Gemcitabine-based chemotherapy in colon squamous cell carcinoma: A case report and literature review

Abstract

Squamous cell carcinoma (SCC) originating from the colon is rare. In terms of its clinicopathological characteristics, this type of cancer has been reported to be more aggressive and have a worse prognosis compared with adenocarcinoma. We herein present a successful therapeutic approach applying neoadjuvant and adjuvant gemcitabine-based chemotherapy in a patient with colon SCC. A 58-year-old male patient received two cycles of neoadjuvant chemotherapy with a regimen including gemcitabine, oxaliplatin and capecitabine, followed by radical excision and six cycles of adjuvant chemotherapy. Contrast-enhanced computed tomography and serum tumor markers were used for reassessment and evaluation was based on the World Health Organization criteria. Following neoadjuvant chemotherapy, the mass had shrunk and the patient was classed as having stable disease. Surgery and adjuvant chemotherapy were then performed and the patient had achieved a progression-free survival of 10 months when this report was submitted. Therefore, gemcitabine may be a treatment option for colon SCC in the neoadjuvant and/or adjuvant chemotherapy setting.

Introduction

Colon cancer is one of the most common cancers worldwide, with the predominant type being adenocarcinoma (1). Squamous cell carcinoma (SCC) of the colon is a rare pathological type, representing ~0.06% of all colorectal malignancies (2). The clinical characteristics of colon SCC are similar to those of adenocarcinoma. The treatment of SCC is mainly surgical resection. In terms of chemotherapy, there is currently no standard regimen for the treatment of colon SCC and its prognosis has been reported to be worse compared with that of adenocarcinoma. We herein present the case of a 58-year-old male patient diagnosed with adenosquamous carcinoma of the colon, who was treated with systemic gemcitabine-based neoadjuvant chemotherapy, followed by surgery and adjuvant chemotherapy.

Case report

A 58-year old male patient was hospitalized with a 5-month history of abdominal pain accompanied by a mass in the right lower quadrant. The symptoms gradually worsened and the patient experienced hematochezia, anorexia and weight loss of ~10% body weight. The patient had a history of smoking and alcohol consumption.

The contrast-enhanced computed tomography (CT) scan revealed a mass located in the lower part of the ascending colon. On enteroscopy, space-ocuppying lesions were identified in the rectum and ascending colon. The result of the pathological examination of the rectal lesion was moderately differentiated adenocarcinoma, while sampling from the colon was unsuccessful. In order to obtain a sample from the lesion of the ascending colon, the patient underwent CT-guided biopsy twice. The first time the pathology result was poorly differentiated carcinoma, while the immunohistochemistry findings were consistent with adenosquamous carcinoma with a predominant SCC component, whereas the second biopsy was used for verification due to the atypical pathological characteristics (Table I).

Table I.

Pathological characteristics of the tumors.

A, Pathology of the colon tumor
1st CT guided biopsy	2nd CT guided biopsy	Surgery
Poorly differentiated carcinoma, tumor cells arranged in nests, partially seen intercellular junctions. CK+, P63+, Syn−, CgA−, CD56−, CK7+, CK20−, CDX-2−, GATA-3−, Ki-67 70%	Poorly differentiated carcinoma, consistent with adenosquamous carcinoma with a predominant SCC component. P63+, P40+, CK7+, CK20−, CDX-2−, Syn−	Poorly differentiated SCC (ulcerative type) with involvement of outer serosal fat and vessels, with or without PNI. Infiltration of pericolic lymph nodes (1/22). CK5/6+, P40+, P63+, CK7+ (partly) CK20−,CDX 2−, Syn−, CD31+ (indicating vascular invasion)
B, Pathology of the rectal tumor
	Endoscopic biopsy	Surgery
	Rectal adenocarcinoma	Moderately differentiated adenocarcinoma (ulcerative type) with serosal involvement, without resection margin involvement. Perirectal lymph nodes free of metastasis (0/13). PMS-2+, MLH1+, MSH2−, MSH6−, Her-2 (0), S-100− (neural invasion), CD31+ (indicating extensive vascular invasion), Ki 67 80–90%.

CT, computed tomography; SCC, squamous cell carcinoma; CK, cytokeratin; Syn, synaptophysin; CgA, chromogranin A; CDX-2, caudal type homeobox 2; PMS-2, mismatch repair endonuclease PMS 2; MLH1, mutL homolog 1; MSH, mutS homolog; Her-2, human epidermal growth factor receptor 2.

After excluding distant metastasis by thoracic CT, whole-abdomen CT, whole-body bone scan emission computed tomography and head magnetic resonance imaging, the patient received neoadjuvant chemotherapy. The chemotherapy regimen was designed based on the therapeutic regimen for adenocarcinoma and the poor prognosis of this pathological subtype. The chemotherapy was conducted every 21 days and included gemcitabine (1,000 mg/m² intravenously, 1,800 mg on d1 and 1,600 mg on d8), oxaliplatin (130 mg/m² intravenously, 200 mg on d1) and capecitabine (625 mg/m² orally, 1,000 mg bid on days d1-14). The capecitabine dose was reduced by 50% in order to avoid severe side effects. Between August 18th, 2015 and September 24th, 2015, the patient received two cycles of neoadjuvant chemotherapy. Contrast-enhanced CT (Fig. 1) and measurement of tumor marker serum levels were used to evaluate treatment efficacy (Table IB). According to the World Health Organization criteria, the evaluation was stable disease.

Figure 1.

Computed tomography scan of the abdomen showing the changes in the colon lesion following neoadjuvant chemotherapy and surgery. (A-C) Images prior to chemotherapy; (D-F) images after two cycles of neoadjuvant chemotherapy; (G-I) images after six cycles of adjuvant chemotherapy.

On October 19th, 2015, the patient underwent radical right hemicolectomy and radical resection of rectal carcinoma (Dixon operation). The postsurgical pathology of the colon lesion revealed poorly differentiated SCC (ulcerative type) with infiltration of pericolic lymph nodes (1/22). The postsurgical pathology of the rectal lesion was moderately differentiated adenocarcinoma with no perirectal lymph node metastasis (0/13) (Fig. 2).

Figure 2.

Microscopic findings. (A and B) The colon mass was composed of poorly differentiated squamous carcinoma cells; (C and D) the rectal mass was a moderately differentiated adenocarcinoma. Hematoxylin and eosin staining; magnification, ×100.

After surgery, the patient received six cycles of adjuvant chemotherapy within 2 months and remained disease-free (Figs. 1 and 3) up to the time this article was submitted (date of last follow-up, June 10th, 2016; follow-up time, 10.5 months).

Figure 3.

Gradual decrease in tumor marker levels during the treatment process. CEA, carcinoembryonic antigen; CA, carbohydrate antigen; CYFRA, cytokeratin-19 fragments; SCC, squamous cell carcinoma.

Discussion

SCC is uncommon in the colon and rectum and was first reported by Herxheimer in 1907 (3). In 1927, White et al published the first report of primary adenosquamous cell carcinoma of the colon in the English medical literature (4). From then on, apart from a few small series from large institutions, the majority of the data comes from individual case reports (5–10).

Generally, SCC in the colon and rectum occurs in the anal canal, the lining of which is squamous epithelium, or in the lower part of the rectum adjacent to the anal canal, where it may originate from the nearby squamous or transitional cells. Adenosquamous carcinoma is a malignancy containing glandular and squamous histological components. However, the histogenesis of the squamous component remains unclear. There are several opinions as follows: i) Differentiation from stem cells (11–15); ii) squamous metaplasia (16–23); and iii) differentiation from adenocarcinoma (24–29).

The optimal treatment for SCC has not been determined due to its low incidence. Generally, the treatment is based on that for adenocarcinomas, which is predominantly surgery combined with chemotherapy and radiotherapy. With the advances in chemotherapy and radiotherapy, the accuracy of determining stage and evaluating response, a multitude of recent studies utilizing various treatment regimens have been reported, which included 5-fluorouracil (5FU)/mitomycin C, 5FU, 5FU/cisplatin, capecitabine/cisplatin, capecitabine, raltitrexed/oxaliplatin and S-1 (10,11,30–52).

The most important prognostic predictor is cancer stage. Colorectal SCC follows the same route of lymphatic spread as adenocarcinoma; additionally, they share similar metastatic sites, such as the liver, lung and bone (53). In 1996, Petrelli et al described the cases of 5 men and 2 women diagnosed with adenosquamous carcinoma originating from the colon or rectum. All the patients were treated surgically. Chemotherapy was used as adjuvant treatment, or in patients with local recurrence and distant metastasis. The median overall survival was 23 months (7). In 1999, Cagir et al reported a review of 145 cases of adenosquamous carcinoma using the National Cancer Institute Surveillance, Epidemiology, and End Results database program over a 20-year period (1973–1992). Patients with localized disease (stages I and II) exhibited survival curves similar to those with comparably staged adenocarcinoma. Adenosquamous cancer patients with regional disease (stages IIB and III) had a shorter survival compared with patients with similar-stage colorecal adenocarcinoma. Patients with stage IV adenosquamous carcinoma had a significantly shorter survival compared with those with comparably staged adenocarcinoma (2). Frizelle et al published a report on 44 patients with adenosquamous carcinoma and SCC. In that study, they found the prognosis to be similar to that of colorectal adenocarcinoma for stage I–II node-negative disease. However, when nodal disease occurs, the prognosis is worse than that expected for adenocarcinoma of similar stage. The characteristics predicting a poor prognosis included right-sided lesions, ulcerated or annular carcinomas, node-positive disease, grade 3–4 cancer and stage IV disease (54).

Gemcitabine (2′-deoxy-2′,2′-difluorocytidine monohydrochloride) is a potent and specific pyrimidine nucleoside antimetabolite, which is structurally analogous to deoxycytidine. In in vitro and phase I studies, gemcitabine had shown activity against various types of hematological and solid tumors (55–58). Furthermore, its antitumor activity had been confirmed in clinical practice. Gemcitabine has been used to treat patients with non-small-cell lung cancer, pancreatic, bladder and breast cancer, malignant mesothelioma and ovarian cancer. In preclinical studies, gemcitabine was found to act synergistically with a number of DNA-damaging agents, including platinum drugs and irradiation. Gemcitabine also has an extremely mild toxicity profile, which has prompted investigations of the agent in combination with other cytotoxic compounds. To the best of our knowledge, gemcitabine was selected as part of the chemotherapy regimen in colon SCC for the first time in the present case. As a result, the patient had achieved a PFS of 10 months by the time this article was submitted.

Colorectal SCC is rare, and its treatment is currently largely based on that applied for adenocarcinoma cases. As reported, SCC patients with stage III–IV disease have a poorer prognosis compared with those with adenocarcinoma. Thus, a more aggressive chemotherapeutic approach may be a viable choice for patients with a good performance status. In the present case, gemcitabine, oxaliplatin and capecitabine were selected as the chemotherapy regimen, which has never been reported in clinical practice. The PFS was 10 months until this manuscript was submitted. Thus, this new regimen may provide a reference for the future treatment for SCC of the colorectum.