Kaplan-Meier method and log-rank test were used to compare the survival rates of patients in different groups. Cox regression models were developed to assess the predictive value of potential predictors for patients' clinical outcomes. Results: A total of 495 patients with MC were included in this study, and Multivariate analysis revealed that AJCC stage III+IV (HR=2.514, 95%CI: 1.796-3.519, P<0.001), positive tumor deposition (HR=1.723, 95%CI: 1.187-2.499, P=0.004), undergoing surgical treatment (HR=0.16, 95%CI: 0.065-0.393, P<0.001) and receiving chemotherapy (HR=2.328, 95%CI: 1.538-3.523, P<0.001) were potential independent risk factors on OS in MC patients. In addition, the OS and CSS of MC patients were significantly better than those of NEC patients before and after PSM matching (P<0.05); and the OS of MC patients was also better than that of CRC-NET patients before PSM matching (P<0.05), while the OS of MC patients was not significantly different from that of CRC-NET patients after PSM matching (P>0.05). Conclusion: MC has unique clinicopathological features and its prognosis is better than that of CRC-NET and CRC-NEC.

Clinicopathologic features and prognosis of histologic subtypes in the right-sided colon cancer

Article

Full-text available

Sep 2020
J BUON

Purpose: Differentiation of the histopathologic subtypes can be clinically important as it can affect the course of treatment and the prognosis. The aim of this study was to investigate both the clinicopathological features and prognosis of histologic subtypes in right-sided colon cancer. Methods: This study included 138 patients who underwent surgery for right-sided colon cancer. The patients were divided into three groups according to histopathological subtypes as follows: medullary carcinoma (MC, n=11), mucinous adenocarcinoma (MAC, n=29), and classic adenocarcinoma (AC, n=98). The groups were compared in terms of demographic characteristics, type of surgery, pathological outcomes and survival. Results: The rate of laparoscopic surgery was significantly lower in the MC group compared with MAC and AC groups (45.4% vs 54.5% vs 35.7%, respectively, p=0.001). In MC group, T4 stage was significantly higher than in other groups (90.0% vs 34.5% vs 35.7%, respectively, p=0.001). While patients with MAC had no distant metastasis, 18.2% and 15.3% of patients with MC and AC respectively, had distant metastasis (p=0.07). MAC vs MC, p=0.01, MAC vs AC, p=0.03). Tumor size, tumor volume, and the rate of microsatellite instability were found significantly higher in the MC group (p<0.05). The 5-year overall (OS) and disease-free survival (DFS) were better in the MAC group compared with MC and AC groups, but these differences did not reach statistical significance (OS: 92.8% vs 72.7% and 68.7%, p=0.16 and DFS 87.3% vs 58.2% and 64%, p=0.10, respectively). Conclusion: MC is associated with more advanced tumor size and T stages, and therefore entails reduced rate of minimally invasive procedures. In our series, the absence of distant metastasis in the patients of MAC also had a positive effect on survival.

A Comparison of Treatments and Outcomes for Medullary versus Nonmedullary Colon Cancer: A Single Institutional Experience Showing a Worse Prognosis for Stage 3 Disease

Article

Full-text available

Mar 2020

Background: Prior studies have shown a better prognosis with medullary colon cancer (MCC) compared to nonmedullary colon carcinomas (NMC); however, data are inconsistent and lacking the evaluation of treatments received. As we did not see similar survival outcomes, we aimed to retrospectively examine survival and receipt of treatment differences between MCC and NMC within the Geisinger Health System. Methods: The Cancer Registry was retrospectively reviewed for MCC and NMC from 2006 to 2017. Demographics and treatments were compared using T-test and chi-squared analyses, also comparing MCC to poorly differentiated (PD) or undifferentiated (UD) NMC. Overall survival was analyzed using Kaplan-Meier curves and log-rank tests. Results: 33 MCC and 1775 NMC patients were identified and 31 (93.9%) MCC and 1433 (87.0%) NMC underwent resection. MCC were older (p=0.0002), had a higher Charlson Comorbidity Index (p=0.013) and were more likely right sided (p=0.013). Seven patients (22.6%) with MCC vs. 149 (10.4%) NMC underwent resection of contiguous organs. Overall median survival was significantly worse for MCC as compared to NMC (19.6 vs. 60.5 months, p=0.0002). Only stage 3 patients had a significantly worse median survival when compared to PD/UD NMC (9.6 vs. 47.2 months, p < 0.001). Contiguous organ resection and failure to receive chemotherapy were not found as contributing factors to decreased survival. Conclusion: Multiple previous studies showed a better prognosis for MCC compared to PD/UD NMC. We, however, found stage 3 patients had a worse prognosis which may be secondary to higher comorbidities, increased stage, and higher rate of UD.

A Rare Case of Medullary Carcinoma of the Ileum

Article

Full-text available

Dec 2018

Medullary carcinoma of the small intestine is an exceedingly rare tumor. These tumors account for less than 0.04% of all colorectal cancers and only one case to date has been reported in the ileum. Although the clinical manifestations can be consistent with signs of intestinal obstruction, often times they are discovered incidentally in an asymptomatic patient. Major contributing risk factors to the development include long standing inflammation such as Crohn's disease, and other chronic inflammatory illnesses. Tumor markers and imaging can aid in the diagnosis, however biopsy is needed for definitive diagnosis. Despite the fact that the development of these tumors in the ileum is rare, further enhancement of awareness can aid in the appropriate early detection and appropriate treatment modalities.

Colonic Medullary Carcinoma: A Rare Case

Article

Full-text available

Dec 2017

Medullary carcinoma is a rare subtype of colorectal cancer making up less than 0.1% of all colorectal malignancies. This subtype can be confused with poorly differentiated colorectal carcinoma due to undifferentiated complexion morphology and high mitotic activity. Medullary carcinoma is a subtype of colonic adenocarcinoma with a better prognosis than other subtypes. This subtype is important because of the expansive growth pattern and high microsatellite instability. Medullary carcinoma is often right sided and is more frequent in older females and has lower incidence of lymph node metastases. In our case, the patient presented with complaints of abdominal pain and rectal bleeding due to a 5 cm wide colonic mass located at the transverse colon. Resection of the specimen revealed medullary colonic carcinoma.

Diagnostic problems and immune contexture in a case of cecal medullary carcinoma

Article

Full-text available

Jul 2017

Medullary carcinoma (MC) of the colon has recently been described as a separate variant of colorectal carcinoma, associated with microsatellite instability. Despite its morphological similarities to poorly differentiated adenocarcinomas (PDAs) and neuroendocrine carcinomas (NECs), the prognosis seems to be more favorable. A case of an adult female patient who presented with obstructive ileus due to a right-sided colon mass is reported. A specimen of right hemicolectomy was received and a large tumor was observed at the cecum. Tumor sections revealed a poorly differentiated carcinoma, without elements of intestinal differentiation on histologic or immunohistochemical examination. Further investigation lead to the diagnosis of MC of the cecum. The majority of lymphocytic populations of the microenvironment were granzyme B and T-cell intracellular antigen-1 (TIA-1) positive, with an abundant intraepithelial compartment. There were only a few Forkhead box P3(FOXP3) positive T-regulatory cells. It is emphasized that an undifferentiated large bowel carcinoma characterized by black-tan color on gross examination, expressing epithelial keratins and calretinin, proven to be microsatellite unstable with abundant intratumoral cytotoxic lymphocytes should be diagnosed as MC.

A critical reappraisal for the value of tumor size as a prognostic variable in rectal adenocarcinoma

Article

Full-text available

Jul 2017

Background and Objectives: To investigate critical prognostic factors for local recurrence in patients with rectal adenocarcinoma. Methods: We enrolled 221 consecutive patients who had histologically confirmed adenocarcinoma of the rectum and underwent surgery in our hospital between January 2000 and December 2014. Total mesorectal excision was performed in all patients undergoing a sphincter-sparing procedure or abdominal perineal resection of rectal cancer. To evaluate prognostic factors for local recurrence, we performed univariate and multivariate Cox regression analyses of the local recurrence rate in all patients. Overall survival rates were calculated using the Kaplan-Meier method, and Kaplan-Meier survival curves were compared using the log-rank test. Results: After the inclusion of only model variables of local recurrence with the highest or lowest univariate risk, a tumor size of <5 cm, a negative circumferential margin, well-to-moderately differentiated adenocarcinoma, low anterior resection, not receiving adjuvant RT, pathological T1-T3 stages, and upper- and middle-third rectal cancers were identified as strong prognostic factors with hazard ratios of 0.18, 0.20, 0.03, 0.01, 0.25, 0.18 and 0.18, respectively (95% confidence intervals [CIs], 0.06-0.58, 0.05-0.82, 0.03-0.38, 0.04-0.23, 0.05-0.64,0.09-0.70 and 0.06-0.54, respectively). After the multivariate Cox regression analysis of the local recurrence rate, a pathological tumor size of ≥5 cm was identified as the only prognostic risk factor (95% CI, 0.03-0.66; P = 0.013). The 5-year local recurrence rates among the patients having tumors measuring <5 cm and ≥5 cm in size were 1.40% and 23.00%, respectively (log-rank, P = 0.0001). The 5-year overall survival rates in the patients having tumors measuring <5 cm and ≥5 cm in size were 82.60% and 71.20%, respectively (log-rank, P = 0.001). Conclusion: A pathological tumor size of ≥5 cm is an independent prognostic factor for local recurrence in rectal adenocarcinoma.

Groupe de Travail et de suivi de la Commission d'élaboration du projet des protocoles thérapeutiques sur le cancer colorectal sous l'égide du ministre de la santé et de la protection sociale Edition 2023

Chapter

Full-text available

Apr 2024

Najwa Touil

Medullary colon carcinoma with microsatellite instability: case report

Article

Full-text available

Feb 2024

Colorectal cancer is the third most common neoplasm and the second most lethal worldwide. The most common histological type is adenocarcinoma, characterized by its glandular pattern. Medullary colon carcinoma is a rare histological variant of colorectal cancer, characterized by a predominantly solid architecture, poorly differentiated or undifferentiated morphology, often associated with an anomalous immunophenotype and microsatellite instability. The present study reports a case in an academic service of general surgery of a 74-year-old patient who presented with a tumor of the ascending colon, histologically with an exuberant lymphocytic infiltrate, suggestive of large cell lymphoma, but which was revealed by subsequent immunohistochemistry to be medullary carcinoma of the colon with microsatellite instability.

Medullary colonic carcinomas present with early-stage disease and do not express neuroendocrine markers by immunohistochemistry

Article

Full-text available

Apr 2023

Background: Medullary colonic carcinoma (MCC) is a rare and distinct phenotype of colorectal cancers characterized histologically by sheets of malignant cells with vesicular nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm, exhibiting prominent infiltration by lymphocytes and neutrophilic granulocytes. We present the clinicopathologic and immunohistochemical characteristics of this rare tumor in our patient population. Methods: Eleven cases diagnosed with MCC from 1996-2020 met the diagnostic histologic criteria and had tissue blocks available for further analysis. Immunohistochemistry for mismatch repair deficiency, CDX2, synaptophysin, and chromogranin, and microsatellite instability testing by polymerase chain reaction were performed. Additional clinical information was obtained from the electronic medical records. Results: The median age at diagnosis was 69 years. MCC was more common in women (64%) than men (36%) and all (100%) cases involved the right colon. The median carcinoembryonic antigen level at diagnosis was 2.8 ng/mL. Lymphovascular invasion and perineural invasion occurred in 64% and 9% of cases, respectively. Synaptophysin and chromogranin showed no expression in any of the cases (0%), and CDX2 was only expressed in 18% of cases by immunohistochemistry. Most patients (73%) presented with stage II disease and 7 (64%) cases were microsatellite instability-high. Only lymph node metastasis showed an association with overall survival (OS) (hazard ratio 0.04, 95% confidence interval 0.0003-0.78; P=0.035). During a median follow up of 1.25 years, the median OS was not estimable as the survival curve did not reach the median point of survival, indicating that more than half of the patients were still alive at the end of the study. Conclusion: Based on our experience, neuroendocrine markers, including synaptophysin and chromogranin, are not expressed in MCC, and many patients present with early-stage disease.

Cerebral Metastases in Appendiceal Cancer: Comprehensive Review and Report of Rare Medullary Carcinoma Histology

Article

Full-text available

Jul 2022

Appendiceal cancer is an extremely rare malignancy, and its metastatic spread to the brain is even more unusual. We describe a 47-year-old female who presented with a rare cerebral appendiceal carcinoma metastasis, a case that is further remarkable for representing the first histologic diagnosis of primary medullary carcinoma in the appendix. Based on a comprehensive review of the English literature using PubMed, Embase, and Google Scholar, only six other cases of cerebral appendiceal metastases have been described.

Medullary Carcinoma of the Colon: A Histopathologic Challenge

Article

Full-text available

Jun 2021

Medullary carcinoma (MC) of the colon is a rare and unique histologic subtype of colorectal cancer. It is commonly associated with deficient mismatch repair proteins and has a strong association with Lynch syndrome. Diagnosis is challenging as it does not have the usual immunohistochemical stains on pathology seen in colorectal adenocarcinoma. Here, we discuss an interesting case of MC of the colon that was metastatic on presentation and constituted a diagnostic challenge.

Morphology Matters: A Critical Reappraisal of the Clinical Relevance of Morphologic Criteria From the 2019 WHO Classification in a Large Colorectal Cancer Cohort Comprising 1004 Cases

Article

Apr 2021
AM J SURG PATHOL

The 2019 World Health Organization (WHO) classification of colorectal carcinoma (CRC) profoundly reclassified CRC subtypes and introduces tumor budding as a second major grading criterion, while condensing conventional grade into a 2-tiered system. So far it remains largely unexplored how these parameters interact with each other and whether they truly have an independent impact on patient prognosis. We reclassified a large single-center cohort of 1004 CRCs spanning 2 decades for adjusted WHO grade (low vs. high), tumor budding (Bd1/Bd2/Bd3), and CRC subtype (adenocarcinoma not otherwise specified, micropapillary, mucinous, serrated, medullary, adenoma-like, signet-ring cell, mixed adenoneuroendocrine carcinoma/neuroendocrine carcinoma, undifferentiated) according to the criteria of the 2019 WHO classification. We investigated the interaction of these parameters, their connection to stage/microsatellite status, and their significance for patient survival in the different subgroups. Specific subtypes other than adenocarcinoma not otherwise specified represented one third of all CRCs and were unevenly distributed throughout stage and microsatellite subgroups. Subtypes, WHO grade and tumor budding profoundly impacted all survival parameters (P<0.001 for all analyses), with CRC subtypes and tumor budding-but not WHO grade-being stage-independent prognosticators for all survival comparisons. WHO grade had very limited prognostic value in CRC subtypes, while tumor budding retained its strong prognostic impact in most scenarios. Accurate delineation of CRC subtypes introduced in the 2019 WHO classification provides strong stage-independent prognostic information, arguing that they should be considered in pathology reports and in clinical trials. Of the morphology-based grading schemes included in the 2019 WHO, tumor budding outperforms WHO grade.

Solid‐type poorly differentiated adenocarcinoma of the stomach: Deficiency of mismatch repair and SWI/SNF complex

Article

Full-text available

Jan 2020
CANCER SCI

ARID1A, one of the subunits in SWI/SNF chromatin remodeling complex, is frequently mutated in gastric cancers with microsatellite instability (MSI). The most frequent MSI in solid-type poorly differentiated adenocarcinoma (PDA) has been reported, but the SWI/SNF complex status in solid-type PDA is still largely unknown. We retrospectively analyzed 54 cases of solid-type PDA for the expressions of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, MSH6), SWI/SNF complex subunits (ARID1A, INI1, BRG1, BRM, BAF155, BAF170) and EBER, and mutations in KRAS and BRAF. We analyzed 40 cases of other histological type of gastric cancer as a control group. The solid-type PDAs showed coexisting glandular components (76%), MMR deficiency (39%) and complete/partial loss of ARID1A (31%/7%), INI1 (4%/4%), BRG1 (48%/30%), BRM (33%/33%), BAF155 (13%/41%) and BAF170 (6%/2%), EBER positivity (4%), KRAS mutation (2%), and BRAF mutation (2%). Compared to the control group, MMR deficiency and losses of ARID1A, BRG1, BRM and BAF155 were significantly frequent in solid-type PDAs. MMR deficiency was associated with the losses of ARID1A, BRG1 and BAF155 in solid-type PDAs. In the MMR-deficient group, solid components showed significantly more frequent losses of ARID1A, BRG1, BRM, and BAF155 compared to glandular components (p=0.0268, p=0.0181, p=0.0224, p=0.0071). In the MMR-proficient group, solid components showed significantly more frequent loss of BRG1 compared to glandular components (p=0.012). In conclusion, solid-type PDAs showed frequent losses of MMR proteins and SWI/SNF complex. We suggest that the loss of SWI/SNF complex may induce a morphological shift from differentiated-type adenocarcinoma to solid-type PDA.

Medullary carcinomas of the nonampullary small intestine: association with coeliac disease, mismatch repair deficiency, PD-L1 expression, and favourable prognosis

Article

Full-text available

Aug 2024
HISTOPATHOLOGY

Aim Gastrointestinal medullary carcinoma is a rare histologic subtype of adenocarcinoma. As nonampullary small bowel medullary carcinomas (SB‐MCs) are poorly characterized, we aimed to analyse their clinicopathologic and immunohistochemical features and to compare them with nonmedullary small bowel adenocarcinomas (NM‐SBAs). Methods and Results Surgically resected SBAs collected through the Small Bowel Cancer Italian Consortium were classified as SB‐MCs (carcinomas with ≥50% of tumour fulfilling the typical histologic criteria of MC) or NM‐SBAs. Immunohistochemistry for cytokeratin (CK)7, CK20, CDX2, programmed death‐ligand 1 (PD‐L1) and mismatch repair proteins was performed in both SB‐MCs and NM‐SBAs. SB‐MCs were also tested for CK8/18, synaptophysin, SMARCB1, SMARCA2, SMARCA4, and ARID1A and for Epstein–Barr virus (EBV)‐encoded RNAs by in‐situ hybridization. MLH1 promoter methylation status was evaluated in MLH1‐deficient cases. Eleven SB‐MCs and 149 NM‐SBAs were identified. One (9%) SB‐MC was EBV‐positive, while 10 (91%) harboured mismatch repair deficiency (dMMR). MLH1 promoter hypermethylation was found in all eight dMMR SB‐MCs tested. Switch/sucrose nonfermentable deficiency was seen in two (18%) SB‐MCs, both with isolated loss of ARID1A. Compared with NM‐SBAs, SB‐MCs exhibited an association with coeliac disease ( P < 0.001), higher rates of dMMR ( P < 0.001), and PD‐L1 positivity by both tumour proportion score and combined positive score ( P < 0.001 for both), and a lower rate of CK20 expression ( P = 0.024). Survival analysis revealed a better prognosis of SB‐MC patients compared to NM‐SBA cases ( P = 0.02). Conclusion SB‐MCs represent a distinct histologic subtype, with peculiar features compared to NM‐SBAs, including association with coeliac disease, dMMR, PD‐L1 expression, and better prognosis.

TROP2 in colorectal carcinoma: associations with histopathology, molecular phenotype, and patient prognosis

Article

Full-text available

Aug 2024

Antibody–drug conjugates (ADCs) directed to trophoblast cell surface antigen 2 (TROP2) have gained approval as a therapeutic option for advanced triple‐negative breast cancer, and TROP2 expression has been linked to unfavourable outcomes in various malignancies. In colorectal carcinoma (CRC), there is still a lack of comprehensive studies on its expression frequency and its prognostic implications in relation to the main clinicopathological parameters. We examined the expression of TROP2 in a large cohort of 1,052 CRC cases and correlated our findings with histopathological and molecular parameters, tumour stage, and patient outcomes. TROP2 was heterogeneously expressed in 214/1,052 CRCs (20.3%), with only a fraction of strongly positive tumours. TROP2 expression significantly correlated with an invasive histological phenotype (e.g. increased tumour budding/aggressive histopathological subtypes), advanced tumour stage, microsatellite stable tumours, and p53 alterations. While TROP2 expression was prognostic in univariable analyses of the overall cohort (e.g. for disease‐free survival, p < 0.001), it exhibited distinct variations among important clinicopathological subgroups (e.g. right‐ versus left‐sided CRC, microsatellite stable versus unstable CRC, Union for International Cancer Control [UICC] stages) and lost its significance in multivariable analyses that included stage and CRC histopathology. In summary, TROP2 is quite frequently expressed in CRC and associated with an aggressive histopathological phenotype and microsatellite stable tumours. Future clinical trials investigating anti‐TROP2 ADCs should acknowledge the observed intratumoural heterogeneity, given that only a subset of TROP2‐expressing CRC show strong positivity. The prognostic implications of TROP2 are complex and show substantial variations across crucial clinicopathological subgroups, thus indicating that TROP2 is a suboptimal parameter to predict patient prognosis.

TREATMENT AND HISTOPATHOLOGICAL PROGNOSTIC FACTORS OF COLORECTAL CANCER PULMONARY METASTASES

Thesis

Full-text available

May 2024

Topias Karjula

Lungs are the most common site of metastasis. One of the most common sources of pulmonary metastases is colorectal cancer (CRC), which is also the third most common cancer globally. The treatment and prognostic evaluation of CRC is mainly based on tumor-node-metastasis -classification, however, complementary prognostic categorization is needed. While CRC is extremely heterogenous genetically, it can be categorized based on morphology, genetics and also on the host immune response. The prognostic value of several known independent prognostic factors within the primary tumors, are less clear in the metastases. This doctoral thesis was based on two cohorts. The postoperative trends and results were analyzed in the first cohort (n=154) including all intended pulmonary metastasectomies performed in Oulu University Hospital (OYS) during 2000–2020. The second cohort (n=74) included patients treated with pulmonary metastasectomy for CRC in OYS and Central-Finland Central Hospital during 2000–2020. The prognostic value of tumor budding, tumor-stroma ratio (TSR), CD3+ and CD8+ T-cell density-based immune cell score (ICS), tertiary lymphoid structures, macrophage density and macrophage polarization in the resected CRC pulmonary metastases was analyzed, with a comparison to the primary tumors. According to the results, a significant proportion of the intended pulmonary metastasectomies turn out as incidental primary lung cancers. In the resected CRC pulmonary metastases, tumor budding and TSR had no prognostic value. CD3+/CD8+ T-cell infiltration was higher in the pulmonary metastases compared to the primary tumors and the ICS had independent prognostic value in the metastases. High PD-1 expression was associated with favorable prognosis, especially in metastases with high ICS. Tertiary lymphoid structures in the metastases had no survival effect. Tumor-associated macrophages had a more pro-tumoral M2- polarized phenotype in the metastases compared to the primary tumors, and higher densities of M2-like macrophages were associated with worse survival. The present studies demonstrate the differences between resected CRC metastases and corresponding primary tumors and elucidates the significant prognostic role of the immune system in the metastases. The results of this doctoral thesis might have clinical implications in future therapy planning.

Colonic medullary carcinoma: an exceedingly rare type of colorectal malignancy: a case report and review of the literature

Article

Full-text available

Oct 2023
J Med Case Rep

Background Medullary carcinoma of the colon is a rare subtype of colorectal cancer that has a unique, and sometimes varied, clinical and histologic profile. It usually presents in adult patients older than 50 years. Here, we report a unique case of young male patient who initially presented with abdominal pain followed by a large bowel obstruction. Case presentation A 40-year-old SriLankan male presented with right-sided abdominal pain and on examination, there was a palpable right iliac fossa mass. Colonoscopy and a computed tomography scan revealed cecal mass. Later, while waiting for elective resection, the patient developed symptoms and signs of a large bowel obstruction. He underwent a laparoscopic right hemicolectomy with an uneventful postoperative course. The histopathologic evaluation of the resected specimens showed invasive carcinoma with syncytial growth pattern, foci of lymphoid host response, and dirty necrosis, in keeping with a medullary carcinoma pT4a pN2b. Unlike most reported medullary carcinoma cases, this patient was young and caudal-related homeobox transcription factor 2 positive. Conclusion We have reported another case of medullary carcinoma of the colon in a young patient with unique histologic characteristics. Reporting such cases helps in refine understanding of the histologic and genetic, as well as clinical, phenotypes of medullary carcinoma of the colon.

Both MLH1 deficiency and BRAFV600E mutation are a unique characteristic of colorectal medullary carcinoma: An observational study

Article

Full-text available

Sep 2023

Although immunohistochemistry (IHC) for mismatch repair (MMR) proteins (MMR IHC) is used to identify DNA MMR status, universal screening of all patients with colorectal cancer (CRC) using a combination of both MMR IHC and genetic testing for the BRAF V600E mutation is limited in Japan. This study aimed to better understand the histopathological characteristics of CRCs, which exhibit both deficient mismatch repair (dMMR) and BRAF V600E mutation. MMR IHC of formalin-fixed paraffin-embedded tissues from tumor areas obtained from 651 patients with CRC who underwent surgical resection at Hamamatsu University Hospital (Hamamatsu, Japan) between August 2016 and March 2022 were used to evaluate MMR status, which was determined by staining for the expression of 4 MMR proteins (MLH1, MSH2, PMS2, and MSH6). All dMMR tumors were additionally evaluated for BRAF V600 mutation status via Sanger sequencing. Patient clinical characteristics (age, sex, tumor location, size, and tumor pathology) were then classified using their dMMR and BRAF V600 mutation statuses. Among the 651 patients with CRC, 58 carried tumors with dMMR, of which 52 were deficiency in MLH1 (dMLH1). Interestingly, all 16 medullary carcinomas that were analyzed showed characteristics corresponding to the presence of both dMLH1 and BRAF V600E mutation ( P = .01). These results suggest that colorectal medullary carcinomas can be diagnosed based on their unique characteristics of harboring the BRAF V600E mutation and exhibiting dMLH1 expression.

The Value of Tumor Size as a Prognostic Factor in Rectal Adenocarcinoma

Article

Full-text available

Nov 2022

Background: Colorectal cancer (CRC) is the third frequent diagnosed cancer and third cause of cancer death. Curative intent surgery followed by chemoradiotherapy are the standard of care for patients with CRC to reduce local recurrence and enhance overall survival (OS). This study aimed to evaluate tumor size as a prognostic factor for rectal adenocarcinoma local recurrence. Patients and Methods: This retrospective phase II study reviewed 100 rectal adenocarcinoma patients who were treated and followed up for 5 years after treatment. The medical records were reviewed for all cases including demographic data, medical history, personal habits, uncontrolled chronic medical condition, presenting symptoms and signs, pathological data, laboratory investigations, diagnosis, radiological examination, treatment details and treatment outcome assessed by OS and disease-free survival (DFS). Results: During 5 years of follow up in our study, 12 patients (12%) had local recurrence. Patients with tumor size > 5 cm has a significantly shorter DFS. DFS within 2-yrs for tumours ≤5 cm 96%, while 5-years DFS was 90%. While for tumours >5cm, 2-years DFS was 70% and 55% for 5-years and more. In tumours size >5cm, 2-years OS was 75%, 3-years OS was 72% and 5-years was 70% While In tumours ≤ 5cm, overall survival was 84%. Patients who had neoadjuvant chemoradiation also had a significant low local recurrent rate with (p=.042) in multivariate analysis. Conclusions: Tumor size has a prognostic value in rectal adenocarcinoma. Tumor size >5 cm is associated with higher rate of local recurrence and worse DFS.

Loss of CDX2 in colorectal cancer is associated with histopathologic subtypes and microsatellite instability but is prognostically inferior to hematoxylin–eosin-based morphologic parameters from the WHO classification

Article

Full-text available

Oct 2021

Background Immunohistochemical loss of CDX2 has been proposed as a biomarker of dismal survival in colorectal carcinoma (CRC), especially in UICC Stage II/III. However, it remains unclear, how CDX2 expression is related to central hematoxylin–eosin (HE)-based morphologic parameters defined by 2019 WHO classification and how its prognostic relevance is compared to these parameters. Methods We evaluated CDX2 expression in 1003 CRCs and explored its prognostic relevance compared to CRC subtypes, tumour budding and WHO grade in the overall cohort and in specific subgroups. Results CDX2-low/absent CRCs were enriched in specific morphologic subtypes, right-sided and microsatellite-instable (MSI-H) CRCs ( P < 0.001) and showed worse survival characteristics in the overall cohort/UICC Stage II/III (e.g. DFS: P = 0.005) and in microsatellite stable and left-sided CRCs, but not in MSI-H or right-sided CRCs. Compared with CDX2, all HE-based markers showed a significantly better prognostic discrimination in all scenarios. In multivariate analyses including all morphologic parameters, CDX2 was not an independent prognostic factor. Conclusion CDX2 loss has some prognostic impact in univariate analyses, but its prognostic relevance is considerably lower compared to central HE-based morphologic parameters defined by the WHO classification and vanishes in multivariate analyses incorporating these factors.

Medullary Carcinoma of the Gastrointestinal Tract: Report on Two Cases with Immunohistochemical and Molecular Features

Article

Full-text available

Sep 2021

Medullary carcinoma of the colon is a rare histological variant characterized by a poorly differentiated morphology, an aberrant immunophenotype, and microsatellite instability. Despite the lack of glandular differentiation, medullary carcinoma is reported to have a good prognosis. It is typically located in the right colon and frequently affects older women. Due to its clinical, histological, biological, and genetic peculiarity, medullary carcinoma requires an accurate diagnosis and the awareness of this diagnostic possibility. We describe the morphological, immunohistochemical, and molecular findings of two interesting cases, the first one in the right colon of a patient and the second one in the terminal ileum of a patient with Crohn’s disease. Deeper knowledge of all the biological and clinical features will allow appropriate and specific treatment of this tumor in the future.

Clinicopathological and Molecular Characterization of Crohn’s Disease-Associated Small Bowel Adenocarcinomas

Article

Aug 2019

Background and Aims Small bowel adenocarcinoma (SBA) is a recognized complication of Crohn’s disease (CD) but its low absolute prevalence limits opportunities for clinicopathological characterization. Methods We compared the clinical, pathological and molecular features of 48 SBA from patients with CD (CDSBA) and 29 SBAs from patients without CD (NSBA) who underwent treatment at our tertiary care center between 2000 and 2018. Results Patients of CDSBA were younger than those of NSBA (mean age, 56 vs. 64, P=0.02). Males predominated in both groups. Most CDSBA (69%) occurred in the ileum whereas most NSBA occurred in the duodenum (38%) and jejunum (31%, P<0.001). Stage I tumors were more prevalent in the CDSBA (33% vs. 3%, P=0.002), although the rates of Stage IV disease and disease-specific mortality were similar in both groups. CDSBA were less likely to present a discrete mass (35% vs. 93%, P<0.001) and were more often stricturing or fistulizing (75% vs. 10%, respectively, P<0.001) than NSBA. Microscopically, CDSBA were relatively heterogeneous, exhibiting at least 3 distinct growth patterns in 39% compared with 1% of NSBA (P=0.01). Low-grade tubuloglandular adenocarcinoma was the predominant pattern in 19% of CDSBA compared with 0% of NSBA (P=0.003). CDSBA were more frequently DNA mismatch repair proficient (90% vs. 62%, P=0.04), exhibited similar profiles of frequently mutated genes as NSBA, except IDH1 (18%) and SMAD4 (12%) mutations that occurred uniquely in CDSBA. Conclusions These observations, based on the largest single center series described hitherto, establish that CDSBA is a distinct clinical, pathological and molecular entity.

Colon Cancer Sidedness, Presentation, and Survival at Different Stages

Article

Full-text available

Feb 2019

Background: Several prognostic factors have been used to guide therapy for colon cancer (CC). However, the relationship between CC laterality (sidedness) and prognosis remains under investigation. Objectives: To assess the effect of laterality on CC presentation and survival, using a Surveillance, Epidemiology, and End Results (SEER) population-based cohort. Methods: A retrospective cohort study using data from the SEER program (2007-2015). Results: Of the 163,980 patients with CC, 85,779 (52.3%) presented with right-sided CC (RCC) and 78,201 (47.7%) with left-sided CC (LCC). Stage distributions were as follows: stage I, 24.1%; stage II, 27.3%; stage III, 28.2%; and stage IV, 20.4%. In an adjusted modified Poisson regression approach for risk ratio (RR), patients with LCCs were more likely to be male (RR = 1.14; 95% CI 1.12-1.15, p<0.001). As compared to stage I, stage II cancers (RR = 0.88, 95% CI 0.87-0.90, p<0.001) were less likely to be LCC. Stage IV CC was slightly less likely to be left-sided (RR = 0.98, 95% CI 0.98, 0.96-1.00, p = 0.028). The median overall survival (OS) for RCC was 87 months. The median OS for LCC was not established, as more than half of the patients diagnosed with LCC were still living at the time of the analysis. In adjusted Cox proportional Hazard model, individuals with stage I, III, and IV LCCs had superior OS as compared to those with matched-stage RCC (adjusted HR = 0.87; 95% CI 0.85-0.88, p<0.001). However, OS was worse among those with stage II disease who presented with LCC (adjusted Hazard ratio [aHR] = 1.06; 95% CI 1.02-1.11, p = 0.004). CC-specific survival (CSS) was superior for LCC versus RCC for stages III and IV but worse for II. Conclusions: In this population-cohort study, LCC is associated with superior OS and CSS survival. The overall survival advantage was attributed to stage I, III, and IV disease. Individuals presenting with stage II disease exhibit superior survival if the CC is right-sided.

The density of Tbet+ tumor-infiltrating T lymphocytes reflects an effective and druggable preexisting adaptive antitumor immune response in colorectal cancer, irrespective of the microsatellite status

Article

Full-text available

Jan 2019

Purpose: The recent success of anti-PD1 antibody in metastatic colorectal cancer (CRC) patients with microsatellite instability (MSI), known to be associated with an upregulated Th1/Tc1 gene signature, provides new promising therapeutic strategies. However, the partial objective response highlights a crucial need for relevant, easily evaluable, predictive biomarkers. Here we explore whether in situ assessment of Tbet+ tumor infiltrating lymphocytes (TILs) reflects a pre-existing functional antitumor Th1/Tc1/IFNγ response, in relation with clinicopathological features, microsatellite status and expression of immunoregulatory molecules (PD1, PDL1, IDO-1). Methodology: In two independent cohorts of CRC (retrospective n = 80; prospective n = 27) we assessed TILs density (CD3, Tbet, PD1) and expression profile of PDL1 and IDO-1 by immunohistochemistry/image analysis. Furthermore, the prospective cohort allowed to perform ex vivo CRC explant cultures and measure by Elisa the IFNγ response, at baseline and upon anti-PD1 treatment. Results: The density of Tbet+ TILs was significantly higher in MSI CRC, especially in the medullary subtype but also in a subgroup of MSS (microsatellite stable), and positively correlated with PD1 and PDL1 expression, but not with IDO-1. Finally, a high number of Tbet+ TILs was associated with a favorable overall survival. These Tbet+ TILs were functional as their density positively correlated with basal IFNγ levels. In addition, the combined score of Tbet+ PD1+ TILs coupled with IDO-1 expression predicted the magnitude of the IFNγ response upon anti-PD1. Conclusion: Altogether, immunohistochemical quantification of Tbet+ TILs is a reliable and accurate tool to recapitulate a preexisting Th1/Tc1/IFNγ antitumor response that can be reinvigorated by anti-PD1 treatment.

Factors associated with short recurrence-free survival in completely resected colon cancer

Article

Full-text available

Dec 2017

Background: Several factors could affect disease recurrence in surgically resected colon cancer. While the role of certain factors such as cancer stage and grade is well established, the role of other factors (e.g., histological subtypes) is yet to be determined. Objective:Therefore, we conducted a study to evaluate the impact of several factors in recurrence-free survival (RFS) in patients who were disease free following surgical resection of the colon cancer. Design/Methods: Data were collected for patients with Stage I–III colon cancer who underwent complete surgical resection of the tumor between January 2010 and December 2015 in our institution. A total of 90 subjects met the inclusion criteria and were included in the study. The following factors were collected at the time of surgical resection of the colonic tumor: patient’s age, gender, colon cancer stage, grade and histological subtype, body mass index, hemoglobin A1c, and smoking history. Results: A total of 28 patients (31%) developed recurrence and had a mean follow-up time of 19.8 months (range: 2–54.4 months). Median RFS was 54.4 months with a 5-year RFS of 49%. Advanced colonic cancer stage and mucinous histological subtype were associated with shorter RFS with an HR of 2.37, 95% CI = 1.38–4.06, and 95% CI = 1.02–5.90, respectively. Current smokers or those who quit less than 15 years earlier tended to have worse RFS with an HR of 2.47, 95% CI = 0.98–6.27. Conclusion: Advanced colon cancer stage and mucinous histological subtype are independent risk factors for cancer recurrence and shorter RFS in completely resected colonic tumor.

A resected case of medullary carcinoma of the ascending colon followed by infarction of the greater omentum mimicking anastomotic leakage

Article

Full-text available

Nov 2017

Introduction Medullary carcinoma is a rare type of colorectal adenocarcinoma, and omental infarction is a rare cause of acute abdomen. Presentation of case A 72-year-old woman underwent single-incision laparoscopic right hemicolectomy for ascending colon cancer. Pathological examination showed a medullary carcinoma (MC) of T4aN0M0 Stage IIB. Her postoperative course was uneventful, and she was discharged on postoperative day (POD) 6. From POD 7, she suffered from fever, and she returned to the hospital on POD 9. Plain computed tomography showed free air beside the anastomotic site around the elevated density of fat tissue and gallbladder wall thickening with a gallstone. Suspecting anastomotic leakage with acute cholecystitis, probe laparotomy was performed. Intraoperative observation confirmed omental infarction with acute cholecystitis, and no leakage was found at the anastomotic site. Therefore, the necrotic part of the greater omentum was resected, and cholecystectomy was performed. She has remained well, with no evidence of recurrent cancer during the 12 months of follow-up without chemotherapy after the surgery for MC of the ascending colon. Discussion MC should be distinguished from other more aggressive, non-glandular tumors of the colon because MC appears to have a better survival outcome than undifferentiated colon adenocarcinoma. Omental infarction should be considered in the differential diagnosis of acute abdomen after surgery. Conclusion A rare case of medullary carcinoma of the ascending colon followed by infarction of the greater omentum mimicking anastomotic leakage is presented.

Association between clinicopathological characteristics and RAS mutation in colorectal cancer

Article

Full-text available

Oct 2017

In colorectal cancer, KRAS (exons 2, 3, and 4) and NRAS (exons 2, 3, and 4) mutations are associated with resistance to antiepidermal growth factor receptor monoclonal antibodies, and BRAF mutation is a molecular marker of poor prognosis. KRAS exon 2 and BRAF-mutated colorectal cancers have well-known distinct clinicopathological characteristics. Comparison of tumors with different RAS status (exons 2, 3, and 4 of KRAS and NRAS) based on their clinicopathological characteristics has never been established. All colorectal cancer patients with RAS and BRAF testing from 2011 to 2015 were included in this observational retrospective study. Patient and tumor characteristics were collected and correlation with RAS and BRAF status was evaluated. A total of 1735 patients with colorectal cancer were included. RAS-mutated colorectal cancers (n=1002), compared with RAS wild-type colorectal cancers (n=733), were significantly associated with male gender, classical adenocarcinoma subtype, well/moderately differentiated tumors, and microsatellite stable phenotype. KRAS codon 13-mutated colorectal cancers (n=171), compared with RAS wild-type colorectal cancers, more frequently presented classical adenocarcinoma subtype and microsatellite stable phenotype. In comparison with other RAS mutations, KRAS exon 3-mutated colorectal cancers (n=23) were associated with mucinous/rare histological subtypes and, most likely to located in the rectum. KRAS exon 4-mutated colorectal cancers (n=33) were more frequently associated with mucinous/rare histological subtypes. There was no significant association between NRAS mutation (n=37) and clinicopathological features. Colorectal cancers are associated with different clinicopathological features according to the type of RAS mutation. Consequently, these particular characteristics must be considered when assessing the prognostic value of RAS status in colorectal cancer.

Survival Outcomes of Poorly Differentiated Colorectal Carcinoma Variants: Insights from a Single Teaching Institute

Article

Dec 2024
Hum Pathol

Pathologic Features of Primary Colon, Rectal, and Anal Malignancies

Chapter

Aug 2024
Canc Treat Res

In USA, colorectal cancer is the third most commonly diagnosed cancer in men, second in women, as well as the third leading cause of cancer deaths (Siegel et al. in Cancer J Clin 73:1–112, 2023 [109]). Worldwide, colorectal cancer is the second leading cause of death and causes almost 916,000 deaths each year (Ferlay in Global cancer observatory: cancer today. International Agency for Research on Cancer, Lyon, 2020 [28]). Fortunately, due to the colon’s surgical and endoscopic accessibility and functional redundancy, colorectal cancer is very treatable. Colonoscopic surveillance has the potential for not only providing tissue for the diagnosis of precancerous polyps and invasive carcinoma, but also preventing development of invasive carcinoma by the removal of precancerous lesions. This chapter discusses the clinical and pathologic features of the spectrum of epithelial, hematolymphoid, and mesenchymal malignant tumors of the colon, rectum, appendix, and anus.

Mismatch repair deficiency: how reliable is the two-antibody approach? A national real-life study

Article

Jun 2024
HISTOPATHOLOGY

Aims Traditionally, mismatch repair (MMR) status is determined by a panel of four antibodies (MLH1, PMS2, MSH2, MSH6). If all proteins are retained, cases are MMR proficient (pMMR), while loss of one or more proteins is indicative of MMR deficiency (dMMR). This approach has been challenged in favour of a two‐antibody approach, using PMS2 and MSH6 as a first screening. Their retainment is deemed sufficient to declare cases pMMR. In this study we aim to verify the validity of the two‐antibody approach. Methods and Results We performed a nationwide study in colorectal cancer (CRC) and endometrial cancer (EC) diagnosed between 2016 and 2023, including 47,657 patients to evaluate the two‐antibody approach. In 0.17% and 0.4% of cases of CRC and EC, respectively, dMMR cases would be missed with the two‐antibody approach. Subgroup analyses pointed towards slightly increased miss rates in younger patients (under the age of 50 years) in both groups and identified special subtypes (signet ring cell carcinoma, medullary carcinoma, and mucinous carcinoma in CRC and clear cell carcinoma in EC) with increased miss rates. For these specific subgroups, a low threshold should be used for further testing. In case of ambiguous or heterogeneous staining patterns, four antibodies should be used. Conclusion In general, the application of a two‐antibody MMR testing strategy does not lead to considerable failure of dMMR identification and saves costs.

Colorectal medullary carcinoma: a pathological subtype with intense immune response and potential to benefit from immune checkpoint inhibitors

Article

Mar 2024
Expet Rev Clin Immunol

Introduction: Different pathological types of colorectal cancer have distinguished immune landscape, and the efficacy of immunotherapy will be completely different. Colorectal medullary carcinoma, accounting for 2.2-3.2%, is characterized by massive lymphocyte infiltration. However, the attention to the immune characteristics of colorectal medullary carcinoma is insufficient. Area covered: We searched the literature about colorectal medullary carcinoma on PubMed through November 2023to investigate the hallmarks of colorectal medullary carcinoma's immune landscape, compare medullary carcinoma originating from different organs and provide theoretical evidence for precise treatment, including applying immunotherapy and BRAF inhibitors. Expert opinion: Colorectal medullary carcinoma is a pathological subtype with intense immune response, with six immune characteristics and has the potential to benefit from immunotherapy. Mismatch repair deficiency, ARID1A missing and BRAF V600E mutation often occurs. IFN-γ pathway is activated and PD-L1 expression is increased. Abundant lymphocyte infiltration performs tumor killing function. In addition, BRAF mutation plays an important role in the occurrence and development, and we can consider the combination of BRAF inhibitors and immunotherapy in patients with BRAF mutant. The exploration of colorectal medullary carcinoma will arouse researchers' attention to the correlation between pathological subtypes and immune response, and promote the process of precise immunotherapy.

A Case Report of MSI-high Medullary Carcinoma Arising from the Ascending Colon with Unusual Postoperative Recurrence抗PD-1抗体薬が奏効したMSI-high上行結腸髄様癌の1例

Article

Apr 2023

We herein report a case of medullary carcinoma of the ascending colon. An 82-year-old female was hospitalized at our hospital with complaints of nausea and dizziness. Colonoscopy demonstrated an infiltrative ulcerated tumor in the ascending colon. A contrast-enhanced computed tomography scan showed regional lymph node swelling but no distant metastasis. Under the preoperative diagnosis of ascending colon cancer (stage IIIb), laparoscopic ileocecal resection with regional lymph node dissection was performed. The resected specimen revealed medullary carcinoma with no regional lymph node metastasis. Although the tumor partially invaded the abdominal wall, adjuvant chemotherapy was not administered because of her age. Postoperative recurrence in the left adrenal gland and para-aorta and right external iliac lymph nodes was recognized seven months after surgery. Genetic examination revealed microsatellite instability (MSI)-high and BRAF V600E mutation in this tumor. Progression was observed despite first-line therapy of four cycles of capecitabine and bevacizumab, but second-line therapy of nivolumab reduced the size of the recurrent lesion during 33 months after surgery. Programmed death-1 blockade therapy may be feasible for recurrent medullary carcinoma with MSI-high.

Encapsulation for general cancer treatment

Chapter

Jan 2023

Prognostic nomogram for predicting overall survival in patients with medullary carcinoma of the colon

Preprint

Full-text available

Mar 2023

Objective Medullary carcinoma (MC) of the colon is a rare malignancy, and there is no survival prediction for this tumor. This study aimed to construct a nomogram to predict the overall survival (OS) of patients with MC Methods We included 276 patients with a pathological diagnosis of MC between 2010 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. The random forest method and multivariate Cox proportional risk model were used to identify independent prognostic factors for MC. The consistency index (C-index), the receiver operating characteristic (ROC) curve, and the calibration curve determined the nomogram's predictive accuracy and discriminative ability. Decision curve analysis (DCA) was used to evaluate the net clinical benefit of the nomogram. Results The Cox regression analysis showed that age, N-stage, M-stage, tumor size, and chemotherapy were associated with OS of MC. Based on the identified independent factors, we constructed a nomogram for predicting OS in MC patients. The C-index value of the nomogram for predicting OS was superior to the TNM staging system (0.705 vs. 0.673). ROC and calibration curves showed the nomogram's good discriminatory and calibration ability. DCA showed that the nomogram had a more significant net clinical benefit than the TNM staging system. Conclusion We developed a nomogram to accurately predict MC patients’ survival. The nomogram had excellent predictive efficacy and could help clinicians to assess the prognosis of MC patients.

Gut-associated Lymphoid Tissue/Dome-Type Carcinoma of the Colon: A Rare Case Report With Review of the Literature

Article

Feb 2023

Gut-associated lymphoid tissue (GALT) carcinoma, also termed dome-type carcinoma, is an infrequent distinctive subtype of colorectal adenocarcinoma and only 18 cases have been reported in the English medical literature. These tumors have unique clinicopathological features and are considered to have a low malignant potential with favorable prognosis. Herein, we described a case of a 49-year-old male with intermittent hematochezia for 2 years. Colonoscopy revealed a sessile broad-based polyp of approximately 20 mm × 17 mm in the sigmoid colon 260 mm away from the anus, with a slightly hyperemic surface. Histologically, this lesion showed typical GALT carcinoma. The patient was followed up for one and a half year and he did not experience any discomfort, such as abdominal pain or hematochezia, and no tumor recurrence occurred. Moreover, we reviewed the literature, summarized the clinicopathological features of GALT carcinoma, and highlighted its pathological differential diagnosis to further explore this infrequent type of colorectal adenocarcinoma.

Medullary Carcinoma of the Ampulla Has Distinct Clinicopathologic Characteristics Including Common Association with Microsatellite Instability and PD-L1 Expression

Article

Dec 2022
Hum Pathol

Medullary carcinomas have not yet been fully characterized in the ampulla. Here, 359 ampullary carcinomas (ACs) were reviewed and 11 medullary type carcinomas (3%) were found and analyzed. In addition to diagnostic medullary pattern, six showed focal mucinous, and 8 had focal abortive gland-like formations. They occurred in younger patients (57 vs 65 y; p=0.02), had larger invasion size (mean, 3.2 vs 1.9 cm; p=0.01), formed nodular polypoid or plaque-like tumors, often lacked pre-invasive component. In addition to the lymphoplasmacytic infiltrates, they also had prominent eosinophils in 5/11 cases. Eight were papilla Vateri-NOS (not otherwise specified) tumors, two were ampullary-duodenal origin, one had a minor intra-ampullary papillary tubular neoplasm component, and none were ampullary-ductal. Although they had pushing-border infiltration, perineural and vascular invasion was common. They were strongly associated with DNA mismatch repair (MMR) protein deficient (7/11, 64%). The 5-yr survival rate (53%) appeared to be comparable with, and perhaps even better than that of non-medullary ACs (47%), although this did not reach statistical significance (p=0.47). Programed cell death ligand-1 (PD-L1) expression levels were assessed in 8, and all 4 that were MMR deficient were positive both by combined positive score (CPS) ≥1 and tumor proportion score (TPS) ≥1, and of the 4 MMR proficient cases, three were positive by CPS; two by TPS. Overall, only one of 8 available for analysis failed to show PD-L1 positivity by CPS. In contrast, non-medullary MMR-deficient carcinomas expressed PD-L1 in only 33% of tumors by CPS, and none by TPS. One medullary carcinoma was also EBV associated. Unlike "medullary carcinomas" of the kidney, INI1 was retained in all 8 cases tested. In conclusion, medullary carcinomas are 3% of ACs, have a strong association with MMR-D, and may be less aggressive despite their larger size. PD-L1 expression appears to be closely associated with medullary ACs regardless of MMR status, and thus targeted therapies can be considered for all medullary carcinomas of this site.

Medullary carcinoma in the colon

Article

Jul 2022

Madeleine Kelly

Colorectal Cancer Diagnosis and Therapeutic Updates

Book

Full-text available

May 2022

Cancer is a disease in which cells develop abnormally and may involve any part of the body. Cancer is distinguished by the sudden development of irregular cells. It spreads to other areas of the body and eventually to other organs; this is referred to as metastasizing. The most common cause of cancer-related death is metastasis. According to a World Health Organization (WHO) survey, about 9.6 million deaths were reported worldwide in 2018, and 7.6 million deaths were estimated in 2008 due to cancer. Lung, breast, colorectal, stomach, and liver cancers are some of the more prevalent cancers diagnosed in men. Breast cancer, colorectal cancer, lung cancer, cervical cancer, and thyroid cancer are some of the more prevalent cancers among women. Changing one's lifestyle and adopting more sustainable habits could prevent about 30 percent of cancer deaths. According to a study released on September 12, 2018 in "A Cancer Journal for Clinicians" by the International Agency for Research on Cancer (IARC), the top three cancer forms are prostate, female breast, and colorectal cancer, both of which are mainly present in humans. Colorectal cancer is the third most commonly diagnosed cancer (1.8 million patients, or 10.2 percent of all cases), followed by prostate cancer (1.3 million cases, or 7.1 percent), and stomach cancer (the fifth most commonly diagnosed cancer) (1.0 million cases, 5.7 percent). Per year, it is projected that 1.2 million people are diagnosed with colorectal cancer.Colorectal cancer (CRC) is a complex disorder caused by the interaction of hereditary and environmental causes, which can be classified according to the importance of each of these factors. CRCs are often seasonal (70-80%), with age being the most important risk factor; hereditary variants account for just a small percentage of incidents. Colorectal cancer develops as a result of the accumulation of hereditary and epigenetic modifications. The most advanced CRCs grow from adenomas (adenoma-carcinoma sequence). The neoplastic transfer cycle is estimated to be about 10-15 years, which refers to the amount of time required to detect and remove these adenomas before they progress to invasive carcinoma. The three main carcinogenesis pathways for colorectal cancer (CRC) are currently being debated.This book reflects on the most basic clinical and medical methods for colorectal cancer care. Furthermore, we concentrate on recent advancements in colorectal cancer science as well as the critical mechanisms involved in colorectal cancer treatment.The chapters of this book are structured in such a manner that even readers with no prior awareness of the topic will learn about it in the book. As a result, the book's contents have been divided into eleven chapters.We did our best to include relevant knowledge in a clear and concise manner. We hope that by the end of the book, readers will be able to follow other researchers in their pursuit of the topic's estimated supremacy. Furthermore, we hope to be able to contribute to the development of research in this area.

Colorectal medullary carcinoma: heterogeneous presentations of a rare clinico-pathological entity. Report of two cases

Article

Mar 2022

Colorectal medullary carcinoma (CMC) is a rare subset of minimally differentiated carcinomas. CMC tend to be right-sided and present at an advanced stage. Despite this, distant metastases are rare at presentation. The liver and the regional lymph nodes represent the most common sites of metastases. Most of the time, CMCs exhibit mismatch repair deficiency and a strong association with high-level microsatellite instability. There is no conspicuous data regarding treatment strategies and short-term outcomes. CMC is supposed to be related to better prognosis compared to poorly-differentiated and undifferentiated colonic adenocarcinomas, but reports are controversial. This lesion, with heterogeneous presentations and unclear prognostic significance, may be unfamiliar to histopathologists and can lead to diagnostic uncertainty and overtreatments. Our aim is to renew the attention to this rare histological subtype through the report of two cases.

Pathology of Malignant Lesions of the Gastrointestinal Tract

Chapter

Mar 2022

Malignant epithelial tumors of the gastrointestinal tract are especially common worldwide, including in Asia. This chapter carefully brings out the differences of demography of various epithelial malignancies between Asian and western countries. With globalization, the incidence and prevalence of malignant gastrointestinal tract carcinomas are changing rapidly and currently the incidences of most malignant gastrointestinal tract carcinomas are showing an upwards trend. If we take the example of colorectal adenocarcinomas, its incidence and age-adjusted death rates are increasing both in western countries and Asia in patients less than 50-years old; while, the incidence in patients aged more than 50-years is increasing in Asia, but decreasing in America and European countries. Also, the classifications of these malignant epithelial tumors are changing, especially in stomach, and their pathogenetic mechanisms are undergoing rapid updation, especially owing to availability of molecular data. Nowadays, all histologically similar malignant epithelial tumors of the gastrointestinal tract, as adenocarcinomas of the esophagus, stomach, small bowel, right colon and left colon are appearing as distinct entities. This chapter, along will chap. 21 will give the readers an comprehensive view of the current epidemiology, classifications, clinical and histological details, prognostic factors, pathogenesis and molecular classifications and recommended work up. The chapter has been supplemented with numerous images, tables, diagrams, learning tips and case studies.

SWI/SNF complex (SMARCA4, SMARCA2, INI1/SMARCB1) deficient colorectal carcinomas are strongly associated with microsatellite instability: An incidence study in 4508 colorectal carcinomas

Article

Dec 2021

Aims Loss of expression of mammalian SWI/SNF (BAF) complex subunits including SMARCA4, SMARCA2 and INI1/SMARCB1 (termed SWI/SNF deficiency) has been reported in colorectal carcinomas (CRCs) but its frequency and clinical significance is uncertain.. Methods and Results We performed immunohistochemistry for SMARCA4, SMARCA2 and SMARCB1 on 4508 consecutive resected CRCs. SMARCA4 loss was found in 13 CRCs (0.3%), SMARCA2 in 59 (1.3%) and SMARCB1 in 21 (0.4%). Some CRCs showed loss of expression of more than one subunit, so that 84 CRCs (1.7%) were deficient for at least one component. SWI/SNF deficiency was associated with higher-grade, right-sided location, mismatch repair deficiency (MMRd) and BRAFV600E mutation (p<0.05). 5.8% of MMRd and 5.4% of BRAFV600E-mutant cases were SWI/SNF deficient; compared to 0.9% and 0.4% of MMRp and BRAF wild-type cases, (p<0.001). Any loss of expression of SMARCB1 and global loss of expression of SMARCA2 were associated with statistically significant worse overall survival, while SMARCA4 deficient CRCs demonstrated a trend only towards poor overall survival (p=0.121). In multivariate analysis, any loss of SMARCA4 and global loss of SMARCA2 were associated with worse survival (OR: 3.33; p=0.019 and OR: 3.39; p<0.001). Of particular note, among the subgroup of CRCs that were MMRd and BRAFV600E mutated (otherwise considered a good prognostic group) SMARCA4 loss was associated with much worse median survival (10.5 vs 110.9 months; p=0.003). Conclusions SWI/SNF deficiency is rare in CRC but enriched in MMRd tumors. Identifying these cases has morphologic associations and prognostic significance, and in the future may have potential therapeutic implications. Abstract

The 2019 World Health Organization Classification of appendiceal, colorectal and anal canal tumours: an update and critical assessment

Article

Full-text available

Jan 2021

The recently published 5th edition 2019 World Health Organization (WHO) Classification of Tumours of the Digestive System brings significant changes from the 2010 4th edition. An emphasis on uniformity in nomenclature and grading for tumours across all organ systems is a particular feature of the 5th edition blue book series that is reflected in the gastrointestinal tract (GIT) classification. For example, simplified two tiered grading is reinforced for preinvasive lesions throughout the GIT, with dysplasia at all sites now being considered either low or high grade. Similarly, a uniform approach to classification and grading of GIT neuroendocrine neoplasms has been consolidated, with an emphasis on distinguishing grade 3 neuroendocrine tumours from neuroendocrine carcinomas. In this review, we discuss and critically assess the important and sometimes controversial changes made to the classification of tumours of the lower GIT, comprising the colorectum, vermiform appendix and anal canal. The particularly controversial decision to endorse the term ‘sessile serrated lesion’ for lesions previously termed ‘sessile serrated polyp/adenoma’ is explored. The morphological, molecular, and clinical insights behind the substitution of the term ‘goblet cell adenocarcinoma’ for ‘goblet cell carcinoid’ are assessed. The evolution of the classification of appendiceal mucinous neoplasms is considered. Inflammatory bowel disease related dysplasia and its evolving subtypes, with major implications for pathologists in routine practice, is explained.

Is Medullary Carcinoma of the Colon Underdiagnosed ? An Audit of Poorly Differentiated Colorectal Carcinomas in a large NHS Teaching Hospital

Article

Nov 2020

Aims Medullary carcinoma is an uncommon colorectal tumour which appears poorly differentiated histologically. Consequently it may be confused with poorly differentiated adenocarcinoma NOS. The principal aim of this study was to review a large series of poorly differentiated colorectal cancers resected at a large NHS Teaching Hospital to determine how often medullary carcinomas were misclassified . Secondary aims were to investigate how often neuroendocrine differentiation or metastatic tumours were considered in the differential diagnosis, and compare clinico‐pathological features between medullary and poorly differentiated adenocarcinoma NOS. Methods Histology slides from 302 colorectal cancer resections originally reported as poorly differentiated adenocarcinoma were reviewed and cases fulfilling WHO criteria for medullary carcinoma identified. The original pathology report was examined for any mention of medullary phenotype, consideration of neuroendocrine differentiation or metastasis from another site. Clinico‐pathological features were compared to poorly differentiated adenocarcinoma NOS. Results Only one third of medullary carcinomas were correctly identified between 1997 and 2018. The other two thirds were reported as poorly differentiated adenocarcinoma NOS. The possibility of an extracolonic origin or neuroendocrine carcinoma was considered in 21% and 27% of reports. Most medullary tumours exhibited mismatch repair deficiency, were located in ascending colon and caecum, and had a lower rate of vascular channel invasion and lymph node metastasis compared to poorly differentiated adenocarcinoma. Conclusions Medullary carcinoma of the colon is often mistaken for poorly differentiated adenocarcinoma NOS and occasionally for neuroendocrine or metastatic carcinoma. Greater familiarity with morphological criteria and use of mismatch repair protein staining should improve diagnosis.

Pathologic Features of Colorectal Carcinomas

Chapter

Jan 2021

Colorectal carcinoma is observed as the second most common cancer in women and the third most common cancer in men. These lesions may show the macroscopic appearance of a polypoid vegetating mass or of a flat infiltrating lesion. These tumours are mostly adenocarcinomas (96%), and they show a mucinous component in some cases. The signet ring cell carcinoma, squamous carcinoma, undifferentiated neoplasms and medullary-type adenocarcinoma (solid carcinoma with minimal glandular differentiation or slight cellular pleomorphism) are the rare malignancies of the large bowel. Colorectal carcinoma can be graded into well, moderately and poorly differentiated lesions, but there is only little evidence supporting that grading may help evaluating the prognosis of affected patients. In our chapter, pathologic features of colorectal carcinoma are given with detailed knowledge.

Medullary Carcinoma in the Sigmoid Colon: A Case ReportS状結腸に発生した大腸髄様癌の1例

Article

Full-text available

Jan 2020

We describe a 74-year-old male patient who suffered medullary carcinoma of the sigmoid colon. He presented to our hospital with melena, and total colonoscopy revealed adenocarcinoma with infiltrative ulcerative type at the sigmoid colon (40 cm above the anal verge). A contrast-enhanced computed tomography (CT) scan showed no apparent or distant metastasis. We performed laparoscopic sigmoidectomy with D3 lymph node resection on the diagnosis of adenocarcinoma of the sigmoid colon ［T3(SS)N0M0; cStage IIa］. The specimen showed medullary carcinoma of the sigmoid colon. The postoperative course was uneventful, and he was discharged 13 days later. Medullary carcinoma of the colon is a relatively new concept described for the first time in the 8th Japanese Classification of Colon Cancer. It is most commonly found in the right-sided colon and has a relatively good prognosis, whereas it is relatively rarely found in the left-sided colon such as in the present case. We report this case, along with a review of the relevant literature.

Clinicopathological importance of colorectal medullary carcinoma

Article

Oct 2019

Purpose Medullary carcinoma (MC) is a rare tumor with a solid growth pattern without glandular differentiation and constitutes less than 1% of colorectal cancers. Lymph node positivity and distant organ metastasis were reported to be lower than in other poorly differentiated adenocarcinomas. Therefore, the diagnosis of MC is pathologically important in terms of follow-up and treatment. We aimed to investigate the characteristics of medullary cancer in our case series. Methods 427 patients with colorectal cancer (CRC) who underwent surgery between January 2011 and December 2017 were evaluated retrospectively in 2 groups as MC (n = 13) and non-MC (n = 414) in terms of demographic characteristics, pathological data, and oncological outcomes. Results 76.9% (n = 10) of the MC group were female while 36% (n = 149) of the non-MC group were female (p = 0.003). The tumors were located in the right colon in 84.6% (n = 11) of the MC patients and in 26.6% (n = 110) of the non-MC patients (p < 0.001). The rate of laparoscopy was 83.8% for all CRC patients, and 53.8% for the MC group (p = 0.01). T4 cases (69.2%) and tumor volume (131 ± 87 cm³) in the MC group were significantly higher than in the non-MC group (p < 0.05). The rate of high microsatellite instability (MSI) was 85%. 5‑year overall survival was 75% for the patients with MC and 82% for non-MC (p = 0.13). Conclusion MC is commonly localized in the right colon, has a large tumor size, and is mostly diagnosed in the T4 stage. As MC most likely have defects in DNA MMR, correct pathological diagnosis is important for postoperative treatment and the prognosis of the patients.

Gut-associated lymphoid tissue or so-called “dome” carcinoma of the colon: Review

Article

Full-text available

Jan 2019

Aim: To present a comprehensive review of the etiology, clinical features, macroscopic and pathological findings, and clinical significance of Gut-associated lymphoid tissue or "dome" carcinoma of the colon. Methods: The English language medical literature on gut- or gastrointestinal-associated lymphoid tissue (GALT) or "dome" carcinoma of the colon was searched and appraised. Results: GALT/dome-type carcinomas of the colon are thought to arise from the M-cells of the lymphoglandular complex of the intestine. They are typically asymptomatic and have a characteristic endoscopic plaque- or "dome"-like appearance. Although the histology of GALT/dome-type carcinomas displays some variability, they are characterized by submucosal localization, a prominent lymphoid infiltrate with germinal center formation, tumor-infiltrating lymphocytes, absence of desmoplasia, and dilated glands lined by columnar epithelial cells with bland nuclear features and cytoplasmic eosinophilia. None of the patients reported in the literature with follow-up have developed metastatic disease or local recurrence. Conclusion: Increased awareness amongst histopathologists of this variant of colorectal adenocarcinoma is likely to lead to the recognition of more cases.

A Prognostic Model Based on Circulating Tumour Cells is Useful for Identifying the Poorest Survival Outcome in Patients with Metastatic Colorectal Cancer

Article

Full-text available

Jan 2018
INT J BIOL SCI

Background: There is an urgency to develop robust prognostic biomarkers for metastatic colorectal cancer (mCRC) patients receiving chemotherapy. The current study aimed to examine the prognostic significance of circulating tumour cells (CTCs) and to develop a prognostic model incorporating CTCs in predicting the outcomes of mCRC patients treated with chemotherapy. Methods: Our study prospectively enrolled 55 mCRC patients who had undergone palliative chemotherapy between 2011 and 2014. Baseline CTCs and clinicopathological variables predictive of survival outcome were identified using univariate analysis. Negative selection-based protocol plus flow cytometry was used for CTC identification. Results: The median overall survival (OS) and progression-free survival (PFS) were 24.2 months and 8.7 months, respectively. CTCs were detected in all the patients, and the median number of CTCs was 30.8/mL (range: 5.8-431.3/mL). The median OS and PFS were 37.1 and 13.3 months, respectively, for patients with CTC number ≤30/mL, while the median OS and PFS were 14.9 months and 5.1 months, respectively, for patients with CTC number >30/mL (both P<0.001). A prognostic model using CTCs in conjunction with other independent clinical variables further stratified patients into good and poor prognostic groups. The median OS and PFS were 32.4 and 11.5 months, respectively, in the good prognostic group and 5.4 and 2.7 months, respectively, in the poor prognostic group. Conclusions: We developed a reliable CTC-based prognostic model for the prediction of clinical outcomes in mCRC patients treated with chemotherapy. This model may be used to assist clinicians in identifying those with the poorest prognosis before treatment.

Immunohistochemistry for Myc Predicts Survival in Colorectal Cancer

Article

Full-text available

Feb 2014
PLOS ONE

MYC over-expression as determined by molecular means has been reported as a favorable prognostic biomarker in colorectal carcinoma (CRC). However MYC expression analysis is not available in the routine clinical setting. We investigated whether immunohistochemistry (IHC) for the myc protein using a novel commercially available rabbit monoclonal antibody [clone Y69] which is currently in widespread clinical use for lymphoma diagnosis could be used to predict outcome in resected CRC. Myc IHC was performed on a tissue microarray (TMA) comprising a retrospective cohort of 1421 CRC patients and scored blinded as to all clinical and pathological data. IHC was also performed on a subcohort of whole section CRCs to assess staining characteristics and concordance with TMA expression. MYC over-expression was found in 980 (69%) of CRCs and was associated with tumor stage and DNA mismatch repair/BRAF status. There was substantial agreement between TMA and whole section myc IHC (kappa = 0.742, p<0.01). CRCs with MYC over-expression demonstrated improved 5-year survival (93.2% vs. 57.3%), with the effect significantly modulated by the dominant effect of tumor stage, age at diagnosis and lymphovascular space invasion status on survival. We conclude that myc status as determined by IHC alone can be used to predict overall survival in patients with CRC undergoing surgical resection.

Review of Histopathological and Molecular Prognostic Features in Colorectal Cancer

Article

Full-text available

Jun 2011

Prediction of prognosis in colorectal cancer is vital for the choice of therapeutic options. Histopathological factors remain paramount in this respect. Factors such as tumor size, histological type and subtype, presence of signet ring morphology and the degree of differentiation as well as the presence of lymphovascular invasion and lymph node involvement are well known factors that influence outcome. Our understanding of these factors has improved in the past few years with factors such as tumor budding, lymphocytic infiltration being recognized as important. Likewise the prognostic significance of resection margins, particularly circumferential margins has been appreciated in the last two decades. A number of molecular and genetic markers such as KRAS, BRAF and microsatellite instability are also important and correlate with histological features in some patients. This review summarizes our current understanding of the main histopathological factors that affect prognosis of colorectal cancer.

BRAFV600E immunohistochemistry in conjunction with mismatch repair status predicts survival in patients with colorectal cancer

Article

Full-text available

Oct 2013
Mod Pathol

Immunohistochemistry has recently been validated for the detection of the BRAFV600E mutation across a range of tumor types. In colorectal carcinoma, the presence of the BRAFV600E mutation can be used to virtually exclude Lynch syndrome in mismatch repair-deficient tumors. In mismatch repair-proficient tumors, BRAFV600E mutation assessed by molecular methods has been proposed as a poor prognostic factor. We investigated whether combined BRAFV600E and mismatch repair status assessment by immunohistochemistry alone can be used as a prognostic marker in the routine clinical setting. We performed immunohistochemistry for BRAFV600E, MLH1, PMS2, MSH2, and MSH6 on 1426 consecutive unselected colorectal carcinomas. Ninety-one (6.4%) carcinomas were mismatch repair-proficient and BRAFV600E mutant, and these tumors demonstrated a significantly worse 5-year survival of 49.7% compared with mismatch repair-proficient BRAF wild type (74.1% of tumors, 65.4% survival), mismatch repair-deficient BRAFV600E mutant (12.9% of tumors, 70.1% survival), and mismatch repair-deficient BRAF wild type (6.6% of tumors, 73.6% survival). The poor survival was confirmed by univariate analysis (P<0.01) but fell away in multivariate analysis (P=0.68) because of the strong effect of tumor stage and age on overall survival. We conclude that in addition to its utility in screening for Lynch syndrome, reflex BRAFV600E and mismatch repair assessment by immunohistochemistry can be used as a powerful predictor of all-cause survival.Modern Pathology advance online publication, 25 October 2013; doi:10.1038/modpathol.2013.200.

BRAFV600E Immunohistochemistry Facilitates Universal Screening of Colorectal Cancers for Lynch Syndrome

Article

Full-text available

Jun 2013

BRAFV600E mutation in microsatellite-unstable (MSI) colorectal carcinomas (CRCs) virtually excludes Lynch syndrome (LS). In microsatellite-stable (MSS) CRCs it predicts poor prognosis. We propose a universal CRC LS screening algorithm using concurrent reflex immunohistochemistry (IHC) for BRAFV600E and mismatch-repair (MMR) proteins. We compared BRAFV600E IHC with multiplex polymerase chain reaction (PCR) and matrix-assisted laser desorption/ionization-time of flight mass spectrometry in 216 consecutive CRCs from 2011. Discordant cases were resolved with real-time PCR. BRAFV600E IHC was performed on 51 CRCs from the Australasian Colorectal Cancer Family Registry (ACCFR), which were fully characterized for BRAF mutation by allele-specific PCR, MMR status (MMR IHC and MSI), MLH1 promoter methylation, and germline MLH1 mutation. We then assessed MMR and BRAFV600E IHC on 1403 consecutive CRCs. By matrix-assisted laser desorption/ionization-time of flight mass spectrometry 15 cases did not yield a BRAF result, whereas 38/201 (19%) were positive. By IHC 45/216 (20%) were positive. Of the 7 discordant cases, real-time PCR confirmed the IHC result in 6. In the 51 CRCs from the ACCFR, IHC was concordant with allele-specific PCR in 50 cases. BRAFV600E and MSI IHC on 1403 CRCs demonstrated the following phenotypes: BRAF/MSS (1029 cases, 73%), BRAF/MSS (98, 7%), BRAF/MSI (183, 13%), and BRAF/MSI (93, 7%). All 11/1403 cancers associated with proven LS were BRAF/MSI. We conclude that BRAF IHC is highly concordant with 2 commonly used PCR-based BRAFV600E assays; it performed well in identifying MLH1 mutation carriers from the ACCFR and identified all cases of proven LS among the 1403 CRCs. Reflex BRAFV600E and MMR IHC are simple cheap tests that facilitate universal LS screening and identify the poor prognosis of the BRAFV600E-mutant MSS CRC phenotype.

Utilization of a MAB for BRAFV600E detection in papillary thyroid carcinoma

Article

Full-text available

Sep 2012
ENDOCR-RELAT CANCER

Identification of BRAFV600E in thyroid neoplasia may be useful because it is specific for malignancy, connotes a worse prognosis and is the target of novel therapies currently under investigation. Sanger sequencing is the 'gold-standard' for mutation detection but is subject to sampling error and requires resources beyond many diagnostic pathology laboratories. In this study, we compared immunohistochemistry using a BRAFV600E mutation-specific monoclonal antibody to Sanger sequencing on DNA from formalin fixed paraffin embedded tissue, in a well characterised cohort of 101 PTC patients. For all cases an IHC result was available, however five cases failed Sanger sequencing. Of the 96 cases with molecular data, 68 (71%) were BRAFV600E positive by IHC and 59 (61%) were BRAFV600E positive by sequencing. Eleven cases were discordant. One case was negative by IHC and initially positive by sequencing. Repeat sequencing of that sample and sequencing of a macrodissected sample were negative for BRAFV600E. Of 10 cases positive by IHC but negative by sequencing on whole sections, repeat sequencing on macrodissected tissue confirmed the IHC result in 7 cases (suggesting these were false negatives of sequencing on whole sections). In 3 cases repeat sequencing on recut tissue remained negative (including using massive parallel sequencing), but these cases demonstrated relatively low neoplastic cellularity. We conclude that immunohistochemistry for BRAFV600E is more sensitive and specific than Sanger sequencing in the routine diagnostic setting and may represent the new gold standard for detection of BRAFV600E mutation in PTC.

Predictive and prognostic roles of BRAF mutation in stage III colon cancer: Results from intergroup trial CALGB 89803

Article

Full-text available

Dec 2011

Alterations in the RAS-RAF-MAP2K (MEK)-MAPK signaling pathway are major drivers in colorectal carcinogenesis. In colorectal cancer, BRAF mutation is associated with microsatellite instability (MSI), and typically predicts inferior prognosis. We examined the effect of BRAF mutation on survival and treatment efficacy in patients with stage III colon cancer. Methods: We assessed status of BRAF c.1799T>A (p.V600E) mutation and MSI in 506 stage III colon cancer patients enrolled in a randomized adjuvant chemotherapy trial [5-fluorouracil and leucovorin (FU/LV) vs. irinotecan (CPT11), FU and LV (IFL); CALGB 89803]. Cox proportional hazards model was used to assess the prognostic role of BRAF mutation, adjusting for clinical features, adjuvant chemotherapy arm, and MSI status. Compared with 431 BRAF wild-type patients, 75 BRAF-mutated patients experienced significantly worse overall survival [OS; log-rank P = 0.015; multivariate HR = 1.66; 95% CI: 1.05-2.63]. By assessing combined status of BRAF and MSI, it seemed that BRAF-mutated MSS (microsatellite stable) tumor was an unfavorable subtype, whereas BRAF wild-type MSI-high tumor was a favorable subtype, and BRAF-mutated MSI-high tumor and BRAF wild-type MSS tumor were intermediate subtypes. Among patients with BRAF-mutated tumors, a nonsignificant trend toward improved OS was observed for IFL versus FU/LV arm (multivariate HR = 0.52; 95% CI: 0.25-1.10). Among patients with BRAF wild-type cancer, IFL conferred no suggestion of benefit beyond FU/LV alone (multivariate HR = 1.02; 95% CI: 0.72-1.46). BRAF mutation is associated with inferior survival in stage III colon cancer. Additional studies are necessary to assess whether there is any predictive role of BRAF mutation for irinotecan-based therapy.

Poorly differentiated colonic adeno-carcinoma, medullary type: clinical Phenotypic, and molecular characteristics

Article

Full-text available

May 1997

Clinicopathological evidence has accumulated that colorectal adenocarcinoma with minimal or no glandular differentiation constitutes two entities with different prognosis. In a series of 20 predominantly nonglandular, poorly differentiated adenocarcinomas, histological features, DNA content, p53 protein expression, Ki-ras mutation, and microsatellite instability were analyzed and correlated to the biology of the tumors. In addition, the presence of Epstein-Barr virus (EBV) transcripts was tested by RNA in situ hybridization and EBV DNA was demonstrated by nested polymerase chain reaction. Histologically, 13 tumors showed small uniform cells and 7 tumors showed large pleomorphic cells. Tumors with uniform cells exhibited more commonly an expansive growth pattern (69.2% versus 0%; P < 0.025) and a dense peritumor lymphoid infiltrate (84.6% versus 14.3%; P < 0.01) resembling their gastric counterpart, solid or medullary carcinoma. These tumors showed less frequent lymph node as well as hematogeneous metastases than pleomorphic carcinomas. In addition, they were usually diploid (84.6% versus 28.6%; P < 0.05) and lacked stabilization of the p53 protein (0% versus 42.9%; P < 0.05). No significant difference between the medullary and the pleomorphic tumor type was found with respect to bcl2 expression and the occurrence of Ki-ras mutations at codon 12. In contrast, microsatellite instability was almost totally restricted to poorly differentiated adenocarcinomas of the medullary type (100% versus 14.3%; P < 0.001). Finally, polymerase chain reaction revealed EBV DNA in 5 tumor specimens, which was, however, restricted to the peritumor lymphoid infiltrate as shown by in situ hybridization. Correlation with the biology of the tumors revealed that only one patient with the uniform cell type died due to metastastic disease during the follow-up period (median, 31 months), which was the case in five of the seven patients with the pleomorphic-type carcinoma (P < 0.025). Our results clearly indicate that the poorly differentiated colonic carcinoma with minimal or no glandular structures constitute two different entities, a medullary and a pleomorphic variant, which markedly differ in their phenotype, genotype, and prognosis.

Sporadic Medullary Carcinoma of the Colon A Clinicopathologic Comparison With Nonhereditary Poorly Differentiated Enteric-Type Adenocarcinoma and Neuroendocrine Colorectal Carcinoma

Article

Full-text available

Feb 2005

We studied 68 sporadic colorectal carcinomas (CRCs) with medullary features (MCRCs) and compared them with 35 poorly differentiated purely "enteric" CRCs (ECRCs) and 15 purely neuroendocrine carcinomas (NECs) of grades II and III, all in patients lacking a family history of CRC. Potential clinicopathologic differences between the study groups were assessed. MCRCs were significantly more common in the ascending colon than were ECRCs, but there was no significant dissimilarity to NECs. ECRCs occurred more often in the rectosigmoid than MCRCs or NECs. MCRCs arose in older patients, and a marked sex difference also was noted. Despite an infiltrative growth pattern, MCRC was less likely than ECRC to manifest with stage III or IV disease, but there was no stage-related difference from NECs. Although the histologic images of MCRCs were evocative of neuroendocrine differentiation, chromogranin positivity and synaptophysin reactivity in that group did not differ meaningfully from that of ECRCs but was dissimilar to the 100% labeling of NECs. p53 immunolabeling was similar in the 3 tumor groups. Follow-up data in the study cases showed that 5-year mortality was 40% (27/68) for MCRC, 59% (19/32) for ECRC, and 93% (14/15) for NEC. Medullary CRC seems to be a distinct clinicopathologic variant of CRC, which does not have a neuroendocrine lineage. The biologic behavior of MCRC was better than that of ECRC or NEC.

Carcinoma of the colon and rectum

Article

Jan 2010

Medullary carcinoma of the large intestine: A population based analysis

Article

Sep 2010

Bartlett

Medullary carcinoma (MC) of the colorectum is a relatively new histological type of adenocarcinoma characterized by poor glandular differentiation and intraepithelial lymphocytic infiltrate. To date, there has been no epidemiological study of this rare tumor type, which has now been incorporated as a separate entity in the World Health Organization (WHO) classification of colorectal cancers. We used the population-based registries of the Surveillance, Epidemiology and End Results (SEER) database to identify all cases of colorectal MC between 1973 and 2006 and compared them to poorly and undifferentiated colonic adenocarcinomas (PDA and UDA, respectively). We observed that MCs were rare tumors, constituting approximately 5–8 cases for every 10,000 colon cancers diagnosed, with a mean annual incidence of 3.47 (±0.75) per 10 million population. Mean age at diagnosis was 69.3 (±12.5) years, with incidence increasing with age. MCs were twice as common in females, who presented at a later age, with a lower stage and a trend towards favorable prognosis. MCs were extremely rare among African- Americans. MCs were most common in the proximal colon (74%), where they present at a later age than the sigmoid colon. There were no cases reliably identified in the rectum or appendix. Serum carcinoembryonic antigen levels (CEA) were elevated prior to first course of treatment in 40% of the patients. MCs were more commonly poorly differentiated (72%), with 22% being undifferentiated. MCs commonly presented with Stage II disease, with 10% presenting with metastases. Only one patient presented with N2b disease (>7 positive nodes). Early outcome analyses showed that MCs have 1- and 2-year relative survival rates of 92.7 and 73.8% respectively. Although MCs showed a trend towards better early overall survival, undifferentiated MCs present more commonly with Stage III, with comparatively worse early outcomes.

Should the grading of colorectal adenocarcinoma include microsatellite instability status?

Article

Jul 2014

ALK and ROS1 Overexpression is Very Rare in Colorectal Adenocarcinoma

Article

Jul 2014

Crizotinib, a small molecule tyrosine kinase inhibitor, has shown tremendous promise in the treatment of lung adenocarcinomas harboring either ALK or ROS1 rearrangements. Recently, small studies of colorectal carcinomas (CRCs) have suggested an incidence of EML4-ALK translocations of 0.4% to 2.4% and FIG-ROS1 translocations of 0.8%. In lung cancer, screening immunohistochemical staining for ALK and ROS1 has been validated as highly sensitive for these translocations, but this has not been investigated in CRC. We therefore sought to investigate the incidence of ALK and ROS1 overexpression as detected by immunohistochemical staining in a large cohort of CRCs. Of the 1889 CRCs, only 1 case (0.05%) demonstrated diffuse strong positive staining for ALK, whereas 14 (0.7%) showed weak nonspecific staining; the remainder were negative. The 1 positive case was confirmed to harbor an ALK rearrangement by fluorescent in situ hybridization (FISH), whereas the 14 tumors with weak staining were FISH-negative. The ALK positive case demonstrated positive expression in all dysplastic and malignant cells indicating that the translocation was an early clonal event. No cases were positive for ROS1 by immunohistochemical staining, although 2 cases did show some nonspecific staining and were shown to be negative for ROS1 translocation by FISH. We conclude that although diffuse strong positive staining for ALK is likely to be highly specific for ALK rearrangement in CRC, both ALK and ROS1 immunohistochemical staining are very low-yield tests and difficult to justify in the routine clinical setting.

Loss of ARID1A expression in colorectal carcinoma is strongly associated with mismatch repair deficiency

Article

Apr 2014

ARID1A is a tumor suppressor gene involved in chromatin remodelling. ARID1A mutations and loss of protein expression occur commonly in endometrioid and gynecological clear cell carcinoma where they are associated with mismatch repair (MMR) deficiency. We assessed ARID1A expression in a large cohort of colorectal carcinomas (CRCs). Immunohistochemistry for ARID1A was performed on whole sections from 100 CRCs and on 1876 CRCs in tissue microarray format. There was complete concordance between the staining on whole slides and tissue microarray sections. Loss of staining was found in 110 (5.9%) of 1876 CRCs and was strongly associated with older age, right sided location, large size, BRAF V600E mutation, MMR deficiency, high histological grade and medullary morphology, (all P < .01). There was a trend towards loss of expression being more common in females (P = .06). When subclassified by combined BRAF V600E mutation and MMR status, loss of ARID1A expression was found most commonly in CRCs with the BRAF V600E mutated, MMR- deficient phenotype (58 of 232 cases, 25%, P < .01). In univariate and multivariate analysis, loss of ARID1A expression was not associated with overall survival-hazard ratio 1.05 (0.68-1.64) and 0.60 (0.24-1.44), respectively. All carcinomas arising in patients with known Lynch syndrome (n = 12) were ARID1A positive. We conclude that loss of ARID1A expression occurs in a small but significant proportion of CRCs where it is strongly correlated with mismatch repair deficiency and other clinical and pathological features associated with somatic hypermethylation.

Sporadic colorectal adenocarcinomas with high-frequency microsatellite instability: Pathobiologic features, hMLH1 and hMSH2 expression, and clinical outcome

Article

Nov 2000

BACKGROUND. Widespread microsatellite instability (MSI) occurs in nearly 15% of sporadic colorectal cancers. Large bowel carcinomas with high-frequency MSI (MSI-H) (instability at ≥ 30% of microsatellite loci) are believed to display distinctive pathologic features and to behave less aggressively than microsatellite-stable (MSS) tumors and carcinomas with low-frequency MSI (MSI-L) (instability at < 30% of microsatellite loci). The aim of the current study was to accurately define the clinicopathologic and biologic features of MSI-H sporadic colorectal carcinomas. METHODS. MSI status was evaluated in 216 large bowel adenocarcinomas using polymerase chain reaction (PCR) and 6 microsatellite markers. Tumors that showed instability with at least two microsatellite markers were classified as MSI-H, whereas the other tumors were classified as MSI-L (instability at one locus) or MSS (no instability). Expression of p53, hMLH1, and hMSH2 gene products was determined by immunohistochemistry, and DNA ploidy pattern was determined by flow cytometry. The prognostic significance of MSI status was assessed by univariate and multivariate survival analyses. RESULTS. The significantly different pathologic features of MSI-H carcinomas were proximal location; large size; mucinous and medullary histotype; poor differentiation; expanding pattern of growth; more frequent Crohn-like conspicuous lymphoid reaction; and low incidence of extramural vein invasion. Most MSI-H tumors were DNA diploid (33 of 40 tumors; 82.5%) and p53 negative (34 of 44 tumors; 77.3%). Conversely, DNA aneuploidy and p53 overexpression were observed in 82.3% (130 of 158 tumors; P < 0.0001) and 54.1% (93 of 172 tumors; P = 0.0002) of MSI-L/MSS tumors, respectively. Loss of hMLH1 or hMSH2 expression was detected in a high fraction of MSI-H carcinomas (86.0%). Patients with MSI-H tumors showed a better clinical outcome than patients with MSI-L/MSS tumors (P = 0.0017). Furthermore, in multivariate analysis that included conventional clinicopathologic parameters, MSI status, and p53 expression as covariates, MSI status was a significant independent prognostic indicator of disease specific survival. CONCLUSIONS. Assessment of MSI status is an essential step in the genetic characterization of large bowel carcinomas and identifies a subset of tumors with distinct clinical, pathologic, and biologic features.

Colorectal carcinoma: Pathologic aspects

Article

Sep 2012
J Gastrointest Oncol

Colorectal carcinoma is one of the most common cancers and one of the leading causes of cancer-related death in the United States. Pathologic examination of biopsy, polypectomy and resection specimens is crucial to appropriate patient managemnt, prognosis assessment and family counseling. Molecular testing plays an increasingly important role in the era of personalized medicine. This review article focuses on the histopathology and molecular pathology of colorectal carcinoma and its precursor lesions, with an emphasis on their clinical relevance.

Sporadic colorectal adenocarcinomas with high‐frequency microsatellite instability

Article

Nov 2000
CANCER-AM CANCER SOC

Background: Widespread microsatellite instability (MSI) occurs in nearly 15% of sporadic colorectal cancers. Large bowel carcinomas with high-frequency MSI (MSI-H) (instability at > or = 30% of microsatellite loci) are believed to display distinctive pathologic features and to behave less aggressively than microsatellite-stable (MSS) tumors and carcinomas with low-frequency MSI (MSI-L) (instability at < 30% of microsatellite loci). The aim of the current study was to accurately define the clinicopathologic and biologic features of MSI-H sporadic colorectal carcinomas. Methods: MSI status was evaluated in 216 large bowel adenocarcinomas using polymerase chain reaction (PCR) and 6 microsatellite markers. Tumors that showed instability with at least two microsatellite markers were classified as MSI-H, whereas the other tumors were classified as MSI-L (instability at one locus) or MSS (no instability). Expression of p53, hMLH1, and hMSH2 gene products was determined by immunohistochemistry, and DNA ploidy pattern was determined by flow cytometry. The prognostic significance of MSI status was assessed by univariate and multivariate survival analyses. Results: The significantly different pathologic features of MSI-H carcinomas were proximal location; large size; mucinous and medullary histotype; poor differentiation; expanding pattern of growth; more frequent Crohn-like conspicuous lymphoid reaction; and low incidence of extramural vein invasion. Most MSI-H tumors were DNA diploid (33 of 40 tumors; 82.5%) and p53 negative (34 of 44 tumors; 77.3%). Conversely, DNA aneuploidy and p53 overexpression were observed in 82.3% (130 of 158 tumors; P < 0.0001) and 54.1% (93 of 172 tumors; P = 0.0002) of MSI-L/MSS tumors, respectively. Loss of hMLH1 or hMSH2 expression was detected in a high fraction of MSI-H carcinomas (86. 0%). Patients with MSI-H tumors showed a better clinical outcome than patients with MSI-L/MSS tumors (P = 0.0017). Furthermore, in multivariate analysis that included conventional clinicopathologic parameters, MSI status, and p53 expression as covariates, MSI status was a significant independent prognostic indicator of disease specific survival. Conclusions: Assessment of MSI status is an essential step in the genetic characterization of large bowel carcinomas and identifies a subset of tumors with distinct clinical, pathologic, and biologic features.

Medullary carcinoma of the large intestine: A population based analysis

Article

Oct 2010
INT J ONCOL

Medullary carcinoma (MC) of the colorectum is a relatively new histological type of adenocarcinoma characterized by poor glandular differentiation and intraepithelial lymphocytic infiltrate. To date, there has been no epidemiological study of this rare tumor type, which has now been incorporated as a separate entity in the World Health Organization (WHO) classification of colorectal cancers. We used the population-based registries of the Surveillance, Epidemiology and End Results (SEER) database to identify all cases of colorectal MC between 1973 and 2006 and compared them to poorly and undifferentiated colonic adenocarcinomas (PDA and UDA, respectively). We observed that MCs were rare tumors, constituting approximately 5-8 cases for every 10,000 colon cancers diagnosed, with a mean annual incidence of 3.47 (+/-0.75) per 10 million population. Mean age at diagnosis was 69.3 (+/-12.5) years, with incidence increasing with age. MCs were twice as common in females, who presented at a later age, with a lower stage and a trend towards favorable prognosis. MCs were extremely rare among African-Americans. MCs were most common in the proximal colon (74%), where they present at a later age than the sigmoid colon. There were no cases reliably identified in the rectum or appendix. Serum carcinoembryonic antigen levels (CEA) were elevated prior to first course of treatment in 40% of the patients. MCs were more commonly poorly differentiated (72%), with 22% being undifferentiated. MCs commonly presented with Stage II disease, with 10% presenting with metastases. Only one patient presented with N2b disease (>7 positive nodes). Early outcome analyses showed that MCs have 1- and 2-year relative survival rates of 92.7 and 73.8% respectively. Although MCs showed a trend towards better early overall survival, undifferentiated MCs present more commonly with Stage III, with comparatively worse early outcomes.

Immunohistochemistry for PMS2 and MSH6 alone can replace a four antibody panel for mismatch repair deficiency screening in colorectal adenocarcinoma

Article

Aug 2010
Pathology

Currently, testing for mismatch repair deficiency in colorectal cancers is initiated by performing immunohistochemistry with four antibodies (MLH1, PMS2, MSH2 and MSH6). If any one of these stains is negative the tumour is considered microsatellite unstable and, if clinical circumstances warrant it, the patient is offered genetic testing for Lynch's syndrome. Due to the binding properties of the mismatch repair heterodimer complexes, gene mutation and loss of MLH1 and MSH2 invariably result in the degradation of PMS2 and MSH6, respectively, but the converse is not true. We propose that staining for PMS2 and MSH6 alone will be sufficient to detect all cases of mismatch repair deficiency and should replace routine screening with all four antibodies. The electronic database of the department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia, was searched for all colorectal carcinomas on which a four panel immunohistochemical microsatellite instability screen was performed. An audit of the slides for concordant loss of MLH1-PMS2 and MSH2-MSH6 was then undertaken. Unusual or discordant cases were reviewed and, in some cases, re-stained to confirm the staining pattern. Of 344 cases of colorectal cancer which underwent four antibody immunohistochemistry, 104 displayed loss of at least one mismatch repair protein. Of these, 100 showed concordant mismatch repair loss (i.e., loss of MLH1 and PMS2 or loss of MSH2 and MSH6). The four discordant cases comprised two single negative cases (1 MSH6 negative/MSH2 positive case, 1 PMS2 negative/MLH1 positive) and two triple negative (both MLH1/PMS2/MSH6 negative). The microsatellite instability (MSI) group showed a relatively high median age (69.3 years) due to the departmental policy of testing all cases with possible MSI morphology regardless of age. The sensitivity and specificity of a two panel test comprised of PMS2 and MSH6, compared to a four panel test, is 100%. No false negatives or positives were identified. We conclude that the two panel test should replace a four panel protocol for immunohistochemical screening for mismatch repair deficiency.

Histopathological Identification of Colon Cancer with Microsatellite Instability

Article

Feb 2001

Cancer with high levels of microsatellite instability (MSI-H) is the hallmark of hereditary nonpolyposis colorectal cancer syndrome, and MSI-H occurs in ∼15% of sporadic colorectal carcinomas that have improved prognosis. We examined the utility of histopathology for the identification of MSI-H cancers by evaluating the features of 323 sporadic carcinomas using specified criteria and comparing the results to MSI-H status. Coded hematoxylin and eosin sections were evaluated for tumor features (signet ring cells; mucinous histology; cribriforming, poor differentiation, and medullary-type pattern; sponge-like mucinous growth; pushing invasive margin) and features of host immune response (Crohn’s-like lymphoid reaction, intratumoral lymphocytic infiltrate, and intraepithelial T cells by immunohistochemistry for CD3 with morphometry). Interobserver variation among five pathologists was determined. Subjective interpretation of histopathology as an indication for MSI testing was recorded. We found that medullary carcinoma, intraepithelial lymphocytosis, and poor differentiation were the best discriminators between MSI-H and microsatellite-stable cancers (odds ratio: 37.8, 9.8, and 4.0, respectively; P = 0.000003 to <0.000001) with high specificity (99 to 87%). The sensitivities, however, were very low (14 to 38%), and interobserver agreement was good only for evaluation of poor differentiation (kappa, 0.69). Mucinous histopathological type and presence of signet ring cells had low odds ratios of 3.3 and 2.7 (P = 0.005 and P = 0.02) with specificities of 95% but sensitivities of only 15 and 13%. Subjective interpretation of the overall histopathology as suggesting MSI-H performed better than any individual feature; the odds ratio was 7.5 (P < 0.000001) with sensitivity of 49%, specificity of 89%, and moderate interobserver agreement (kappa, 0.52). Forty intraepithelial CD3-positive lymphocytes/0.94 mm2, as established by receiver operating characteristic curve analysis, resulted in an odds ratio of 6.0 (P < 0.000001) with sensitivity of 75% and specificity of 67%. Our findings indicate that histopathological evaluation can be used to prioritize sporadic colon cancers for MSI studies, but morphological prediction of MSI-H has low sensitivity, requiring molecular analysis for therapeutic decisions.

Differentiating the undifferentiated: immunohistochemical profile of medullary carcinoma of the colon with an emphasis on intestinal differentiation

Article

Nov 2008

Undifferentiated or medullary carcinoma is characterized by its distinct histologic appearance and relatively better prognosis compared to poorly differentiated colonic carcinoma. These 2 entities may be difficult to differentiate by light microscopy alone. Only limited immunohistochemical studies investigating medullary carcinoma have been reported. These studies suggest a loss of intestinal differentiation, exemplified by a high percentage of CDX2 negativity. Our aim was to further characterize the immunohistochemical profile of medullary carcinoma, with particular emphasis on intestinal markers. Paraffin blocks from 16 cases of medullary carcinoma and 33 cases of poorly differentiated colonic carcinoma were retrieved, and tissue microarrays were constructed and stained with an immunohistochemical panel including CDX2, CK7, CK20, p53, intestinal trefoil factor 3, chromogranin, synaptophysin, MLH-1, MUC-1, MUC-2, and calretinin. A significantly higher proportion of medullary carcinomas, as opposed to poorly differentiated colonic carcinomas, showed loss of staining for MLH-1 and for the intestinal transcription factor CDX2, in accordance with previous studies. MLH-1 staining was present in only 21% of medullary carcinoma cases compared with 60% of the poorly differentiated colonic carcinoma cases (P = .02), whereas CDX2 was positive in 19% of medullary carcinomas and 55% of poorly differentiated colonic carcinomas (P = .03). Interestingly, calretinin staining was strongly positive in 73% of medullary carcinomas compared to only 12% of poorly differentiated colonic carcinomas (P < .0001). Evidence of intestinal differentiation by MUC-1, MUC-2, and TFF-3 staining was seen in 67%, 60%, and 53% of the medullary carcinomas, respectively. These 3 markers were frequently positive in many of the CDX2-negative medullary carcinoma cases. Medullary carcinoma of the colon retains a significant degree of intestinal differentiation as evidenced by its high percentage of staining for MUC-1, MUC-2, and TFF-3. Calretinin, MLH-1, and CDX2 may help to differentiate medullary carcinoma from poorly differentiated colonic carcinoma of the colon.

Undifferentiated carcinoma of the large bowel

Article

Feb 1977

N M Gibbs

Eight cases of the rare undifferented carcinoma of the large intestine are described. The histological distinction between undifferentiated and poorly differentiated colonic adenocarcinoma and malignant carcinoid is discussed. It is concluded that undifferented carcinoma is a variant of adenocarcinoma which tends to grow to a large size before symptoms are produced but which nevertheless has a good prognosis when locally resectable. Five patients survived between 6 and 28 years, one is well 6 months after operation and two cases where local removal could not be achieved, died within a year.

Improved prognosis of solid-type poorly differentiated colorectal adenocarcinoma: A clinicopathological and immunohistochemical study

Article

Aug 1997

We rarely encounter solid-type poorly differentiated colorectal carcinoma, and their histogenesis and biological behaviour are not fully disclosed. A review of 60 poorly differentiated carcinomas of the colorectum was undertaken, 36 (59%) of which were located in the right side of the colorectum. Although, on the basis of the World Health Organization (WHO) classification solid carcinomas are included among undifferentiated carcinomas, the poorly differentiated carcinomas were divided into four types; 27 solid carcinomas (Sol.), 17 poorly differentiated adenocarcinomas (PDA), six signet-ring cell carcinomas (Sig,) and 10 mucinous carcinomas (Muc.). Solid carcinomas revealed a solid alveolar growth of fairly uniformly sized tumour cells with occasional mitotic figures. This type of tumour had a relatively lower percentage of lymphatic permeation and lymph node metastasis compared with the other three types. The 5-year survival rates were 31% for all poorly differentiated carcinomas, 47% for the Sol. type, 32% for the PDA type, and 0% for both the Sig. and the Muc. types, with a rate of 72% for well-differentiated adenocarcinomas selected as controls. Immunohistochemically, bcl-2 protein expression was demonstrated in 38% of the Sol. type, but in only 12% of the other three non-solid types, this difference being significant (P < 0.05). These findings suggest that solid carcinomas of the colorectum should be regarded as a distinct type of poorly differentiated carcinoma, leading to a good prognosis.

Medullary adenocarcinoma of the colon: Clinicopathologic study of 11 cases

Article

Aug 1999
Hum Pathol

Colonic carcinomas with minimal or no glandular differentiation are a heterogeneous group of neoplasms which differ in their histologic appearance, clinical features, prognosis and molecular characteristics. Since 1990, we prospectively identified 11 patients with a predominantly solid (nonglandular) adenocarcinoma of the colon for which the term medullary adenocarcinoma of the colon (MAC) is proposed. The clinical, histological, histochemical, and immunohistochemical features of these neoplasms were studied. All patients with MAC were women with tumors in the cecum or proximal colon. Histological analysis showed nests or trabeculae of regular small to medium-sized cells with moderate amounts of eosinophilic cytoplasm; some cells contained mucin vacuoles. The nuclei had an open chromatin pattern and exhibited prominent nucleoli. Lymphatic permeation was present in most cases. Immunohistochemical reactions were positive for cytokeratin, carcinoembryonic antigen, and epithelial membrane antigen. Despite its histological resemblance with endocrine tumors, MAC is negative for endocrine markers. Of the eight patients for whom follow-up is available, four patients (two Dukes B and two Dukes C) are alive and well 1 to 4 years after surgery, one patient (Dukes C) died of tumor, one patient is alive with liver metastasis 4 years after surgery, and two patients died in the postoperative period. MAC appears to be a distinctive clinicopathologic entity. This tumor should be distinguished from other more aggressive, nonglandular tumors of the colon.

Medullary-Type Poorly Differentiated Adenocarcinoma of the Large Bowel: A Distinct Clinicopathologic Entity Characterized by Microsatellite Instability and Improved Survival

Article

Aug 1999

Recent studies suggest the existence of a distinct class of poorly differentiated large bowel adenocarcinomas, usually termed medullary-type adenocarcinomas (MTAs). The aim of the present study was to accurately define the clinical, histopathologic, biologic, and genetic features of this tumor type. Among 1,265 surgically resected sporadic colorectal carcinomas, 45 MTAs were identified on the basis of the following criteria: predominantly solid growth pattern (at least 70% of the tumor area) and lack of marked nuclear pleomorphism. The clinicopathologic, biologic, and genetic characteristics of MTAs were compared with those of a series of 457 common glandular colorectal adenocarcinomas. The significantly different clinicopathologic features of MTAs were proximal location, large size, invasion into adjacent organs, expanding pattern of growth, low incidence of distant metastases, more frequent conspicuous peritumoral lymphocytic infiltration, and Crohn's-like lymphoid reaction. Furthermore, young patients with MTAs often demonstrated a family history highly suggestive of a hereditary background. Unlike glandular adenocarcinomas, the large majority of MTAs were DNA diploid by flow cytometric analysis (21 of 25, 84%) and p53 negative by immunohistochemistry (36 of 41, 87.8%). In addition, 18 of the 20 MTAs examined by DNA microsatellite analysis demonstrated widespread microsatellite instability (90% of cases). Patients with MTAs showed a better clinical outcome with respect to patients with common poorly differentiated adenocarcinomas (PDAs) (P <.0001) and well- or moderately differentiated adenocarcinomas (WMDAs) (P =.133). In particular, none of the 33 patients with completely resectable stage II and III MTAs developed tumor recurrence during the observation period. Conversely, 24.7% of patients with stage II and III WMDAs and 48.9% of patients with stage II and III PDAs, who had undergone curative surgical resection, died of recurrent disease (P =.01 and P <.0001, respectively). All these data strongly indicate that MTAs represent a distinct pathologic entity, with specific histologic appearance and peculiar clinical and genetic features. These tumors need to be classified separately from other poorly differentiated colorectal carcinomas.

Sporadic colorectal adenocarcinomas with high‐frequency microsatellite instability

Article

Nov 2000

Widespread microsatellite instability (MSI) occurs in nearly 15% of sporadic colorectal cancers. Large bowel carcinomas with high-frequency MSI (MSI-H) (instability at > or = 30% of microsatellite loci) are believed to display distinctive pathologic features and to behave less aggressively than microsatellite-stable (MSS) tumors and carcinomas with low-frequency MSI (MSI-L) (instability at < 30% of microsatellite loci). The aim of the current study was to accurately define the clinicopathologic and biologic features of MSI-H sporadic colorectal carcinomas. MSI status was evaluated in 216 large bowel adenocarcinomas using polymerase chain reaction (PCR) and 6 microsatellite markers. Tumors that showed instability with at least two microsatellite markers were classified as MSI-H, whereas the other tumors were classified as MSI-L (instability at one locus) or MSS (no instability). Expression of p53, hMLH1, and hMSH2 gene products was determined by immunohistochemistry, and DNA ploidy pattern was determined by flow cytometry. The prognostic significance of MSI status was assessed by univariate and multivariate survival analyses. The significantly different pathologic features of MSI-H carcinomas were proximal location; large size; mucinous and medullary histotype; poor differentiation; expanding pattern of growth; more frequent Crohn-like conspicuous lymphoid reaction; and low incidence of extramural vein invasion. Most MSI-H tumors were DNA diploid (33 of 40 tumors; 82.5%) and p53 negative (34 of 44 tumors; 77.3%). Conversely, DNA aneuploidy and p53 overexpression were observed in 82.3% (130 of 158 tumors; P < 0.0001) and 54.1% (93 of 172 tumors; P = 0.0002) of MSI-L/MSS tumors, respectively. Loss of hMLH1 or hMSH2 expression was detected in a high fraction of MSI-H carcinomas (86. 0%). Patients with MSI-H tumors showed a better clinical outcome than patients with MSI-L/MSS tumors (P = 0.0017). Furthermore, in multivariate analysis that included conventional clinicopathologic parameters, MSI status, and p53 expression as covariates, MSI status was a significant independent prognostic indicator of disease specific survival. Assessment of MSI status is an essential step in the genetic characterization of large bowel carcinomas and identifies a subset of tumors with distinct clinical, pathologic, and biologic features.

Loss of CDX2 Expression and Microsatellite Instability Are Prominent Features of Large Cell Minimally Differentiated Carcinomas of the Colon

Article

Dec 2001

Most large bowel cancers are moderately to well-differentiated adenocarcinomas comprised chiefly or entirely of glands lined by tall columnar cells. We have identified a subset of poorly differentiated colon carcinomas with a distinctive histopathological appearance that we term large cell minimally differentiated carcinomas (LCMDCs). These tumors likely include a group of poorly differentiated carcinomas previously described by others as medullary adenocarcinomas. To better understand the pathogenesis of these uncommon neoplasms, we compared molecular features of 15 LCMDCs to those present in 25 differentiated adenocarcinomas (DACs) of the colon. Tumors were examined for alterations commonly seen in typical colorectal carcinomas, including increased p53 and beta-catenin immunoreactivity, K-ras gene mutations, microsatellite instability, and loss of heterozygosity of markers on chromosomes 5q, 17p, and 18q. In addition, tumors were evaluated by immunohistochemistry for CDX2, a homeobox protein whose expression in normal adult tissues is restricted to intestinal and colonic epithelium. Markedly reduced or absent CDX2 expression was noted in 13 of 15 (87%) LCMDCs, whereas only 1 of the 25 (4%) DACs showed reduced CDX2 expression (P < 0.001). Nine of 15 (60%) LCMDCs had the high-frequency microsatellite instability phenotype, but only 2 of 25 (8%) DACs had the high-frequency microsatellite instability phenotype (P = 0.002). Our findings provide support for the hypothesis that the molecular pathogenesis of LCMDCs is distinct from that of most DACs. CDX2 alterations and DNA mismatch repair defects have particularly prominent roles in the development of LCMDCs.

Hypermethylation of the hMLH1 promoter with absent hMLH1 expression in medullary-type poorly differentiated colorectal adenocarcinoma in the elderly

Article

Feb 2004

To clarify the significance of hMLH1 promoter hypermethylation in the development of medullary-type poorly differentiated colorectal adenocarcinoma, we studied the status of promoter methylation and hMLH1 expression in 23 medullary-type and 12 pleomorphic-type carcinomas, as well as the pathology and microsatellite status. In medullary-type carcinomas, the percentages of cases with promoter methylation (83%) and an absence of hMLH1 expression (91%) were significantly higher than in pleomorphic-type carcinomas (14 and 17%), respectively. The rate of microsatellite instability in the medullary type was significantly higher than that of the pleomorphic type (87 vs 40%, P<0.01). Compared with pleomorphic-type carcinomas, medullary-type carcinomas were significantly associated with hMLH1 promoter methylation, absent expression of hMLH1 protein, microsatellite instability, as well as a proximal location, a Crohn's-like lymphoid reaction, a low incidence of lymph node metastasis, and a favorable outcome. Medullary-type carcinomas accumulated with advancing age, especially in the female. These results indicated that hMLH1 hypermethylation, concurrent with a lack of its protein expression, may play an important role in the development of medullary-type poorly differentiated colorectal adenocarcinomas in the elderly.

Microsatellite-unstable mucinous colorectal carcinoma occurring in the elderly: Comparison with medullary type poorly differentiated adenocarcinoma

Article

Apr 2007

Mucinous carcinoma and poorly differentiated adenocarcinoma of the large intestine have a high frequency of microsatellite instability, and their occurrence increases gradually with age. To elucidate the clinicopathological and immunohistochemical features of microsatellite-unstable mucinous carcinoma and compare the tumor with medullary type poorly differentiated adenocarcinoma, the clinicopathological status and expression of mucin core and hMLH1 proteins were studied in 15 microsatellite-unstable and 20 microsatellite-stable mucinous colorectal carcinomas occurring in elderly patients, and compared with 23 cases of medullary type poorly differentiated adenocarcinoma in which 21 cases were microsatellite-unstable. Thirteen (87%) of 15 microsatellite-unstable carcinomas exhibited absent hMLH1 expression compared with three (15%) of 20 microsatellite-stable carcinomas (P < 0.01). The proportion (87%) of positive MUC5AC expression in microsatellite-unstable mucinous carcinoma was significantly higher than that (45%) in microsatellite-stable mucinous carcinoma (P = 0.01). Compared with microsatellite-stable mucinous carcinoma, microsatellite-unstable mucinous carcinomas were significantly associated with a proximal location, intra- and peritumoral inflammatory cell infiltration, frequent MUC5AC expression, a low incidence of lymph node metastasis and absent hMLH1 protein expression, which is not different to medullary type poorly differentiated adenocarcinoma except for MUC2 expression and age-related occurrence. These results suggest that microsatellite-unstable mucinous carcinoma occurring in the elderly shares clinicopathological and molecular features with medullary type poorly differentiated adenocarcinoma and that microsatellite instability with absent hMLH1 expression plays an important role in the development of these two carcinomas.

AJCC cancer staging handbook

Jan 2010
173

S B Edge
D R Byrd
C C Compton
SB Edge

Edge SB, Byrd DR, Compton CC, et al. AJCC cancer staging handbook. 7th ed. New York: Springer, 2010:173–206.

Regression modeling strategies package for R, version 4

Fe Harrell
Jr

Harrell FE Jr. Regression modeling strategies package for R, version 4.2-0.http://cran.r-project.org/web/packages/rms/index. html. Accessed Jul 2014.

Sporadic colorectal adenocarcinomas with high

R Gafà
I Maestri
M Matteuzzi
A Santini
S Ferretti

Regression modeling strategies package for R

F E Harrell

Medullary Colorectal Carcinoma Revisited: A Clinical and Pathological Study of 102 Cases

Abstract

No full-text available