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Year : 2015  |  Volume : 58  |  Issue : 4  |  Page : 491-495
Mismatch repair protein deficient endometrioid adenocarcinomas, metastasizing to adrenal gland and lymph nodes: Unusual cases with diagnostic implications

Department of Surgical Pathology, Tata Memorial Centre, Parel, Mumbai, Maharashtra, India

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Date of Web Publication4-Nov-2015


Recently, certain endometrial carcinomas have been found to be associated with mismatch repair (MMR) protein defects/deficiency. A 39-year-old female presented with cough, decreased appetite and significant weight loss since 2 months. Earlier, she had undergone total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH-BSO) for endometrioid adenocarcinoma. Imaging disclosed an 8 cm-sized adrenal mass that was surgically excised. Histopathology of the adrenal tumor, endocervical tumor, and endometrial biopsy revealed Federation of Gynecology and Obstetrics (FIGO) Grade II to III endometrioid adenocarcinoma. By immunohistochemistry, tumor cells were positive for cytokeratin 7, epithelial membrane antigen, PAX8, MLH1 and PMS2 while negative for estrogen receptor (ER), progesterone receptor (PR), MSH2 and MSH6. She underwent adjuvant radiotherapy and chemotherapy. A 34-year-old lady presented with vaginal bleeding since 9 months. She underwent TAH-BSO, reported as FIGO Grade III endometrioid adenocarcinoma. By immunohistochemistry, tumor cells were negative for ER, PR, MLH1, and PMS2 while positive for MSH2 and MSH6. She underwent adjuvant radiotherapy and chemotherapy. However, she developed multiple nodal and pericardial metastases and succumbed to the disease within a year post-diagnosis. Certain high-grade endometrioid adenocarcinomas occurring in younger women are MMR protein deficient and display an aggressive clinical course. Adrenal metastasis in endometrial carcinomas is rare.

Keywords: Endometrial adenocarcinoma, MLH1, mismatch repair deficient, MSH2, MSH6, PMS2

How to cite this article:
Rekhi B. Mismatch repair protein deficient endometrioid adenocarcinomas, metastasizing to adrenal gland and lymph nodes: Unusual cases with diagnostic implications. Indian J Pathol Microbiol 2015;58:491-5

How to cite this URL:
Rekhi B. Mismatch repair protein deficient endometrioid adenocarcinomas, metastasizing to adrenal gland and lymph nodes: Unusual cases with diagnostic implications. Indian J Pathol Microbiol [serial online] 2015 [cited 2021 Nov 27];58:491-5. Available from: https://www.ijpmonline.org/text.asp?2015/58/4/491/168859

   Introduction Top

Endometrial carcinomas invariably afflict postmenopausal women. Only 2–14% endometrial carcinomas occur in women <40 years of age.[1],[2] While most cases are associated with unopposed estrogen excess, a small group are characterized by defects/deficiency in mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6, and PMS2, leading to immunohistochemical (IHC) loss of expression of these paired (mostly) proteins (MLH1 and PMS2 or MSH2 and MSH6), in 9% cases of endometrial carcinomas occurring in patients below 50 years of age.[3] Besides endometrium, defects in MMR have been observed in 10% ovarian carcinomas in patients <50 years old, including 50% cases presenting with synchronous endometrial carcinomas.[4]

Histopathologically, most common endometrial carcinomas are endometrioid adenocarcinomas that are further graded according to the International Federation of Gynecology and Obstetrics (FIGO) grading system, from Grades I to III, based on architectural pattern and nuclear features. Clinically, endometrial carcinomas are subtyped as Type I, and Type II. While Type I are mostly associated with a favorable prognosis; Type II are invariably associated with poor prognosis, including a propensity for lymph node metastasis.[5] Among various metastatic sites in cases of endometrial adenocarcinomas, the adrenal gland is rare.[6]

While studies from the western population have shown an association of MMR deficient endometrial carcinomas with poor prognosis, there is no such documentation from the Indian subcontinent.[7],[8]

   Case Reports Top

Case 1

The first case is about a 39-year-old female patient, who presented at our institution with a history of cough, decreased appetite, and weight loss of 3 kg in the last 2 months. She disclosed a past history of menorrhagia, 2 years back, following which she was diagnosed with Stage II endometrial carcinoma, for which she underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH-BSO), omentectomy, and bilateral pelvic lymphadenectomy. She did not have a history of colonic, endometrial or ovarian cancers in her family members. However, her father suffered from melanoma of eye with liver metastasis.

At present, her vitals were normal. Her local abdominal and vaginal examination did not reveal any significant abnormality.

Her laboratory investigations were within normal limits, except alkaline phosphatase level was high (217 IU. Normal range = 20–140 IU/L). Her 24 h urinary vanyl-mandelic acid level was normal.

She underwent radiological examination, followed by robotic adrenalectomy at another hospital. The paraffin blocks from the tumor were submitted to us for review.

Radiological findings

Ultrasonogram showed a well-defined lobulated mass, measuring 8.3 cm × 7.9 cm × 4.1 cm anterior and medial to the upper pole of the left kidney, with a small internal irregular focus of necrosis inferiorly. Bilateral kidneys were normal.

Computed tomogram (CT) thorax showed an 8 cm × 7.2 cm × 3.6 cm sized well-defined, mixed density, heterogeneous lesion with central hypodensity in the left adrenal region with mild enhancement and delayed washout on postcontrast study.

Positron emission tomogram - CT disclosed a heterogeneously enhancing fluorodeoxyglucose avid metabolically active lesion involving the entire left adrenal gland [Figure 1]a.
Figure 1: Case 1. (a) Positron emission tomogram scan showing a heterogeneously enhancing fluorodeoxyglucose avid metabolically active lesion in the left adrenal gland. Inset: Gross appearance of left adrenalectomy showing a gray-white multilobulated tumor with the necrotic cut surface. (b) Microscopy showing Federation of Gynecology and Obstetrics Grade III endometrioid adenocarcinoma (H and E, ×200). (c) Cytokeratin 7 positivity within the tumor (DAB, ×200). (d) PAX8 positivity (DAB, ×200). (e) MLH1 positivity within tumor cells (DAB, ×400). (f) MSH6 negativity (DAB, ×400)

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Pathological findings

Grossly, the adrenalectomy specimen weighed 116 g and measured 7.5 cm × 6.5 cm × 5 cm. It was well encapsulated. Cut surface showed a gray-white multilobulated tumor with areas of necrosis [[Figure 1]a: Inset].

As per previous reports, TAH-BSO specimen weighed 125 g, including uterus and cervix measuring 8.5 cm × 4.3 cm × 3 cm. Endometrial thickness was 0.6 cm. Myometrial thickness was 2 cm. Endocervical canal measured 1.7 cm and revealed a granular tumor measuring 2 cm × 1.3 cm. Ectocervix with bilateral tubes and ovaries were normal.

Histopathological examination of the adrenalectomy specimen also showed high-grade endometrioid adenocarcinoma, including tumor cells arranged in diffuse and glandular patterns with moderate to marked nuclear pleomorphism, prominent nucleoli, interspersed mitotic figures and chronic inflammatory cells. Focal areas of undifferentiated carcinoma were also noted [Figure 1]b.

Endometrial biopsy showed endometrioid adenocarcinoma, FIGO Grade II (architectural Grade II, nuclear Grade II).

Endocervical tumor, on microscopy also revealed endometrioid adenocarcinoma, FIGO Grade II, involving one-third of the endocervical wall thickness with 10 reactive regional lymph nodes [Figure 2]a. Sections from bilateral adnexa were unremarkable.
Figure 2: Case 2. (a) Microscopy showing Federation of Gynecology and Obstetrics Grade III carcinoma with areas of necrosis (H and E, ×200). (b) Tumor cells showing MSH2 positivity (DAB, ×400). (c) Tumor cells showing MSH6 positivity (DAB, ×400). (d) Tumor cells showing loss of MLH1 expression (DAB, ×400). (e) Tumor cells showing lack of PMS2 expression (DAB, ×400)

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By immunohistochemistry, tumors from endometrial biopsy, endocervical canal and adrenal gland showed diffuse positivity for epithelial membrane antigen (EMA), PAX8, vimentin; variable positivity for cytokeratin (CK) and HBME-1, and negativity for estrogen receptor (ER), progesterone receptor (PR), p53 and CD10. Tumor cells from adrenalectomy showed CK7 positivity and were negative for melan-A, inhibin, calretinin, synaptophysin.

In additional, tumor cells showed negative MSH2 and MSH6 staining while positive MLH1 and PMS2 staining [Figure 1]c,[Figure 1]d,[Figure 1]e,[Figure 1]f.

Diagnosis of "MMR protein deficient" endometrioid adenocarcinoma metastasizing to the adrenal gland was finally made.


Following TAH-BSO, omentectomy, and bilateral pelvic lymphadenectomies, the patient underwent 25 cycles of 45 Gy radiation, followed by 2 cycles of 65 Gy of external beam radiotherapy. Following adrenalectomy, the patient was recommended paclitaxel-based chemotherapy.

Case 2

A 34-year-old lady presented with vaginal bleeding since 9 months with recent onset of cough with expectoration, vomiting along with giddiness and vertigo. She denied any family history of colonic, endometrial, or ovarian cancers.

Radiological findings

Magnetic resonance imaging revealed endometrial thickening at the lower uterine segment (LUS), extending into the endocervical canal. She underwent TAH-BSO, along with omentectomy and bilateral pelvic lymphadenectomy. Her recent chest radiograph revealed right hilar and pretracheal lymphadenopathies.

CT scan thorax showed extensive conglomerate and partially necrotic lymphadenopathies in the superior mediastinum, largest measuring 3 cm in diameter. Multiple enlarged nodes were also noted at level VI, and level IV of the neck. In addition, 1 cm × 0.9 cm sized well-defined hypodense nodule was seen in the left adrenal gland.

Representative paraffin blocks were submitted to us for a review.

Pathological findings

TAH-BSO revealed FIGO Grade III endometrioid adenocarcinoma, including a focal component of undifferentiated carcinoma, with tumor involving the isthmus, along with lymphovascular emboli [Figure 2]a. Pelvic lymph nodes and omentum were free of tumor. By immunohistochemistry, tumor cells were negative for ER, PR, MLH1 and PMS2 while positive for MSH2 and MSH6 [Figure 2]b,[Figure 2]c,[Figure 2]d,[Figure 2]e. Biopsy from the left supraclavicular lymph node and subsequently, pericardial fluid cytology revealed metastatic deposits.


Following Wertheim's hysterectomy, the patient underwent adjuvant intensity modulated radiation therapy/emission guided radiation therapy (small bowel sparing EMRT). Vault brachytherapy was planned 3–4 cm upper vagina, including two cycles 6 Gy, 1-week-apart. She also underwent six cycles of chemotherapy, including paclitaxel and carboplatin. Thereafter, she was prescribed oral etoposide and tamoxifen but eventually succumbed to the disease within a year postdiagnosis.

   Discussion Top

Endometrial carcinoma is the most common invasive female genital tract neoplasm in the western population, forming the fourth most frequently diagnosed cancer among North American women.[9] It is on the rise globally. Most cases of endometrial adenocarcinomas present with a low clinical stage and low histopathological grade.

While most cases are related to unopposed estrogen excess, lately, Lynch syndrome/hereditary nonpolyposis colon cancer has been associated with endometrioid adenocarcinomas, especially in younger women, <40 years of age. There is 20–60% risk of endometrial cancer in patients with Lynch syndrome.

Several studies have shown an association between MMR defects and poor prognostic features, including higher grade, myometrial and lymphovascular invasion, as noted in the present cases that constitute as, the first two reported cases of MMR deficient endometrioid carcinomas from the Indian subcontinent, both in women <40 years of age.[7],[8]

The main diagnostic challenge in the first case was to differentiate deposits of endometrioid adenocarcinoma in the adrenal gland from a primary adrenal tumor. Despite the patients' past surgical history, in view of clear cell morphology and the absence of ER, PR immunoexpression, a second primary from adrenal or kidney had to be ruled out. Histopathological comparison with the primary tumor and the similar IHC expression including EMA, CK7 and PAX8 immunoexpression with the lack of synaptophysin, inhibin, and calretinin immunostaining, helped in ruling out a primary adrenal tumor. Noteworthy, PAX8 is also expressed in renal cell carcinomas. CK7 positivity, CD10 negativity, and imaging ruled out a kidney primary.

Until date, only four cases endometrioid adenocarcinoma metastasizing to adrenal gland have been reported.[6]

The second case, despite adjuvant treatment, developed extensive metastasis and died-of-disease. Immunohistochemically, both cases were high-grade and MMR protein deficient, reinforcing this association with poor prognosis.[8] Tafe et al.[10] showed abnormal MMR proteins staining pattern in 58% endometrial undifferentiated carcinomas, a feature noted focally in both the present study cases. It has also been noted that the tumors originating from the LUS are associated with MMR defects, as observed in both cases. There was endocervical involvement in the first case. It has been noted that unlike endometrium and ovary, there is no association between Lynch syndrome and endocervical carcinoma.[11] Therefore, secondary endocervical involvement from LUS in the second case seems a possible explanation. Ideally, such patients should be referred for further genetic testing.

In a recent study from Southeast Asia, among the three different ethnic groups tested, MMR deficient endometrial carcinomas were relatively more frequently associated with the Indian group, as compared to Malays and Chinese.[12]

In summary, endometrioid adenocarcinomas in younger patients, especially with high-grade might be MMR protein deficient, and associated with an aggressive clinical course. Therefore, such cases should be tested for MMR protein defects. It would be worthwhile to have larger studies on MMR deficient endometrial carcinomas from India.


I would like to thank Dr. Shailesh Soni, Consultant Pathologist, Muljibhai Patel Urological Hospital, Gujarat for his valuable inputs in the first case.

I would like to thank Dr. Pramod Biradar, Senior Resident, Department of Surgical Pathology, Tata Memorial Hospital for retrieving some clinical details pertaining to the first case.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Gallup DG, Stock RJ. Adenocarcinoma of the endometrium in women 40 years of age or younger. Obstet Gynecol 1984;64:417-20.  Back to cited text no. 1
Ota T, Yoshida M, Kimura M, Kinoshita K. Clinicopathologic study of uterine endometrial carcinoma in young women aged 40 years and younger. Int J Gynecol Cancer 2005;15:657-62.  Back to cited text no. 2
Lu KH, Schorge JO, Rodabaugh KJ, Daniels MS, Sun CC, Soliman PT, et al. Prospective determination of prevalence of lynch syndrome in young women with endometrial cancer. J Clin Oncol 2007;25:5158-64.  Back to cited text no. 3
Jensen KC, Mariappan MR, Putcha GV, Husain A, Chun N, Ford JM, et al. Microsatellite instability and mismatch repair protein defects in ovarian epithelial neoplasms in patients 50 years of age and younger. Am J Surg Pathol 2008;32:1029-37.  Back to cited text no. 4
Ellenson LH, Ronnett BM, Soslow RA, Zaino RJ, Kurman RJ. Mesenchymal tumors of the uterus. In: Kurman RJ, Ellenson LH, Ronnett BM, editors. Blaustein's Pathology of the Female Genital Tract. 6th ed. Heidelberg: Springer-Verlag; 2011. p. 393-452.  Back to cited text no. 5
Zaidi SS, Lakhani VT, Fadare O, Khabele D. Adrenal gland metastasis is an unusual manifestation of endometrial cancer. Case Rep Surg 2013;2013:428456.  Back to cited text no. 6
Shih KK, Garg K, Levine DA, Kauff ND, Abu-Rustum NR, Soslow RA, et al. Clinicopathologic significance of DNA mismatch repair protein defects and endometrial cancer in women 40 years of age and younger. Gynecol Oncol 2011;123:88-94.  Back to cited text no. 7
An HJ, Kim KI, Kim JY, Shim JY, Kang H, Kim TH, et al. Microsatellite instability in endometrioid type endometrial adenocarcinoma is associated with poor prognostic indicators. Am J Surg Pathol 2007;31:846-53.  Back to cited text no. 8
Society AC. 2000 cancer statistics. CA Cancer J Clin 2000;50:1-64.  Back to cited text no. 9
Tafe LJ, Garg K, Chew I, Tornos C, Soslow RA. Endometrial and ovarian carcinomas with undifferentiated components: clinically aggressive and frequently underrecognized neoplasms. Mod Pathol 2010;23:781-9.  Back to cited text no. 10
Mills AM, Liou S, Kong CS, Longacre TA. Are women with endocervical adenocarcinoma at risk for Lynch syndrome? Evaluation of 101 cases including unusual subtypes and lower uterine segment tumors. Int J Gynecol Pathol 2012;31:463-9.  Back to cited text no. 11
Woo YL, Cheah PL, Shahruddin SI, Omar SZ, Arends M. The immunohistochemistry signature of mismatch repair (MMR) proteins in a multiethnic Asian cohort with endometrial carcinoma. Int J Gynecol Pathol 2014;33:554-9.  Back to cited text no. 12

Correspondence Address:
Dr. Bharat Rekhi
Department of Surgical Pathology, Eighth Floor, Annex Building, Tata Memorial Hospital, Dr. E.B. Road, Parel, Mumbai - 400 012, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.168859

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