May 2021 – Gynecological Pathology

The correct answer is: carcinosarcoma (malignant mixed Mullerian tumor) with heterologous elements (rhabdomyosarcomatous differentiation).

Carcinosarcoma (malignant mixed Mullerian tumor) is a malignant biphasic tumor (carcinomatous and sarcomatous elements, arising from the same malignant clone) that are intimately admixed (at least focally) (1). The incidence is less than 5% of all uterine malignancy, typically affects postmenopausal women (mean age: 65 years) with slight predilection in African American women. The clinical picture is abnormal vaginal bleeding, enlarged uterus by imaging, polyploid mass (might protrude through cervical os), and pelvic pain. Recurrence and metastases are often that of the carcinomatous element in 70% of the cases (2). Some studies mentioned that the risk factors are similar to that of endometrial carcinoma, including obesity, smoking, nulliparity, estrogen exposure, tamoxifen therapy, and pelvic irradiation (3).

The core treatment is total hysterectomy with bilateral salpingo-oopherectomy with biopsy staging, followed by chemotherapy and/or radiotherapy. The prognosis is worse than that of patients with high-grade endometrial carcinoma (particularly high stage). An adverse outcome in the stage I disease might be associated with one of the following: deep myometrial invasion, lymphovascular invasion, serous and clear cell type carcinomatous elements, extensive sarcomatous elements, and presence of heterologous elements (4,5). The molecular studies showed frequent PIK3CA, FBXW7, KRAS, and TP53 mutations (6). 

Grossly, the tumor presents as a polypoid mass filling the endometrial cavity, often protrude from the cervix (measures from 1.8 cm -17 cm; mean 6.6 cm). Necrosis and hemorrhage are common findings. Cystic degeneration is rarely seen. Microscopically, the carcinomatous component (typically predominant) is usually high-grade endometrioid, serous or clear cell. It might be hard to classify if poorly differentiated carcinoma. Immunohistochemical stains will be positive for cytokeratin and EMA. ER and PR are positive in endometroid and negative in serous carcinoma. The sarcomatous component is either homologous or heterologous (mesenchymal components that are not normally present in the uterus) in descending order (rhabdomyosarcoma, chondrosarcoma, osteosarcoma, and liposarcoma). Immunohistochemical stains will be positive for cytokeratin, vimentin, desmin, actin, CD10, and CD34. Myogenin and MyoD1 stain the rhabdomyosarcomatous component. SATB2 could identify the osteosarcomatous elements. Mutant-pattern P53 expression and diffuse p16 staining are usually present in both carcinomatous and sarcomatous elements. 

Low-grade Mullerian adenosarcoma is a biphasic tumor with benign or low-grade epithelial component and low-grade malignant stroma showing phyllodes growth pattern and periglandular condensation. Sarcomatous overgrowth and heterologous elements can occur in this tumor as well.

Undifferentiated uterine sarcoma is a high-grade sarcoma arising from the endometrium or myometrium with no specific differentiation. Usually, it is a diagnosis of exclusion. 

Endometrioid carcinoma with corded hyalinized and spindle cell morphology with areas of dense hyalinization, calcification, and metaplastic bone formation can mimic carcinosarcoma. However, the glandular component is usually low-grade, and squamous metaplasia could help to render the lesion's endometrioid nature. The spindle cell component of this tumor also shows bland morphology, and gradual transition from epithelial areas to spindle cell areas are notable (versus usually abrupt transition in the carcinosarcoma).

References

1. Denschlag D, Ulrich UA. Uterine Carcinosarcomas – Diagnosis and Management. Oncol Res Treat. 2018;41(11):675-679. doi: 10.1159/000494335. Epub 2018 Oct 13. PMID: 30317231.
2. Abdulfatah E, Lordello L, Khurram M, Van de Vijver K, Alosh B, Bandyopadhyay S, Oliva E, Ali-Fehmi R. Predictive Histologic Factors in Carcinosarcomas of the Uterus: A Multi-institutional Study. Int J Gynecol Pathol. 2019 May;38(3):205-215. doi: 10.1097/PGP.0000000000000497. PMID: 30958427.
3. Zelmanowicz A, Hildesheim A, Sherman ME, Sturgeon SR, Kurman RJ, Barrett RJ, Berman ML, Mortel R, Twiggs LB, Wilbanks GD, Brinton LA. Evidence for a common etiology for endometrial carcinomas and malignant mixed mullerian tumors. Gynecol Oncol. 1998 Jun;69(3):253-7. doi: 10.1006/gyno.1998.4941. PMID: 9648597.
4. Matsuo K, Takazawa Y, Ross MS, Elishaev E, Podzielinski I, Yunokawa M, Sheridan TB, Bush SH, Klobocista MM, Blake EA, Takano T, Matsuzaki S, Baba T, Satoh S, Shida M, Nishikawa T, Ikeda Y, Adachi S, Yokoyama T, Takekuma M, Fujiwara K, Hazama Y, Kadogami D, Moffitt MN, Takeuchi S, Nishimura M, Iwasaki K, Ushioda N, Johnson MS, Yoshida M, Hakam A, Li SW, Richmond AM, Machida H, Mhawech-Fauceglia P, Ueda Y, Yoshino K, Yamaguchi K, Oishi T, Kajiwara H, Hasegawa K, Yasuda M, Kawana K, Suda K, Miyake TM, Moriya T, Yuba Y, Morgan T, Fukagawa T, Wakatsuki A, Sugiyama T, Pejovic T, Nagano T, Shimoya K, Andoh M, Shiki Y, Enomoto T, Sasaki T, Fujiwara K, Mikami M, Shimada M, Konishi I, Kimura T, Post MD, Shahzad MM, Im DD, Yoshida H, Omatsu K, Ueland FR, Kelley JL, Karabakhtsian RG, Roman LD. Significance of histologic pattern of carcinoma and sarcoma components on survival outcomes of uterine carcinosarcoma. Ann Oncol. 2016 Jul;27(7):1257-66. doi: 10.1093/annonc/mdw161. Epub 2016 Apr 6. PMID: 27052653.
5. Ferguson SE, Tornos C, Hummer A, Barakat RR, Soslow RA. Prognostic features of surgical stage I uterine carcinosarcoma. Am J Surg Pathol. 2007 Nov;31(11):1653-61. doi: 10.1097/PAS.0b013e3181161ba3. PMID: 18059221.
6. Cherniack AD, Shen H, Walter V, Stewart C, Murray BA, Bowlby R, Hu X, Ling S, Soslow RA, Broaddus RR, Zuna RE, Robertson G, Laird PW, Kucherlapati R, Mills GB; Cancer Genome Atlas Research Network, Weinstein JN, Zhang J, Akbani R, Levine DA. Integrated Molecular Characterization of Uterine Carcinosarcoma. Cancer Cell. 2017 Mar 13;31(3):411-423. doi: 10.1016/j.ccell.2017.02.010. PMID: 28292439; PMCID: PMC5599133.