Endometrial stromal neoplasia: An uncommon tumor at a tertiary health centre in coastal India

Introduction and Aim: Stromal malignancies of uterus are rare and accounts for 1-3% of all female genital tract malignancies. They are known to pose a diagnostic challenge to the clinicians and the pathologists. They show non-specific clinical features, gross appearance, varying histological and immunohistochemical features. This study highlights the important clinical, morphologic and immunohistochemical features of these tumors. Methodology: Histopathologically diagnosed cases of endometrial stromal neoplasia over a period of 5 years from 2013 to 2017 were retrieved. The cases were analysed based on age, tumor size and histological types. Immunohistochemistry (IHC) was done whenever feasible. Results: During the study period, we found 25 cases of endometrial stromal neoplasia. They were composed of four cases of endometrial stromal nodule (ESN), six cases of low grade endometrial stromal sarcoma (ESS) and three cases of ESS with smooth muscle differentiation. Twelve cases of carcinosarcomas and adenosarcomas and a single case of undifferentiated uterine sarcoma were seen. The mean age at presentation of Mixed epithelial stromal sarcoma (Carcinosarcoma) was 61 years while that of ESS and ESN was 46 and 47 years respectively. The mean size of ESN was 3.6cm (1.5-6cm), ESS was 4.5 cm (2-9.9 cm) and carcinosarcomas was 4.9 cm (2.5-16 cm). Conclusion: Endometrial stromal neoplasia should be diagnosed after proper evaluation of gross morphology, histological features and immunohistochemical findings in correlation with the clinical presentation. In addition, genetic profiling is useful as an ancillary test. The spectrum of endometrial stromal neoplasia is a beginner’s ordeal if not aware of.


INTRODUCTION
tromal malignancies of the uterus are rare and account for 1-3% of all female genital tract malignancies.They are known to pose a diagnostic challenge to the clinicians and the pathologists.They show non-specific clinical features, gross appearance, varying histological and immunohistochemical features.World health organization (WHO) has classified the endometrial stromal tumors into four main categories such as endometrial stromal nodule (ESN), low-grade endometrial stromal sarcoma (ESS-LG), high-grade endometrial stromal sarcoma (ESS-HG) and Undifferentiated Uterine Sarcoma (UUS).Mixed epithelial mesenchymal sarcomas are also seen (1,2).This study documents the important clinical, morphologic and immunohistochemical expression of these tumors in our setup.

MATERIALS AND METHODS
Histopathologically diagnosed cases of endometrial stromal neoplasia received in the department of Pathology of a tertiary care hospital over a period of 5 years from 2013 to 2017 were retrieved.The gross and microscopic features were analysed.The clinical data was collected from the medical records department.The cases were classified into ESN, ESS-Low grade, ESS High grade, Undifferentiated sarcoma, and mixed epithelial mesenchymal sarcomas as per WHO classification of tumors.Frequency of such histological subtypes were analysed.Immunohistochemistry (IHC) was done whenever feasible.

RESULTS
During the study period, we found 25 cases of endometrial stromal neoplasia (

Endometrial stromal nodule
We encountered 4 cases (16%) of endometrial stromal nodules.The mean age of presentation was 47.5 years.These patients did not have significant clinical symptoms of menorrhagia.They were incidentally detected in hysterectomy specimens.Two cases showed presence of intramural nodule while other 2 cases presented with polyp.The size of the nodule ranged from 1.5 cm to 6 cm.These cases had associated lesions such as mucinous cystadenoma and borderline mucinous tumor of the ovary and leiomyoma of the uterus (Fig. 1 AB).

Endometrial stromal sarcoma
ESS was the most common endometrial stromal neoplasia encountered in our study (9 cases, 36%).The mean age of presentation was 46.5 years ranging from 40-57 years.Most of the cases presented with endometrial polyp (66.7%) while others showed presence of intramural nodule (33.3%).The size ranged from 2 cm to 9.9 cm.Three cases showed ESS with smooth muscle differentiation which was proved by immunohistochemical expression of CD10, smooth muscle actin (SMA), and desmin in tumor cells.These cases had associated lesions such as bilateral low grade mucinous cystadenocarcinoma, brenner tumor and endometriosis of the ovary and leiomyoma of the uterus (Fig. 1 C-F).

Undifferentiated uterine sarcoma
We encountered one case of undifferentiated uterine sarcoma in a 26-year-old female who presented with menorrhagia.Her initial biopsy was done 9 months before which showed stromal hyperplasia with few mitotic figures.After 9 months she developed severe bleeding and this time the curetting's showed a highgrade uterine sarcoma.Immunohistochemical analysis showed positivity for INI-1, vimentin and MIB (50%) and negative IHC for CD10, CD45, SMA, desmin, CD34, CK, ALK, S100, CD31, EMA and myogenin (Fig. 2 GH).

Mixed epithelial and stromal sarcoma
We encountered 11 cases of mixed epithelial stromal tumor, composed of 3 cases of adenosarcoma (Fig. 2 EF) and 8 cases of carcinosarcoma (Fig. 2 A-D).The mean age of presentation of carcinosarcomas was 61 years while that of adenosarcoma was 46.5 years.The mean size of carcinosarcomas was 4.9 cm (2.5-16 cm) and adenosarcoma was 7.8 cm (5-13 cm).One case of adenosarcoma showed positivity for CD 10, Vimentin, ER and PR.

DISCUSSION
Endometrial stromal tumors are currently categorized by WHO 2014 as endometrial stromal nodule (ESN), endometrial stromal sarcoma, low-grade (ESS-LG), endometrial stromal sarcoma, high-grade (ESS-HG), and undifferentiated uterine sarcoma (UUS).Mixed epithelial and stromal tumors are classified as adenomyoma, adenofibroma, adenosarcoma and carcinosarcoma (2).These main categories of stromal tumors have been documented and evident in the present study.
The ESN comprised 3 cases with 2 cases in postmenopausal age group and one in the young adult and were mainly polypoid masses in the uterine cavity in 2 cases and one older patient of 60 years had intramural mass of 3.5 cm size.As described in literature, these nodules are well circumscribed, tan to yellow in color and have soft consistency.Histologically these nodules have circumscribed borders with occasional lobulated projections into adjacent myometrium.The criteria followed is less than 3 in number with < 3 mm in size.The stromal nodule is composed of cells resembling the proliferative phase of endometrium with uniform nuclei of round to oval shape and scanty cytoplasm.Nuclear atypia is minimal.These neoplastic cells are organized around thin-walled vascular channels.These vessels are uniform in calibre and are evenly spaced in the neoplasm.A few foci of thick-walled blood vessels may be evident occasionally.IHC for CD10 is often positive.These patients usually have a good prognosis; however, it is important to extensively sample the interphase between the endometrium and stroma to look for a permeative pattern and lymphovascular invasion to rule out a low-grade sarcoma lurking behind (1,2 Uterine sarcomas at the regional cancer centre of North India found the median overall survival to be 7.67 months and 1-year actuarial survival of 45.4%.Median survival in patients with ESS and USS were 18.7 and 9.38 months (11).The differential diagnosis of endometrial neoplasia encompasses benign lesions such as adenomyosis, cellular leiomyoma, cellular endometrial polyp, and malignant lesions such as lowgrade Mullarian adenosarcoma (12).

CONCLUSION
Endometrial stromal neoplasia should be diagnosed after proper evaluation of gross morphology, histological features and immunohistochemical findings in correlation with the clinical presentation.
In addition, genetic profiling is useful as an ancillary test.The spectrum of endometrial stromal neoplasia is a beginner's ordeal if not aware of.

CONFLICT OF INTEREST
Authors declare no conflicts of interest.

Fig. 1 :
Fig. 1: AB: Endometrial stromal nodule (ESN) is composed of cells resembling a proliferative phase of endometrium with uniform nuclei of round to oval shape and scanty cytoplasm.Nuclear atypia is minimal.These neoplastic cells are arranged around thin-walled blood vessels (B).CD: Endometrial stromal sarcoma (ESS) low grade shows tumor islands of atypical endometrial stromal cells with extensive invasion of the myometrium.The nuclei are often oval to spindle shaped and mitotic activity being low (<5/10 hpf) with absence of necrosis.The vascular network is rich in the stroma with tumor cells arranged around these vessels.The vessels may be hyalinized.EF: Immunohistochemical expression of CD10 (E) and smooth muscle actin (SMA)(F) in ESS.

Fig. 2 :
Fig. 2: A-D.Carcinosarcoma shows tumours comprising hyper and hypocellular areas with morphology of highgrade tumour cells.The high-grade cells exhibit nested to cord-like growth patterns.Round epithelioid cells, eosinophilic cytoplasm, irregular nuclear contours with pleomorphic vesicular nuclei and some with nucleoli were seen.Mitosis of >10/10 hpf was evident.EF: Adenosarcoma consisting of atypical stromal cells giving a pseudo papillary and glandular appearance.GH: Undifferentiated uterine sarcoma revealed sheets of atypical medium sized cells having vesicular to hyperchromatic nuclei with brisk mitosis of >2/hpf with extensive areas of necrosis.

Table 1 :
).They are composed of four cases of ESN, six cases of lowgrade ESS, three cases of ESS with smooth muscle Characteristics of endometrial stromal neoplasia