Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 
Print this page Email this page Users Online: 2624

 
ORIGINAL ARTICLE
Ahead of print publication  

Malignant mixed Müllerian tumor: Analysis of 21 cases at tertiary care rural hospital


 Department of Pathology, MGIMS, Sevagram, Wardha, Maharashtra, India

Date of Submission09-Jun-2021
Date of Decision14-Dec-2021
Date of Acceptance14-Dec-2021

Correspondence Address:
Nitin M Gangane,
Department of Pathology, MGIMS, Sevagram - 442 102, Maharashtra
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mjdrdypu.mjdrdypu_443_21

  Abstract 


Introduction: Malignant mixed Müllerian tumor (MMMT)/carcinosarcoma is an exceptionally rare tumor, representing just 1%–5% of all gynecological malignancies, but leading to 15% of gynecological malignancy-related deaths, with an occurrence of <2/1,00,000 women/year. Material and Methods: Twenty-one patients with MMMT of the uterus accounting for 1.7% of total uterine malignancies were included in the study. The histologic subtypes of the carcinoma and sarcoma components were examined and recorded. The proportions of carcinoma and sarcoma components were semi-quantitatively evaluated and recorded within the primary tumor site in the hysterectomy specimen. Among the metastatic sites and recurrent tumors, the histologic component (carcinoma vs. sarcoma) was evaluated. Results: Of these 21 cases, the carcinomatous component was further subtyped as 11 cases with endometrioid morphology, four cases each of clear cell and serous morphology, and two cases had undifferentiated epithelial component. Most of the tumors had carcinomatous components and 55% of tumors were high grade. Prognostic factors include the presence of bleeding (P = 0.05) which is associated with poor outcomes. Other known prognostic factors like myometrial invasion (P = 0.46) and stage of disease (P = 0.86) did not show any prognostic significance in present study. Conclusions: The elderly age, higher stage, and a poorly differentiated tumor are associated with poor outcomes. Utmost efforts should be made to educate women in early cancer detection by creating awareness on risk factors and symptoms. Study on the trends of gynecological cancers is essential to plan and evaluate cancer control programs.

Keywords: Carcinoma, carcinosarcoma, outcome, sarcoma



How to cite this URL:
Patil BU, Singh S, Shivkumar V B, Gangane NM. Malignant mixed Müllerian tumor: Analysis of 21 cases at tertiary care rural hospital. Med J DY Patil Vidyapeeth [Epub ahead of print] [cited 2022 Dec 6]. Available from: https://www.mjdrdypv.org/preprintarticle.asp?id=338912




  Introduction Top


Malignant mixed Müllerian tumor (MMMT), also known as uterine carcinosarcoma, is an exceptionally rare tumor, representing just 1%–5% of all gynecological malignancies, but leading to 15% of gynecological malignancy-related deaths,[1] with an occurrence of <2/1,00,000 women/year.[2]

MMMTs are aggressive and biphasic neoplasms that are defined as tumors consisting of high-grade malignant epithelial and mesenchymal elements.[3]

Regardless of the level of diagnosis and even in the early stage of illness, they bear a poor prognosis; survival is 50% or less.

These tumors are a type of endometrial carcinoma that is dedifferentiated or metaplastic.[4]

Uterine carcinosarcomas were originally categorized as sarcomas of the uterus. However, because in vitro studies, immunohistochemistry and molecular studies have shown that they are derived from a monoclonal cancer cell that exhibits sarcomatous metaplasia, these tumors are carcinomas.[4],[5]

MMMTs were thought to develop either from a collision between independent, geographically adjacent carcinomas and sarcomas (collision theory) or as a combination of cellular masses that underwent early divergence from a common precursor stem cell (combination theory).[4]

The origin of the tumor is thought to follow the embryological development path of the Müllerian ducts and is most likely derived from a pluripotent stem cell that differentiates into both epithelial and mesenchymal cell types. Further characterization of the tumor histology supports the “conversion theory,” which states that an epithelial–mesenchymal transition occurs because the sarcomatous portion of the tumor exhibits markers consistent with an epithelial origin.[6]

Recently, a Harvard group identified PIK3CA mutations in 19% of gynecological carcinosarcomas with mutations in the phosphatidylinositol 3-kinase (PI3K) pathway, mainly in the uterine carcinosarcomas. Preliminary studies on the PI3K pathway may lead to prospective clinical trials designed to target PIK3CA mutations.[7]

The aim of this study is to examine clinicopathological patterns of uterine carcinosarcoma.


  Materials and Methods Top


The present study is a retrospective study of 13 years from January 2008 to April 2020. Institutional ethical committee approval was obtained for the study.

During this 13-year period, we had 3306 patients with gynecological cancers, of which 1158 patients had cancer of the uterine corpus. There were 21 patients with carcinosarcoma of the uterus, accounting for 1.7% of total uterine malignancies.

The hospital records of all 21 patients of uterine carcinosarcoma operated during the period January 2008–April 2020 at Kasturba Hospital campus and sent to the histopathology section of the Department of Pathology were reviewed. Patients who presented with clinical evidence of recurrent disease or those who had incomplete medical records were excluded from our analysis. Age incidence, clinical symptoms, signs at presentation, and histopathologic diagnosis were reviewed and analyzed. Furthermore, information regarding treatment, including surgery, chemotherapy, and/or radiation therapy, and follow-up was retrieved from the hospital information system and patient file maintained at Medical Records Department.

The histologic subtypes of the carcinoma and sarcoma components were examined and recorded. The carcinoma components were grouped into low-grade (Grades 1 and 2 endometrioid) and high-grade (Grade 3 endometrioid, serous, clear cell, undifferentiated, and mixed histology) subtypes. The proportions of carcinoma and sarcoma components were semi-quantitatively evaluated and recorded within the primary tumor site in the hysterectomy specimen. Among the metastatic sites and recurrent tumors, the histologic component (carcinoma vs. sarcoma) was evaluated.

All patients with a pathological diagnosis of carcinosarcoma or MMMTs of the uterus were included in the study.

All statistical analyses were done using statistical software SPSS (IBM Corp. Released 2013. IBM SPSS Statistics for Window, Armonk, NY).

This study involved analysis of existing data without subject identifiers or intervention.


  Results Top


The median age of presentation was 65.55 ± 11.97 years. Only two patients were below 50 years of age and only one case was nulliparous. The most common presenting symptom was vaginal bleeding (n = 16, 80%), followed by pain in lower abdomen. Postmenopausal bleeding was associated with a lower rate of survival [Figure 1]. None of our patients had a history of pelvic irradiation or history of use of tamoxifen or noncontraceptive estrogens. Endometrial biopsy was done in all patients.
Figure 1: Outcome of disease in the presence of postmenopausal bleeding

Click here to view


All patients underwent abdominal hysterectomy with bilateral salpingo-oophorectomy. The diagnosis of carcinosarcoma is based on histologic evidence of a dual population of carcinomatous and sarcomatous cells with invasion of the stroma. This is typically based on histopathology evaluation following hysterectomy, but in some cases, the diagnosis is made with endometrial biopsy.

Of these 21 cases, the carcinomatous component was further subtyped as 11 cases with endometrioid morphology, four cases each of clear cell and serous morphology, and two cases had undifferentiated epithelial components. Similarly, these 21 cases also had sarcomatous component which was further subdivided into three categories comprised six cases each with leiomyosarcomatous and rhabdomyosarcomatous morphology and nine cases depicted chondrosarcomatous histology.

These tumors were more common in the uterus as compared to other sites, most probably because the epithelial and mesenchymal cells at this site share a common embryonic origin. In our study, three cases were reported from the ovary and one case from the  Fallopian tube More Details.

[Table 1] shows the different types of uterine carcinoma sarcoma diagnosed during this period.
Table 1: Clinicopathological data of the cases

Click here to view


Thirteen patients (61.90%) had over superficial myometrial invasion. Increasing depth of myometrial invasion was associated with eight cases. Increasing depth of myometrial invasion was not associated with a lower rate of survival, as shown in [Figure 2].
Figure 2: Outcome of disease related to myometrial invasion

Click here to view


Only eight patients had Stage I at diagnosis, another five were Stage III, and five were in stage II and IV. For all patients who underwent total abdominal hysterectomy, surgical staging was done except for two patients who were unstaged [Figure 3].
Figure 3: Outcome of disease related to staging

Click here to view


Most of the tumors had carcinomatous components and 55% of tumors were high grade (grade 2/3) at diagnosis. Majority of the tumor size were <5 cm.


  Discussion Top


The incidence of uterine cancer varies in different regions of the world. Endometrial carcinoma is the most common gynecologic malignancy in developed countries and the second most common gynecologic malignancy in developing countries after cervical cancer.[8]

The primitive paramesonephric (Müllerian) duct develops from the mesenchyme of the urogenital ridge and the lining of celomic epithelium. This primitive duct ultimately undergoes differentiation into the body of the uterus, Fallopian tubes, cervix, and upper part of the vagina. This analog gives rise to all the uterine elements such as myometrial smooth muscles, endometrial stroma, and endometrial glands. Hence, the term “mixed Müllerian tumor” is applicable to all uterine tumors that are formed from both mesenchymal and epithelial elements.[9]

There is a scarcity of data in the Indian context about this disease. This is one of the most aggressive malignant neoplasms known to occur in the uterus, accounting for more than 15% of uterine cancer-associated deaths.[10]

In our study, there were 21 cases of MMMT reported of total uterine cancer during 13 years study period account for 1.7% of total cases.

In other clinical studies,[2],[11],[12],[13] the relative incidence of carcinosarcoma is about 1.5%–3% of all uterine malignancies. Its incidence begins to increase at approximately 50 years of age and reach a maximum at the age of 75 years, and thereafter plateaus.[14]

The most common site of presentation MMMT in our study was endometrium followed by the ovary and Fallopian tube. A similar finding was reported by Ahuja et al.[15]

Occasionally, it may develop from benign endometrial polyp.[16] In our study, we have reported one case received as an endometrial polyp.

Extragenital MMMTs have also been shown to arise in sites such as the pelvic peritoneum, colon, retroperitoneum, cul-de-sac, rectal peritoneum, anterolateral abdominal peritoneum, diaphragm peritoneum, and omentum.[17]

It was observed in the present study that uterine cancer was found in the fifth and sixth decades. The mean age and median age of diagnosis were 65.55 ± 11.97 and 67 years, respectively.

Gadduci et al. reported the median age of diagnosis as 62–67 years.[18]

Risk factors for the development of carcinosarcoma are similar to those of endometrial carcinoma and include nulliparity, advanced age, obesity, exposure to exogenous estrogens, and long-term use of tamoxifen[19],[20] Specifically, carcinosarcomas have been reported to occur 7–20 (median of 9 years) years after the initiation of this regimen.[21] On the contrary, oral contraceptives are reported to provide a protective effect against these tumors.[22]

As observed in our study, patients with MMMTs are mainly in the postmenopausal age group, and they commonly present with vaginal bleeding, this has been reported in other studies.[23],[24]

Among the prognostic factors, the presence of bleeding was associated with poor survival outcome (P = 0.05), while myometrial invasion and advance stage of disease did not show association with poor outcome in the present study. (P = 0.86) [Figure 2] and [Figure 3].

Contrary to findings of other studies,[25],[26] our study reported that prognostic factors such as deep myometrial invasion and advanced stage of disease were associated with poor outcomes.

Microscopically in carcinosarcomas, the epithelial component found in our study was endometrioid (52.38%), serous and clear (19.04% each), and undifferentiated (9.52%). The epithelial component in other studies was a high-grade carcinoma such as papillary serous (66%) or endometrioid (42%),[10] though it may be composed of a variety of histological subtypes including squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, or an undifferentiated carcinoma.[15]

The mesenchymal element accounted for leiomyosarcoma, rhabdomyosarcoma, and chondrosarcoma 28.57%, 28.57%, and 42.84%, respectively, in the present study. The mesenchymal element may be (a) homologous, containing cells native to the uterus including stromal sarcoma, fibrosarcoma, undifferentiated sarcoma, or leiomyosarcoma (2%) or (b) heterologous with mixed components including rhabdomyosarcoma (18%), chondrosarcoma (10%), osteosarcoma (5%), or liposarcoma (1%). Solid areas of marked pleomorphism, bizarre cells, embryonal glandular growth patterns, and lace-like arrangement of cells may be present.[22]

All patients in our study underwent endometrial biopsy for diagnosis. Since the amount of tissue obtained by this procedure is small, a high proportion of the biphasic nature of MMMTs may be missed at some occasions.[27] This may lead to misdiagnosis and mismanagement.


  Conclusions Top


The carcinosarcomas are a rare aggressive tumor of the uterus. The clinician should have a high index of suspicion for postmenopausal patients presenting with per vaginal bleeding and should consider the possibility of MMMT. Advanced stage, elderly age, and invasion of myometrium are associated with poor outcomes. Utmost efforts should be made to educate women in early cancer detection by creating awareness on risk factors and symptoms. More research is required to be done in understanding the behavior of this tumor in a better way.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Guttmann DM, Li H, Sevak P, Grover S, Jacobson G, Feldman A, et al. The impact of adjuvant therapy on survival and recurrence patterns in women with early-stage uterine carcinosarcoma: A multi-institutional study. Int J Gynecol Cancer 2016;26:141-8.  Back to cited text no. 1
    
2.
Cantrell LA, Havrilesky L, Moore DT, O'Malley D, Liotta M, Secord AA, et al. A multi-institutional cohort study of adjuvant therapy in stage I-II uterine carcinosarcoma. Gynecol Oncol 2012;127:22-6.  Back to cited text no. 2
    
3.
Kurman RJ, Carcangiu ML, Herrington CS, Young RH, editors. WHO Classification of Tumours of Female Reproductive Organs. Volume 6. 4th ed. Lyon: IARC Press; 2014. p. 307.  Back to cited text no. 3
    
4.
McCluggage WG. Malignant biphasic uterine tumours: Carcinosarcomas or metaplastic carcinomas? J Clin Pathol 2002;55:321-5.  Back to cited text no. 4
    
5.
Amant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I. Endometrial cancer. Lancet 2005;366:491-505.  Back to cited text no. 5
    
6.
Cimbaluk D, Rotmensch J, Scudiere J, Gown A, Bitterman P. Uterine carcinosarcoma: Immunohistochemical studies on tissue microarrays with focus on potential therapeutic targets. Gynecol Oncol 2007;105:138-44.  Back to cited text no. 6
    
7.
Growdon WB, Roussel BN, Scialabba VL, Foster R, Dias-Santagata D, Iafrate AJ, et al. Tissue-specific signatures of activating PIK3CA and RAS mutations in carcinosarcomas of gynecologic origin. Gynecol Oncol 2011;121:212-7.  Back to cited text no. 7
    
8.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90.  Back to cited text no. 8
    
9.
Singh R. Review literature on uterine carcinosarcoma. J Cancer Res Ther 2014;10:461-8.  Back to cited text no. 9
    
10.
El-Nashar SA, Mariani A. Uterine carcinosarcoma. Clin Obstet Gynecol 2011;54:292-304.  Back to cited text no. 10
    
11.
Tanaka YO, Tsunoda H, Minami R, Yoshikawa H, Minami M. Carcinosarcoma of the uterus: MR findings. J Magn Reson Imaging 2008;28:434-9.  Back to cited text no. 11
    
12.
Brooks SE, Zhan M, Cote T, Baquet CR. Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989-1999. Gynecol Oncol 2004;93:204-8.  Back to cited text no. 12
    
13.
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11-30.  Back to cited text no. 13
    
14.
Robboy SJ, Mutter GL, Prat J, Bentley RC, Russel P, Anderson MC, et al. Robboy's Pathology of The Female Reproductive Tract. 2nd ed. China: Churchill Livingstone Elsevier; 2009. p. 443.  Back to cited text no. 14
    
15.
Ahuja A, Safaya R, Prakash G, Kumar L, Shukla NK. Primary mixed mullerian tumor of the vagina – A case report with review of the literature. Pathol Res Pract 2011;207:253-5.  Back to cited text no. 15
    
16.
Chaudhary YS, Illahi F, Moatasim A. Carcinosarcoma uterine unusual histologic presentation. Rawal Med J 2009;34:1202.  Back to cited text no. 16
    
17.
Del Papa M, D'Amata G, Manzi F, Musmeci L, Crovaro M, Buonocore C, et al. Extragenital malignant mixed mesodermal tumor: A case report. Int J Surg Case Rep 2017;41:323-6.  Back to cited text no. 17
    
18.
Gadduci A, Cosio S, Romanini A, Genazzani AR. The management of patients with uterine sarcoma: A debated critical challenge. Crit Rev Oncol Hematol 2008;65:129-42.  Back to cited text no. 18
    
19.
de Jong RA, Nijman HW, Wijbrandi TF, Reyners AK, Boezen HM, Hollema H. Molecular markers and clinica behaviorof uterine carcinosarcomas: Focus on the epithelial tumor component. Mod Pathol 2011;24:1368-79.  Back to cited text no. 19
    
20.
Arora P, Rao S, Khurana N, Talwar D, Tanwar R. Malignant mixed mullerian tumor of broad ligament with synchronous ovarian and endometrial carcinoma: A rare association. J Cancer Res Ther 2011;7:88-91.  Back to cited text no. 20
    
21.
Kloos I, Delaloge S, Pautier P, Di Palma M, Goupil A, Duvillard P, et al. Tamoxifen-related uterine carcinosarcomas occur under/after prolonged treatment: Report of five cases and review of the literature. Int J Gynecol Cancer 2002;12:496-500.  Back to cited text no. 21
    
22.
Kernochan LE, Garcia RL. Carcinosarcomas (malignant mixed Müllerian tumor) of the uterus: Advances in elucidation of biologic and clinical characteristics. J Natl Compr Canc Netw 2009;7:550-6.  Back to cited text no. 22
    
23.
Ho SP, Ho TH. Malignant mixed Mullerian tumours of the uterus – A ten-year experience. Singapore Med J 2002;43:452-6.  Back to cited text no. 23
    
24.
Song T, Choi CH, Lee YY, Kim TJ, Lee JW, Kim BG, et al. Which is worse: Uterine papillary serous carcinomas or carcinosarcomas? J Gynecol Oncol 2011;22:83-8.  Back to cited text no. 24
    
25.
Gonzalez Bosquet J, Terstriep SA, Cliby WA, Brown-Jones M, Kaur JS, Podratz KC, et al. The impact of multi-modal therapy on survival for uterine carcinosarcomas. Gynecol Oncol 2010;116:419-23.  Back to cited text no. 25
    
26.
Rajshekar SK, Guruprasad B, Shakunthala P, Rathod P, Devi U, Bafna U. Malignant mixed Mullerian tumour of the uterus. Ecancermedicalscience 2013;7:302.  Back to cited text no. 26
    
27.
Afonso JF. Mixed mesodermal tumors of the uterus. West J Med 1974;120:17-26.  Back to cited text no. 27
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1]



 

 
Top
 
 
  Search
 
     Search Pubmed for
 
    -  Patil BU
    -  Singh S
    -  Shivkumar V B
    -  Gangane NM
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
   Abstract
  Introduction
   Materials and Me...
  Results
  Discussion
  Conclusions
   References
   Article Figures
   Article Tables

 Article Access Statistics
    Viewed507    
    PDF Downloaded10    

Recommend this journal