Uterine Serous Carcinoma Following the Insertion of Levonorgestrel Intrauterine System: A Case Report and Literature Review

A 44-year-old married, parous woman was admitted to the hospital due to “irregular vaginal bleeding for over 1 month”. She denied any history of obesity, diabetes, or hypertension and had no family history of endometrial cancer. Five years ago, she presented to our hospital with a one-year history of menorrhagia and progressive dysmenorrhea. Transvaginal ultrasound at that time revealed a normal-sized uterus with thickened, heterogeneous myometrial echoes ( Figure 1 ), leading to a clinical diagnosis of adenomyosis. As the patient had no future fertility wishes and declined surgery, an LNG-IUS was inserted after thorough counselling to reduce menstrual blood loss and relieve dysmenorrhoea. Because the patient had regular menses, no identifiable risk factors for endometrial carcinoma, and imaging showed no endometrial abnormality, endometrial biopsy was therefore omitted before LNG-IUS insertion. She reported significant relief of pain and a marked reduction in menstrual bleeding during the first 4 years after insertion. However, over the past year she began experiencing recurrent abnormal vaginal bleeding, characterized by scanty, intermittent spotting. Additionally, she noticed an increase in the size of her adenomyoma. The patient did not seek any specific treatment for these symptoms. One month before admission, the patient had the LNG-IUS removed at another hospital because it needed to be replaced. However, because of intra-operative bleeding, re-insertion was deferred. Persistent vaginal bleeding thereafter prompted her to seek further care at our institution. On gynecological examination, the vulva is normally developed and consistent with the findings expected in a parous, married woman. The vagina was patent with a small amount of blood visible inside. The cervix was smooth and of normal size. The uterus was anteverted, enlarged to the size of a 3-month pregnancy, firm in consistency, and without tenderness. No significant abnormalities were palpated in the bilateral adnexa. Figure 1 Transvaginal ultrasonographic images of the uterus. Transvaginal ultrasonographic images of the uterus. Ancillary Examinations: Pelvic MRI: A mass-like signal abnormality was observed in the left uterine fundus and corpus. The adjacent endometrial–myometrial junction appeared irregular and discontinuous. The lesion extended outward to the serosal layer, with a smooth adjacent uterine serosal surface. The findings suggested a malignant uterine lesion, with a high possibility of endometrial cancer involving deep myometrial invasion. The possibility of malignant transformation of a uterine fibroid could not be ruled out ( Figure 2 ). Tumor Markers: Carbohydrate antigen 125 was 641 IU/mL, and Carbohydrate antigen 199 was 111 IU/mL. Figure 2 Preoperative MRI. ( A ) Sagittal plane. ( B ) Coronal plane. Preoperative MRI. ( A ) Sagittal plane. ( B ) Coronal plane. After admission, diagnostic curettage was performed. Histopathology suggested endometrial carcinoma; to determine the subtype, immunohistochemistry was carried out and showed: estrogen receptor (ER) (focal +, weak–moderate); oncogene (P53) (-, suggestive of nonsense mutation); nucleus related antigen (Ki-67) (+, ~70%), cyclin-dependent kinase inhibitor 2A (P16) (+); progesterone receptor (PR) (focal +, weak). Immunoprofile analysis supported a diagnosis of SEIC. Because an early serous lesion was identified and imaging suggested deep myometrial invasion, comprehensive surgical staging for endometrial cancer was performed (total hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, and omentectomy). Intraoperatively, the uterus was found to be anteverted and enlarged to the size of a 3-month pregnancy, with a smooth surface and firm consistency. No significant enlargement of pelvic or abdominal lymph nodes was observed. Examination of the intestines, mesentery, peritoneum, omentum, appendix, liver, spleen, gallbladder, and stomach revealed no metastatic nodules. On gross examination of the surgical specimen, the myometrium exhibited a wood-grain-like appearance. A 3×3×2 cm infiltrative lesion was identified in the left cornual region of the uterus, with an invasion depth greater than 1/2 of the myometrial thickness ( Figure 3A ). Figure 3 Postoperative pathology. ( A ) Gross specimen of total hysterectomy with bilateral adnexa. ( B ) HE staining of the lesion×40. ( C ) HE staining of the lesion×200. Postoperative pathology. ( A ) Gross specimen of total hysterectomy with bilateral adnexa. ( B ) HE staining of the lesion×40. ( C ) HE staining of the lesion×200. Postoperative Pathological Findings: A tumor measuring 32×25×15 mm was identified in the uterine cornu. The tumor involved adenomyosis and exhibited multifocal infiltration with an invasion depth greater than 1/2 of the myometrial thickness. The pathological diagnosis was serous carcinoma ( Figure 3 ). SEIC was also observed in the lower segment of the uterine corpus. The cervix, cervical canal, bilateral adnexa, and omentum were not involved. There was no evidence of neural invasion. The surgical margins were free of tumor. No metastasis was found in the pelvic or para-aortic lymph nodes, and no tumor cells were detected in the peritoneal fluid. Immunohistochemistry was routinely performed on the radical specimen, which had already been confirmed as invasive carcinoma on histopathology ( Table 1 and Figure 4 ). The low PR expression, complete p53 loss, and diffuse p16 positivity collectively corroborate the diagnosis of SEIC. Intact expression of the mismatch repair proteins (MMR) excludes Lynch-associated mismatch-repair deficiency and suggests a low likelihood of hyper-mutated endometrial cancer. Post-operative staging in accordance with the 2023 FIGO criteria established a diagnosis of stage II USC. 1 The patient had a good recovery after the surgery and was discharged on the 5th postoperative day. Table 1 Macroscopic Specimen Immunohistochemistry Results Macroscopic Specimen Immunohistochemistry Results Item Result ER +(70%) PR + (≈5%) P53 Completely absent Ki-67 + (≈40%) P16 Strong positive HER2 2+ MMR (MLH-1 / MSH-2 / MSH-6) All positive Abbreviations : ER, estrogen receptor; PR, progesterone receptor; P53, oncogene; Ki-67, nucleus related antigen; P16, cyclin-dependent kinase inhibitor 2A; HER2, Human Epidermal Growth Factor Receptor 2; MMR, mismatch repair proteins; MLH-1, mutL homolog 1; MSH-2, mutS homolog 2; MSH-6, mutS homolog 6. Figure 4 Gross specimen immunohistochemistry images: ( A ) ER IHC of the lesion×200. ( B ) PR of the lesion×200. ( C ) P53 IHC of the lesion×200. ( D ) Ki-67 IHC of the lesion×200. ( E ) P16 of the lesion×200. ( F ) Her2 IHC of the lesion×200. ( G ) MLH-1 IHC of the lesion×200. ( H ) MSH-2 IHC of the lesion×200. ( I ) MSH-6 IHC of the lesion×200. Macroscopic Specimen Immunohistochemistry Results Abbreviations : ER, estrogen receptor; PR, progesterone receptor; P53, oncogene; Ki-67, nucleus related antigen; P16, cyclin-dependent kinase inhibitor 2A; HER2, Human Epidermal Growth Factor Receptor 2; MMR, mismatch repair proteins; MLH-1, mutL homolog 1; MSH-2, mutS homolog 2; MSH-6, mutS homolog 6. Gross specimen immunohistochemistry images: ( A ) ER IHC of the lesion×200. ( B ) PR of the lesion×200. ( C ) P53 IHC of the lesion×200. ( D ) Ki-67 IHC of the lesion×200. ( E ) P16 of the lesion×200. ( F ) Her2 IHC of the lesion×200. ( G ) MLH-1 IHC of the lesion×200. ( H ) MSH-2 IHC of the lesion×200. ( I ) MSH-6 IHC of the lesion×200. The patient began adjuvant chemotherapy in the third postoperative week, receiving the TC regimen (paclitaxel plus carboplatin) every 3 weeks for a total of six cycles. Concomitant pelvic radiotherapy was delivered to a total dose of 45 Gy in 25 fractions. At the 6-month post-treatment follow-up, no evidence of recurrence was found; thereafter, she was scheduled for outpatient follow-up every 3 months.

The LNG-IUS is now widely used not only for the treatment of heavy menstrual bleeding and contraception but also for the management of endometrial hyperplasia and fertility-sparing treatment of early-stage endometrial cancer. The development of endometrial cancer following long-term use of LNG-IUS is infrequent, and there have been no reported cases of progression to USC. Here, we present a case of a patient who developed USC despite long-term LNG-IUS therapy. This case provides valuable insights and experience for clinicians to reduce the risk of missed diagnosis of endometrial cancer.

In conclusion, the occurrence of endometrial cancer, especially uterine serous carcinoma, in patients with long-term use of LNG-IUS is extremely rare. Reviewing and summarizing relevant cases highlights the importance of performing an endometrial biopsy before LNG-IUS insertion to rule out any pre-existing endometrial pathology. Patients who experience any change in vaginal bleeding pattern after LNG-IUS insertion should be closely evaluated; this symptom warrants serious attention. A repeat endometrial biopsy may be necessary to exclude endometrial pathology and reduce the risk of missed diagnosis of endometrial cancer or other related diseases. Furthermore, the indications and contraindications for LNG-IUS placement should be strictly assessed. For patients with a uterine cavity depth greater than 10 cm, pre-treatment should be considered before LNG-IUS insertion to ensure adequate distribution of the progestin within the endometrium and to avoid potential therapeutic failure due to an enlarged uterine cavity.

The LNG-IUS is an intrauterine sustained-release system of highly effective progestin, containing 52 mg of levonorgestrel (LNG), which is released at a rate of 20 µg/day within the uterine cavity. Clinically, it is commonly used for contraception, heavy menstrual bleeding, dysmenorrhea, and the treatment of endometrial hyperplasia. Current guidelines recommend the LNG-IUS as the first-line treatment for atypical endometrial hyperplasia 2 and also as a fertility-sparing first-line treatment for young patients with early-stage endometrial cancer. 3 From a pathophysiological perspective, endometrial carcinoma is broadly divided into two subtypes: type I, which is estrogen-driven, and type II, which arises independently of estrogen stimulation. Type I endometrial carcinogenesis hinges on the disruption of the estrogen–progesterone balance: a relative estrogen excess coupled with insufficient progesterone drives continuous endometrial proliferation and impairs normal cyclic shedding and repair. Type I endometrial carcinogenesis hinges on the disruption of the estrogen–progesterone balance: a relative estrogen excess coupled with insufficient progesterone drives continuous endometrial proliferation and impairs normal cyclic shedding and repair. Chronic, unopposed estrogen exposure markedly increases the probability that endometrial cells will acquire gene mutations during successive rounds of replication. 4 , 5 In contrast, the pathogenesis of type II endometrial carcinoma remains incompletely understood. The LNG-IUS creates a high-concentration progestin environment within the uterine cavity, inhibiting the endometrium and causing endometrial atrophy, thinning, and stromal swelling with decidualization. 5 , 6 Therefore, the occurrence of endometrial cancer in patients using LNG-IUS long-term is infrequent. To date, only 11 related cases have been reported worldwide ( Table 2 ). 6–15 Seven of the 11 patients were perimenopausal, and the LNG-IUS had been inserted principally to control heavy menstrual bleeding. In addition, four patients in this series had co-existing uterine fibroids or adenomyosis. Both disorders have been firmly linked to estrogen-driven pathophysiology, and their presence usually signals a chronic, high-estrogen microenvironment. 16 , 17 High estrogenic stimulation may partially override the local progestogenic effect of the LNG-IUS, creating an “estrogen-escape” phenomenon that ultimately permits progression of endometrial pathology. 18 Of particular concern, seven of the eleven patients had not undergone adequate endometrial sampling before LNG-IUS insertion, raising the possibility that pre-existing occult lesions were missed and allowed to evolve unchecked. Clinically, these cases were strikingly uniform: ten patients developed abnormal uterine bleeding while carrying the LNG-IUS, with most presenting as breakthrough bleeding after secondary amenorrhea or as irregular cycles that had re-established after device insertion. This consistent clinical signature carries a critical warning: any alteration in bleeding pattern among long-term LNG-IUS users should raise strong suspicion of underlying endometrial pathology, and an endometrial biopsy may be necessary to rule out the disease. Table 2 Reported in Literature Cases of Endometrial Cancer in Patients with LNG-IUS Author Age (y) Reasons for Use LNG-IUS Time Endometrial Biopsy Develop symptoms High-Risk Factors BMI Complications Ending Ref David 52 N/A Four years None Amenorrhea None 26.73 Uterine fibroids EEC IA [ 7 ] Franz 55 Menorrhagia Four years None Secondary amenorrhea followed by intermittent vaginal bleeding None N/A None EEC(G2) IC [ 8 ] J. ABU 36 Contraception One year None After 3 months of amenorrhea, regular menses resumed, followed by 2 months of irregular vaginal bleeding None N/A None EEC(G2) IA [ 9 ] Rhonda 39 Menorrhagia Four years Non-secretory endometrium She has an 8-month history of prolonged bleeding, followed by amenorrhea. Obesity 39.5 Uterine fibroids and adenomyosis;Enlarged uterus EEC(G2) Ib [ 10 ] JingjingJiang 34 Atypical endometrial hyperplasia Two years Atypical hyperplasia—secretory endometrium Irregular vaginal bleeding for 5 months, with the discovery of a pelvic mass Obesity 28.4 None EEC(G2) IIIb [ 11 ] Kevin Jones 48 Menorrhagia Three years None Six months of irregular vaginal bleeding None N/A None EEC(G2) IIIc [ 12 ] Kevin Jones 54 Irregular vaginal bleeding One year Proliferative endometrium After amenorrhea, irregular heavy vaginal bleeding reoccurred None N/A Uterine fibroids EEC(G1) IIB [ 12 ] HongfaPeng 30 Menorrhagia Seventeen months Atypical endometrial polyps Vaginal bleeding occurred 17 months later None 22.3 None EEC(G1) [ 13 ] Melisa 50 Persistent heavy vaginal bleeding N/A None Persistent vaginal bleeding None N/A None EEC(G1) IA [ 14 ] A. C. L. van der Meer 56 Irregular and severe vaginal bleeding Five years Negative Examination revealed endometrial thickening Obesity 50.5 Enlarged uterus EEC(G1) [ 15 ] Alexander Steshenko 52 Menorrhagia Fourteen years None Subsequently, intermittent vaginal bleeding occurred. None N/A None EEC(G1) IA [ 6 ] In this case 44 Adenomyosis Five years None In the fourth year, persistent vaginal bleeding occurred None 20.5 Adenomyosis USC IIC   Abbreviations : N/A, information not available; EEC, endometrioid adenocarcinoma; USC, uterine serous carcinoma. Reported in Literature Cases of Endometrial Cancer in Patients with LNG-IUS Abbreviations : N/A, information not available; EEC, endometrioid adenocarcinoma; USC, uterine serous carcinoma. All 11 cases reported to date have been endometrioid adenocarcinomas—type I, hormone receptor-positive, low-grade, diploid tumours, typically associated with a favorable prognosis. In contrast, the patient in this case was diagnosed with Type II endometrial cancer, specifically USC, after using the LNG-IUS. To date, no relevant literature has been identified reporting such a case. USC accounts for approximately 10% of all diagnosed endometrial cancers but is responsible for 40% of endometrial cancer-related deaths. Compared to endometrioid adenocarcinoma, USC has a higher risk of recurrence and a poorer prognosis. 19 In Type II endometrial cancer, the primary genetic alteration is a p53 mutation, which is present in 95% of cases and plays a significant role across almost all stages of the disease. In contrast, p53 alterations occur in less than 10% of Type I endometrial cancers. 20 Additionally, approximately one-third of USC cases exhibit HER2 overexpression, which is closely associated with a poor prognosis. 21 In this patient, the complete absence of p53 expression and the overexpression of HER2 were identified, both of which are consistent with the diagnosis of uterine serous carcinoma and suggest an unfavorable prognosis for the patient. The pathogenesis of endometrial cancer occurring despite the use of LNG-IUS remains unclear. This patient did not have typical high-risk factors for endometrial cancer, such as obesity, diabetes, exposure to endogenous or exogenous estrogens, infertility, or use of tamoxifen, yet she still developed USC. The possible contributing factors may include the following: (1) The patient had LNG-IUS inserted due to heavy menstrual bleeding, but no endometrial biopsy was performed before insertion. It remains plausible that an occult endometrial focus with pre-existing malignant clonal features was already present before device insertion. 22 (2) In this patient, adenomyosis progressively enlarged the uterine cavity to 11 cm, so the 20 µg/day levonorgestrel release was “diluted” over a much larger endometrial surface. Consequently, local concentrations never reached the threshold required for full decidualization, creating a functionally hypo-progestogenic, high-estrogen milieu that permitted tumor progression. This is consistent with the findings by Pal et al, 23 who suggested that an enlarged uterus is associated with non-responsiveness to LNG-IUS. Additionally, adenomyosis-induced thickening and fibrosis of the myometrium impeded uniform drug distribution, further facilitating carcinogenic progression. 17 (3) Studies show that the LNG-IUS release rate declines with time, falling to ≈14 µg/day by year 5; 24 this progressive waning further eroded suppression of residual disease and coincides with the patient’s new-onset spotting during years 4–5. (4) This patient exhibited a complete nonsense-mutation-mediated loss of p53 and HER2 protein over-expression (2+). Loss of p53 inactivates cell-cycle checkpoints and enables escape from progesterone-induced apoptosis, serving as an independent predictor of progestin resistance; 25 whereas HER2 activates the PI3K/AKT proliferative axis and counteracts progesterone’s anti-growth signaling—both features portending a poor prognosis. 26 (5) With ER positivity at 70% and PR positivity barely 5%, the endometrium is locked in a state of severe signal imbalance: ER-driven proliferative signaling overwhelmingly outweighs the residual PR-mediated tumor-suppressive input, thereby fostering a high-estrogen, pro-carcinogenic microenvironment. 27