Colorectal clear cell carcinoma: a literature review.

In our systematic review study, we used PubMed, Google Scholar, and ScienceDirect to investigate cases of colorectal clear cell carcinoma. Relevant reports were identified in the databases using the search terms in Fig.  1 . Searches were performed between 31 December 2022 and 3 January 2023. We implemented a Boolean approach using Medical Subject Heading (MeSH) keywords. MeSH keywords searched in PubMed are summarized in Table  1 . Fig. 1 PRISMA flow diagram Table 1 Search strategy used to extract data Search Strategy PubMed and Mesh results (#1) Adenocarcinoma, Colon OR Adenocarcinomas, Colon OR Colon Adenocarcinoma OR Colon Adenocarcinomas OR(“Colonic Neoplasms/anatomy and histology”[Mesh] OR “Colonic Neoplasms/classification”[Mesh] OR “Colonic Neoplasms/cytology”[Mesh] OR “Colonic Neoplasms/diagnosis”[Mesh] OR “Colonic Neoplasms/diagnostic imaging”[Mesh] OR “Colonic Neoplasms/drug therapy”[Mesh] OR “Colonic Neoplasms/epidemiology”[Mesh] OR “Colonic Neoplasms/pathology”[Mesh] OR “Colonic Neoplasms/surgery”[Mesh]) 106,629 studies (#2) Adenocarcinomas, Clear Cell OR Clear Cell Adenocarcinoma OR ( “Adenocarcinoma, Clear Cell/anatomy and histology” [Mesh] OR “Adenocarcinoma, Clear Cell/classification”[Mesh] OR “Adenocarcinoma, Clear Cell/complications”[Mesh] OR “Adenocarcinoma, Clear Cell/cytology”[Mesh] OR “Adenocarcinoma, Clear Cell/diagnosis”[Mesh] OR “Adenocarcinoma, Clear Cell/diagnostic imaging”[Mesh] OR “Adenocarcinoma, Clear Cell/drug therapy”[Mesh] OR “Adenocarcinoma, Clear Cell/epidemiology”[Mesh] OR “Adenocarcinoma, Clear Cell/pathology”[Mesh] OR “Adenocarcinoma, Clear Cell/” [Mesh]) 7895 studies (#1) AND (#2) 79 studies Science direct (Adenocarcinoma, Colon OR Adenocarcinomas, Colon OR Colon Adenocarcinoma OR Colon Adenocarcinomas) AND (Adenocarcinomas, Clear Cell OR Clear Cell colon carcinoma) 292 studies Google scholar Clear cell carcinoma AND colon cancer 340 studies PRISMA flow diagram Search strategy used to extract data When establishing the inclusion/exclusion criteria listed below, article titles and abstracts were evaluated. In this review, Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards for 2020 were followed) Fig.  1  [ 13 ]. We used only English-language case reports, case series, and original research. We included all reported cases of colon, rectal, and anal clear cell carcinoma identified on histology until January 2023. However, studies reported secondary or metastatic colon clear cell carcinoma were excluded.

In our systematic review, the search approach generated 340 articles, of which 261 duplicates were eliminated using Zotero. A total of 79 records were reviewed, and 61 were discarded on the basis of inclusion/exclusion and relevance criteria. The final screening yielded 18 articles for quality and eligibility evaluation, which were all included in this review. A quality assessment tool using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports was performed. The PRISMA flowchart is illustrated in Fig.  1 . Regarding data from such 18 case studies, 34 patients were diagnosed with primary colon clear cell carcinoma. Considering the gender distribution, 18 were male (53%) and 16 were female (47%). The age distribution was from 26 to 89 years with mean of 57.6 years. The most common symptoms were abdominal pain and/or discomfort in 17 patients (50%) and lower GI bleeding in 15 patients (44.1%). The tumor was found on the descending colon and rectum in 27 patients (79.4%) and right colon in 5 (14.7%). The tumor size ranged from 1 to 13 cm in greatest diameter with average size of 4.1 cm. Computed tomography (CT) scan and colonoscopy were the most commonly used diagnostic tools. Colorectal adenocarcinoma with clear cell component associated with endometriosis [Müllerian type (mCCC)] was found in 6 patients (17.6%); 18 patients went through tumor staging and metastasis to regional lymph nodes was found in 6 patients (Table  2 ). Table 2 Summery of demographic data, clinical findings, pathology, and treatment of colon clear cell carcinoma Author Gender Age Chief complaints Location Clinical/paraclinical data Size (cm) Histopathological findings Staging and grading of tumor Molecular testing, PAS staining, and Alicen blue Management Hellstorm [ 39 ] M 67 Melena Rectum Sessile ulcerating lesion in 10 cm anus 2 – – – Abdominoperineal resection Jewel [ 21 ] M 75 Melena Rectum – – – – – Abdominoperineal resection F 56 Melena Left colon – 6 – – – Abdominoperineal resection Watson [ 5 ] M 53 – Anal canal – 3.5 Composite – PAS =  +  Alican blue = – Abdominoperineal resection Rubio [ 15 ] M 68 Weight loss, alternating bowel habits, abdominal pain Left colon – 6 Pure CCC T4N2M1 PAS =  +  Alican blue = – hemicolectomy Sasaki [ 40 ] F 49 Abdominal pain Rectum History of endometriosis – Composite SCC – – Abdominoperineal resection McCluggage [ 4 ] F 65 Abdominal pain Rectum History of endometriosis 3 Pure clear cell adenocarcinoma – PAS =  +  Abdominoperineal resection Malik [ 41 ] F 36 Rectal bleeding and constipation Rectum Ulcerated mass in 2 anus 5 Pure clear cell adenocarcinoma T3N1M0 PAS =  +  Alican blue =  +  Abdominoperineal resection Braumann [ 42 ] M 89 Positive occult blood test, abdominal pain, wight loss Transverse colon and splenic flexture an exophytic, central exulceric malignant tumor 70 cm from the anal verge 2.2 Pure clear cell adenocarcinoma T2N0M0 PAS = – Alican blue = – Partial colectomy Ko [ 43 ] M 62 Abdominal pain, melena Sigmoid Three descending colonic polyps and fungating masses approximately 2 cm in size that were below the level of polyps in the sigmoid colon 1.5 composite clear cell adenocarcinoma T2N0M0 – Low anterior resection Hao [ 20 ] M 37 Abdominal pain, weight loss Rectum Solid tumor mass measuring approximately 8.0 cm in maximum diameter located in the wall of the descending colon, 55 cm from the anal verge 12 Pure clear cell adenocarcinoma T3N0M0 – Left hemicolectomy Sawai [ 40 ] F 56 Abdominal pain Rectum Previous history of endometriosis – Pure clear cell adenocarcinoma – – Abdominoperineal resection Houma [ 40 ] F 50 Abdominal pain and rectal bleeding Rectum Previous history of endometriosis – Pure clear cell adenocarcinoma – – Abdominoperineal resection Soga [ 26 ] F 71 Abdominal pain, melena Descending colon and sigmoid Revealed healing ischemic lesions at the descending colon and a 7-mm diameter “berry-like” polyp in the sigmoid colon 3 Clear cell adenocarcinoma and adenoma T2N0M0 PAS =  +  Alican blue = – Partial colectomy Barisella [ 38 ] M 54 – Colon 14 flat lesions with a diameter of 5–15 mm were found extending throughout the large intestine, positive family history 1 Composite clear cell adenocarcinoma and adenoma T2N0M0 KRAS sequencing: point mutation GGT > GTT at codon 12 Total colectomy Bressenot [ 44 ] F 84 Anemia left colon Ulcerated, stenotic, and infiltrated tumor developed in the left colon at 40 cm from anal margin 3.5 Primary clear cell carcinoma T4N0M0 PAS =  +  Alican blue = – Left colectomy Finkelstein [ 36 ] F 41 Rectal bleeding Rectum and sigmoid Mass in upper rectum, history of endometriosis 5 Clear cell carcinoma T2N0M0 – Partial colectomy Shi [ 45 ] M 52 Rectal bleeding Rectum – 1 Composite clear cell adenocarcinoma and adenoma – – Partial colectomy M 51 Abdominal pain Sigmoid – 1.4 Clear cell adenocarcinoma – – Partial colectomy M 35 Abdominal pain Sigmoid – 1.4 Clear cell adenocarcinoma – – Partial colectomy M 63 Abdominal pain Sigmoid – 1.3 Clear cell adenocarcinoma – – Partial colectomy F 68 Anemia Sigmoid – 3.5 clear cell adenocarcinoma – – Partial colectomy F 30 Abdominal pain Sigmoid – 1.4 clear cell adenocarcinoma – – Partial colectomy F 63 Abdominal pain Ascending colon – 0.5 Clear cell adenocarcinoma – – Partial colectomy Furuya [ 31 ] M 81 Anemia, dizziness Ascending colon Stenotic tumor mass in the ascending colon near the hepatic flexure 10 Composite clear cell adenocarcinoma T3N2M1 PAS =  +  Right hemicolectomy, including partial omentectomy, removal of the lymph nodes, biopsy of peritoneal tuberculum, and cholecystectomy Bakshi [ 7 ] M 42 Abdominal pain, rectal bleeding Ascending colon CT abdomen showed circumferential wall thickening in proximal transverse colon and adjacent hepatic flexure; circumferential growth occluding the lumen at hepatic flexure was visualized on colonoscopy 4 Composite clear cell adenocarcinoma T3N0M0 – Right hemicolectomy Barrera-Maldonado [ 3 ] F 41 Abdominal pain and GI obstruction Left colon Contrast CT scan of the abdomen and pelvis revealed mild atelectasis in the lung bases, moderate distension of the gall bladder, and apple core lesion in distal descending colon measuring 3.4 cm and resulting in prominent dilation of the colon and small bowel proximal to lesion 3.5 Composite clear cell adenocarcinoma T2N1M0 – Partial colectomy Yilmaz [ 46 ] F 50 Bloody stool Rectum Reddish polypoid mass was noted in the rectum, previous history of endometriosis 2.5 Pure clear cell carcinoma T2N0M0 – Low anterior resection Gurzu [ 47 ] M 82 GI obstruction Rectum Obstruction in sigmoidoscopy 5 Pure clear cell carcinoma T4N2M1 PAS =  +  Alican blue = – K-rasgene mutations in codons 12 and 13 Proctectomy Wang [ 10 ] M 26 Abdominal pain, weight loss Left colon Abdominal CT revealed an ill‑defined mass (12 × 10 cm in size) located in the left upper quadrant. On unenhanced images, mass was hypo-attenuated in relation to liver. Colonoscopy revealed stenotic tumor mass in transverse colon close to spleen flexure 13 Pure clear cell carcinoma T4N0M1 – Left hemicolectomy Okazawa [ 40 ] F 83 Rectal bleeding Rectum CT showed a heterogeneous enhanced wall thickness of the rectum. Colonoscopy revealed tumor sizes around half of the rectal circumference, at the upper rectum, 13 cm from the anal verge 4 Pure clear cell carcinoma T4N0M0 – Low anterior resection Remo [ 37 ] M 58 Rectal bleeding Right colon CT showed a right colon mass 7 Composite clear cell carcinoma T4N2M0 KRAS wild type with BRAF Mutation (V600E/EC) Right hemicolectomy Tochio [ 48 ] M 48 Positive fecal occult blood Left colon Colonoscopy showed a 7 mm in diameter, reddish, oval sessile polyp with a smooth surface pattern in the descending colon 1 Composite clear cell adenocarcinoma with adenoma – PAS = – Alican blue = – Polypectomy Khefacha [ 14 ] F 75 Abdominal pain Right colon Abdominal CT scan showed suspicious thickening of colonic wall with infiltration of surrounding fat. No collection or free liquid was found. Lower GI endoscopy showed a circumferential, ulcerating, and burgeoning mass that prevented optic from passing through 10 Pure clear cell carcinoma T4N0M0 – Right hemicolectomy Summery of demographic data, clinical findings, pathology, and treatment of colon clear cell carcinoma PAS =  + Alican blue = – PAS =  + Alican blue = – PAS =  + Alican blue =  + PAS = – Alican blue = – PAS =  + Alican blue = – KRAS sequencing: point mutation GGT > GTT at codon 12 PAS =  + Alican blue = – PAS =  + Alican blue = – K-rasgene mutations in codons 12 and 13 PAS = – Alican blue = – Periodic acid-Schiff (PAS) staining of tumor cells was carried out for ten patients and it was positive in 80%. Alcian blue staining of tumor cells was carried out on eight patients and was negative in seven and positive in one. Thus, positive predictive value of PAS in colon CCC was 80%. Meanwhile, negative predictive value of Alcian blue staining was 87.5% (Table  2 ). Turning to the immunohistochemistry panel, out of 26 cytokeratin (CK) 20 tests, 22 were positive, showing positive predictive value of (84.6%). Vimentin was tested in 12 patients, resembling a negative predictive value of 100%. Villin was tested in one patient, which was positive. Caudal-type homeobox (CDX) 2 was positive in seven out of ten tested patients with 70% positive predictive value. Out of 23 patients tested for CK7, it had a negative predictive value of 74%. Moreover, alpha-fetoprotein (AFP) was evaluated in seven cases, which showed a negative predictive value of 85.7%. Carcinoembryonic antigen (CEA) testing done for 20 cases was positive in 16 patients with 80% positive predictive value. Despite the fact that epithelial membrane antigen (EMA) showed 100% positive predictive value in all eight patients tested for it, human melanoma black (HMB)-45 had 100% negative predictive value (five negatives out of five tests) Table  3 . Table 3 Immunohistochemistry (IHC) study of colon clear cell carcinoma Marker CK20 CK7 CDX2 CEA AFP HMB-45 Villin EMA Vimentin Positive 22 6 7 16 1 0 1 8 0 Negative 4 17 3 4 6 5 0 0 12 Total 26 23 10 20 7 5 1 8 12 Immunohistochemistry (IHC) study of colon clear cell carcinoma Molecular testing was reported in the following: one patient with (KRAS) wild type with (BRAF) mutation (V600E/EC), one patient with KRAS mutation at codon 12 with BRAF wild type, one patient with only KRAS point mutation at codon 12, and one patient (KRAS) with gene mutation in codon 12 and 13. On the contrary, microsatellite instability-high (MSI-H) was found in one patient and in four patients microsatellites showed stability. Moreover, one of three patients either showed empty cytoplasmic vacuoles or multiple cytoplasmic lipid-like vacuoles negative for adipophilin or cytoplasm containing clear empty spaces on electron microscopy (Table  2 ).

Our study summarized the literature mainly focused on colon clear cell carcinoma. The most common symptom is abdominal pain and GI bleeding. Tumor was commonly found in the left side of colon. Surgical intervention was the chosen option for treatment. On the basis of pathological investigation of patients, CK20, CK7, AFP, CEA, and CDX2 were most used for diagnosis. However, due to rarity of colic CCC and small sample size, the etiology of colon CCC is unknown and no pathognomonic diagnostic criteria is introduced. Future clinical studies are required to shed light on this scarce type of colon cancer.

Colorectal clear cell carcinoma is a rare finding that is distinguished by clear cytoplasm, first described in 1964 by Hellstrom and Fisher [ 14 ]. The clear cell nuclei are typically pyknotic upon histological inspection. Furthermore, the cytoplasm in clear cells is usually clear and occasionally vacuolated. The arrangement of tumor glands composed of clear cells tends to cluster closely together, with little stroma in between. The clear cell component of tumor glands can occasionally contain necrotic material. When a cell undergoes necrosis or apoptosis, the chromatin in its nucleus condenses irreversibly, a process known as pyknosis Sometimes the clear cell portion is also accompanied by an ordinary portion of tubular adenoma [ 11 ]. Empty cytoplasmic vacuoles [ 15 ] or lipid-like vacuoles negative for adipophilin are seen under the electron microscope in clear cells [ 16 ]. In comparison, conventional colon adenocarcinoma is a malignant epithelial tumor that develops from the surface glandular epithelial cells lining the colon and rectum. Tumor cells characterize atypical tubular formations with several lumens, numerous stratifications, and a decreased stroma [ 17 ]. In colon adenocarcinoma, the cause of clear cells is uncertain. Carbohydrate elution, leading to glycogen accumulation or autolysis and ultimately to lipid accumulation, are all possibilities, as reported by Karačić et al . [ 18 ]. Clear cell change can be diagnosed without the presence of glycogen and mucin buildup in the cytoplasm [ 19 ]. It is claimed that degenerative alterations brought on by accumulation of lipid-like substances in the cytoplasm could be responsible for the subsequent clarity of the cytoplasm [ 15 ]. The primitive colon clear cell carcinoma is a scarce diagnosis. On the basis of our review of literature, since 1964, 34 cases of primary clear cell carcinoma of colon have been reported. Meanwhile, clear cell carcinoma of Müllerian source, naming kidneys, ovarian, and cervix is more prevalent than primitive colon clear cell carcinoma [ 14 ]. On the basis of our own data, 18% of cases of colic CCC had Müllerian origin. According to gender, it affected both men and women. The mean age of patients was 58 years. However, it was diagnosed in women at a younger age. The most common clinical finding of colic CCC was abdominal discomfort and gastrointestinal (GI) bleeding, melena. Although it was mostly detected in the left colon and rectum, anemia and fatigue were the symptoms of right-sided colon CCC. In all of the cases of colon CCC, the precise diagnosis was made after surgical removal of the tumor site through pathological investigation. Since clear cell components can be seen in other types of colon adenocarcinoma, tubular adenoma, and colon metastasis, immunohistochemical analysis of CK7, CK20, and CDX2 plays a major role in highlighting the colon clear cell carcinoma. PAS, Alcian blue staining, or AFP immunostaining were used as well [ 16 ]. Nonetheless, patients were initially investigated by lab data, colonoscopy, and imaging such as abdominal CT scan. Confirmation of the colonic origin of the tumor cells by immunohistochemical analysis is crucial because it is difficult to differentiate between metastatic carcinomas, such as metastatic clear cell carcinoma, and colon clear cell carcinoma [ 18 ]. Metastatic renal clear cell carcinoma and malignant clear cell melanoma are two key differential diagnoses to consider [ 20 ]. Primary renal cell cancer can be ruled out with preoperative imaging and surgical investigation [ 20 ]. Reactivity to carcinoembryonic antigen (CEA) [ 21 – 23 ] and epithelial membrane antigen (EMA), and the absence of vimentin and cytokeratin (CK) expression, could help ruling out renal cell carcinoma as the main location [ 24 ]. Malignant clear cell melanoma cannot be diagnosed in the absence of reactivity to the melanogenesis-associated antigen human melanoma black (HMB)-45 [ 20 ]. Cytokeratin (CK) staining is useful in the pathological investigation for distinguishing between different types of primary intestinal neoplasia [ 4 , 25 ]. There are 20 different cytokeratins, all of which are found in epithelial cells and serve as structural proteins. The pattern of cytokeratin expression differs among epithelial cells depending on where they are located. Type I keratin CK20 [also known as keratin (KRT) 20] has a molecular weight of 46 kilodaltons (kDa) and is represented by the keratin (KRT) 20 gene. Nonkeratinizing epithelia express CK7, a type II keratin with a molecular weight of 54 kDa [ 26 ]. Given that CK20 is expressed in the intestinal and gastric epithelial cells while CK7 is detected in the breast, lung, ovary, and urothelium, positive CK20 and negative CK7 test are thus highly suggestive of an intestinal origin of tumor cells [ 9 ]. Considering our data analysis, CK20 had 84.6% positive predictive value while CK7 resembled 74% negative predictive value. Villin, similar to cytokeratins, has been demonstrated to be a helpful aid in the differential diagnosis of metastatic gastrointestinal cancers [ 27 ]. Furthermore, intestinal neoplasia can be detected by measuring CDX2 expression, a homeobox transcription factor. It plays a crucial role in the maturation of intestinal epithelial cells. Despite the claims of some authors that loss of caudal-type homeobox CDX2 is common among dysplastic and intestinal malignant cells, later research has discovered CDX2 antibodies as a good specific tumor marker for intestinal neoplasia [ 25 , 27 , 28 ]. CDX 2 had 70% positive predictive value in our review. We compare our findings to a retrospective study conducted by Llieva et al . to assess the immunohistochemistry of 71 cases of colorectal carcinoma. CK20 was positive in 66.2% of colorectal carcinomas as compared with 84.6% in our review. CDX2 showed positive staining in 87.3% of cases of colorectal cancers [ 29 ]. Bae et al . evaluated the expression of CDX2 in 730 cases of CRCs and stated that patients with negative CDX2 showed poor prognosis overall [ 30 ]. On the basis of these findings, the nature of colon clear cell carcinoma would be more aggressive than the conventional colorectal adenocarcinoma, but further clinical studies are essential to reach to a conclusion in colon clear cell carcinoma survival and prognosis. The role of alpha-fetoprotein (AFP) in immunohistochemistry is tracing the etiology of clear cell colon cancer [ 31 ]. Primary colorectal cancer that produces AFP is highly rare and is said to have poor prognosis [ 32 ]. Numerous studies have focused on primary gastric clear cell adenocarcinoma and primary AFP-producing gastric cancer, since their incidence is higher than other types of GI malignancies. The conversion of tumor cells into fetal cells capable of producing AFP is generally thought to be the cause of AFP production [ 33 ]. In gastric cancer, two distinct tumor morphologies, hepatoid and clear cell, have been correlated with AFP production. Matsunou et al . suggested that AFP-positive gastric carcinomas differentiate toward the fetal intestine or hepatocytes. They concluded that their patient had AFP-producing gastric cancer with enteroblastic differentiation [ 34 ]. Furuya et al . documented a case of clear cell adenocarcinoma of the colon, which they diagnosed as clear cell adenocarcinoma with enteroblastic differentiation on the basis of its histopathologic characteristics and immunohistochemistry staining [ 31 ]. However, it is important to note that the histologic type of colon cancer known as clear cell carcinoma with enteroblastic differentiation is not included in the AJCC (American Joint Committee on Cancer) Cancer Staging Manual, 7th Edition. Alpha-fetoprotein (AFP) was positive in one patient reported by Yoshitaka Furuya [ 35 ]. Special staining, such as periodic acid-Schiff (PAS) and Alican blue, play a significant role in the diagnosis of clear cell carcinoma [ 12 ]. Hao et al . noted that the presence of PAS suggests that clear cells contain glycogen granules in their cytoplasm, while the absence of PAS may be attributable to the inevitable autolysis of the specimens or the elution of glycogen granules during processing or fixation [ 20 ]. Another theory proposes that the Müllerian tubes are the original site of clear cell adenocarcinoma. Endometriosis-associated intestinal tumors have been described as endometriotic dysplastic glands in the colon characterized by obvious cellular alterations (EIAT) [ 36 ]. Five cases have been described in our review of CCC with associated endometriosis (Table  2 ). In our review, six patients of mCCC were female with a mean age of 59.7 years and history of endometriosis. All cases (100%) were CD 20 negative and CD 7 positive on immunohistochemistry, and like other cases, surgery was the mainstay of their treatment. Barisella et al . conducted molecular testing on clear cell colon carcinoma to see whether it shared molecular features with conventional colorectal carcinoma. During (KRAS) sequencing, they discovered the previously described point mutation GGT > GTT at codon 12, which resulted in the activating amino acid substitution Gly12Val. Therefore, Barisella et al . hypothesized that the analyzed clear cell colon adenocarcinoma shares the KRAS genotype of the conventional colorectal carcinomas, and they further hypothesized that the different morphology of clear cell colon carcinoma does not seem to reflect a distinct biological entity but an unusual morphological variant with a similar molecular profile of conventional colorectal carcinoma [ 37 , 38 ]. Surgery was the mainstay of the treatment in all cases and postoperative chemotherapy was administered in five cases. Because of the small number of case reports, especially without adequate and long-term follow-ups, the prognosis of this subtype of colon adenocarcinoma cannot be established.

Globally, colorectal cancer (CRC) ranks third among malignant neoplasms in terms of frequency [ 1 , 2 ]. Clear cell carcinoma (CCC) is one of the rare histological subtypes of colon adenocarcinoma [ 3 , 4 ]. The first case of clear cell carcinoma of the colon was reported in 1964 [ 1 , 3 , 5 – 10 ]. Almost all of the previous studies on CCC are case reports. Due to its scarcity, incidence and prevalence have not been established. Nonetheless, in one study, a probability of 0.086% for the occurrence of CCC in a retrospective analysis was reported. Considering demographic data, the majority reported that CCC resembled no gender preference. In addition, the mean age of the patients was roughly 56 years old. Clear cell carcinoma can present itself either in its pure form or in composition of other morphological components [ 11 ]. Two types of CCC are categorized as intestinal and Müllerian, which contain different pathological features and diagnostic criteria. The intestinal variant (iCCC) originates from the intestinal mucosa and the Müllerian type (mCCC) arises from endometriosis. Correct identification of this entity by combining morphology and immunohistochemistry is crucial, since the differentiation of the pure CCC of colon from other types clear cell tumors, which may be secondary at this site, is challenging [ 12 ]. In the following study, we aim to review all the reported cases of primary colon clear carcinomas to establish its clinical features as well as to focus on various pathological methods used for diagnosis.