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==Overview==
==Overview==


'''Mixed Mullerian tumor''' (MMMT) is a rare [[uterine sarcoma]] or carcinosarcoma. Mixed Mullerian tumors are normally composed of both carcinomatous (epithelial) and sarcomatous (mesodermal) components. Mixed Mullerian tumor may be classified according to pathology findings into 2 types: epitheloid subtype and sarcomatoid subtype. Mixed Mullerian tumor may also be classified according to anatomical location into 7 types:  uterine corpus, cervix, ovaries
'''Malignant mixed mullerian tumor''' (MMMT) is a rare [[uterine sarcoma]] or carcinosarcoma. Mixed Mullerian tumors are normally composed of both carcinomatous (epithelial) and sarcomatous (mesodermal) components. Mixed Mullerian tumor may be classified according to pathology findings into 2 types: epitheloid subtype and sarcomatoid subtype. Mixed Mullerian tumor may also be classified according to anatomical location into 7 types:  [[Uterine corpus cancer|uterine corpus]], [[cervix]], [[ovaries]], [[fallopian tubes]], [[Vaginal Cancer|vagina]], [[peritoneum]], and extragenital sites. Common risk factors in the development of mixed Mullerian tumor are [[Radiation|exposure to radiation]], [[Estrogen|excessive estrogen exposure]], [[obesity]], and nulliparity.<ref name="pmid20642852">{{cite journal |vauthors=Kanthan R, Senger JL, Diudea D |title=Malignant mixed Mullerian tumors of the uterus: histopathological evaluation of cell cycle and apoptotic regulatory proteins |journal=World J Surg Oncol |volume=8 |issue= |pages=60 |year=2010 |pmid=20642852 |pmc=2913917 |doi=10.1186/1477-7819-8-60 |url=}}</ref> Mixed Mullerian tumor is more commonly observed among postmenopausal women  between 50 and 60 years old. Early clinical features include [[Vaginal bleeding|postmenopausal vaginal bleeding]], [[pelvic pain]], and [[vaginal discharge]]. Mixed Mullerian tumors are rare, and they only account for 3 to 4% of all uterine malignancies. The estimated prevalence of mixed Mullerian tumor is 3 cases per 100,000 women in the United States. The diagnosis of mixed Mullerian tumor is made with biopsy. Biopsy findings of mixed Mullerian tumor, include: tumor with carcinomatous and sarcoma-like elements and angiolymphatic invasion. Surgery is the mainstay of therapy for mixed Mullerian tumor. Total hysterectomy in conjunction with surgical staging is the most common approach to the treatment of mixed Mullerian tumor. Prognosis is generally poor, and the 5-year survival rate of patients with mixed Mullerian tumor is approximately 33% to 39%.<ref name="pmid9656116">{{cite journal |vauthors=Clement PB, Zubovits JT, Young RH, Scully RE |title=Malignant mullerian mixed tumors of the uterine cervix: a report of nine cases of a neoplasm with morphology often different from its counterpart in the corpus |journal=Int. J. Gynecol. Pathol. |volume=17 |issue=3 |pages=211–22 |year=1998 |pmid=9656116 |doi= |url=}}</ref>
fallopian tubes, vagina, peritoneum, and extragenital sites. Common risk factors in the development of mixed Mullerian tumor are exposure to radiation, excessive estrogen exposure, obesity, and nulliparity.<ref name="pmid20642852">{{cite journal |vauthors=Kanthan R, Senger JL, Diudea D |title=Malignant mixed Mullerian tumors of the uterus: histopathological evaluation of cell cycle and apoptotic regulatory proteins |journal=World J Surg Oncol |volume=8 |issue= |pages=60 |year=2010 |pmid=20642852 |pmc=2913917 |doi=10.1186/1477-7819-8-60 |url=}}</ref> Early clinical features include postmenopausal vaginal bleeding, abdominal distention, and dysmenorrhea.


==Historical Perspective==
==Historical Perspective==
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*Mixed Mullerian tumor may be classified according to pathology findings into 2 types:  
*Mixed Mullerian tumor may be classified according to pathology findings into 2 types:  
'''Epitheloid subtype'''  
'''Epitheloid subtype'''  
:*Endometroid adenocarcinoma (most common)
:*[[Adenocarcinoma - endometrium|Endometroid adenocarcinoma]] (most common)
:*Clear cell carcinoma
:*[[Clear cell tumor|Clear cell carcinoma]]
:*Mucinous carcinoma
:*[[Mucinous carcinoma]]
:*Papillary-serous carcinoma
:*Papillary-serous carcinoma
'''Sarcomatoid subtype'''
'''Sarcomatoid subtype'''
:*Undifferentiated sarcoma
:*Undifferentiated sarcoma
:*Rhabdomyosarcoma
:*[[Rhabdomyosarcoma]]


*Mixed Mullerian tumor may also be classified according to anatomical location into 7 types:  
*Mixed Mullerian tumor may also be classified according to anatomical location into 7 types:  
:*Uterine corpus
:*[[Uterine corpus cancer|Uterine corpus]]
:*Cervix
:*[[Cervix]]
:*Ovaries
:*[[Ovaries]]
:*Fallopian tubes
:*[[Fallopian tubes]]
:*Vagina
:*Vagina
:*Peritoneum
:*[[Peritoneum]]
:*Extragenital sites
:*Extragenital sites


==Pathophysiology==
==Pathophysiology==
*The pathogenesis of mixed Mullerian tumor is characterized by  
*The pathogenesis of mixed Mullerian tumor is characterized by epithelial and stromal growth, and the transdifferentiation of uterine carcinoma into sarcoma.<ref name="pato">D'Angelo E, Prat J. Pathology of mixed Mullerian tumours. Best Pract Res Clin Obstet Gynaecol. 2011;25:705-718.</ref>
*Mixed Mullerian tumor arises from malignant epithelial and stromal components, which are normally involved in the  
*The PIK3CA gene has been associated with the development of mixed Mullerian tumor, involving the PI3K pathway.
*Genes involved in the pathogenesis of mixed Mullerian tumor, include: <ref name="MMM">Mutation Profiling in Uterine Carcinosarcoma / Malignant Mixed Mullerian Tumors. Melissa McConechy; David Huntsman, MD. ESUN. http://sarcomahelp.org/carcinosarcoma.html Accessed on April 7, 2016</ref>
:*PIK3CA (50% of the tumors)
:*[[PTEN gene|PTEN]] (30% of the tumors)
:*PIK3R1 (30% of the tumors)
*On gross pathology, a large cervical mass is a characteristic finding of mixed Mullerian tumor.
*On gross pathology, a large cervical mass is a characteristic finding of mixed Mullerian tumor.
*On microscopic histopathological analysis, high-grade stromal sarcoma, poorly differentiated epithelial cells, and angiolymphatic invasion are characteristic findings of mixed Mullerian tumor.<ref name="pmid16813659">{{cite journal |vauthors=Maheshwari A, Gupta S, Shet T, Wuntkal R, Tongaonkar HB |title=Diagnostic dilemma in a case of malignant mixed mullerian tumor of the cervix |journal=World J Surg Oncol |volume=4 |issue= |pages=36 |year=2006 |pmid=16813659 |pmc=1526432 |doi=10.1186/1477-7819-4-36 |url=}}</ref>
*On microscopic histopathological analysis, high-grade stromal sarcoma, poorly differentiated epithelial cells, and angiolymphatic invasion are characteristic findings of mixed Mullerian tumor.<ref name="pmid16813659">{{cite journal |vauthors=Maheshwari A, Gupta S, Shet T, Wuntkal R, Tongaonkar HB |title=Diagnostic dilemma in a case of malignant mixed mullerian tumor of the cervix |journal=World J Surg Oncol |volume=4 |issue= |pages=36 |year=2006 |pmid=16813659 |pmc=1526432 |doi=10.1186/1477-7819-4-36 |url=}}</ref>


==Causes==
==Causes==
* Mixed Mullerian tumor may be caused by chronic estrogen stimulation.  
*The most important cause of mixed Mullerian tumors is the mutation in genes PTEN, ARID1A, PIK3R1, and POLE.<ref name="MMM">Wada H, Enomoto T, Fujita M, et al. Molecular evidence that most but not all carcinosarcomas of the uterus are combination tumors. Cancer Res. 1997;57:5379-5385.</ref>
* Mixed Mullerian tumor is caused by a mutation in the
*Mixed Mullerian tumor may also be caused by chronic estrogen stimulation.
* There are no established causes for mixed Mullerian tumor.
 
==Differentiating Mixed Mullerian tumor from other Diseases==
==Differentiating mixed Mullerian tumor from other Diseases==
*Mixed Mullerian tumor must be differentiated from other diseases that cause abnormal vaginal bleeding, abdominal pain, and uterus enlargement such as:
*Mixed Mullerian tumor must be differentiated from other diseases that cause abnormal vaginal bleeding, abdominal pain, and metrorrhagia, such as:
:*[[Leiomyosarcoma|Uterine leiomyosarcoma]]
:*Uterine leiomyosarcoma
:*[[Adenocarcinoma - endometrium|Adenocarcinoma of the uterus]]
:*Adenocarcinoma of the uterus
:*[[Endometrial cancer differential diagnosis|Endometrial cancer]]
:*Endometrial cancer
 
==Epidemiology and Demographics==
==Epidemiology and Demographics==
* The prevalence of mixed Mullerian tumor is approximately [number or range] per 100,000 individuals worldwide.
* Mixed Mullerian tumor is rare, it only accounts for 3 to 4% of all uterine malignancies.<ref name="pmid15047237">{{cite journal |vauthors=Brooks SE, Zhan M, Cote T, Baquet CR |title=Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989-1999 |journal=Gynecol. Oncol. |volume=93 |issue=1 |pages=204–8 |year=2004 |pmid=15047237 |doi=10.1016/j.ygyno.2003.12.029 |url=}}</ref>
* In [year], the incidence of mixed Mullerian tumor was estimated to be [number or range] cases per 100,000 individuals in [location].
* The estimated prevalence of mixed Mullerian tumor is 3 cases per 100,000 women  in the United States.<ref name="pmid15047237">{{cite journal |vauthors=Brooks SE, Zhan M, Cote T, Baquet CR |title=Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989-1999 |journal=Gynecol. Oncol. |volume=93 |issue=1 |pages=204–8 |year=2004 |pmid=15047237 |doi=10.1016/j.ygyno.2003.12.029 |url=}}</ref>
===Age===
===Age===
*The median age at diagnosis of Mixed Mullerian tumor is 66 years
*The median age at diagnosis of Mixed Mullerian tumor is 66 years
*Mixed Mullerian tumor is more commonly observed among patients aged between 50 and 60 years old.
*Mixed Mullerian tumor is more commonly observed among patients aged between 50 and 60 years old.
*Mixed Mullerian tumor is more commonly observed among postmenopausal women
*Mixed Mullerian tumor is more commonly observed among postmenopausal women
===Race===
===Race===
*There is no racial predilection for mixed Mullerian tumor.
*There is no racial predilection for mixed Mullerian tumor.<ref name="pmid15047237">{{cite journal |vauthors=Brooks SE, Zhan M, Cote T, Baquet CR |title=Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989-1999 |journal=Gynecol. Oncol. |volume=93 |issue=1 |pages=204–8 |year=2004 |pmid=15047237 |doi=10.1016/j.ygyno.2003.12.029 |url=}}</ref>
 
==Risk Factors==
==Risk Factors==
*Common risk factors in the development of mixed Mullerian tumor are exposure to radiation, excessive estrogen exposure, obesity, and nulliparity.<ref name="pmid20642852">{{cite journal |vauthors=Kanthan R, Senger JL, Diudea D |title=Malignant mixed Mullerian tumors of the uterus: histopathological evaluation of cell cycle and apoptotic regulatory proteins |journal=World J Surg Oncol |volume=8 |issue= |pages=60 |year=2010 |pmid=20642852 |pmc=2913917 |doi=10.1186/1477-7819-8-60 |url=}}</ref>
*Common risk factors in the development of mixed Mullerian tumor are [[Radiation|exposure to radiation]], [[Estrogen|excessive estrogen exposure]], [[obesity]], and nulliparity.<ref name="pmid20642852">{{cite journal |vauthors=Kanthan R, Senger JL, Diudea D |title=Malignant mixed Mullerian tumors of the uterus: histopathological evaluation of cell cycle and apoptotic regulatory proteins |journal=World J Surg Oncol |volume=8 |issue= |pages=60 |year=2010 |pmid=20642852 |pmc=2913917 |doi=10.1186/1477-7819-8-60 |url=}}</ref>
   
   
== Natural History, Complications and Prognosis==
== Natural History, Complications and Prognosis==
*Early clinical features include postmenopausal vaginal bleeding, abdominal distention, and dysmenorrhea.
*Early clinical features include [[Vaginal bleeding|postmenopausal vaginal bleeding]], [[pelvic pain]], and [[vaginal discharge]].
*If left untreated, the majority of patients with mixed Mullerian tumor may progress quickly to develop lymph node invasion, metastasis, and death.  
*If left untreated, the majority of patients with mixed Mullerian tumor may progress quickly to develop lymph node invasion, [[metastasis]], and death.  
*Prognosis is generally poor, and the 5-year survival rate of patients with Mixed Mullerian tumor is approximately 33% to 39%.
*Prognosis is generally poor, and the 5-year survival rate of patients with Mixed Mullerian tumor is approximately 33% to 39%.
*Findings associated with good prognosis include p16 and Mcl-1 gene expression.<ref name="pmid16813659">{{cite journal |vauthors=Maheshwari A, Gupta S, Shet T, Wuntkal R, Tongaonkar HB |title=Diagnostic dilemma in a case of malignant mixed mullerian tumor of the cervix |journal=World J Surg Oncol |volume=4 |issue= |pages=36 |year=2006 |pmid=16813659 |pmc=1526432 |doi=10.1186/1477-7819-4-36 |url=}}</ref>
*Findings associated with good prognosis include p16 and Mcl-1 gene expression.<ref name="pmid16813659">{{cite journal |vauthors=Maheshwari A, Gupta S, Shet T, Wuntkal R, Tongaonkar HB |title=Diagnostic dilemma in a case of malignant mixed mullerian tumor of the cervix |journal=World J Surg Oncol |volume=4 |issue= |pages=36 |year=2006 |pmid=16813659 |pmc=1526432 |doi=10.1186/1477-7819-4-36 |url=}}</ref>
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== Diagnosis ==
== Diagnosis ==
===Diagnostic Criteria===
===Diagnostic Criteria===
*The diagnosis of mixed Mullerian tumor is made with biopsy.  
*The diagnosis of mixed Mullerian tumor is made with biopsy.
*Biopsy findings of mixed Mullerian tumor, include:<ref name="pmid9656116">{{cite journal |vauthors=Clement PB, Zubovits JT, Young RH, Scully RE |title=Malignant mullerian mixed tumors of the uterine cervix: a report of nine cases of a neoplasm with morphology often different from its counterpart in the corpus |journal=Int. J. Gynecol. Pathol. |volume=17 |issue=3 |pages=211–22 |year=1998 |pmid=9656116 |doi= |url=}}</ref>
*Biopsy findings of mixed Mullerian tumor, include:<ref name="pmid9656116">{{cite journal |vauthors=Clement PB, Zubovits JT, Young RH, Scully RE |title=Malignant mullerian mixed tumors of the uterine cervix: a report of nine cases of a neoplasm with morphology often different from its counterpart in the corpus |journal=Int. J. Gynecol. Pathol. |volume=17 |issue=3 |pages=211–22 |year=1998 |pmid=9656116 |doi= |url=}}</ref>
:*Tumor with carcinomatous and sarcoma-like elements  
:*Tumor with carcinomatous and sarcoma-like elements  
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=== Symptoms ===
=== Symptoms ===
*Mixed Mullerian tumor is usually asymptomatic.
*Mixed Mullerian tumor may be initially asymptomatic.
*Symptoms of mixed Mullerian tumor may include the following:<ref name="pmid20642852">{{cite journal |vauthors=Kanthan R, Senger JL, Diudea D |title=Malignant mixed Mullerian tumors of the uterus: histopathological evaluation of cell cycle and apoptotic regulatory proteins |journal=World J Surg Oncol |volume=8 |issue= |pages=60 |year=2010 |pmid=20642852 |pmc=2913917 |doi=10.1186/1477-7819-8-60 |url=}}</ref>
*Symptoms of mixed Mullerian tumor may include the following:<ref name="pmid20642852">{{cite journal |vauthors=Kanthan R, Senger JL, Diudea D |title=Malignant mixed Mullerian tumors of the uterus: histopathological evaluation of cell cycle and apoptotic regulatory proteins |journal=World J Surg Oncol |volume=8 |issue= |pages=60 |year=2010 |pmid=20642852 |pmc=2913917 |doi=10.1186/1477-7819-8-60 |url=}}</ref>
*Early symptoms may include:
*Early symptoms
:* Abnormal [[vaginal bleeding]], abnormal menstrual periods  
:* Abnormal [[vaginal bleeding]], abnormal menstrual periods  
:* [[Metrorrhagia]] in premenopausal women  
:* [[Metrorrhagia]] in premenopausal women  
:* Postmenopausal [[vaginal bleeding]] <ref name="pmid22513918">{{cite journal| author=Kong A, Johnson N, Kitchener HC, Lawrie TA| title=Adjuvant radiotherapy for stage I endometrial cancer. | journal=Cochrane Database Syst Rev | year= 2012 | volume= 4 | issue=  | pages= CD003916 | pmid=22513918 | doi=10.1002/14651858.CD003916.pub4 | pmc=PMC4164955 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22513918  }} </ref>
:* Postmenopausal [[vaginal bleeding]] <ref name="pmid22513918">{{cite journal| author=Kong A, Johnson N, Kitchener HC, Lawrie TA| title=Adjuvant radiotherapy for stage I endometrial cancer. | journal=Cochrane Database Syst Rev | year= 2012 | volume= 4 | issue=  | pages= CD003916 | pmid=22513918 | doi=10.1002/14651858.CD003916.pub4 | pmc=PMC4164955 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22513918  }} </ref>
:* Postcoital bleeding
:* Postcoital bleeding
*Advanced symptoms may include:
*Advanced symptoms
:* [[Polyuria]] and [[dysuria]], If a tumor places pressure on the bladder or urethra  
:* [[Polyuria]] and [[dysuria]], If a tumor places pressure on the bladder or urethra  
:* [[Pelvic pain]] and [[dyspareunia]]
:* [[Pelvic pain]] and [[dyspareunia]]
Line 95: Line 95:
*Patients with mixed Mullerian tumor may have a normal appearance.
*Patients with mixed Mullerian tumor may have a normal appearance.
*Pelvic examination may be remarkable for:<ref name="pmid9656116">{{cite journal |vauthors=Clement PB, Zubovits JT, Young RH, Scully RE |title=Malignant mullerian mixed tumors of the uterine cervix: a report of nine cases of a neoplasm with morphology often different from its counterpart in the corpus |journal=Int. J. Gynecol. Pathol. |volume=17 |issue=3 |pages=211–22 |year=1998 |pmid=9656116 |doi= |url=}}</ref>
*Pelvic examination may be remarkable for:<ref name="pmid9656116">{{cite journal |vauthors=Clement PB, Zubovits JT, Young RH, Scully RE |title=Malignant mullerian mixed tumors of the uterine cervix: a report of nine cases of a neoplasm with morphology often different from its counterpart in the corpus |journal=Int. J. Gynecol. Pathol. |volume=17 |issue=3 |pages=211–22 |year=1998 |pmid=9656116 |doi= |url=}}</ref>
:*Vaginal bleeding
:*[[Vaginal bleeding]]
:*Enlarged uterus (advanced stage)
:*[[Enlarged uterus]] (advanced stage)


=== Laboratory Findings ===
=== Laboratory Findings ===
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*On MRI,  findings of mixed Mullerian tumor, may include:<ref name="pmid4705156">{{cite journal |vauthors=Abell MR, Ramirez JA |title=Sarcomas and carcinosarcomas of the uterine cervix |journal=Cancer |volume=31 |issue=5 |pages=1176–92 |year=1973 |pmid=4705156 |doi= |url=}}</ref>
*On MRI,  findings of mixed Mullerian tumor, may include:<ref name="pmid4705156">{{cite journal |vauthors=Abell MR, Ramirez JA |title=Sarcomas and carcinosarcomas of the uterine cervix |journal=Cancer |volume=31 |issue=5 |pages=1176–92 |year=1973 |pmid=4705156 |doi= |url=}}</ref>
:*T1: predominantly isointense to both myometrium (75%) and endometrium (70%)
:*T1: predominantly isointense to both myometrium (75%) and endometrium (70%)
:*T2:hyper-intense to myometrium (90%) either hypo-intense (55%) or isointense (41%) to endometrium.  
:*T2: hyper-intense to myometrium (90%) either hypo-intense (55%) or isointense (41%) to endometrium.  
*On enhanced CT, findings of mixed Mullerian tumor, may include:   
*On enhanced CT, findings of mixed Mullerian tumor, may include:   
:*Heterogeneously hypodense and ill defined mass
:*Heterogeneously hypodense and ill defined mass
:*Dilatation of uterine cavity
:*Dilatation of uterine cavity
=== Other Diagnostic Studies ===
=== Other Diagnostic Studies ===
*Mixed Mullerian tumor may also be diagnosed using laparoscopy, and FDG PET/CT.  
*Mixed Mullerian tumor may also be diagnosed using [[laparoscopy]], and FDG PET/CT.  
   
   
== Treatment ==
== Treatment ==
=== Medical Therapy ===
=== Medical Therapy ===
*There is no treatment for mixed Mullerian tumor; the mainstay of therapy is supportive care.
*There is no treatment for mixed Mullerian tumor; the mainstay of therapy is supportive care.
*The medical management for mixed Mullerian tumor, include:
*The medical management for mixed Mullerian tumor, include:<ref name="pmid4705156">{{cite journal |vauthors=Abell MR, Ramirez JA |title=Sarcomas and carcinosarcomas of the uterine cervix |journal=Cancer |volume=31 |issue=5 |pages=1176–92 |year=1973 |pmid=4705156 |doi= |url=}}</ref>
:*Chemotherapy ifosfamide-based regimen
:*[[Chemotherapy]] [[ifosfamide]]-based regimen
:*Radiotherapy (vaginal brachytherapy)
:*[[Radiotherapy]] (vaginal brachytherapy)
:*Chemotherapy plus radiation therapy
:*Chemotherapy plus radiation therapy


Line 126: Line 125:
*Surgery is the mainstay of therapy for mixed Mullerian tumor.
*Surgery is the mainstay of therapy for mixed Mullerian tumor.
*Total hysterectomy in conjunction with surgical staging is the most common approach to the treatment of mixed Mullerian tumor.
*Total hysterectomy in conjunction with surgical staging is the most common approach to the treatment of mixed Mullerian tumor.
*Different surgical procedures for the treatment of  mixed Mullerian tumor, include:
*Different surgical procedures for the treatment of  mixed Mullerian tumor, include:<ref name="pmid4705156">{{cite journal |vauthors=Abell MR, Ramirez JA |title=Sarcomas and carcinosarcomas of the uterine cervix |journal=Cancer |volume=31 |issue=5 |pages=1176–92 |year=1973 |pmid=4705156 |doi= |url=}}</ref>
:*Total hysterectomy
:*[[Hysterectomy|Total hysterectomy]]
:*Bilateral salpingo-oophorectomy
:*Bilateral salpingo-oophorectomy
:*Pelvic and para-aortic lymph node dissection
:*Pelvic and para-aortic lymph node dissection
Line 133: Line 132:
:*Omentectomy
:*Omentectomy
:*Biopsies of peritoneal surfaces
:*Biopsies of peritoneal surfaces
 
=== Prevention ===
=== Prevention ===
*There are no primary preventive measures available for mixed Mullerian tumor.
*There are no primary preventive measures available for mixed Mullerian tumor.

Latest revision as of 23:32, 23 May 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

Synonyms and keywords: Mixed Müllerian tumor; MMMT; Malignant mixed Müllerian tumor; Carcinosarcoma of the uterus; Sarcomatoid carcinoma of the uterus; Malignant mesodermal mixed tumor; Metaplastic carcinoma

Overview

Malignant mixed mullerian tumor (MMMT) is a rare uterine sarcoma or carcinosarcoma. Mixed Mullerian tumors are normally composed of both carcinomatous (epithelial) and sarcomatous (mesodermal) components. Mixed Mullerian tumor may be classified according to pathology findings into 2 types: epitheloid subtype and sarcomatoid subtype. Mixed Mullerian tumor may also be classified according to anatomical location into 7 types: uterine corpus, cervix, ovaries, fallopian tubes, vagina, peritoneum, and extragenital sites. Common risk factors in the development of mixed Mullerian tumor are exposure to radiation, excessive estrogen exposure, obesity, and nulliparity.[1] Mixed Mullerian tumor is more commonly observed among postmenopausal women between 50 and 60 years old. Early clinical features include postmenopausal vaginal bleeding, pelvic pain, and vaginal discharge. Mixed Mullerian tumors are rare, and they only account for 3 to 4% of all uterine malignancies. The estimated prevalence of mixed Mullerian tumor is 3 cases per 100,000 women in the United States. The diagnosis of mixed Mullerian tumor is made with biopsy. Biopsy findings of mixed Mullerian tumor, include: tumor with carcinomatous and sarcoma-like elements and angiolymphatic invasion. Surgery is the mainstay of therapy for mixed Mullerian tumor. Total hysterectomy in conjunction with surgical staging is the most common approach to the treatment of mixed Mullerian tumor. Prognosis is generally poor, and the 5-year survival rate of patients with mixed Mullerian tumor is approximately 33% to 39%.[2]

Historical Perspective

  • Mixed Mullerian tumor was first described by Ferriera and colleagues in 1951.[3]

Classification

  • Mixed Mullerian tumors are normally composed of both carcinomatous (epithelial) and sarcomatous (mesodermal) components.
  • Mixed Mullerian tumor may be classified according to pathology findings into 2 types:

Epitheloid subtype

Sarcomatoid subtype

  • Mixed Mullerian tumor may also be classified according to anatomical location into 7 types:

Pathophysiology

  • The pathogenesis of mixed Mullerian tumor is characterized by epithelial and stromal growth, and the transdifferentiation of uterine carcinoma into sarcoma.[4]
  • The PIK3CA gene has been associated with the development of mixed Mullerian tumor, involving the PI3K pathway.
  • Genes involved in the pathogenesis of mixed Mullerian tumor, include: [5]
  • PIK3CA (50% of the tumors)
  • PTEN (30% of the tumors)
  • PIK3R1 (30% of the tumors)
  • On gross pathology, a large cervical mass is a characteristic finding of mixed Mullerian tumor.
  • On microscopic histopathological analysis, high-grade stromal sarcoma, poorly differentiated epithelial cells, and angiolymphatic invasion are characteristic findings of mixed Mullerian tumor.[6]

Causes

  • The most important cause of mixed Mullerian tumors is the mutation in genes PTEN, ARID1A, PIK3R1, and POLE.[5]
  • Mixed Mullerian tumor may also be caused by chronic estrogen stimulation.

Differentiating Mixed Mullerian tumor from other Diseases

  • Mixed Mullerian tumor must be differentiated from other diseases that cause abnormal vaginal bleeding, abdominal pain, and uterus enlargement such as:

Epidemiology and Demographics

  • Mixed Mullerian tumor is rare, it only accounts for 3 to 4% of all uterine malignancies.[7]
  • The estimated prevalence of mixed Mullerian tumor is 3 cases per 100,000 women in the United States.[7]

Age

  • The median age at diagnosis of Mixed Mullerian tumor is 66 years
  • Mixed Mullerian tumor is more commonly observed among patients aged between 50 and 60 years old.
  • Mixed Mullerian tumor is more commonly observed among postmenopausal women

Race

  • There is no racial predilection for mixed Mullerian tumor.[7]

Risk Factors

Natural History, Complications and Prognosis

  • Early clinical features include postmenopausal vaginal bleeding, pelvic pain, and vaginal discharge.
  • If left untreated, the majority of patients with mixed Mullerian tumor may progress quickly to develop lymph node invasion, metastasis, and death.
  • Prognosis is generally poor, and the 5-year survival rate of patients with Mixed Mullerian tumor is approximately 33% to 39%.
  • Findings associated with good prognosis include p16 and Mcl-1 gene expression.[6]

Diagnosis

Diagnostic Criteria

  • The diagnosis of mixed Mullerian tumor is made with biopsy.
  • Biopsy findings of mixed Mullerian tumor, include:[2]
  • Tumor with carcinomatous and sarcoma-like elements
  • Angiolymphatic invasion

Symptoms

  • Mixed Mullerian tumor may be initially asymptomatic.
  • Symptoms of mixed Mullerian tumor may include the following:[1]
  • Early symptoms
  • Advanced symptoms

Physical Examination

  • Patients with mixed Mullerian tumor may have a normal appearance.
  • Pelvic examination may be remarkable for:[2]

Laboratory Findings

  • Laboratory findings associated with mixed Mullerian tumor, may include:
  • Anemia
  • Elevated CA-125

Imaging Findings

  • Enhanced CT scan and MRI is the imaging modalities of choice for mixed Mullerian tumor.
  • On MRI, findings of mixed Mullerian tumor, may include:[9]
  • T1: predominantly isointense to both myometrium (75%) and endometrium (70%)
  • T2: hyper-intense to myometrium (90%) either hypo-intense (55%) or isointense (41%) to endometrium.
  • On enhanced CT, findings of mixed Mullerian tumor, may include:
  • Heterogeneously hypodense and ill defined mass
  • Dilatation of uterine cavity

Other Diagnostic Studies

  • Mixed Mullerian tumor may also be diagnosed using laparoscopy, and FDG PET/CT.

Treatment

Medical Therapy

  • There is no treatment for mixed Mullerian tumor; the mainstay of therapy is supportive care.
  • The medical management for mixed Mullerian tumor, include:[9]

Surgery

  • Surgery is the mainstay of therapy for mixed Mullerian tumor.
  • Total hysterectomy in conjunction with surgical staging is the most common approach to the treatment of mixed Mullerian tumor.
  • Different surgical procedures for the treatment of mixed Mullerian tumor, include:[9]
  • Total hysterectomy
  • Bilateral salpingo-oophorectomy
  • Pelvic and para-aortic lymph node dissection
  • Cytology of peritoneal washings
  • Omentectomy
  • Biopsies of peritoneal surfaces

Prevention

  • There are no primary preventive measures available for mixed Mullerian tumor.
  • Once diagnosed and successfully treated, patients with mixed Mullerian tumor are followed-up every 6 or 12 months.
  • Follow-up testing include pelvic examination, ultrasound, and biomarker monitorization.

References

  1. ↑ 1.0 1.1 1.2 Kanthan R, Senger JL, Diudea D (2010). "Malignant mixed Mullerian tumors of the uterus: histopathological evaluation of cell cycle and apoptotic regulatory proteins". World J Surg Oncol. 8: 60. doi:10.1186/1477-7819-8-60. PMC 2913917. PMID 20642852.
  2. ↑ 2.0 2.1 2.2 Clement PB, Zubovits JT, Young RH, Scully RE (1998). "Malignant mullerian mixed tumors of the uterine cervix: a report of nine cases of a neoplasm with morphology often different from its counterpart in the corpus". Int. J. Gynecol. Pathol. 17 (3): 211–22. PMID 9656116.
  3. ↑ Wright JD, Rosenblum K, Huettner PC, Mutch DG, Rader JS, Powell MA, Gibb RK (2005). "Cervical sarcomas: an analysis of incidence and outcome". Gynecol. Oncol. 99 (2): 348–51. doi:10.1016/j.ygyno.2005.06.021. PMID 16051326.
  4. ↑ D'Angelo E, Prat J. Pathology of mixed Mullerian tumours. Best Pract Res Clin Obstet Gynaecol. 2011;25:705-718.
  5. ↑ 5.0 5.1 Mutation Profiling in Uterine Carcinosarcoma / Malignant Mixed Mullerian Tumors. Melissa McConechy; David Huntsman, MD. ESUN. http://sarcomahelp.org/carcinosarcoma.html Accessed on April 7, 2016
  6. ↑ 6.0 6.1 Maheshwari A, Gupta S, Shet T, Wuntkal R, Tongaonkar HB (2006). "Diagnostic dilemma in a case of malignant mixed mullerian tumor of the cervix". World J Surg Oncol. 4: 36. doi:10.1186/1477-7819-4-36. PMC 1526432. PMID 16813659.
  7. ↑ 7.0 7.1 7.2 Brooks SE, Zhan M, Cote T, Baquet CR (2004). "Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989-1999". Gynecol. Oncol. 93 (1): 204–8. doi:10.1016/j.ygyno.2003.12.029. PMID 15047237.
  8. ↑ Kong A, Johnson N, Kitchener HC, Lawrie TA (2012). "Adjuvant radiotherapy for stage I endometrial cancer". Cochrane Database Syst Rev. 4: CD003916. doi:10.1002/14651858.CD003916.pub4. PMC 4164955. PMID 22513918.
  9. ↑ 9.0 9.1 9.2 Abell MR, Ramirez JA (1973). "Sarcomas and carcinosarcomas of the uterine cervix". Cancer. 31 (5): 1176–92. PMID 4705156.
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