Right Colon Clear Cell Carcinoma of Müllerian Type.

Clear cell carcinoma (CCC) is usually seen in tissues originating from the paramesonephric (Müllerian) ducts such as the kidneys, the ovaries, the cervix and the vagina. The pathogenesis has not yet been elucidated. The diagnostic hallmark is the clear cytoplasm. Primitive CCC of the colon is a very rare entity. There are two types of CCC of the colon; the intestinal type and the Müllerien type. The differential diagnosis arises mainly with secondary metastases of renal or ovarian origin. Immunohistochemistry allows retaining the primitive character. The treatment is not yet consensual. It depends on the type of tumor and its stage. The treatment is based on surgery and possibly chemotherapy. We report the case of a 75-year-old female patient who underwent surgery for a tumor of the ascending colon. Microscopic examination concluded an extensively necrotic carcinomatous growth which infiltrated all the layers of the intestinal wall and the peritoneum. The tumor was made of clusters and spans of clear cells which were separated by thin conjunctivo-vascular septa. The tumor cells were round to polygonal with a clear, optically empty, pseudo-vegetative (physaliferous) cytoplasm. Immunohistochemistry study showed a positive staining with CK7 and a negative staining with CK20, CDX2, PAX8, P63, CD10, chromogranin, and synaptophysin. We performed a Medical Literature databases (Pubmed and Google Scholar) research. Only forty-two cases were reported in English literature. The main age is 55.7 (25-89). The sex ratio is one, but female cases were younger (52 vs. 61). The rectum is the most involved site. The left colon location is more frequent than the right one. The Müllerian type was found only at the level of the left colon and rectum. There was no CCC in the right colon of Müllerien type. The case we report herein is the first right colon CCC which is positive in CK7 staining.

Introduction

Clear cell carcinoma (CCC) is usually seen in tissues originating from the paramesonephric (Müllerian) ducts such as the kidneys, the ovaries, the cervix and the vagina. Primary colic CCC is a very rare entity with only 41 cases reported in medical literature since 1964. It is characterized by cells with a clear cytoplasm associated with an adenoma or a component of an adenocarcinoma. The pathogenesis has not yet been elucidated, and the diagnosis is based on microscopic immunohistochemical study. There are two types of CCC; the intestinal CCC and Müllerien CCC. It was mostly described at the level of the left colon.

Objectives: we report herein a new case of colic CCC, and through a review of English literature, we studied the epidemiological and the immunohistochemical characteristics of this entity. Medical Literature databases (Pubmed and Google Scholar) were searched.

Primary CCC of the colon, rectum, anus, and small bowel were included. The statistical analysis was made with SPSS (Statistical Package for the Social Science version 21.0).

Observation

A 75-year-old female patient with a personal history of diabetes mellitus, hypertension and a laparoscopic cholecystectomy was admitted for right lower quadrant pain which had been present for 2 months. Physical exam found a right lower quadrant sensitivity. No other notable findings were recorded. In particular, the gynecological exam was normal. Laboratory studies showed a high white blood cell count at 20,300/mm3. An abdominal CT scan showed a suspicious thickening of the colonic wall with infiltration of the surrounding fat. No collection or free liquid was found. Lower GI endoscopy showed a circumferential, ulcerating, and burgeoning mass which prevented the optic to pass through. Biopsy examination was inconclusive (these involved the superficial leucocytic coating). The assessment for metastatic extension was negative. The patient was operated on by midline laparotomy. Intrasurgical observations found a 10-cm tumor which was perforated and covered by the lateral abdominal wall. The kidneys and the ovaries looked healthy. The patient underwent a right colectomy with an ileo-transverse anastomosis. Surgical follow-up was complication-free. The gross examination of the surgical specimen showed an 8 cm, circumferential tumor which was highly necrotic (Fig. 1). Microscopic examination concluded an extensively necrotic carcinomatous growth which infiltrated all the layers of the intestinal wall and the peritoneum. The tumor was made of clusters and spans of clear cells which were separated by thin conjunctivo-vascular septa. The tumor cells were round to polygonal with a clear, optically empty, pseudo-vegetative (physaliferous) cytoplasm. The nucleolus was visible at low magnification (Fig. 2, 3). Immunohistochemistry study showed an intense and diffuse staining of tumor cells with CK7 and a negative staining with CK20, CDX2, PAX8, P63, CD10, chromogranin, and synaptophysin (Fig. 4).

Fig. 1

Gross examination of the surgical specimen showing an 8 cm, circumferential tumor (arrow) which was highly necrotic.

Fig. 2

Microscopic examination (×4 objective) showing clusters and spans of clear cells, separated by thin conjunctivo-vascular septa.

Fig. 3

Microscopic examination (×10 objective) showing the tumor cells, which were round to polygonal with a clear, optically empty, pseudo-vegetative (physaliferous) cytoplasm.

Fig. 4

Immunohistochemistry study (×10 objective) showing an intense and diffuse staining of tumor cells with CK7.

rorty-two cases of primary colon CCC are reported in the literature. The mean age is 55.7 years (25–89). There is no difference between the two sexes. The mean age of onset in men is 59.38 years and 52.85 years in women.

The digestive tract from the small bowel down to anal canal can be concerned (Table 1). The rectum and the left colon are the most concerned parts (33.3% and 21.4%, respectively). The right colon is affected in 19% of cases, the sigmoid in 9.5%, the transverse and the small intestine both in 7.1%, and only one case of CCC of the anus is described (i.e., 2.4%). Other results are detailed in Table 1.

Table

Main characteristics of patients, tumor site, size, and TNM state

Authors	Age	Sex	Tumor site	Size (cm)	T	N	M
Hellestrom and Fisher [1] 1964	67	M	Rectum	2	NM	+	0
Reed et al. [9] 1983	71	M	Transverse colon	7	NM	NM	NM
Jewell et al. [10] 1988	75	M	Rectum	2	NM	0	0
	56	F	Left colon	6	NM	0	0
Watson [11] 1990	53	M	Anal canal	3.5	NM	+	0
Hitti et al. [29] 1990	39	F	Sigmoid	6.5	NM	0	0
Young and Hart [12] 1998	27	F	Small intestine	NM	4	+	1
	33	F	Transverse colon	NM	NM	NM	NM
	33	F	Left colon	NM	NM	NM	NM
	49	F	NM	NM	NM	NM	NM
	71	F	NM	NM	NM	NM	NM
Rubio [13] 1995	68	M	Left colon	6	4	2	1
Sasaki et al. [30] 1996	49	F	Rectum	NM	NM	NM	NM
McCluggage et al. [28] 2001	65	F	Rectum	NM	3	NM	1
Mallikand Katchy [14] 2005	36	F	Rectum	5	3	1	0
Braumann et al. [15] 2004	89	M	Left colon	2.2	2	0	0
Ko et al. [16] 2007	62	M	Left colon	1.5	In situ	0	0
Hao et al. [17] 2007	37	M	Rectum	NM	3	+	NM
Sawai [35] 2007	56	F	Rectum	NM	NM	NM	NM
Houma 2007 [27]	50	F	Rectum	NM	NM	NM	NM
Eloy et al. [5] 2009	48	F	Transverse colon	2.5	In situ	0	0
Soga et al. [18] 2008	71	F	Right colon	NM	In situ	0	0
Barisella et al. [19] 2008	54	M	Right colon	0.9	2	0	0
Bressenot et al. [20] 2008	84	F	Left colon	3.5	4	0	0
Finkelstein et al. [21] 2010	41	F	Rectum	5	2	0	0
Shi et al. [6] 2010	52	M	Rectum	0.9	1	NM	NM
	51	M	Sigmoid	1.4	1	0	0
Furuya et al. [22] 2011	81	M	Right colon	10	3	2	1
Bakshi et al. [23] 2012	42	M	Right colon	4	3	0	0
Kanstrup et al. [24] 2012	69	M	Sigmoid	NM	3	0	0
Barrera-Maldonado et al. [25] 2014	41	F	Left colon	NM	2	1	0
Min et al. [33] 2013	50	F	Rectum	2.5	2	0	0
Gurzu et al. [32] 2014	82	M	Rectum	5	4	2	1
Wang et al. [31] 2014	26	M	Left colon	13	4	NM	1
Okazawa et al. [27] 2014	83	F	Rectum	4	4	0	0
Thelin et al. [34] 2014	25	M	Right colon	3	NM	NM	NM
Remo et al. [3] 2017	58	M	Right colon	7	4	2	0
	79	M	Right colon	4.5	4	0	0
Tochio et al. [8] 2018	48	M	Left colon	2.5	NM	NM	NM
Oyama et al. [4] 2019	58	M	Sigmoid	2.5	1	NM	NM
Current case	75	F	Right colon	8	4	0	0

M, male; F, female; NM, not mentioned.

In gross and microscopic examination, all the tumors show cells with clear cytoplasm. PAS staining was positive in 8 patients. Other markers are detailed in Table 2.

Table 2

Staining characteristics and type of CCC cases

Authors	Coloration (positivity)	Immunohistochemistry (positivity)	Associated lesion	Type (intestinal/Müllerien)
Hellestrom and Fisher [1] 1964	PAS, D-PAS, Alcian blue
Jewell et al. [10] 1988		CEA, EMA, low-molecular weight keratin		Intestinal
		CEA, EMA, low-molecular weight keratin		Intestinal
Watson [11] 1989	PAS	CEA, EMA, low-molecular weight keratin	Adenoma	Intestinal
Hitti et al. [29] 1990			Endometriosis	Müllerien
Rubio [13] 1995	PAS	CEA, TPA	−
Sasaki et al. [30] 1996			Endometriosis	Müllerien
Young and Hart [12] 1998			Crohn's disease Crohn's disease
McCluggage et al. [28] 2001	PAS, laminin type IV collagen	CA125, CK7, Ber-EP4	Endometriosis	Müllerien
Braumann et al. [15] 2004		CEA, EMA, CK18, CK20	Hyperplastic polyps	Intestinal
Mallik and Katchy [14] 2005	PAS, Alcian Blue	CEA, EMA	−
Ko et al. [16] 2007			Adenoma
Hao et al. [17] 2007	PAS	CEA, EMA
Swai [35] 2007		CK7	Endometriosis	Müllerien
Houma [27] 2007		CK7	Endometriosis	Müllerien
Soga et al. [18] 2008	PAS	CD10, CK20, p53, Ki67	Adenoma	Intestinal
Barisella et al. [19] 2008		CEA, CK20, p53, hMLH1, hMSH2, B-catenin	Adenoma	Intestinal
Bressenot et al. [20] 2008		CEA, CK20, Ki67	−	Intestinal
Eloy et al. [5] 2009		CK20, CDX2, CEA, p53	Adenoma	Intestinal
Finkelstein et al. [21] 2010		CK7, p53, ER, PR, CD10	Endometriosis	Müllerien
Shi et al. [6] 2010		CK20, CDX2	Adenoma	Intestinal
		CK20, CDX2	Adenoma	Intestinal
Furuya et al. [22] 2011	PAS, D-PAS	CEA, EMA, CK AE1/3, CK20, c-kit, B-catenin		Intestinal
Kanstrup et al. [24] 2012			Adenoma
Min et al. [33] 2013		CK7, ER, CD10	Endometriosis	Müllerien
Barrera-Maldonado et al. [25] 2014		CK20, CK10, CDX2, villin		Intestinal
Gurzu et al. [32] 2014		AE1/AE3, CK20, CK7, EMA, CEA, CD10, maspin
Wang et al. [31] 2014		Cytokeratin, EMA
Okazawa et al. [27] 2014		CK7, ER	Endometriosis	Müllerien
Remo et al. [3] 2017		CK20, CEA, MUC2, CDX-2		Intestinal
		CK20, CEA, MUC2, CDX-2, E-cadherin, p53	Prostate carcinoma	Intestinal
Tochio et al. [8] 2018		CK20, CDX-2, MUC2, CEA, Ki67, p53, B-catenin	Adenoma	Intestinal
Oyama et al. [4] 2019		CK20, CDX2, MUC2, CEA, CD10, C0X2, APC, Ki67	Adenoma	Intestinal
Current case		CK7		Müllerien

CK, cytokeratin; CDX2, caudal type homeobox 2; CEA, carcinoembryonic antigen; CD, cluster differentiation; MUC, mucin; C0X2, cyclooxygenase 2; APC, adenomatous polyposis coli; PAS, periodic acid-Schiff; D-PAS, periodic acid-Schiff with diastase treatment; EMA, epithelial membrane antigen; TPA, tissue polypeptide antigen; p53, p53 protein; Ki67, Ki67 labeling index.

Two types of CCC have been described: the Müllerian type and the intestinal type. The typing was based on immunohistochemistry data in 23 cases (56.09%) or in front of the association with other lesions in 2 patients (histological evidence of endometriosis in close proximity to the tumor).

The Müllerien type was found in 9 patients (36%) and the intestinal type was found in 16 patients (64%). The latter is found in the right colon in 5 cases (31.25%) and in the left colon in 9 patients (56.25%), while the Müllerian type characterizes the left colon (88.89%). Only one case of Müllerian type is found in the right colon. All cases of Müllerian CCC are found in female patients. In 2 patients (22.2%), the Müllerian-type diagnosis was retained in the presence of other associated lesions (histological evidence of endometriosis in close proximity to the tumor).

Discussion

The primitive colon CCC is a rare entity. Described for the first time in 1964 by Hellstrom and Fisher [1].

Since then, 41 cases have been reported in the literature (see Tables 1, 2), the last of which dates back to 2019. At the colonic level, the incidence of this pathology remains low [2] and is usually seen in tissues of Müllerian origin such as the kidneys, the ovaries, the cervix, and the vagina.

After a review of the literature, colic CCC occurs at an average age of 55.7 years, equally in both sexes. The woman is affected at a younger age (52.85 vs. 59.38 years). The rectum and left colon are the two most concerned sites (63.41%).

The positive diagnosis of this entity is based on the microscopic and immunohistochemical study of the specimen. Microscopically, the tumor shows cells with a clear cytoplasm. Some authors require the presence of at least 50% of the clear cell contingent to consider the diagnosis of CCC [3]. The tumor can be well differentiated defined by cells arranged in columns with an eccentric nucleus, or undifferentiated with polygonal cells, central nucleus, and solid architecture [3].

The nature of “clear” cytoplasmic inclusions is still controversial. They could be due to an accumulation of mucin, lipid, or to an enteroblastic or glycogen differentiation which justifies the positivity of PAS [4]. The lipidic nature seems the most probable etiology. This finding was confirmed by immunohistochemical studies and by electron microscopy [2, 5, 6, 7, 8, 9].

There are currently two types of CCCs; the intestinal type and the Müllerian type. Three diagnostic criteria are necessary to retain the intestinal type: the presence of colonic adenoma near the tumor or a composite tumor with a classic adenocarcinoma component, the absence of endometriotic lesions, and immunohistochemical expression of intestinal differentiation (CEA, CK20, CDX-2) [1, 6, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25].

The pathogenesis of intestinal-type clear cell colon carcinomas has not yet been elucidated. Two hypotheses are suggested. The first reports the classic evolution from clear cell adenoma to carcinoma of the same type [4, 6], the other reports a degeneration of inflammatory diseases such as Crohn's disease [12].

Three diagnostic criteria are also recommended to retain the Müllerian type: presence of endometriosis lesions (with histological evidence) in close proximity, absence of other primitive clear cell tumors, and a histological appearance of the tumor compatible with endometriosis [26, 27, 28]. In this case, the tumor cells express CK7 and CA125 [26, 27, 28].

This type affects young women in the 4th and 5th decade with an average age of 56.44 years and has a more negative prognosis than the intestinal type [21]. Almost all (88.89%) of cases of Müllerian colonic CCC described in the literature siege at the level of the left colon [27, 28, 29, 30, 31]. To the best of our knowledge, the case described above is the first case of CCC of Müllerian type described at the level of the right colon.

This predominance at the level of the left colon is explained by the embryological hypothesis: an inducing role of the primordial germ cells which appear in the mesoderm of the yolk sac near the allantoic diverticulum could be at the origin of extra ovarian endometriosis. Another hypothesis suggests that ovarian migration during fetal life leaves ectopic foci of Müllerian cells which degenerate secondarily. This hypothesis seems more plausible for our patient to explain the right involvement [21].

The differential diagnosis arises mainly with secondary metastases of renal or ovarian origin. There are several histological and immunohistochemical means to retain the primitive character. The clear histological boundary between clear cells and dysplastic lesions is a means of retaining the primitive character [32].

Treatment will depend on the type of tumor and its stage. CCCs of the intestinal type join colorectal adenocarcinoma and respond to the same indications for adjuvant treatment. Some offer targeted therapy associated with the immunohistochemical profile [32]. On the other hand, the treatment of the Müllerian type is based on surgical resection of the affected segment associated with adjuvant treatment which remains nonconsensual, and the treatment of associated lesions.

CCC of the colon is a very rare entity. Its ontology remains unclear. There are two types: the intestinal type and the Müllerien type. The latest, exclusively described in the sigmoid, the rectum and the anal canal, is identified for the first time in the right colon. Further studies are needed to gain a better knowledge of this entity.

Statement of Ethics

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. This retrospective review of patient data did not require ethical approval in accordance with local/national guidelines.

Conflict of Interest Statement

The authors have no conflicts of interest to disclose in association with this study.

Funding Sources

The authors received no funding for this research.

Author Contribution

The authors' contribution was as follows: Fahd Khefacha and Wissem Triki participated in the conception, interpretation of data, drafting of the work, and final approval of the version to be published. Imed Abbassi and Abdelmajid Baccar participated in the acquisition of data, analysis of data, and final approval of the version to be published. Karim Ayed, Oussema Baraket, and Sami Bouchoucha participated in the analysis of data, critical revising of the work, and final approval of the version to be published. All authors agree to be responsible for all aspects of the work ensuring that questions relating to the accuracy or integrity of any part of the work are investigated and resolved appropriately.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.