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Endometrial Stromal Tumour: Clinicopathological Series of Seven Cases
Correspondence Address :
Dr. Manisha Sarkar,
Flat-2C, Anushka Tower, 10/2A, Umakanta Sen Lane, Kolkata-700030, West Bengal, India.
E-mail: manishasarkar1979@gmail.com
Endometrial Stromal Tumour (EST) mimics other neoplasms and is difficult to diagnose due to its wide range of morphologies. This is a clinicopathological study of seven cases of EST, which includes Endometrial Stromal Nodule (ESN), Low-grade Endometrial Stromal Sarcoma (LGESS), and High-grade Endometrial Stromal Sarcoma (HGESS). The age ranges from 34 to 75 years. Five out of seven cases presented with abnormal uterine bleeding, abdominal pain, and were radiologically suspected to be leiomyomas. After histopathological and Immunohistochemical (IHC) examination, one was diagnosed as ESN, three as LGESS, and the remaining three cases as HGESS. One case was initially diagnosed as a cellular leiomyoma and experienced multiple recurrences, eventually being diagnosed as HGESS with a fatal outcome within 36 months of the onset of the first symptoms. ESN and LGESS should be differentiated from leiomyoma and leiomyosarcoma. IHC plays an important role in distinguishing these tumours from the more common smooth muscle counterparts.
Cluster of differentiation 10, Mimics, Wilms tumour gene 1
The EST are a rare group of tumours, accounting for <1% of all uterine tumours (1). However, accurate diagnosis is important as most of them fall under the malignant category unlike their smooth muscle counterparts. There are four main categories, include ESN, LGESS, HGESS and Undifferentiated Stromal Sarcoma (USS). LGESS is the most common type (2). While a few case reports are available [2-6], there is a lack of large case series with follow-up data. The present study describes a series of seven EST cases, detailing gross findings, morphology, IHC findings, and follow-up data.
The present case series describes a study of seven ESTs collected over a period of four years (from 2018 to 2022), with ages ranging from 34 to 75 years. Detailed clinical, radiological, and treatment histories of each case were recorded before histopathological examination. IHC staining was done with formalin-fixed paraffin-embedded sections using a detection system based on the peroxidase-antiperoxidase method. Heat-induced epitope retrieval and enzymatic activation of chromogen were conducted for visualising the antigen-antibody reaction product. A positive tissue control and the same tissue for internal negative control were used for each case. The clinicopathological profiles of the cases are summarised in (Table/Fig 1).
Case 1
The first case involved a 35-year-old parous woman who presented with abnormal uterine bleeding for two years, with no significant past medical history. Ultrasonography (USG) revealed an intramural mass suggestive of a leiomyoma. On gross examination, a well-circumscribed yellowish nodule measuring 4×4 cm was observed (Table/Fig 2)a. Microscopically, densely packed round to oval cells resembling the proliferative phase of the endometrium were seen, with low mitotic activity (<3/10HPF) (Table/Fig 2)b,c. Periarteriolar whorling arrangement and expansile non infiltrative margins were noted. The neoplastic cells were positive for CD10, leading to a diagnosis of ESN (Table/Fig 2)d. The patient had an uneventful long-term postoperative follow-up period.
Case 2
A 40-year-old woman who presented with menorrhagia, pelvic pain, and an abdominal mass lasting for one year. The sonographic diagnosis was a fibroid uterus, and she underwent myomectomy (Table/Fig 3)a. However, she returned with menorrhagia after three months. Subsequently, a total abdominal hysterectomy and omental sampling were performed. The provisional clinical diagnosis was leiomyosarcoma. On gross examination, multiple grayish-white intrauterine masses were observed, with the largest measuring 7×4×3 cm. Microscopically, the tumour masses consisted of proliferating round to oval stromal cells arranged in sheets with prominent vascularity and the presence of spiral vessels. Hyalinised stroma with myxoid change, as well as lymphatic invasion and myometrial invasions, were noted (Table/Fig 3)b. The neoplastic cells exhibited mild to moderate pleomorphism, moderate nuclear atypia, and increased mitotic activity (>4/10 HPF). The presence of focal atypical spindle cells and collagen deposition (Table/Fig 3)c made it challenging to differentiate between LGESS, leiomyosarcoma, and sex cord stromal tumour. Omental tissue sampling revealed the presence of sarcomatous deposits. IHC showed diffuse positive staining for CD10, WT1 (Table/Fig 3)d, Estrogen Receptor (ER), Progesterone Receptor (PR), and negative staining for desmin, inhibin, and CD56. The final diagnosis was LGESS.
Case 3
A 75-year-old postmenopausal woman presented with pelvic pain and a mass that had been present for two and a half years. She had a history of myomectomy 15 years ago. The clinical and radiological diagnosis was a fibroid uterus, and the patient underwent abdominal hysterectomy and Bilateral Salpingo-Oophorectomy (BSO). On gross examination, multiple intramural fleshy white masses were identified, with the largest measuring 8×6 cm (Table/Fig 4)a. Morphologically, it shared similar features with the second case. It was a cellular round cell tumour that exhibited tongue-like myometrial invasion, moderate nuclear atypia, brisk mitoses, and areas of vascular prominence (Table/Fig 4)b,c. The differential diagnosis was LGESS versus leiomyosarcoma. Immunohistochemically, the tumour cells were positive for CD10, WT1, ER (Table/Fig 4)d, PR, and negative for desmin. Therefore, the final diagnosis was LGESS.
Case 4
A 54-year-old woman presented with complaints of postmenopausal bleeding lasting for eight months. She underwent hysterectomy following a radiological diagnosis of a fibroid uterus. On gross examination, intramural fleshy masses were noted, with the largest measuring 8×4 and 4×3 cm (Table/Fig 5)a. Microscopically, there was proliferation of round to oval stromal cells arranged in sheets, with lymphovascular and myometrial invasion (Table/Fig 5)b. The neoplastic cells exhibited nuclear atypia and increased mitotic activity (7/10 HPF) (Table/Fig 5)c. The diagnosis of LGESS was made after conducting an IHC study using a similar antibody panel as in previous two cases. The tumour cells were positive for CD10, WT1 [Table/Fig-5d], ER, PR, and negative for desmin. In all three cases of LGESS, the initial differential diagnosis was leiomyosarcoma. The postoperative follow-up period was unremarkable in these cases.
Case 5
A 60-year-old woman presented with postmenopausal bleeding and a pelvic mass lasting for two months, without any significant past medical history. Her serum CA-125 level was mildly elevated (45 U/mL), and the radiological diagnosis was a possibly malignant endometrial polyp.
Following hysterectomy and BSO an irregular ulcerated polypoid lesion measuring 6×5 cm was observed, filling up the uterine cavity (Table/Fig 6)a. Microscopically, there were sheets of neoplastic round to oval cell proliferation with areas of necrosis, haemorrhage, arborising vasculature, and a high mitotic count (15/10 HPF) (Table/Fig 6)b,c. The tumour had invaded into the myometrium. The differential diagnoses were HGESS and poorly differentiated carcinoma. IHC study showed focal CD10 positivity (Table/Fig 6)d, positive staining for Cyclin D1, and negative staining for WT1, ER, PR, EMA, and desmin. Therefore, the final diagnosis of HGESS was made. Unfortunately, the patient was lost within one month of the operation despite her receiving initial chemotherapy.
Case 6
A 60-year-old woman with a clinical suspicion of intraabdominal malignancy. The CT abdomen revealed a tumour arising from the 17fundus of the uterus and adhering to a segment of the small bowel. Palliative surgery was performed, which involved resection of the mass along with a portion of the attached small bowel. On gross examination, a fragile mass measuring 6x5x4 cm with necrotic areas was observed (Table/Fig 7)a. Microscopically, it demonstrated an atypical proliferation of round to spindle cells, tumour giant cells, hyalinised vessels, lymphovascular invasion, myxoid areas, necrosis, haemorrhage, and a high mitotic activity (15/10HPF) (Table/Fig 7)c. The tumour invaded the small bowel wall through the muscularis propria (Table/Fig 7)b. The closest differential diagnoses included Gastrointestinal Stromal Tumour (GIST), spindle cell sarcoma, HGESS and desmoplastic small round cell tumour. The tumour showed focal positivity for CD10, Cyclin D1 (Table/Fig 7)d, and negativity for desmin, myogenin, WT1, S-100, ER, PR, and EMA. The final diagnosis was HGESS; however, the patient did not return for follow-up.
Case 7
A 34-year-old female presented in 2019 with abdominal swelling and pain lasting for eight months. She had a history of cholecystectomy with myomectomy in 2018, with a histopathological report of chronic cholecystitis and leiomyoma. Following abdominal hysterectomy in June 2019, a histopathological diagnosis of cellular leiomyoma was given. She returned back in February 2020 with a large recurrent mass and an Magnetic Resonance Imaging (MRI) showed a pelvic mass with mixed intensity and solid cystic areas, herniating into subcutaneous tissue. The mass was separated from the liver, pancreas, kidney, and spleen, and it displaced the stomach and bowel loops. The patient underwent debulking surgery, and a 5 kg tumour mass was removed (Table/Fig 8)a. A provisional histopathological diagnosis of desmoplastic small round cell tumour was made. Microscopically, it was a hypercellular oval to spindle cell tumour with areas of necrosis, lymphovascular invasion, high mitotic count, and focal fibro-myxoid appearance (Table/Fig 8)b-d. She underwent chemo-radiation but eventually presented with abdominal and lung metastasis in November 2020. IHC study was conducted, which showed negative staining for Cytokeratin, EMA, desmin, and WT1. Vimentin and cyclin D1 were positive, and CD10 was focally positive. Finally, the diagnosis of HGESS was made, but unfortunately, the patient had already succumbed to death within a month of the last surgery.
Endometrial Stromal Tumours (ESTs) are a rare group of tumours that typically occur in perimenopausal women. Due to their rarity, diagnosing ESTs can be challenging. LGESS tends to occur at a younger age than HGESS and USS with a median age ranging from 45 to 55 years (3). The most common clinical presentation of EST is abnormal uterine bleeding, although patients may also experience pelvic pain and dysmenorrhoea (7). ESNs are clinically considered benign, while LGESSs are tumours of low malignant potential, often exhibiting indolent clinical behaviour. Some cases may experience late recurrence after hysterectomy, as seen in two cases. HGESS, on the other hand, is a tumour of high malignant potential with a more aggressive clinical outcome. UUS displays high-grade morphological features and exhibits very aggressive clinical behaviour (8). The differential diagnosis for ESN includes cellular leiomyoma and LGESS. ESNs typically exhibit uniform bland ovoid cells resembling proliferative phase endometrial stroma. The vascular pattern, composed of typical arterioles, is not a prominent feature of cellular leiomyoma. While ESNs may contain large blood vessels, a characteristic of cellular leiomyoma, they are not as conspicuous as in cellular leiomyoma (9). Additionally, CD10 can be useful in differentiating ESN from cellular leiomyoma. The presence of a pushing margin and the absence of lymphovascular invasion help differentiate ESN from LGESS. Therefore, a definitive diagnosis of ESN can be rendered on resected specimens, allowing for extensive sampling, and cannot be confidently established on small biopsies (8).
The differential diagnosis for LGESS includes HGESS, cellular leiomyoma, leiomyosarcoma with an extensive intravascular component, Uterine Tumours Resembling Ovarian Sex-Cord Tumours (UTROSCT), and adenosarcoma (10). LGESS is morphologically characterised by uniform ovoid cells with mild to moderate atypia, tongue-like invasion into the myometrium, lymphovascular permeation, and a mitotic activity ranging from 1-13/10HPF (11). IHC panel including CD10, inhibin, calretinin, and CD56 can be useful in distinguishing ESS from sex cord-stromal tumours, although it is important to note that markers of sex cord-like differentiation may be strongly positive in sex cord-like areas of ESS. CD56 is typically positive in sex cord-stromal tumours but negative in ESS. In the abdominal cavity, GIST is an important differential consideration (12). Morphologically, both tumours are usually distinct. GIST demonstrates cellular, plump, and uniformly spindle cell proliferation with nuclear palisading and characteristic perinuclear vacuolisation, in contrast to the plump, round to oval cell proliferation of EST. GISTs typically show limited atypia, with mitotic activity rarely exceeding 10/50 HPF (13). GISTs are positive for c-Kit, CD34, and DOG1, while LGESS shows diffuse positivity for ER, PR, and CD10.
There can be significant overlap in staining for CD10 and desmin between ESS and smooth muscle tumours, making it helpful to include additional smooth muscle markers, such as h-caldesmon or calponin, which are usually negative in ESS. In cases presenting with urinary symptoms and a bladder mass, the differential diagnosis includes Solitary Fibrous Tumour (SFT), synovial sarcoma, carcinoid, Primitive Neuroectodermal Tumours (PNET) and large nested variants of urothelial carcinoma. The focal presence of spindle cell morphology, bland cytology, and abundant collagen in LGESS may lead to a differential diagnosis of SFT. Additionally, endometrial stromal sarcoma can occasionally show stag horn-like vessels similar to those seen in SFT. However, these findings are seen only in focal areas of LGESS, and the presence of typical small round arterioles helps establish the diagnosis. CD34 and STAT6 are positive in SFT and negative in EST.
Carcinoid tumours and ESS can exhibit overlapping IHC staining. ESS is focally positive for CD56 and synaptophysin, while carcinoid tumours variably stain positive for ER, PR, or CD10. However, the characteristic organoid pattern and salt and pepper nuclear chromatin in carcinoid tumours, along with diffuse ER, PR, and CD10 positivity in LGESS, aid in distinguishing these two entities. LGESS typically shows negative CD99 staining, which is seen in PNET. The wormlike pattern of invasion observed in LGESS is similar to the infiltration seen in the large, nested variant of urothelial carcinoma. GATA3 and thrombomodulin are positive in large, nested variants of urothelial carcinoma and negative in ESS (12). WT1 positivity has been observed in non neoplastic endometrial stroma. Diffuse WT1 positivity is characteristic of endometrial stromal neoplasms and can aid in the differential diagnosis (14). All three of the LGESS cases showed positive staining for WT1.
The term HG-ESS has been reintroduced in the classification of EST following the discovery of t(10;17)(q22;p13) resulting in YWHAE-NUTM2A/B fusion, which is associated with distinct morphological characteristics (15). The characteristic morphological features of HG-ESS include a tumour with high mitotic activity (>20-30 mitoses/10 HPF), a fibrous or myxoid appearance, extensive lymphovascular invasion, diffuse positivity for cyclin D1, and negative staining for smooth muscle markers and WT1 (16). Genetic analysis may assist in identifying HG-ESS in cases where the diagnosis is challenging (15). Patients with HG-ESS often lack expression of ER and PR. Therefore, it remains unclear whether the ovaries should be preserved in premenopausal women with HG-ESS. In a study by Zhang YY et al., six patients underwent ovarian preservation surgery, and four of them were in Stage I without recurrence. Two additional patients, who were misdiagnosed as uterine leiomyoma, underwent hysterectomy and BSO. Both patients died due to the disease (survival was 10 and 12 months, respectively). Furthermore, the research found that the prognosis of postmenopausal patients was poor (17).
UUS is a rare uterine sarcoma that encompasses a diverse group of neoplasms with no specific line of differentiation, and its diagnosis is made by exclusion (8). UUS typically shows positive staining with p16 and focal positivity with CD10, PR, cyclin D1, and beta-catenin (18). The most common cytogenetic abnormality observed in LGESS is a recurrent translocation involving chromosomes 7 and 17, t(7;17) (p15;q21), resulting in a fusion between JAZF1 and SUZ12. Highgrade endometrial stromal sarcoma typically harbours the YWHAEFAM22 genetic fusion as a result of t(10;17)(q22;p13) (1).
Endometrial stromal neoplasms are rare uterine tumours that can have a fatal outcome. They can mimic a variety of benign and malignant neoplasms, making accurate diagnosis challenging. In the present case series, an equal number of Low-grade and High-grade Endometrial Stromal Sarcomas (LGESS and HGESS) were observed, while Endometrial Stromal Nodules (ESN) were the rarest. The age of presentation ranged from 34 to 75 years. Given that EST can resemble various abdominopelvic tumours, thorough pathological sampling is necessary to identify the characteristic histomorphology. Cyclin D1 and WT1 play important roles in differentiating LGESS from HGESS, as WT1 positivity is seen in LGESS and Cyclin D1 positivity is seen in HGESS. Tumour size and grade are two important factors for disease progression. Therefore, an integrated morphological and immunohistochemical study, including a large number of cases in the future, will be helpful in planning specific therapeutic strategies for each subcategory.
DOI: 10.7860/JCDR/2023/64407.18372
Date of Submission: Apr 03, 2023
Date of Peer Review: May 10, 2023
Date of Acceptance: Jun 23, 2023
Date of Publishing: Aug 01, 2023
AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. Yes
PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: Apr 07, 2023
• Manual Googling: May 17, 2023
• iThenticate Software: Jun 19, 2023 (13%)
ETYMOLOGY: Author Origin
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