Durable Response to Letrozole in a Patient with Relapsed Low Grade Endometrial Stromal Sarcoma Metastatic to the Lung-A Case Report

Low Grade Endometrial Stromal Sarcomas (LGESS) are rare uterine neoplasms, with high propensity for local recurrence and an indolent course. Distant metastasis is rare. Hormonal therapy with progestin or aromatase inhibitors has been used successfully to treat relapsed and unresectable disease. We report a 55-year-old female patient with relapsed LGESS in the lungs, who achieved almost complete response to letrozole for more than 6 years. To our knowledge, this is the longest reported durable response with letrozole in patients with LGESS and lung metastasis.


Introduction
Low grade endometrial stromal sarcomas (LGESS) are rare malignant neoplasms with an estimated incidence of 1-2 per million women [1]. This tumor accounts for only 0.2% of all uterine malignancies and less than 10% of uterine sarcomas [2]. Although the pathogenesis of LGESS remains uncertain, unopposed estrogen and use of Tamoxifen have been implicated [3]. Affected women are typically peri-menopausal and of younger age (median age 45-55 years) compared to patients with other uterine sarcomas [3]. LGESS has high local recurrence rates. Nevertheless, distant metastasis is rare [3].
There is an increasing evidence supporting efficacy of aromatase inhibitors for relapsed LGESS. However, efficacy data is mainly derived from case reports and small series, showing objective responses [4][5][6][7]. In the current paper we report a case of LGESS with lung metastasis, who achieved unprecedented almost complete response to letrozole that is ongoing beyond 6 years.

Case Report
A 55-year-old female patient presented with menorrhagia and was referred to our center after she had hysterectomy and right salpingo-oophorectomy in October 2010.  Pathology evaluation of her resected uterus revealed LGESS, which was confirmed upon review at our center ( Figure 1A). Her first post-operative computed tomography (CT) scan in 3 months after surgery showed no evidence of disease.
In April 2011, a follow up CT scan of the abdomen and pelvis revealed recurrence with a mass lesion infiltrating the vagina and pathologically enlarged pelvic lymph nodes. She initiated megestrol acetate in May 2011 at a dose of 80 mg orally daily, and initially had partial response. However, in November 2012, imaging studies showed progression of the pelvic mass, the pelvic lymph nodes, and interval development of lung nodule suggestive of metastasis (Figure 2A). A CT guided lung biopsy was performed and confirmed the diagnosis of metastatic LGESS (Figures 1B-1D).
In November 2012, therapy with letrozole 2.5 mg orally daily was initiated. Her subsequent CT scan showed partial response of the pelvis and lung metastasis. Further regression was demonstrated on subsequent scans following initiation of letrozole ( Figure 2B). Follow up CT scans at more than 6 years of initiating letrozole showed almost complete remission in lung metastasis and stable pelvic soft tissue mass ( Figure 2C).
She was also maintained on calcium and vitamin-D supplements as preventive measures for osteoporosis. She has tolerated letrozole without any appreciable toxicities. Her treatment with letrozole is still ongoing at 78 months from the date of its initiation.

Discussion
Surgical resection is the mainstay therapy for LGESS [1,2]. Pre-operatively, it is often difficult to differentiate LGESS from uterine leiomyoma, and the diagnosis is often made after hysterectomy. Similar to leiomyoma, LGESS usually present with abnormal uterine bleeding, pelvic mass, or abdominal pain.
Gross examination of LGESS reveals intracavitary or mural tumor masses with nodular or diffuse permeation of the uterine wall. Commonly, the tumor may be found as intravenous tumor plugs. The cut surfaces are tan-yellow, fleshy and soft. Necrosis and cystic formation can be seen but are generally not common. Histologically, the tumor is composed of monomorphic population of tumor cells arranged in sheets that infiltrate the myometrium. The tumor cells are oval in shape with scant cytoplasm that resembles the normal proliferative endometrial stroma cells. LGESS is often confined to the uterus at initial presentation. However, up to a third may present with disease that extends to surrounding structures such as the fallopian tubes, ovaries, and urinary bladder. Local recurrence is common after
However, efficacy of progestins such as megesterol acetate, and aromatase inhibitors (AI) have been demonstrated for patients with unresectable advanced disease [6,7]. Owing to its rarity, the data showing objective responses with these agents are derived from case reports and small series, mainly with megesterol acetate and letrozole [8]. Serkies et al., in their retrospective study, identified only 5 cases treated with aromatase inhibitors from two institutions over a 10-year period, which highlights the rarity of this disease [9].
Typically, LGESS are slow growing tumors with an indolent course and a good prognosis. Patients with relapsed disease can have long term survival with repeated surgery and hormonal therapy [1,7]. Although most relapses are confined to pelvis and abdomen, lung metastasis is extremely rare [1]. Therefore, it is not clear if lung metastasis is associated with a more aggressive course or with durable responses to aromatase inhibitors. In the reported literature we identified a few cases with lung metastasis treated with letrozole (Table 1) [6][7][8][9][10][11][12][13][14][15][16][17][18][19].

Conclusion
To our knowledge, the duration of response to letrozole in our patient represent the longest durable response of LGESS and lung metastasis and suggests that a durable control can be achieved with aromatase inhibitors when the disease spreads outside the abdomen and pelvis. Given the rarity of lung metastasis in LGESS, we performed a lung biopsy for our patient. In our opinion, biopsy is needed to exclude the possibility of more aggressive histologies, such as high grade undifferentiated uterine sarcomas or other primaries. In conclusion, the reported durable response to letrozole in our case suggests that long term disease control can be achieved in metastatic LGESS to lungs. To our knowledge, this is the first report of lung-metastatic LGESS that had an ongoing response to AI for more than 6 years.