A Case of Medullary Carcinoma of Colon Morphologically Resembling Non-Hodgkin’s Lymphoma

Abstract

Medullary carcinoma of the colon is an unusual and unique histologic subtype of colorectal cancer. It is strongly associated with microsatellite instability, most commonly loss of MLH1 indicative of deficient mismatch repair proteins. Diagnosis is challenging as they do not display the usual histological pattern. Immunohistochemical staining also shows unusual findings like negativity for CD20 and CDX2. Here, we explore an intriguing case of medullary carcinoma of colon which showed loss of MSH2 and MSH6 and a morphology reminiscent of Non-Hodgkin’s lymphoma.

Introduction

Medullary carcinoma (MC) of colon is a rare subtype of colonic adenocarcinoma with an incidence of 0.03% of all colorectal carcinomas [1]. Earlier described as a poorly differentiated or an undifferentiated tumor, it is composed of solid sheets of malignant cells lacking gland formation which differentiates it from nonmedullary colon cancer. Other features characteristic of this tumor variant are pushing tumor border, prominent eosinophilic cytoplasm, marked lymphocytic infiltration, small nuclei, prominent nucleoli. Though, the carcinoma appears high grade cytologically, behaviour is that of low grade carcinoma. Due to its clinical, histological, immunohistochemical, and genetic peculiarity, awareness of diagnostic possibility of medullary carcinoma is critical for an accurate diagnosis and correct treatment.

Case History

A 38-year-old man presented with history of intermittent abdominal pain and weight loss since 2–3 months. Pain was continuous in nature for past 1 week and localized to right hypochondrium. There was no history of jaundice, black stools, bleeding per rectum. Examination of the abdomen did not reveal any palpable mass. Investigations revealed mild anemia (haemoglobin 6.3 mmol/L) with normal liver and kidney function tests. Computed tomography (CT) abdomen showed a mass in the proximal colon along with multiple enlarged pericolic lymph nodes. Intraoperatively, a mass measuring 7 × 6 cm was seen in ascending colon. Pathological examination of the right hemicolectomy specimen revealed a non-circumferential ulceroproliferative growth, measuring 5 × 4.5 cm in the anterior wall of ascending colon with a grey white, soft to firm cut surface (Fig. 1a). The tumor had pushing margins and was extending upto the muscularis propria. Microscopic examination showed a poorly differentiated malignant tumor, composed of singly scattered cells in diffuse sheets (Fig. 1b, c). An occasional focus of acinar formation was identified on extensive search (Fig. 1d). The tumor cells showed moderate nuclear pleomorphism, round to irregular nuclear membrane, coarse granular chromatin, conspicuous nucleoli and scant to moderate amount of cytoplasm. Numerous mitotic figures along with dense lymphoid infiltrate were also observed. Neoplastic epithelial cells were positive for panCK and negative for LCA, Synaptophysin, CK20, CK7 and CDX2 ruling out high grade lymphoma, poorly differentiated neuroendocrine carcinoma (Fig. 1e, f). There was loss of MSH2 and MSH6 protein expression on immunohistochemistry (Microsatellite unstable) (Fig. 2a, b). However, MLH1 and PMS2 protein expression were retained (Fig. 2c, d). Hence, a diagnosis of medullary carcinoma of ascending colon was rendered. The patient is on oral chemotherapy (Capecitabine) and has been asymptomatic, in 1 year post-surgical follow-up, with no recurrence or metastasis.

Fig. 1.

a Gross image of right hemicolectomy specimen showing an ulceroproliferative growth in the anterior wall of ascending colon; b Colonic mucosa with diffuse sheets of malignant cells in lamina propria along with few scattered mature lymphocytes (HE 100x); c Tumor with pushing margin, showing malignant cells reaching till the muscularis propria (HE 100x); d An occasional focus of acinar formation (HE 200x); e IHC: CK20 negativity in tumor cells (Control- Normal mucosa showing membranous positivity) (100x); f IHC: CDX2 negativity in tumor cells (Control- Normal mucosa showing nuclear positivity) (100x)

Fig. 2.

MMR panel: a Absence of MSH2 staining in tumor cells with positive staining in normal colonic mucosa and interspersed lymphocytes (100x); b Absence of MSH6 staining in tumor cells with positive staining in normal colonic mucosa and interspersed lymphocytes (100x); c MLH1- Retained nuclear positivity in tumor cells (100x); d PMS2- Retained nuclear positivity in tumor cells (100x)

Discussion

Colorectal cancer (CRC) is a heterogeneous malignant disease, representing 11% of all tumor types worldwide [2]. Majority of them are adenocarcinomas, not otherwise specified. Medullary carcinoma is a new histologic subtype of CRC which was formerly called as ‘large cell adenocarcinoma with minimal differentiation’. It was further subdivided into poorly-differentiated and undifferentiated MC. MC reported to have demographical features contrasting to our case in previous published reports, on as MC patients are usually older and predominantly female [3]. However, the present case was a male patient and belonged to 4th decade of life. Despite the fact that this tumor has a tendency for expansile growth pattern and large tumor size, the chances of nodal involvement and distant metastasis are sparse. It is indispensable to discern this entity, as the published literature propounds a different disease course of MC, as compared to non-medullary adenocarcinoma.

Microsatellites are repeating sequences in the human genome, and they appear because of a disorder in the mismatch repair system (MMR) that corrects replication mistakes in the DNA. Microsatellite instability (MSI) is reported to be seen in 10–20% of sporadic colorectal carcinomas, while it is seen in 100% of hereditary non-polyposis colorectal carcinoma (HNPCC) syndrome. MC show extensive instability, thus designated as microsatellite instability-high (MSI-H) and are quite often associated with Lynch syndrome [4].

According to a recent edition of the WHO Classification of Gastrointestinal Tumors, medullary carcinomas display an aberrant phenotype, with loss of usual markers for intestinal differentiation (CDX2 and CK20). The most frequent microsatellite instability, is loss of expression of MLH1, involving V600E BRAF mutation in more than 80% cases [5, 6]. Lin et al., in their study of 18 cases of medullary carcinoma colon, found negativity for MLH1 and PMS2 in majority of them and only 1 case showed loss of MSH2 and MSH6 [7]. Although, these tumors are associated with a defective DNA mismatch repair mechanism, they show a relatively favourable prognosis as compared to other subtypes of CRC. Microsatellite unstable tumors exhibit intra-tumoral lymphocytosis and lymphovascular invasion. Pyo et al., in their meta-analysis of 16 studies of medullary carcinoma, observed a lower incidence of lymph nodal involvement than poorly or undifferentiated adenocarcinoma [1]. High frequency of microsatellite instability (MSI-H) and negativity for chromogranin and synaptophysin immunohistochemical staining can help to differentiate MCs from undifferentiated colorectal carcinoma and neuroendocrine tumors of colon. With the advancing era of targeted therapy, it is now indispensable to define the different subtypes of carcinomas, especially those tumors with particular inflammatory responses or molecular biomarkers. Ongoing research on immunotherapy, have shown that a higher number of CD8 + cytotoxic T cells, upregulation of programmed cell death protein 1 (PD-1) and interferon-gamma genes in medullary carcinoma as compared to other microsatellite-stable and microsatellite-unstable CRC. Upregulation of PD-1 can have potential therapeutic benefits with the advancement in anti-PD-1 therapy [8]. Despite a poorly differentiated morphology and microsatellite instability in the present case, the cancer was detected at an early stage and thus was amenable for surgery alone without the need of adjuvant chemotherapy. In previous case reports, MC commonly presented with Stage II disease, and only 10% of them presented with metastases at the time of diagnosis. Early outcome analyses exhibited that MCs have 1- and 2-year relative survival rates of 92.7% and 73.8% respectively [3, 9].

Conclusion

Medullary carcinoma appears to be a distinctive clinicopathologic entity, in terms of clinical, immunohistochemical characteristics and good prognosis, thus should be distinguished from other more aggressive, non-glandular tumors of the colon. It is important to know its unique morphological features and mismatch protein expression, especially in small biopsies where this tumor can pose a diagnostic pitfall.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Data Availability

The data sets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Patient Consent

The authors certify that they have obtained the appropriate consent from the patient. The patient has given his consent for the images and other clinical information to be reported in the journal. The patient understands that the name and initials will not be published, and due efforts have been made to conceal the same.

Conflict of Interests

The authors declare that there is no conflict of interest.