Colorectal cancer is the third most common malignancy worldwide [1]. Early detection of colorectal cancer has become more frequent due to regular check-ups. However, about 20% of patients already have distant metastases at the time of diagnosis, and this ratio has remained relatively stable over the past 20 years [2]. Colorectal cancers most commonly metastasize to the liver, lungs, and peritoneum, but various other metastatic sites such as bone, brain, and heart have been reported [3].

Primary duodenal cancer is a rare malignancy, with an incidence rate of about 1 per 1,000,000 people worldwide, accounting for only 1–2% of all gastrointestinal malignancies [4]. Conversely, various neoplasms metastasize to the duodenum, such as lung cancer, renal cell carcinoma, melanoma, and colorectal cancer. Among these, colorectal cancer invasion of the duodenum is infrequent, and several case series have been reported [5-7].

While the most common type of colorectal cancer is adenocarcinoma, the undifferentiated carcinoma type is extremely rare. Therefore, only a few cases have been reported in the studies [8-10].

We present a case of undifferentiated carcinoma of the colon that directly invaded the duodenum and metastasized to the distant lymph nodes.

An 85-year-old woman had anorexia, melena, and a weight loss of 8 kg over 4 months. The patient was admitted to our hospital with a colonic mass detected in a primary clinic using computed tomography (CT). She had a history of hypertension and took iron supplements for dizziness. Her vital signs were stable and there was no palpable mass.

The patient’s laboratory data were normal except for a low hemoglobin level of 10 mg/dl. An abdominal CT scan showed a 7-cm-sized enhancing mass in the ascending colon with invasion into the duodenum and enlarged regional lymph nodes (Fig. 1A). Positron emission tomography (PET) showed fluorodeoxyglucose (FDG) uptake in the ascending colon, the duodenum, and lymph nodes in portocaval and aortocaval areas (Fig. 1B). Colonoscopy revealed a large, ulcerated circumferential mass from the ascending colon to the hepatic flexure (Fig. 1C). Esophagogastroduodenoscopy identified a 2-cm-sized protruding mass with central ulceration in the 2nd portion of the duodenum (Fig. 1D).

Figure 1. A colon cancer metastasis to the duodenum. (A) An abdominal computed tomography scan showed an eccentric wall thickening with an intraluminal enhancing mass in the ascending colon and invasion into the duodenum. (B) Positron emission tomography revealed fluorodeoxyglucose uptake in the ascending colon, the duodenum, and lymph nodes in portocaval and aortocaval areas. (C) Colonoscopy identified a large ulcerated circumferential mass in the ascending colon. (D) Esophagogastroduodenoscopy showed a protruding mass with central ulceration in the 2nd portion of the duodenum.

Pathologic examination found non-glandular, diffusely infiltrating atypical round cells consisting of vesicular nuclei, macro-nucleoli, and abundant cytoplasm in both colonoscopic biopsies (Fig. 2A, B) and duodenoscopic biopsy (Fig. 2C), suggesting undifferentiated carcinoma of the colon.

Figure 2. Pathologic examination. (A) Colonoscopic biopsy showed non-glandular, diffuse atypical round or oval cells (arrows, H&E stain, ×40). (B) The tumor cells disclosed round enlarged nuclei, macro-nucleoli, and abundant cytoplasm, indicating undifferentiated carcinoma (H&E stain, ×400). (C) Duodenoscopic biopsy showed similar findings to the colonoscopic biopsy. Diffuse amorphous cell proliferation indicated undifferentiated carcinoma. Intravascular tumor cell nests in the lamina propria were identified (arrows, H&E stain, ×200). (D) The immunohistochemical staining of the duodenoscopic biopsy showed positive for pan-cytokeratin.

Immunohistochemical (IHC) staining markers were only positive for pan-cytokeratin (pan-CK) (Fig. 2D), and all negative for CK20, CK7, CD56, CDX2, MUC2, and mucicarmine histochemical staining, which indicated the histologic type of this tumor was far from differentiated adenocarcinoma. Moreover, the results of additional markers of tumor cells were intact EBV-in situ hybridization and a loss of MLH1. The final diagnosis was undifferentiated carcinoma of the colon, not otherwise specified (NOS).

A possible differential diagnosis is either primary duodenal cancer that has invaded the colon or synchronous double primary colon and duodenal cancer has occurred. However, pathologic examination confirmed that the undifferentiated carcinomas in both the colon and duodenum were identical. We thought the colon was the primary origin of the tumor because the tumor size in the colon was much larger than that in the duodenum.

Other differential diagnoses regarding the histologic type of colon cancer include neuroendocrine tumor, lymphoma, and poorly differentiated adenocarcinoma. This case was different from the poorly differentiated adenocarcinoma because no gland formation or mucin production was seen on the pathologic examination.

Since she was diagnosed with stage IV colon cancer due to distant lymph node metastases, surgery was not a viable treatment option. She and her family refused systemic chemotherapy because of concerns about chemotoxicity. The patient was discharged home because there were no symptoms related to bowel obstruction.

Supportive care was maintained via analgesics for pain management. Ultimately, hospice care was needed for progressive pain and general weakness. She died of disease progression 6 months after diagnosis.

Colon cancers seldom metastasize to the duodenum. When explaining metastatic spread, the ‘seed and soil’ theory and direct invasion of the adjacent organ, called an anatomical theory, are widely accepted [6]. When it comes to the seed and soil theory, certain cancers, likened to the seed, have their preferences regarding metastatic organs, also done to the soil [11]. Colorectal cancers hardly metastasize to the bone, while prostate cancers frequently do [12]. Some colorectal cancers show the direct invasion of the neighboring peritoneum and ovaries [5], but the invasion of the adjacent duodenum is extremely rare [5,6]. In this case, intravascular tumor cell nests were identified by the duodenal biopsy, and distant lymph node metastases were observed in the PET scan. The lymphatic spread was considered to be the main pathway for metastasis from colon cancer.

The metastatic pattern of colorectal cancers is influenced by histologic types [13]. While poorly differentiated adenocarcinoma accounts for 8–15% of colorectal cancers [14], it is more likely to metastasize and has aggressive outcomes. One study investigated the histologic types of colorectal cancers with duodenal metastases [15], which showed that poorly differentiated or mucinous adenocarcinomas had a higher possibility of invading the duodenum than well- or moderately differentiated types [15].

In this case, the primary origin of the tumor remains uncertain. Colorectal adenocarcinoma has typical IHC markers of CK7 (–) and CK20 (+), while small intestine tumors have CK7 (+) and CK20 (–) [16,17]. Additionally, CDX2 (+) and MUC2 (+) are commonly found in colorectal adenocarcinoma [17]. These IHC markers are useful to distinguish colorectal cancer involving the ovary from primary ovarian cancer [16]. With regard to this patient, it was difficult to determine whether the primary tumor origin was the colon or the duodenum because the tumor had extremely undifferentiated features. It was finally concluded that the colon was the primary tumor origin due to the larger size of the tumor in the colon, compared to the smaller tumor mass in the duodenum.

Nearly 95% of all colorectal cancers are adenocarcinomas, but signet ring cell carcinoma and undifferentiated carcinoma occur infrequently [18]. Undifferentiated carcinoma does not show gland formation or signet ring cells, which can be distinguished from poorly differentiated adenocarcinoma or signet ring cell carcinoma.

A few cases of undifferentiated carcinomas of the colon have been reported [8-10]. Clinical and pathologic characteristics of undifferentiated carcinoma of the colon were summarized in Table 1. Yasui et al. [8] reported a case of the small cell type of undifferentiated carcinoma in which the tumor rapidly recurred after removal of it. Histologically, tumor cells grew in a diffuse sheet-like arrangement. Matsuda et al. [9] reported a case of aggressive undifferentiated colon carcinoma producing granulocyte-colony stimulating factor (G-CSF). A 52-year-old man underwent palliative surgery for ascending colon cancer, but it relapsed very rapidly. Microscopically, pleomorphic tumor cells with acidophilic cytoplasm grew in a diffuse sheet-like arrangement. In IHC staining, the tumor cells were positive for CK, G-CSF, and vimentin, but negative for CK7, CD56, and CD30. Ashitomi et al. [10] reported a case of undifferentiated carcinoma with a rhabdoid feature. In the present study, the morphology of the tumor did not have the same characteristics as rhabdoid or small cell type undifferentiated carcinomas. Despite extensive tests on IHC markers, the undifferentiated carcinoma subtype could not be classified. Therefore, the patient was diagnosed with undifferentiated carcinoma, NOS.

Table 1 . Clinical and Pathologic Characteristics of Undifferentiated Carcinoma of the Colon.

Author, year	Age/sex	Diagnosis	Cancer subtype	Location	Tumor stage	Microscopic findings	Immunohistochemical marker study	Treatment	Outcomes
Lim et al., present study	85/female	Undifferentiated carcinoma of the colon	Not otherwise specified	Ascending colon, metastasis to the duodenum	Stage IV	Diffuse round cell infiltration, pleomorphic macro-nuclei	Pan-CK (+), CK20 (–), CK7 (–), MUC2 (–), mucicarmine (–), EBV-ISH (intact), CD56 (–), loss of MLH1, MSH2 (intact), TTF-1 (–), E-cadherin (–)	Supportive care	Died of disease progression in 6 mo
Ashitomi et al. [10], 2020	58/male	Undifferentiated carcinoma of the colon, lung cancer	Rhabdoid type	Transverse colon	Stage IIIB	Rhabdoid cells	PD-L1 (+), MSI (low), CK6 (–), CK20 (–), TTF-1 (–)	Right hemicolectomy	Free of tumor for 15 mo
Matsuda et al. [9], 2009	52/male	Undifferentiated carcinoma of the colon	G-CSF producing type	Ascending colon, metastasis to the liver	Stage IV	Pleomorphic tumor cells with acidophilic cytoplasm, sheet-like arrangement	G-CSF (+), CK20 (+), Vimentin (+), CK7 (–), CD56 (–), CD30 (–), hCG (–)	Palliative cytoreductive surgery	Died of rapid relapse in 1 mo
Yasui et al. [8], 2006	70/male	Undifferentiated carcinoma of the colon	Small cell type	Cecum-hepatic flexure	Stage II	Spindle shape nuclei, diffuse sheet-like arrangement	Synaptophysin (+), CD56 (+), chromograninA (+), NSE (–)	Non-curative surgery	Died of rapid relapse in 1 mo

NOS, not otherwise specified; G-CSF, granulocyte-colony stimulating factor; Pan-CK, pan-cytokeratin..

One researcher has described the endoscopic feature of duodenal metastatic lesions [19]. It usually appeared to be a submucosal mass with central ulceration, and was referred to as a ‘volcano-like’ lesion [19]. In the present case, the duodenal metastatic lesion also looked like a protruding mass with large ulceration.

Since metastasis to the duodenum of colorectal cancer occurs infrequently, the management has not yet been established. Locally advanced cancer is characterized by the tumor invasion of adjacent organs without distant metastasis [5]. Although there were concerns about high morbidity and mortality of extended resection in patients with locally advanced cancer, some studies found out there was an obvious survival benefit for patients undergoing extended radical resection [5,7]. For instance, a 41-year-old man with right colon cancer that directly invaded the duodenum and pancreas was treated with extended radical resection. His disease had not recurred for 2 years [5].

In this case, colorectal cancer metastasized to the distant lymph nodes, belonging to stage IV disease. Surgery is only beneficial for hepatic or pulmonary metastasis in stage IV colorectal cancer. According to the guidelines [20], systemic chemotherapy regimens including FOLFOX, FOLFIRI, bevacizumab, and/or other targeted therapies are recommended for stage IV disease.

In conclusion, we report a case of undifferentiated carcinoma of the colon with metastasis to the duodenum. As the incidence of primary duodenal cancer is very low, clinicians should consider the possibility of metastasis when a duodenal mass is found.

None.

No potential conflict of interest relevant to this article was reported.

Conceptualization: Jeongmin Choi. Investigation: Jongryeul Lim, Jeongmin Choi, Hyun-Jung Kim. Writing—original draft: Jongryeul Lim, Jeongmin Choi. Writing—review & editing: Jongryeul Lim, Jeongmin Choi, Hyun-Jung Kim, Soo In Choi.