Background
In many organs, including the ovary, uterus, kidney, salivary gland, thyroid gland, skin, and breast, when tumor cells show clear cytoplasm, the diagnoses reflect the clear cell morphology, such as clear cell adenocarcinoma (CCA), clear cell carcinoma, glycogen-rich adenocarcinoma, lipid-rich adenocarcinoma, and other clear cell variants of each tumor [
1]. These diagnoses tend to be used when the clear cell nature of the tumor is evident [
1]. In colorectal tubular adenoma or adenocarcinoma, conversely, clear cells are rarely observed, the reason for which remains uncertain [
2‐
26]. Herein, we report an additional case of tubular adenoma and of tubular adenocarcinoma, both of which have a clear cell component. We describe a thorough investigation of its clear cell etiology and review the literature.
Discussion and conclusions
A clear cell colorectal tumor was first described by Hellstrom’s report of a physaliferous variant of colon adenocarcinoma [
10]. Clear cells were then detected in colorectal tubular adenoma, hyperplastic polyps, and tubular adenocarcinoma [
2‐
9]. Domoto et al. [
5] retrospectively analyzed the probability of clear cell tubular adenoma and its incidence was only 0.086%.
To date, there have been 44 cases of clear cell of colorectal epithelial tumors reported, composed of 20 adenomas (Table
2) and 24 adenocarcinomas (Table
3) [
2‐
26]. The median age was 57.2 and 58.6 years for adenoma and adenocarcinoma, respectively. Both tumors showed a male predilection (adenoma: 11/17, adenocarcinoma: 18/23) and occurred mostly in the left-side colon (adenoma: 14/19, adenocarcinoma: 16/24). Some cases had multiple polyps at the same time [
3,
7,
9,
11,
14,
16,
20] and two cases had multiple tubular adenomas with a clear cell component [
7,
9]. Case 2 reported here had multiple polyps; however, no other polyps had clear cell components.
Table 2
Clinicopathological information for 20 colorectal adenomas with clear cell components
| ND | ND | ND | ND | ND | ND | |
| 61 | F | R | 2 | – | – | Alive |
| 62 | M | D | 1.4 | – | – | Alive |
| 54 | M | S | 6 | – | Scattered | |
45 | M | T | 6 | – | Scattered | |
44 | M | S | 10 | – | Scattered | |
| 48 | F | T | 2.5 | ND | – | |
68 | F | S | 0.5 | ND | – | |
84 | M | S | 1.8 | ND | – | |
| ND | ND | ND | 0.8 | ND | ND | |
61 | M | S | 1.5 | ND | ND | |
ND | ND | ND | 1.8 | ND | ND | |
63 | F | As | 0.5 | – | ND | |
63 | M | R | 1.4 | – | ND | |
68 | F | ND | 3.5 | – | ND | |
30 | F | S | 1.4 | – | ND | |
35 | M | S | 1.3 | ND | ND | |
| 48 | M | S | 0.8 | – | – | |
| 63 | M | As, D, R | ND | – | – | |
Present study | 75 | M | R | 1.8 | – | – | Alive |
Table 3
Clinicopathological information for 24 colorectal adenocarcinomas with clear cell components
Hellstrom and Fisher [ 10] | 67 | M | R | 2 | −/+ | – | Alive |
| 71 | M | T | 7 | + | | ND |
| 75 | M | S | 0.1 | – | – | Died |
56 | F | S | 6 | ND | – | ND |
| 58 | M | AC | 3.5 | + | – | Died |
| 68 | M | D | 6 | −/+ | – | Died |
| ND | ND | R | ND | + | ND | ND |
| 89 | M | T | 2.2 | – | – | Died |
| 36 | F | R | 5 | + | + | ND |
| 62 | M | S | 1.5 | ND | ND | ND |
| 37 | M | D | 12 | + | – | Alive |
| 54 | M | As | 0.9 | ND | ND | Alive |
| 71 | F | S | 0.8 | – | – | ND |
| 84 | F | D | 3.5 | – | – | Alive |
| 52 | M | R | 0.9 | – | ND | ND |
51 | M | S | 1.4 | – | ND | ND |
| 81 | M | As | 9.5 | + | ND | Died |
Barrera-Maldonado et al. [ 22] | 41 | F | D | 3.4 | ND | ND | ND |
| 26 | M | T | 12 | ND | ND | Died |
| 25 | M | As | 3 | ND | ND | Died |
| 58 | M | As | 7 | ND | ND | Died |
79 | M | As | 4.5 | ND | ND | Died |
| 48 | M | D | 0.7 | – | – | Alive |
This study | 58 | M | S | 2.5 | – | – | Alive |
Histologically, the clear cells of colorectal tumors characteristically have pyknotic polygonal nuclei not confined to the basal portion but randomly arranged and clear or vacuolated cytoplasm [
5]. In our cases, it was difficult to assess the nuclear atypia of clear cells, however, conventional tubular adenoma or adenocarcinoma cells accompanied them and there was a transition between both components. This helped us to recognize the clear cell components as the atypical equivalent to adenoma or adenocarcinoma. Moreover, it may be misleading to diagnose metastatic carcinoma if the clear cell component accounts for the vast majority of the tumor. Therefore, it is important to confirm a colorectal origin by immunohistochemical analysis of CK7, CK20, and CDX2 [
7]. Our cases were CK7 negative, CK20 focally positive, and CDX2 diffusely positive, consistent with a colorectal origin.
Differences in staining results between the conventional and clear cell component were found for CEA and CD10. The localization of CEA is associated with tumor differentiation; thus, luminal cell apical expression of CEA is seen in well-differentiated tumors and, in contrast, cytoplasm expression is seen in poorly differentiated tumors [
28]. The tumor cell phenotype correlates with tumor aggressiveness and biological behavior in several cancers. The expression of CD10 suggests colorectal adenocarcinoma with small intestinal differentiation, which is associated with higher venous invasion than large intestinal phenotype of colorectal adenocarcinoma [
29]. The diffuse cytoplasmic expression of CEA and the confined expression of CD10 seen in clear cell areas may indicate that these clear cell components harbor greater malignant potential.
Generally, an accumulation of glycogen, mucin, and lipid, as well as enteroblastic differentiation, are well-known examples of the etiology or substances of clear cells in HE specimens. Colorectal tubular adenoma and adenocarcinoma with clear cell components were reported as tubular adenoma with clear cell change (TAC) and CCA, respectively [
2‐
26]. In TAC, an accumulation of glycogen, mucin, and enteroblastic differentiation have never been verified by PAS, Alcian blue staining, or AFP immunostaining [
2‐
9]. Case 1 is negative for those stains, in accord with previous TAC reports. In CCA, on the other hand, some cases are either positive for PAS [
2,
11,
13,
15,
17,
21], Alcian blue staining [
15], or AFP immunohistochemistry [
21]; however, other cases are negative for these stains [
3,
10,
12,
14,
19,
20,
26]. It seems that some heterogeneity exists among CCA cases [
2,
3,
7,
10‐
26]. Case 2 is negative for PAS, Alcian blue staining, and AFP immunostaining and corresponds to previously reported negative-result cases. The pathogenesis of TAC and some CCA cases, including our cases, remains unclear. It may be more appropriate to diagnose Case 2 and those previously reported negative-result cases as tubular adenocarcinoma with clear cell change, corresponding with the malignant counter part of TAC, rather than CCA.
Electron microscopic examination revealed multiple cytoplasmic lipid-like vacuoles in the clear cells of both cases, and this finding corresponded to previous reports [
3,
5,
10‐
12]. These vacuoles were described as autolysis or elution of glycogen granules during processing or fixation [
5,
10], glycogen-like material with lipid to a lesser extent [
11], and degeneration due to lipid accumulation [
6,
9]. Miyasaka et al. [
9] recently reported one case of TAC positive for adipophilin immunostaining and described that lipid accumulation might be responsible for its clear cell nature. In our report, Case 1 was negative for adipophilin but case 2 showed focal positive staining for it, which caused us to consider lipid accumulation; however, the immunoelectoron microscopy results were mostly negative for adipophilin. Bressenot et al. [
20] reported a CCA and described that they could not detect glycogen in formalin sections but found it in frozen sections. In our study, we could not determine what caused the clear cells in the colorectal tumors; however, autolysis or carbohydrate elution remain possible explanations.