Endometrial Clear Cell Carcinoma with Leiomyoma and Adenomyosis in a Postmenopausal Lady - A Case Report with Review

Endometrial cancer (EC) is the 6th most common cancer in women worldwide and the 14th most common cancer worldwide.[] Endometrioid type of endometrial carcinoma (EEC) is the most common histological type (80%) and endometrial clear cell carcinoma (CCC) is uncommon accounting only 2% of all EC.[] Recently, adenomyosis (AM), is considered by some investigators as a precursor for EC.[] AM is characterized by the ectopic presence of endometrial tissue inside the myometrium, meaning that endometrial glands and stroma are surrounded by reactive smooth muscle cells. However, the data of AM with CCC are extremely rare comprising only a few case reports that are affirmed after scrupulous search from search engines such as PubMed, Google, and Medline. The aim of this study is to describe the clinicopathological and tumorogenesis of patients suffering simultaneously from these three pathologic entities – CCC, uterine leiomyoma (UL), and AM and to review the possibilities of malignant transformation of the adenomyotic tissue. CASE REPORT A 58-year-old woman presented to the gynecology department for postmenopausal bleeding with watery discharge per vaginum on and off for 15 days. She was P2 L2 and was under medication for hypertension and hypothyroidism for the past 6 years. Her biochemical parameters, serum CA 125, and total hemogram were normal. Ultrasonography pelvis revealed bulky uterus with grossly heterogeneous myometrial echotexture and multiple seedling myomas. Thickened endometrial stripe showing a loculated inhomogeneous echogenic mass lesion suspicious of endometrial carcinoma was reported. Magnetic resonance imaging of the pelvis revealed a bulky uterus with multiple intramural leiomyomas and thickened hyperintense endometrium [Figure 1a and b]. Conventional cervical pap smear was also examined and misinterpreted as epithelial cell abnormality suggestive of squamous cell carcinoma [Figure 1d]. Then, the patient underwent endometrial biopsy followed by total abdominal hysterectomy with bilateral salphingo-ophrectomy and pelvic lymph node dissection and submitted for histopathology. While sectioning through the uterus, multiple gray tan ULs were observed along with a single whitish friable polypoidal mass (tumor) [Figure 1c]. Microscopy showed normal endometrial lining transitioning into a tumor component in a polypoidal fashion. The tumor cells were round to polygonal having distinct cell margin, clear vacuolated to pale eosinophilic cytoplasm, and vesicular to hyperchromatic nuclei with prominent nucleoli arranged mostly in acini, papillary pattern, solid sheets, and lobules [Figure 2abc]. Tumor had invaded more than 50% of myometrium. The whole uterine body and cervix showed multiple leiomyomas, some of which showed AM but even after extensive grossing, no transitions from the endometrial epithelium of AM foci to invasive tumor component was observed. Bilateral adnexa, parametrium, cervix, vagina, and regional lymph nodes were free of tumor except the right iliac lymph node that showed metastatic deposit. Immunohistochemistry (IHC) of tumor mass showed panCK, napsin, and progesterone receptor (PR) positivity was negative for estrogen receptor (ER), P63, and CD10 [Figure 2def].

Ovarian and endometrial CCC have been shown to have highly similar gene expression, proteomic, morphologic, and immunophenotype profiles.[] CCC has a distinct cytoarchitectural morphology as described in the current case and typical IHC of HNF1B-positive, napsin A-positive, ER-negative, PR-negative, and p53-wild-type. The expression of ER/PR is variable as in the present case, but HNF1B and napsin A are considered specific markers.[] The frequent coexistence of two diseases may be explained by a possible common risk factor or by a mutual pathogenic mechanism. For that matter, the current study was focused on literature with the keywords of CCC, AM, UL, and malignant transformation but due to scarcity of such association, we could explore the majority of the studies based on two categories of patients – (1) EC coexists with AM (EC-A) and (2) EC arising from AM (EC-AIA). EC encompasses different variants, especially EEC. Malignant tumor arising from AM (6.8%) usually suspected when the serum level of tumor markers such as CA125 is high and when the tumor is intramyometrial. Sampson's or Colman's criteria for the diagnosis of EC-AIA was: (1) the carcinoma must not be situated in the endometrium or elsewhere in the pelvis, (2) the carcinoma must be seen to arise from the epithelium of AM and not to have invaded from other sources, and (3) endometrial (adenomyotic) stromal cells should be surrounding the aberrant glands to support the diagnosis of AM.[] However, Kumar and Anderson[] emphasized the necessity of the presence of transition between the benign adenomyotic endometrial glands and the carcinomatous glands to prove the diagnosis of an ectopic endometrium-derived adenocarcinoma. Based on the above criteria, the current case was categorized as “CCC associated with AM and UL.” Several studies emphasized that EC patients with associated AM (EC-A) is prevalent about 16–42% and may allow early detection with a good probability of diagnosing a disease with a higher grade of differentiation, a lower myocardial infarction (MI), an absence of lymph-vascular space invasion, a small tumor size, and a negative lymph node status than the patients suffering from EC only.[] It has been proposed that age, histology, tumor grade, and stage being constant; EC-AIA cases are associated with decreased disease-free survival compared to EC-A. EC-AIA patients are usually older, associated with myometrial tumors (UL), deep myometrial invasion, and nonendometrioid variants of EC such as CCC in comparison to EC-A.[] The significance of the presence of AM in estimating the prognosis of endometrioid type of endometrial carcinoma (EEC) is still debated as proposed by Gizzo et al., despite the fact that studies have reported an excellent prognosis for EEC with concomitant AM due to the lower histological grade and superficial MI detected in such cases.[] Fadare et al. evaluated rigorously 50 CCC cases and suggested that morphologically unambiguous CCC has more favorable patient outcomes than previously reported; hence ambiguous tumors should be classified separately.[]

It was inferred that CCC is an unique aggressive tumor in comparison to conventional EC but has a better outcome than it was previously thought of. EC-AIA has a poorer survival outcome when compared to EC-A. EC-A has better survival and longer disease-free period when compared to even EC alone. Hence, the pathogenesis of malignant transformation from AM is to be revisited for further chance of future targeted therapy. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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