Mimicry in the Colon: Endometriosis-Associated Carcinoma in a Post-hysterectomy Patient

Abstract

Endometriosis is a benign yet chronic gynecologic condition that, in rare cases, may undergo malignant transformation. Although endometriosis-associated malignancies most commonly arise in the ovary, extragonadal sites may also be affected. Endometriosis-associated intestinal tumors (EAITs) are exceptionally rare and often difficult to diagnose.

We report the case of a 73-year-old woman with a remote history of total hysterectomy and bilateral salpingo-oophorectomy for endometriosis who presented with rectal bleeding and constipation. Imaging and colonoscopy revealed a nearly obstructing mass in the sigmoid colon, initially suspected to be primary colorectal carcinoma. Biopsy demonstrated a poorly differentiated carcinoma with squamous features. Immunohistochemical analysis supported a Müllerian origin, an unexpected finding given the patient’s prior gynecologic surgery. Sigmoidectomy subsequently revealed a high-grade endometrioid carcinoma with extensive squamous differentiation arising from intestinal endometriosis.

This rare case highlights that endometrioid carcinoma can develop from intestinal endometriosis decades after definitive gynecologic surgery. Accurate diagnosis requires the integration of clinical history, histopathological findings, and immunohistochemical results to differentiate this entity from primary colorectal carcinoma. Increased awareness of EAITs is essential to ensure accurate diagnosis and appropriate management.

Introduction

Endometriosis is a chronic medical condition characterized by the presence of endometrial-like tissue outside the uterine cavity [1,2]. It most commonly involves pelvic structures such as the ovaries, fallopian tubes, and peritoneum, but it can also occur in extrapelvic sites, including the intestine, bladder, and other distant locations [1]. Although benign, endometriosis is associated with inflammation, fibrosis, and scarring, often resulting in chronic pain and diminished quality of life [1,2]. Malignant transformation of endometriotic tissue is a rare but well-recognized phenomenon, with an estimated overall incidence of approximately 1% [3-5].

Among all endometriosis-associated malignancies, approximately 80% arise in the ovary, while the remaining ~20% occur at extragonadal sites, including the intestine, rectovaginal septum, abdominal wall, bladder, and pleura [3-8]. Among extragonadal sites, the intestine is the most commonly affected, with the rectosigmoid colon involved in approximately 72-78% of reported intestinal cases [4,5]. To date, approximately 50 cases of endometriosis-associated intestinal tumors (EAITs) have been described in the literature [8,9]. Endometrioid carcinoma is the most frequent histologic subtype, followed by mixed Müllerian tumors and stromal sarcomas; notably, clear cell carcinoma - a common subtype in ovarian endometriosis-associated malignancies - is relatively uncommon in intestinal sites [8,9]. EAITs are diagnostically challenging, as they may closely mimic primary colorectal carcinoma.

Immunohistochemistry plays an essential role in establishing the correct diagnosis in such cases. Endometrioid carcinomas of Müllerian origin typically express PAX8, estrogen receptor (ER), and progesterone receptor (PR), and are negative for CDX2, villin, and CK20, which are markers commonly associated with primary colorectal adenocarcinoma. This immunoprofile, when interpreted alongside morphologic features and clinical history, is critical for an accurate diagnosis.

We report a highly unusual case of high-grade endometrioid carcinoma with extensive squamous differentiation arising in sigmoid colon endometriosis in a patient with a remote history of total hysterectomy and bilateral salpingo-oophorectomy. This case is notable not only because of its rare colonic location, but also because prior removal of the uterus and adnexa had significantly reduced the clinical suspicion of an endometriosis-associated malignancy. This report highlights an important and easily overlooked diagnostic entity, emphasizes the essential role of immunohistochemistry in clarifying such diagnostically challenging presentations, and expands the recognized spectrum of extragonadal endometriosis-associated malignancies.

Case presentation

A 73-year-old woman presented with a single episode of rectal bleeding, along with several weeks of progressive constipation and abdominal cramping. Her medical history was notable for a total abdominal hysterectomy and bilateral salpingo-oophorectomy performed 37 years earlier for endometriosis. Detailed operative and pathologic records from that procedure were unavailable; therefore, the original anatomical distribution of endometriotic foci and whether intestinal involvement was recognized at that time could not be ascertained. Colonoscopy revealed a large, nearly obstructive mass involving the descending and sigmoid colon.

Biopsy performed at an outside institution demonstrated a poorly differentiated carcinoma characterized by marked nuclear atypia, eosinophilic cytoplasm, and high mitotic activity, with associated necrosis, ulceration, and dense stromal fibrosis. Foci suggestive of squamous differentiation were present. The overall configuration of the tumor raised concern for a process extending into the mucosa from deeper layers, rather than originating in the colorectal mucosa itself.

Immunohistochemical studies showed diffuse positivity for CK5/6, CK7, PAX8, and MOC31, with patchy expression of ER and PR. There was weak, focal CK20 staining, while CDX2, GATA3, TTF1, and villin were negative. P16 and p40 showed variable expression, with p40 highlighting areas of squamous differentiation. Although the immunoprofile was not entirely specific, the strong and diffuse PAX8 expression suggested a Müllerian origin. Given the patient’s prior gynecologic surgery, this diagnosis was initially unexpected; however, malignant transformation of residual endometriosis was considered. A subsequent sigmoid colectomy performed at our institution revealed a transmural tumor with two distinct histologic patterns: solid nests with central squamous differentiation and keratinization, and glandular and papillary areas, with the former predominating (Figures 1A-1F).

Figure 1. Histologic findings of poorly differentiated carcinoma in the sigmoid colon.

(A) Solid nests of tumor cells with central squamous differentiation and keratinization (H&E, 100X). (B) Component with glandular/papillary configuration (H&E, 100X). (C) Tumor cells showing strong and diffuse positivity for PAX8 (100X). (D) Tumor cells showing positivity for ER (100X). (E) Tumor cells showing positivity for p40 in areas of squamous differentiation (100X). (F) Positive expression of CDX2 in colonic mucosa but negative in adjacent tumor cells (100X)

A microscopic focus of endometriosis was identified in the muscularis propria adjacent to the tumor (Figures 2A-2D).

Figure 2. Histologic findings of intestinal endometriosis.

(A) Superficial benign colonic mucosa with underlying carcinoma (arrow) in the muscular propria and a focus of endometriosis (triangle) (H&E, 20X). (B) Focus of endometriosis with epithelial and stromal components (H&E, 100X). (C) Focus of endometriosis showing uniform expression for ER in both epithelial and stromal components (100X). (D) Focus of endometriosis showing patchy expression for PR in both epithelial and stromal components (100X)

ER: estrogen receptor; PR: progesterone receptor

No colonic precursor lesions of colorectal carcinoma, such as adenomas, were identified in the overlying mucosa. Immunohistochemical findings in the resection specimen were consistent with those observed in the biopsy, demonstrating strong PAX8 expression in both the carcinoma and the epithelial component of the endometriosis, along with patchy ER and PR positivity. CD10 highlighted the stromal component of the endometriosis. p40 was positive in squamous areas, while CDX2 remained negative in tumor cells. Collectively, the morphologic and immunophenotypic findings, together with the presence of adjacent endometriosis, supported a diagnosis of high-grade endometrioid carcinoma with extensive squamous differentiation arising in intestinal endometriosis. Next-generation sequencing demonstrated microsatellite stability and a low tumor mutational burden. A pathogenic TP53 mutation (NM_000546.5:c.560-1G>C, VAF 80%) with loss of heterozygosity was identified. No pathogenic POLE mutations were detected.

Follow-up and outcomes

Following surgical resection, the patient received adjuvant chemotherapy consisting of carboplatin, paclitaxel, and pembrolizumab for 12 weeks, followed by granulocyte colony-stimulating factor support. She remains under surveillance with no evidence of disease recurrence at three years of follow-up.

Discussion

Endometriosis is a common gynecologic condition, but malignant transformation of endometriotic tissue is rare [3]. Most malignancies arise in ovarian endometriosis, followed by the pelvic peritoneum and, less commonly, the colorectal tract [10-12]. EAITs are particularly uncommon and often pose significant diagnostic challenges, as they may clinically and histologically resemble primary colorectal carcinoma.

In our case, the diagnosis was especially challenging given the patient’s remote history of hysterectomy and bilateral salpingo-oophorectomy performed 37 years earlier. As detailed operative and pathological records from that surgery were unavailable, it could not be determined whether intestinal endometriosis had been identified at that time. This underscores the importance of considering EAITs even in patients with a distant history of endometriosis. Accurate distinction from primary colorectal carcinoma is critical, as management strategies differ. Immunohistochemically, colorectal adenocarcinomas typically express CDX2, CK20, and villin, whereas endometrioid carcinomas more commonly express PAX8, ER, and PR.

The pathogenesis of EAITs remains incompletely understood but likely involves chronic inflammation, hormonal influences, and somatic genetic alterations [13]. Mutations in ARID1A, PTEN, and PIK3CA have been implicated in endometriosis-associated malignancies [14]. Loss of mismatch repair protein expression has been reported in a minority of EAOCs [15]. In this case, a pathogenic TP53 mutation was identified, consistent with the “copy number high” molecular subtype described in The Cancer Genome Atlas (TCGA) classification of endometrial carcinoma, which is associated with aggressive clinical behavior [16].

Squamous differentiation is a recognized feature in endometrioid carcinomas and may complicate diagnosis, particularly in extragonadal sites such as the colon [17]. Histologically, it is characterized by keratinization and intercellular bridges and is supported by immunoreactivity for markers such as CK5/6, p63, and p40 [18]. Although not independently prognostic, its presence may create diagnostic difficulty, especially in the gastrointestinal tract [19]. Rare cases of adenosquamous carcinoma arising from ovarian endometriosis have been reported, further expanding the morphological spectrum of endometriosis-associated malignancies [20].

Currently, there is no standardized treatment protocol for endometriosis-associated malignancies [9]. Surgical resection remains the mainstay of treatment. The efficacy of chemotherapy remains uncertain, although many clinicians adopt treatment approaches used for epithelial ovarian cancer, particularly EAOC [9].

Conclusions

This report illustrates a rare and diagnostically challenging example of high-grade endometrioid carcinoma with extensive squamous differentiation arising from colonic endometriosis decades after definitive gynecologic surgery. Its significance lies in the fact that such tumors can closely mimic primary colorectal carcinoma, potentially leading to diagnostic confusion and inappropriate classification if the possibility of an endometriosis-associated malignancy is not considered. This report highlights the importance of integrating clinical history, morphologic findings, and immunohistochemical results to arrive at the correct diagnosis. Increased awareness of this rare entity may improve recognition in similar unexpected presentations and help guide appropriate clinical management.