The primary CCCRC is defined as a tumor either completely or partially composed of tumor cells with clear cytoplasm similar to clear cell tumors of the lung or genital tract [4]. CCCRC is not recognized as a subtype in the current 5th WHO classification of tumors of the digestive tract, in which clear cell carcinomas are only defined for the stomach, pancreas, bile duct, gall bladder, and liver [6]. Some authors require the presence of more than 50% of the clear cell component to consider the diagnosis of a clear cell adenocarcinoma of the colorectum [7]. However, it must be considered that this cutoff is arbitrary and has not been rigorously evaluated at this point. The mean age of affected individuals is 58.7 years with a median of 59 years (Supplementary Table 1). These patients are younger than those with conventional colorectal adenocarcinoma, which has a median affected age of 70 years at the time of diagnosis [8]. The ratio between female and male is 1:1.8 (Supplementary Table 1). The tumor is most commonly found in the left colon, including the rectum in 72.9% of the reported cases (Supplementary Table 1). Metastases are found in locoregional lymph nodes in 64.3% and in distant regions in 37.1%, affecting the liver in 25.7% (Supplementary Table 1) to 38.7% [5] and the lungs in 11.4% (Supplementary Table 1).

Histologically, CCCRC can present in a pure clear cell or mixed form [4, 7, 9]. The immunohistological marker profile in CCCRC typically shows the expression of colorectal tract antigens, i.e., CK20, CDX2, SATB2, and CEA [2, 7, 10]. Only a small fraction of CCCRC expresses enteroblastic markers with a reported frequency of 5.6% in one series with 303 cases [5]. The expression of enteroblastic markers is a distinctive finding of “colorectal adenocarcinoma with enteroblastic differentiation” (CAED); however, it should be noted that CAED may present with or without clear cell changes [1, 5]. Additional immunohistological markers such as RCC, CD10, carboanhydrase IX, PAX8, and p63 are useful to differentiate CCCRC from other clear cell tumors, e.g., renal cell carcinomas, malignant Müllerian tumors, and squamous cell carcinomas of the anal canal, which all may affect the colorectal tract [2]. The exact cause of clear cell transformation is unknown. The accumulation of glycogen or mucin seems unlikely [11, 12]. Cell clearing may be caused either by degenerative cell processes [9], e.g., lipid-like material [12], or by a transition (metaplasia) of tumor cells from an initially conventional type [11, 12].

In some studies, including one own case, precursor lesions were found, presenting with colorectal clear cell adenomas progressing into invasive CCCRC, however, without yet identifying the underlying molecular pathway [2, 9].

In our cases, mutations in the TP53 gene (exons 5 and 8) were detectable with identical point mutations in the clear cell and conventional component. Molecular pathological investigations in CCCRC are rare and have revealed several mutations most frequently in the genes KRAS and TP53 (Supplementary Table 1), which are not clear cell-specific as shown in our study and by others [1, 13]. However, somatic mutations in the TP53 gene are one of the most frequent genetic changes in human cancers overall. Its prevalence in sporadic colorectal carcinomas is 43.2% [14] and affects most frequently the exons 5 to 8 [15]. In one of our cases, we observed a mutation of the SMAD4 gene in the clear cell component, which has not been previously reported to our knowledge. In gastric adenocarcinoma with enteroblastic differentiation, an inactive SMAD4 is associated with a worse clinical outcome [16].

Clinically, clear cell colorectal adenocarcinoma appears to have a worse prognosis than conventional subtypes [5, 9]. In one study [1], the 3-year overall survival was only 66% compared to 85% for colorectal adenocarcinomas lacking clear cell differentiation. However, due to the small number of cases, there is no valid data on survival times. Suggested therapeutical strategies are based on single case reports and include HER2-targeted and chemoradiotherapy, followed by surgical removal of the tumor [1, 17]. One of our patients received FOLFOX-6 therapy post-surgery and remained cancer-free for 12 years to date. In contrast, in a 26-year-old female patient, a similar therapy resulted in an insufficient significant clinical improvement [10].