Cutaneous Metastasis in the Setting of Both Colon and Breast Primary Malignancies

Colorectal cancer (CRC) is the third most diagnosed cancer in the United States, and many patients unfortunately have metastases at the time of their diagnosis. Cutaneous metastases of CRC have been reported in few journals and primarily as case reports due to their rarity. Here, we present the case of an 83-year-old woman with recently resected colon cancer, T4aN1bMx stage IIIB. She presented to our clinic for evaluation of a right midback mass, and a punch biopsy revealed dermal involvement by invasive, poorly differentiated carcinoma with epidermoid features. The mass was excised, and we ordered a PET scan in search of the primary tumor, which at that time was suspected to be of skin cancer origin. Surprisingly, this revealed a second malignancy triple-negative invasive ductal carcinoma of the left breast. The back mass stained positive for CK20, which was compatible with a metastasis from a colonic primary. After initially declining adjuvant therapy, the patient completed one cycle of capecitabine and oxaliplatin, which she tolerated poorly. She continued to further decline, developed widespread cutaneous metastases, and went home on hospice. Cutaneous lesions are an exceedingly rare site of metastasis for colon adenocarcinoma, and their clinical presentation can vary widely. It is important for providers to investigate any new skin lesion in a patient with a recent or remote history of malignancy, even if there were no sites of distant metastasis at initial diagnosis.

Partial loss of colonic primary cilia promotes inflammation and carcinogenesis

Primary cilia (PC) are important signaling hubs in cells and their deregulation has been associated with various diseases including cancer. Here we explored the role of PC in colorectal cancer (CRC) and colitis. In the colon we found PC to be mostly present on different subtypes of fibroblasts. Colons of mice exposed to either chemically induced colitis-associated colon carcinogenesis (CAC) or dextran sodium sulfate (DSS)-induced colitis had decreased numbers of PC. We employed conditional knock-out strains for the PC essential genes, Kif3A and Ift88, to generate mice with reduced numbers of PC on colonic fibroblasts. These mice showed an increased susceptibility in the CAC model as well as in DSS-induced colitis. Colons from DSS-treated mice with PC-deficiency on fibroblasts displayed an elevated production of the pro-inflammatory cytokine IL-6 and colonic epithelial cells had diminished levels of HES-1, a key transcription factor of Notch signaling. Notably, an analysis of PC presence on biopsies of patients with ulcerative colitis as well as CRC patients revealed decreased numbers of PC on colonic fibroblasts in pathological versus surrounding normal tissue. Taken together, we provide evidence that a decrease in colonic PC numbers promotes colitis and CRC.Graphical Abstract

Natural molecules induce and synergize to boost expression of the human antimicrobial peptide β-defensin-3

Antimicrobial peptides (AMPs) are mucosal defense effectors of the human innate immune response. In the intestine, AMPs are produced and secreted by epithelial cells to protect the host against pathogens and to support homeostasis with commensals. The inducible nature of AMPs suggests that potent inducers could be used to increase their endogenous expression for the prevention or treatment of diseases. Here we aimed at identifying molecules from the natural pharmacopoeia that induce expression of human β-defensin-3 (HBD3), one of the most efficient AMPs, without modifying the production of proinflammatory cytokines. By screening, we identified three molecules isolated from medicinal plants, andrographolide, oridonin, and isoliquiritigenin, which induced HBD3 production in human colonic epithelial cells. This effect was observed without activation of the NF-κB pathway or the expression of associated proinflammatory cytokines. We identified the EGF receptor as the target of these compounds and characterized the downstream-activated MAPK pathways. At the chromatin level, molecules increased phosphorylation of histone H3 on serine S10 and recruitment of the c-Fos, c-Jun, and Elk1 or c-Myc transcription factors at the HBD3 promoter. Interestingly, stimulating cells with a combination of andrographolide and isoliquiritigenin synergistically enhanced HBD3 induction 10-fold more than observed with each molecule alone. Finally, we investigated the molecular basis governing the synergistic effect, confirmed our findings in human colonic primary cells, and demonstrated that synergism increased cellular antimicrobial activity. This work shows the capability of small molecules to achieve induction of epithelial antimicrobial defenses while simultaneously avoiding the deleterious risks of an inflammatory response.

Endometrial Metastasis from an Occult Colonic Primary presenting with Massive Ascites

ABSTRACT In most developed nations, endometrial cancer is the most common gynecological malignancy. However, the endometrium is an extremely rare site for metastasis from an extragenital site. Also, the most common presentation of such metastasis is with uterine bleeding, similar to primary endometrial cancers. We present an unusual case of a 38-year-old female who presented with abdominal pain and distension. Evaluation revealed an endometrial mass lesion with bilateral adnexal masses and massive ascites. An endometrial biopsy was done, which revealed a mucinous adenocarcinoma with signet ring cells. Immunohistochemistry showed cells positive for CK20 and CDX2 and negative for CK7, which was in favor of a colonic primary. A colonoscopy was attempted, but failed due to extrinsic compression at the rectosigmoid junction. There was no evidence of supradiaphragmatic disease. She was started on palliative chemotherapy. This case report highlights the indispensability of histological correlation and immunohistochemistry in the diagnosis of pelvic malignancies. How to cite this article Komaranchath AS, Gopalakrishnan S, John S, Mahadevan P, Mathew J, Kumar L. Endometrial Metastasis from an Occult Colonic Primary presenting with Massive Ascites. J South Asian Feder Menopause Soc 2017;5(2):138-141.

Outcomes of perioperative systemic therapy (ST) in patients with R0 resection of metastatic colorectal cancer (mCRC).

496 Background: Adjuvant fluoropyrimidine (FP) +/- oxaliplatin (OX) ST improves overall survival (OS) following curative resection of stage II or III CRC, while other regimens do not. Utility of pseudo-adjuvant ST in mCRC patients who achieved R0 resection of their metastases remains controversial. We aim to describe population-based outcomes based on choice of ST. Methods: Patients diagnosed with mCRC from 2003 to 2010 and referred to any 1 of 5 cancer centers in British Columbia, Canada were reviewed. We categorized patients who underwent a successful R0 resection of their metastases into 3 groups based on receipt of peri-operative ST: 1) FP alone; 2) OX-based; and 3) non-standard or no ST. We compared OS using multivariate Cox regression models that adjusted for potential confounders. Results: We identified and reviewed 1,641 patients with mCRC among whom 225 achieved R0 resection of their metastases. In this cohort, median age was 63 years (Interquartile range (IQR) 55-70), 118 (52%) were men, 196 (87%) reported ECOG 0/1, 149 (66%) had a colonic primary, and 103 (46%) presented with de novo metastatic disease. The site of metastatic resection was hepatic in 144 (64%), pulmonary in 34 (15%), locoregional in 11(5%), and other in 36 (16%). A total of 122 (54%) received standard ST. Regimens included 28 (12%) FP alone, 94 (42%) OX-based, 25 (11%) irinotecan and 38 (17%) including bevacizumab. The median duration of ST was 10 cycles (IQR 7-12), with 56% and 44% delivered pre- and post-operatively, respectively. In multivariate analyses, liver or lung involvement (HR 0.60, 95% CI 0.40-0.88, p=0.01) predicted for improved OS when compared to metastases affecting other organs or sites. Receipt of OX-based ST was the only regimen associated with better OS, while the rest were not (Table). Conclusions: Findings from this population-based cohort of mCRC suggest that use of a defined course of OX-based ST for pseudo-adjuvant intent around the time of R0 resection of liver or lung metastases is correlated with improved OS. [Table: see text]

A Single Mass Forming Colonic Primary Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin’s lymphoma (NHL) comprising around 7% of adult NHL. It is characterized by a chromosomal translocation t(11:14) and overexpression of Cyclin D1. The incidence of secondary gastrointestinal tract involvement in MCL ranges from 10 to 28% in various series. However primary gastrointestinal MCL is very rare, accounting for only 1 to 4% of primary gastrointestinal lymphomas. The most common endoscopic feature of primary intestinal MCL is multiple lymphomatous polyposis. In rare cases it presents as protruded lesions or superficial lesions. Single colonic mass presentation is an extremely infrequent presentation. MCL has an aggressive course with quick progression, and most cases are discovered in the advanced stages. Colonic biopsies with histologic examination and specific immunohistochemical staining are the gold standard for a proper diagnosis. We report a case of a single mass forming mantle cell lymphoma of the ascending colon in a 57-year-old female patient with unusual colonoscopic and radiologic features and describe the therapy the patient received, thereby adding to the spectrum of clinical presentations of this aggressive lymphoproliferative disorder.