Synchronous colonic B cell lymphoma and adenocarcinoma in an elderly patient treated with R-mini-CHOP followed by resection

Abstract

The simultaneous diagnosis of colonic lymphoma and adenocarcinoma in the same location is rare and presents challenges in its treatment considerations, especially in elderly patients. While previous cases have been described, there is little consistency in treatment regimens, and outcomes are generally poor. We describe the case of a man in his late 80s who presented with primary cecal and colonic B cell lymphoma, treated with R-mini-CHOP chemotherapy, but was found to have a residual adenocarcinoma in the cecum after treatment that was then successfully resected. The patient remains alive and well 3 years postoperation. This case highlights the need to consider lymphoma as a possible diagnosis for any colonic mass, and the need to consider rebiopsy of residual abnormal-appearing tissue postchemotherapy to confirm the diagnosis. Moreover, our report affirms that aggressive, curative-intent treatment with age-adjusted chemotherapy, and subsequent surgical resection is feasible for certain elderly patients with dual malignant diagnoses.

Background

Colorectal adenocarcinoma is the third most common malignancy worldwide, and the second leading cause of cancer death.¹ Primary lymphoma in the colon is comparatively rare, comprising 0.6% of colonic neoplasms.² Initial resection followed by possible adjuvant chemotherapy is the preferred treatment paradigm for invasive colonic adenocarcinoma. Upfront chemotherapy (±sequential radiotherapy) remains the preferred primary therapy for most aggressive-histology lymphomas, the most common of which is diffuse large B cell lymphoma. Beyond diagnostic biopsies and excisions, surgery is rarely required for the management of aggressive lymphomas.

Simultaneous diagnosis of both lymphoma and adenocarcinoma in the colon has been documented in the literature but is very rare. Table 1 summarises the currently available English language reports of these synchronous presentations in the same tissue. In most cases, lymphoma is diagnosed incidentally after the resection of a primary adenocarcinoma. Due to the paucity of reports, there is no standard approach to the treatment of a patient with this synchronous presentation. Here we present the report of an elderly patient presenting with synchronous diffuse large B cell lymphoma and initially occult invasive adenocarcinoma in the cecum that was successfully treated with six cycles of R-mini-CHOP chemotherapy (rituximab with reduced-dose cyclophosphamide, doxorubicin, vincristine and prednisolone) and subsequent right haemicolectomy. As well, we provide a summary of available reports describing concommitant colonic lymphoma and adenocarcinoma.

Table 1.

Summary of previous reports of synchronous colonic lymphoma and adenocarcinoma found in the same tissue

First author	Year	Lymphoma subtype	Initial diagnosis	Location	Treatment	Outcome	Age (years) /sex
Cornes9	1960	Lymphocytic lymphosarcoma	Concurrent	Rectum	Abdominoperineal resection, then deep X-ray therapy	Died 1 year postoperative of urinary obstruction	63 /M
Hopster5	1995	Mantle cell	Concurrent	Cecum	Total colectomy	Unknown	74 /F
Mannweiler10	2003	T cell	Concurrent	Rectum	Colonic resection	Unknown	73 /M
Padmanabhan11	2003	Mantle cell	Adeno	Cecum	Ileocecal resection	Died 1 month postoperative	85 /M
Bhanote12	2005	Follicular	Adeno	Node	Haemicolectomy Chemotherapy	Recurrence 1.5 years post-treatment	55 /M
Sahasrabudhe13	2009	Marginal B cell	Adeno	Node	Haemicolectomy	Alive	77 /F
Eshra14	2010	Marginal B cell + follicular	Concurrent	R colon	Haemicolectomy, referral for unspecified adjuvant treatment	Unknown	67 /M
Silvestris15	2010	Small cell	Adeno	Node	Haemicolectomy Metastectomy Chemotherapy	Lost to follow-up after 1 month of therapy	86 /M
Sasaki7	2010	Follicular	Adeno	Cecum	Haemicolectomy Chemotherapy	‘Complete response’	62 /M
Shigeno16	2011	Diffuse large B cell	Adeno	Cecum	Haemicolectomy	Died 5 months post-treatment	76 /F
Devi17	2011	MALT	Adeno	R colon	Haemicolectomy	Asymptomatic 2 years post-treatment	68 /F
Chang3	2011	Diffuse large B cell	Lymphoma (in sinus)	R colon	Chemotherapy Haemicolectomy of residual mass	Hepatic tumour found 16 months postoperative, not treated	86 /M
Argyropoulos18	2012	MALT	Concurrent	Rectum	Abdominoperineal resection	Alive 20 months post-treatment	75 /F
			Adeno	R colon	Haemicolectomy	Alive 4 years post-treatment	71 /F
Redman4	2013	Indolent B cell	Concurrent	R colon	Haemicolectomy Chemotherapy	Alive 13 months post-treatment	54 /M
Lin19	2014	Indolent B cell	Adeno	Sigmoid colon, node	Anterior resection, then six cycles mFOLFOX6, then capecitabine	Alive 24 months postoperative	81 /M
Sathya20	2014	B cell	Concurrent	Sigmoid colon	Chemotherapy, not specified	Well after two cycles	77 /M
Velu21	2014	MALT	Adeno	Cecum	Haemicolectomy	Alive 6 months postoperative	43 /F
Yu22	2015	Large B cell	Concurrent	R colon	Haemicolectomy	No recurrence 6 months postoperative	86 /F
Acosta23	2016	Follicular	Adeno	Node	Haemicolectomy, adjuvant treatment not specified	Well at 1 month follow-up	62 /M
Kus24	2016	Follicular	Concurrent	Cecum	Haemicolectomy, then six cycles of FOLFOX4, then cyclophosphamide + vincristine + prednisolone +rituximab	Died 2 months into treatment	73 /M
Soto25	2018	Diffuse large B cell	Adeno	Sigmoid colon	Total proctocolectomy, then four cycles R-CHOP, then radiotherapy, then FOLFOX	Survived 30 months after diagnosis	79 /M
Kim26	2019	Diffuse large B cell	Concurrent	Recto-sigmoid colon	Six cycles CHOP + pegfilgrastim, then capecitabine + radiotherapy, then total mesorectal excision	No recurrence after 1.5 years	62 /M
Kataoka27	2021	Diffuse large B cell	Adeno	R colon	Ileocecal resection, adjuvant R-CHOP for 3 months	Complete response after R-CHOP, alive 4 years postoperative	78 /M
Lin6	2021	Follicular	Concurrent	R colon	Haemicolectomy	Unknown	74 /F

Adeno, adenocarcinoma; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; F, female; FOLFOX, leucovorin, fluorouracil, oxaliplatin; M, male; MALT, mucosa-associated lymphoid tissue; R, right; R-CHOP, rituximab+ CHOP.

Case presentation

A Caucasian man in his late 80s presented to his family physician with a history of progressive fatigue, abdominal pain and weight loss of 20 pounds in 6 months. Prior to this presentation, he was otherwise healthy with medical history significant only for previous cutaneous basal cell carcinoma and chronic peptic stricture. He did not have any significant family history of cancer. He lived independently at home. Although initially attributed to his pre-existing peptic stricture, the patient’s symptoms continued to worsen even after his dysphagia had subsided. Initial workup was performed as an outpatient, but before a colonoscopy and biopsy could be performed, the patient’s condition declined substantially and he presented to a tertiary care centre with progressive weakness and inability to cope at home. His Eastern Cooperative Oncology Group (ECOG) performance status score at this presentation was 3. He was admitted under general surgery and further workup was performed in hospital.

Investigations

1. An abdominal CT scan revealed a thickened wall in the cecum and ascending colon, with thickness up to 26 mm, as well as adenopathy in the retroperitoneum and small bowel mesentery (figure 1A), suspected to represent primary colonic adenocarcinoma or lymphoma involving the right colon.

2. Bloodwork on presentation to hospital showed haemoglobin 96 g/L, leucocytes 6.4 × 10⁹/L, thrombocytes 238 × 10⁹/L, creatinine 133 µmol/L, lactate dehydrogenase 212 U/L, CEA 1.3 µg/L and unremarkable electrolytes.

3. A CT of the thorax revealed extensive subcarinal and periaortic adenopathy measuring up to 4 cm, likely representing metastatic disease or lymphoma (figure 1B).

4. Colonoscopy revealed a mass in the cecum appearing to be colorectal cancer, from which multiple biopsies were obtained. Pathology showed diffuse large B cell lymphoma, germinal center B-cell (GCB) subtype (figure 2A). Immunohistochemistry is positive for CD20, BCL6, CD10 and BCL2, and negative for cytokeratin 7/20, CDX2, villin, PSA, PAP, TTF-1, synaptophysin, chromogranin, MUM1, CD23 and cyclin D1. One biopsy sample also revealed a fragment containing villous adenoma with high-grade dysplasia; this assessment was confirmed by a second pathologist (figure 2B–D).

5. Echocardiogram revealed no regional wall motion abnormalities, and an ejection fraction of 77%.

Figure 1.

Diagnostic CT imaging. Coronal sections of baseline diagnostic CT abdomen and pelvis (A) and CT chest (B) showing a thickened cecum (red arrow) and diffuse adenopathy (yellow arrows).

Figure 2.

Histopathology. H&E stained pathology slides from initial biopsy shows atypical lymphocytes percolating through the lamina propria of an adenoma with villous features (A). One biopsy sample shows atypical lymphocytes on left and fragment of high-grade dysplastic villous adenoma on the right (B). At higher magnification, a focus of these abnormal lymphocytes (C) and villous adenoma with high-grade dysplasia (D) are visible. Posthaemicolectomy pathology shows invasive colonic adenocarcinoma at low magnification (E) and high magnification (F).

Differential diagnosis

Differential diagnosis included metastatic colonic adenocarcinoma or lymphoma as imaging investigations were unable to differentiate between these possible aetiologies of the patient’s cecal mass and diffuse adenopathy. While biopsies did confirm a diagnosis of lymphoma, they did not exclude the presence of adenocarcinoma. In fact, the presence of adenoma with high-grade dysplasia noted in a fragment of one pathological sample suggests the presence of both cancers simultaneously. However, given the patient’s deteriorating clinical condition, the decision was made to forego further investigations at this time, including a baseline positron emission tomography (PET) scan and bone marrow biopsy, and begin treatment. The patient’s most responsible diagnosis was stage IV-B diffuse large B cell lymphoma, GCB subtype.

Treatment

The patient was transferred from the care of general surgery to haematology for treatment of the lymphoma. At this time, the patient was experiencing delirium and poor performance status; however, given the potential for rapid response to chemotherapy and potential recovery, the decision was made to pursue curative intent age-adjusted chemotherapy treatment. Consent was obtained from the patient’s family. After initial stabilisation with dexamethosone, the patient began R-mini-CHOP chemotherapy consisting of cyclophosphamide 400 mg/m², doxorubicin 25 mg/m², vincristine 1 mg, prednisolone 40 mg/m² and rituximab 375 mg/m². R-mini-CHOP was given in six cycles, each separated by 3 weeks, with filgrastim prophylaxis. Twenty-four days after transfer to haematology, having received two cycles of R-mini-CHOP, the patient was discharged home and received the remainder of his therapy as an outpatient. The patient’s function and cognition improved rapidly. Reduction in nodal disease was noted by CT scan after the third cycle, showing no mediastinal, retroperitoneal or iliac lymphadenopathy. While therapy was generally well tolerated, toxicities and adverse events included thrush, diarrhoea, pleural effusion and peripherally inserted central catheter associated deep venous thrombosis (DVT) during his course in hospital. The patient continued to lose weight during treatment despite otherwise improving clinically. His DVT was treated with daily subcutaneous dalteparin for 10 months before being discontinued by his haematologist.

Three weeks after the conclusion of his chemotherapy, the patient underwent a PET-CT scan that showed no metabolically active adenopathy. However, this PET-CT revealed focal intense flurodeoxyglucose (FDG) uptake in the cecum, with standardized uptake value (SUV) max 34.4, Deauville V, that was suspicious for a residual mass measuring approximately 21 mm at the same site as the primary tumour (figure 3). Referral to radiation oncology was made for consideration of complementary (salvage) radiation therapy for presumed residual lymphoma. Prior to receiving treatment, confirmatory colonoscopy was pursued and a residual abnormal area was visualised and biopsied, revealing invasive adenocarcinoma with no active lymphoma (figure 2E, F). The patient was then referred to general surgery where he underwent an open right haemicolectomy. Due to the multitude of tests and referrals, the surgery took place 16 weeks after completion of chemotherapy—there was no delay due to functional status or abnormal bloodwork. The patient’s operation was uncomplicated, and he was discharged 5 days postoperatively with no concerns. Final pathology revealed low-grade adenocarcinoma, stage pT2N0, with primary tumour measuring 1.5 × 1.0 × 0.5 cm and invading the muscularis propria. Margins were negative and none of the 13 examined lymph nodes tested positive for malignancy. There was no evidence of residual lymphoma.

Figure 3.

Postchemotherapy PET-CT imaging. Axial sections of CT before chemotherapy treatment (A) and PET-CT after six cycles of R-mini-CHOP chemotherapy (B). Residual tumour showing high FDG uptake is at the same location at the primary tumour site within the cecum (red arrows).

Outcome and follow-up

Following surgery, the patient did not require any further adjuvant treatment for his colon cancer. He recovered from treatment, and underwent routine follow-up with both haematology and general surgery every 3 months for 2 years after treatment. During this time, the patient received serial CT scans for a stable lung nodule—his follow-up course was unremarkable with no concerns. The patient remains well with no evidence of disease three and a half years after his initial diagnosis.

Discussion

The concurrent presentation of primary lymphoma and adenocarcinoma of the colon is very rare but has been documented in the literature (table 1). In most cases, the diagnosis of adenocarcinoma was made initially, while lymphoma was diagnosed after resection, or else the diagnoses of adenocarcinoma and lymphoma were made concurrently on biopsy. As a result, most previous cases outline treatment wherein resection is pursued initially and then followed by chemotherapy or radiation. In cases where lymphoma was diagnosed initially, the patient had a lymphoma-positive biopsy taken from a different site prior to investigation of their colonic mass.³ This report is the first to our knowledge where a primary lymphoma in the colon was diagnosed prior to the diagnosis of colonic adenocarcinoma in the same region.

Mechanisms have been proposed to explain the coincident growth of these two cancers. It has been suggested that cytokines such as VEG-F and TGF-ß secreted by colonic adenocarcinoma may promote lymphoma growth,⁴ and that the presence of lymphoma may help developing adenocarcinoma evade the immune system.⁵ Redman commented on the loss of mismatch repair and resulting microsatellite instability as a contributing factor to this association between carcinoma and lymphoid infiltration.⁴ In reviewing previous reports, only Lin (2021) commented on mismatch repair in their sample, which was negative for MLH1, PMS2 and MSH2/6.⁶ No such immunohistochemistry was performed on our sample for comparison—however, no histological features were present to suggest microsatellite instability, such as intratumoral or peritumor lymphocytic response. Chang (2011) suggests that Epstein-Barr virus (EBV), in addition to being an established risk factor for lymphoma, may also increase the risk of adenocarcinoma in the elderly.³ No EBV testing was done on the patient in this case to support or dispute this possibility. Indeed, given the extreme rarity of these concomitant diagnoses, it is possible that they occur together only by chance.⁷

The diagnosis of two concurrent malignancies presents unique clinical challenges, and often requires repeated investigations. In this case, the initial biopsy revealed diffuse B cell lymphoma as well as a fragment of adenomatous high-grade dysplasia. Rather than pursue further investigations, treatment for the established lymphoma was started due to the patient’s poor clinical condition. If the patient were more fit, or the initial biopsy had shown frank adenocarcinoma, then further testing would have been strongly considered given the suspicion for synchronous primaries. This might have included a repeat biopsy of the primary mass, or a biopsy of his mediastinal lymphadenopathy to rule out metastatic adenocarcinoma. Indeed, when a residual mass was seen on PET-CT after completion of chemotherapy, a second biopsy revealed invasive adenocarcinoma. Had we accepted without repeat attempt at colonoscopic confirmation that the residual hypermetabolic mass represented a partial lymphoma response to chemotherapy, the patient would have received 4 weeks of radiation therapy for residual lymphoma. He thus would have undergone the risks and side effects of radiation at a dose that would have been ineffective at managing an invasive adenocarcinoma of the colon. Thus this case highlights the importance of giving due consideration to repeat biopsy of residual masses post lymphoma chemotherapy when the response to systemic therapy in an area has been discordant to the observed response in other regions, and differing or dual histology is a rare but conceivable risk. In such cases, there is great value in careful consideration of next steps through multidisciplinary discussion between haematology, medical oncology, radiology, pathology, surgical oncology and radiation oncology specialists.

Our report illustrates the management challenges inherent to elderly patients, compounded in this case by the dual malignant diagnoses. The decision to treat systemically with curative intent was approached with some caution given the patient’s deteriorating clinical status at presentation as well as his advanced age. While this case supports the use of R-mini-CHOP for treatment of diffuse large B cell lymphoma in patients over 80 years old,⁸ initial chemotherapy treatment may not have been considered if both diagnoses were established at first presentation, or if the lymphoma had been occult on initial biopsy and the patient’s imaging findings were attributed to metastatic solid tumour such as colonic adenocarcinoma. As both surgery and chemotherapy cause unique stress on the body, it is not always obvious which therapy to initiate first. Multidisciplinary consultation and discussion is paramount, with consideration of the natural tempo and behaviour of the differing histologies, the stages of each individual tumour, the overall tumour burden and resultant symptomatology, and the practical aspects of how best to sequence therapy. In this case, the aggressiveness of diffuse large B cell lymphoma, and had it been known, the usually slower progressive course associated with invasive adenocarcinoma, made initiation of lymphoma systemic therapy paramount. Given the positive clinical outcome for our patient, this case supports the use of initial chemotherapy followed by resection in patients with synchronous diffuse large B cell lymphoma and adenocarcinoma. Moreover, it draws attention to advances in surgical and cytotoxic antineoplastic therapy permitting appropriately aggressive treatment of elderly patients.

Learning points.

• Primary lymphoma should be considered as part of the differential diagnosis for any colonic mass.

• Residual hypermetabolic masses noted after completion of chemotherapy for aggressive lymphoma should be considered for rebiopsy to confirm the pathology of the residual mass if the response in that region has been discordant with an otherwise robust response. Differing or dual histology is a rare but conceivable risk in such cases.

• This case illustrates a successful sequential treatment of synchronous cecal diffuse large B cell lymphoma and colonic adenocarcinoma in an elderly patient, with R-mini-CHOP chemotherapy followed by haemicolectomy.

• Multidisciplinary discussion is vital to managing synchronous tumours.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).