Metastatic squamous cell carcinoma of the colon: a conundrum in colorectal malignancies

Abstract

Small-cell carcinoma of the colon is an extremely rare tumour, with poorly understood pathogenesis and unestablished treatment guidelines. The first case was documented in 1919, and only about 100 cases of this condition have been reported to this date. In this case report, we present a case of sigmoid squamous cell carcinoma that eventually led to bowel perforation and was diagnosed on histopathology after emergent surgical intervention. Additionally, we also review the incidence, epidemiology, pathogenesis, immunohistological markers, neogenomics and therapeutic strategies for the same.

Background

Excluding dermatological cancers, colorectal cancer is the third most commonly diagnosed oncological pathology both in men and women in the United States and the second most common cause of cancer-related mortality in the country.¹ A vast majority of them (~96%) are adenocarcinomas, among which less than 0.5% are squamous, with an estimated incidence of 0.1%.^{2 3} We report a case of a 65-year-old woman with squamous cell carcinoma (SCC) of the sigmoid colon with metastatic disease and present the outcomes of her immunohistochemical panel and neogenomic studies.

Case presentation

A 65-year-old African-American woman presented to the hospital with a history of persistent nausea, vomiting and diarrhoea for 2 months. She also reported diffuse lower abdominal pain.

Her diarrhoea was loose, watery, dark and tarry in colour, despite discontinuation of iron therapy. During further inquiry into the history of her present illness, she revealed weight loss of 40 pounds (18.14 kg) during the same period and poor appetite with a sensation of persistent fullness. She denied any history of fever, recent antibiotic use, hospitalisation or bowel surgery. She has a medical history significant for chronic obstructive pulmonary disease, asthma and hypertension. She had been prescribed ferrous sulphate, hydrochlorothiazide, valsartan and atorvastatin before presenting to our clinic. She is an ex-smoker and had a 20-pack-year smoking history before quitting. She takes alcohol socially and uses marijuana occasionally.

On clinical examination, she was mildly obese. Fullness throughout her abdomen was present with pain on her right lower quadrant and lower pelvic region. There were no palpable masses in the abdomen, and no organomegaly was seen. No obvious cervical, axillary or inguinal lymphadenopathy could be appreciated. There was no free fluid in the abdomen on examination. The chest, cardiac and neurological examination of the patient were unremarkable.

Investigations

Blood investigations showed a white blood cell (WBC) count of 16.9×10⁹/L, platelets of 513×10⁹/L and a haemoglobin of 10g/dL, with a microcytic picture on red cell volumes (slightly decreased mean corpuscular volume (75.7 fL) and mean corpuscular hemoglobin (24.8 pg), a normal mean corpuscular hemoglobin concentration (32.7 g/dL) and an elevated red cell distribution width (16%)). Her potassium was 3 mmol/L on presentation, and blood glucose was 149 mg/dL. An X-ray of the abdomen showed extensive constipation and non-specific bowel gas. Additionally, her absolute neutrophil count was 19, carcinoembryonic antigen was 7.2 ng/mL and CA antigen 125 was 16.8 U/mL.

Given the patient’s age, chronic history of symptoms, significant weight loss and extensive constipation on X-ray, we decided to perform additional imaging. The patient was allergic to the contrast, so she was given steroids and antihistamines prophylactically. The CT scan of her abdomen and pelvis with contrast showed bowel wall thickening of sigmoid colon with evidence of about a 3 cm exophytic pelvic mass on the right side (figures 1 and 2). At least twelve hypoattenuating lesions were seen in the liver, and the largest was about 1.6 cm in size—in the right lower lobe (figure 3). There was a 1.6 cm cystic lesion in her spleen as well. The mesenteric fat stranding was seen along with the thickened bowels. Mild free fluid in the pelvis and moderate stool throughout the large bowel loops were noted.

Figure 1.

The axial CT scan of her abdomen and pelvis with contrast showed bowel wall thickening of sigmoid colon with evidence of about a 3 cm exophytic pelvic mass on the right side.

Figure 2.

The sagittal CT scan of her abdomen and pelvis with contrast showed bowel wall thickening of sigmoid colon with evidence of about a 3 cm exophytic pelvic mass on the right side.

Figure 3.

CT scan of the abdomen showed hypoattenuating lesions were seen in the liver, and the largest was about 1.6 cm in size—in the right lower lobe.

Since this mass could not be definitively excluded in origin from the uterus, further pelvic imaging was performed including ultrasonogram (USG) of pelvis both transabdominal and transvaginal. Her abnormal uterine thickening was unchanged from her prior USGs. They did not show any evidence of a discrete pelvic mass. Her inflammatory findings on abdominal scan also warranted Clostridium difficile toxin Polymerase Chain Reaction (PCR) that came back negative. A preliminary diagnosis of primary colon cancer with liver metastasis versus a mass of pelvic origin was made. The consulting gastroenterologist and haematology specialists recommended outpatient follow-ups with colonoscopy, liver biopsy and relevant oncological markers scheduled in 10–14 days of the discharge as the patient was stable and wanted to go back home.

During the interim period, the patient could not follow up. She presented to the emergency room in September 2020 with acute abdominal pain and weakness. She underwent a repeat CT scan of the abdomen and pelvis and showed free intraperitoneal air suggesting bowel perforation likely at the junction of sigmoid colon and the rectum. Multiple lymph nodes 12–13 mm in size on the left and right pelvic wall were also seen. Retroperitoneal aortocaval lymph node in the mid-abdomen of the same size was spotted as well.

The histopathology revealed a poorly differentiated tumour with areas of keratinising squamous differentiation. Furthermore, caudal-type homeobox 2 (CDX2) was diffusely positive, p40 showed patchy positivity, cytokeratin (CK) 7 is focally positive and CK20 is negative. A neogenomic panel was sent for tumour profiling, which showed wild-type KRAS and NRAS. The holistic picture, putting pathology and immunohistochemistry together, pointed towards poorly differentiated carcinoma with squamous differentiation, likely colorectal in origin.

Differential diagnosis

The patient presented to us with lower abdominal pain, loose stools and constipation. Therefore, we had to rule out the most apparent diagnoses of inflammatory bowel disease, C. difficile colitis and diverticulitis. Despite her elevated WBC count, her physical exam was grossly unremarkable, and PCR for C. difficile toxin came back negative. The patient’s history of weight loss made us suspicious of an underlying malignancy, but to effectively rule out inflammatory bowel diseases, we undertook abdominal imaging with contrast. The exophytic pelvic mass visible on scan in association with metastatic liver lesions and significant lymph nodes further narrowed the diagnosis to CA of the abdomen/pelvis. To narrow down the site of primary CA, we performed pelvic USGs that effectively ruled out the uterus as the site of CA. The bowel wall thickening and fat stranding with accompanying free fluid, along with the exophytic mass, all pointed towards colon CA being the likely primary site. The patient was scheduled for a colonoscopy but failed to follow up due to insurance issues, later presenting with perforated bowels. The resected segments during surgery were evaluated histopathologically clinching our final diagnosis of poorly differentiated SCC of sigmoid colon with squamous differentiation.

Treatment

The patient underwent emergent exploratory laparotomy with washout and colostomy, along with a biopsy of the liver lesion. The excised bowel and the specimen from liver biopsy were sent for histopathological evaluation. The pathology report from sigmoid colon showed transmural involvement by poorly differentiated carcinoma with infiltration of serosa and extensive lymphovascular invasion, and another segment showed ischaemic necrosis. The biopsy of the liver lesion showed metastasised poorly differentiated carcinoma.

Outcome and follow-up

The patient is now postsurgery day 30 after emergent exploratory laparotomy with washout and colostomy; intraoperatively, it was noted that the tumour was strongly adherent to the retroperitoneum with no plane for dissection. She was discharged 7 days after surgery in a stable condition and is recovering well. Her postsurgical course was characterised by low urine output, which improved with intravenous fluids. Twelve days post procedure, she presented with stools throughout midline incision with rapidly increasing drainage and worsening leucocytosis (WBC was 28.0 x10^∧9/L at this time). CT scan on this admission showed tracking of gas and probable stool between medial wall of the mid-subcutaneous segment of colonic pull-through and the laparotomy incision. There was a subcutaneous tract in between the colostomy site and midline incision at the infraumbilical level. She was taken to the operating room for an emergent laparotomy secondary to necrosis of colostomy edge. On opening the abdominal cavity, adhesions of the omentum, colon and small bowel to themselves and the abdominal wall were found. She underwent colostomy revision with colectomy, splenic flexure takedown, new end colostomy site with the removal of the sigmoid rectal tumour, drainage of intra-abdominal collection and abdominal wall debridement.

We plan to start palliative systemic chemotherapy with FOLFOX-6 4 weeks after recovery. And we will add Avastin approximately 6–8 weeks post surgery depending on wound healing.

Discussion

The pathogenesis of SCC of the colon is not well defined. Several pathogenic mechanisms have been suggested including differentiation of pluripotent stem cells into SCC colon after mucosal injury—as they are often found in the midst of poorly differentiated cells, much like our woman.⁴ Another theory is prolonged chronic traumatic irritation or chronic infection—any epithelial damage that causes proliferation and differentiation of basal cells and malignant transformation. They are also postulated to rise in pre-existing adenomas or adenocarcinomas.⁵ These tumours are occasionally seen associated with ulcerative colitis and Human Papilloma Virus (HPV) infections, but this association is not well established.^{6 7} Rarely, SCC colon has been associated with coexisting schistosomiasis and chronic colocutaneous fistula, and colonic duplication has also been reported.^{8 9}

CDX2 is an intestine-specific transcription factor and one of the most sensitive and specific markers of intestinal differentiation. It is implicated in the clinical diagnostics of tumours of unknown origin and helped us in identifying the primary source of CA to be the colon instead of the liver.¹⁰ Additionally, we found a unique immunohistochemical association in our extremely rare case—CK7 and CK20, which are low-molecular-weight CKs. CK20 positivity is seen in virtually all cases of adenocarcinoma colon. A study of 450 epithelial neoplasms revealed 95% CA colon shows CK7−/CK20+-type immunohistochemical image, and 0% showed CK7+/Ck20− samples.¹¹ Another study reported only 2% of samples reporting CD7+/CD20− in colorectal carcinoma. In the CAs, it is frequently seen (ie, oesophageal SCC and CA cervix) that CK7 positivity is associated with worse prognostic outcomes.^{12 13} In colorectal CA, cells expressing CK7 are known to demonstrate invasive capability with metastatic potential.¹⁴

A Mayo Clinic Study based on 52 identifiable cases gave us an insight into the prognosis of this CA. The 5-year survival for node-positive and node-negative disease is 23% and 85%, respectively, and almost half the patients had evident metastasis at presentation.² Advanced SCC appears to have a worse prognosis than advanced adenocarcinoma.¹⁵ Although there are no clear guidelines for the management of SCC colon owing to the rarity of this disease, surgery is the preferred approach for patients with localised disease or regional nodal metastasis.¹⁶ The literature provides sparse evidence regarding adjuvant and neoadjuvant chemotherapy. Juturi et al reported a patient with metastasis to the liver that responded to cisplatin, 5-Fluorouracil (5-FU) and leucovorin.¹⁷ Copur et al used cisplatin and 5-FU with etoposide with the objective response in metastatic disease.¹⁸ We plan to start the patient on FOLFOX 6–8 weeks post procedure.

Lastly, this is the first case of SCC colon with application of immunohistochemical and a neogenomic profile for diagnostics of the tumour. This novel approach would further add to the available literature about this extremely rare tumour and shed light on the lack of management guidelines.

Learning points.

• Squamous cell carcinoma of the colon is an extremely rare, poorly understood oncological pathology, with about 100 cases reported worldwide. They are found in the rectum, right colon and sigmoid in decreasing order of frequency.

• Histopathology is instrumental in the diagnosis and helps in differentiating it from the more prevalent adenocarcinoma colon.

• Novel diagnostic modalities like immunohistochemistry and neogenomics help in confirming this diagnosis and its guide management, therefore reporting these along with such cases will help build standard treatment guidelines in the future.