A post-menopausal female in her 70s (G4P4) presented with a pelvic mass, most likely of uterine origin, and imaging suspicious of pelvic carcinomatosis, and metastatic disease both to the left inguinal lymph node and the iliac bone. Serum CA125 at the time of presentation was 8 U/mL. The patient reported gradually increasing abdominal discomfort over the previous 6 months, which she attributed to an anterior colporrhaphy performed 7 years prior. Bimanual examination revealed an intact cervix, but the uterus enlarged to approximately 12–14 cm in diameter without further suspicious findings. Both her family history and past medical history were unremarkable, reporting only the anterior colporrhaphy, which included implantation of a mesh, and a tubal ligation performed 30 years ago. A routine colonoscopy performed 3 months prior to the first onset of symptoms showed no relevant findings.

Radiology

CT and MRI scans performed at an outside facility revealed an abnormally enlarged uterus of 12 cm with a well defined, 52 mm left fundal mass protruding into the left adnexa and the left inguinal canal (Figure 1). Additionally, two hyperintense lytic lesions in the iliac bones, measuring up to 19 mm, and a solid round lesion in the left inguinal region raised concerns for metastatic deposits. However, it initally remained unclear whether this finding represented a single continuous mass reaching through the inguinal canal or separate lesions. Given the suspicion of malignancy, the patient underwent a PET/CT scan, which incidentally revealed an 8 mm nodule in the right breast with a standardized uptake value (SUV) of 2.5 and bilateral axillary lymph nodes smaller than 10 mm.

Figure 1

(A) Pre-operative sagittal MRI image of the uterus and the tumor lesions, (a) marks a 52 mm heterogeneous mass protruding out from the fundus, along the broad ligament (b), and forming a 37×24 mm lesion in the inguinal canal (c). (B) Axial view of the inguinal lesion (c) of 37×24 mm, separated from the uterine corpus. The connective tumor tissue between the inguinal lesion (c) and the fundus is located more cranially and therefore not depicted in the axial view. ant, anterior; l, left; post, posterior; r, right.

The PET/CT scan further showed a lobulated necrotic mass in the uterus measuring 5.2×4 cm with an SUV of 15.7. The protruding mass in the left inguinal canal measured 3.7×2.4 cm and demonstrated an SUV of 14.6. Several left pelvic peritoneal nodes, measuring up to 7 mm, exhibited increased SUV uptake of 3.2, while a larger nodule adjacent to a lobulated left uterine mass measured 2.3×1.8 cm with an SUV of 13.7. No pathological findings were observed in the pelvic or paraaortic lymph nodes. Review of the osseous structures supported the suspicion of malignancy, with abnormal uptake detected within multiple lytic lesions in the pelvis. In summary, the imaging findings indicated a malignant uterine mass with peritoneal metastasis in the pelvis and osseous metastasis in the pelvis. An incidental finding of a breast lesion appeared unrelated, and the uptake within subcentimeter axillary lymph nodes was favored to be reactive, although further diagnostic work-up was indicated.

Dr Ramirez: at this point, what was the differential diagnosis and what was the recommendation to the patient?

Given both the uncommon disease distribution according to the PET/CT scan and an estimated incidence of primary bone metastases in endometrial cancer below 1%, potential differential diagnoses and/or active secondary malignancies should be considered and warrant further diagnostic work-up. 1 An attempted endometrial biopsy, however, was not feasible due to significant stenosis of the cervix. As the clinical examination was unremarkable and CA125 levels were negative, other malignancies of the gynecologic tract than a uterine neoplasm appeared unlikely. In line, a causal relationship between the subcentimeter breast lesion as reported by imaging studies and the pelvic mass appeared implausible, as primary metastatic deposits of breast cancer in the peritoneum are rare findings, and imaging studies clearly described a lesion with malignant features protruding from the uterus.

A coincidental finding of both breast cancer with deposits to the bone and an independent uterine mass; a coincidental uterine mass and a secondary osseous neoplasm; or a rare malignant uterine tumor histology with metastatic deposits to both the bone and the peritoneum could be considered. Any of these constellations of findings would be rare and would support pathological correlation with the uterine mass.

The initial recommendation to the patient was to proceed with a biopsy of the left inguinal region to help delineate the primary source of disease.

Dr Deavers: what were the pertinent findings at pathology?

A needle biopsy from the left inguinal region revealed a cellular spindle cell neoplasm with moderate nuclear pleomorphism, but rare mitotic activity and no tumor necrosis. Immunohistochemical positivity for smooth muscle actin (SMA), desmin, WT-1, ER, and PR supported a smooth muscle neoplasm originating from the gynecologic tract, with no explicit malignant features ( Figure 2 ). Since the endometrial biopsy was technically not feasible and the benign results of the left inguinal biopsy appeared inconclusive in the light of the highly suspicious PET/CT scan, a biopsy of a pelvic bone lesion was ordered. The histopathological result confirmed previous morphologic findings of a spindle cell tumor with low mitotic activity and limited inflammatory infiltrates. However, following patchy ALK staining, ALK FISH testing was performed, demonstrating ALK rearrangement, supporting the diagnosis of an inflammatory myofibroblastic tumor.

Figure 2

Bioptic samples of the left inguinal mass. (A) Bland, uniform spindle cells arranged in fascicles. No mitotic activity, necrosis, or significant atypia is seen (H&E, 100×). (B) Diffuse staining for desmin by immunohistochemistry (20×). (C) Positive ALK immunohistochemical stain (100×).

Further pathologic correlation of the breast lesion was not yet available at the time of tumor board discussion.

Dr Ramirez: what would be your discussion with the patient following the biopsy result of an inflammatory myofibroblastic tumor?

In cases of suspected uterine malignant mesenchymal tumors, National Comprehensive Cancer Network (NCCN) guidelines recommend expert pathologic review, complemented by immunohistochemical and molecular testing if available. If technically feasible, primary therapeutic management should involve upfront surgical resection with en bloc hysterectomy and bilateral salpingo-oophorectomy, along with additional resection of any extrauterine disease. Transabdominal biopsy is discouraged due to the risk of further tumor dissemination.2

Evidence on doxorubicin-based neoadjuvant approaches is limited and is based on umbrella trials including different types of soft tissue sarcomas, with response rates unlikely to exceed 30%. 3 Given the working hypothesis of a malignant inflammatory myofibroblastic tumor, an exceedingly rare condition with only few published cases available to date, data extrapolated from other uterine malignant mesenchymal tumors should be interpreted with caution. Case series specific to inflammatory myofibroblastic tumors suggest only limited response rates to systemic treatment. It is important to note that diagnosing an extremely rare malignant inflammatory myofibroblastic tumor via biopsy of a suspected metastatic lesion would favor correlation with the specimen of the primary tumor and therefore also upfront surgical management.4

The patient was provided with information on diagnostic findings and underlying evidence and agreed to upfront cytoreductive surgery as indicated above. Given the working diagnosis of a malignant uterine mesenchymal tumor, the decision was made not to wait for biopsy results of the breast lesion to avoid delaying the therapeutic management of the abdominal mass. Intra-operative findings were consistent with those reported by imaging studies; the tumor extended through the uterine serosa along the left round ligament into the insertion of the round ligament with the inguinal canal on the left side. Both the tumor infiltrating the round ligament and limited pelvic carcinomatosis could be resected without macroscopic residual disease, and no further intraperitoneal disease was noted.

The overall surgery time was 190 min, and blood loss was estimated at around 500 mL. The patient underwent the procedure without complications, and the post-operative recovery was uneventful. She was discharged from the hospital on the third post-operative day. Follow-up appointments with the surgical team revealed optimal wound healing and timely return to preoperative function.

Dr Deavers: what were the findings from the cytoreductive surgery?

The final histopathology diagnosed an inflammatory myofibroblastic tumor of the uterus, measuring 7 cm at its greatest dimension. The tumor invaded the full thickness of the myometrium, serosa, paracervical adipose tissue, lower uterine segment, left ovary, left adnexal soft tissue, left and right fallopian tube, and endometrium. Necrosis was present in 40% of the tumor, with 11 mitoses per 10 high-power fields and a Ki67 proliferation index of 15%. No lymphovascular, but perineural invasion was detected. Microscopic residual disease was noted on deep posterior paracervical lower uterine margins and on the surface margin of the left adnexal soft tissue. Molecular testing reported normal mismatch repair protein expression and ALK rearrangement by FISH testing. Biopsies of the iliac bone and the groin were consistent with the primary tumor, confirming the diagnosis of primarily metastasized uterine inflammatory myofibroblastic tumor.

Dr Kieser: based on the post-operative pathology, what would be your recommendations to the patient for adjuvant treatment?

In the present case, surgery achieved a macroscopically complete resection in the abdomen; however, the findings of peritoneal carcinomatosis and infiltration along the broad ligament indicated residual microscopic disease, which was confirmed by the pathology report. Additionally, the presence of bone lesions should be taken into consideration. Recurrence is common in inflammatory myofibroblastic tumors, highlighting the need for adjuvant therapy.

Evidence on response rates following conventional cytotoxic chemotherapy and/or external beam radiotherapy is limited and confined to case series. Such therapeutic approaches could only be derived from data of other uterine mesenchymal tumors on a case-by-case basis. As residual microscopic tumor cells in the inguinal canal pose a risk of local recurrence, the option of adjuvant external beam radiotherapy should be discussed with the patient, as previous responses to external beam radiotherapy have been documented for inflammatory myofibroblastic tumors. 5 In analogy to recommendations for uterine leiomyosarcoma, adjuvant doxorubicin-based chemotherapy should also be considered. 6

Alternatively, a non-randomized phase II trial (EORTC 90101 CREATE) previously assessed the therapeutic efficacy of a tyrosine kinase inhibitor targeting ALK mutations, crizotinib, in a series of non-uterine primary or advanced, incurable ALK-mutated inflammatory myofibroblastic tumors. The trial observed an overall response rate of 66.7%, with a median duration of response of 18.0 months. Responses proved durable in case of confirmed response. 7 Retrospective real-world evidence reported response rates up to 81.3%. 8 A US Food and Drug Administration (FDA) label approving crizotinib for unresectable, recurrent, or refractory inflammatory ALK-positive myofibroblastic tumors has been available since July 2022. Crizotinib, a first-generation ALK inhibitor, is, however, associated with considerable toxicities and limited tolerability. Switching to a second-generation ALK inhibitor such as alectinib could be an option, as alectinib demonstrated superior efficacy and lower toxicity in primary treatment of ALK-positive non-small cell lung cancers.9

Of note, the patient underwent a mammogram and ultrasound as suggested, which diagnosed three subcentimeter masses in the right breast, indicating a BI-RADS four classification. Pathologic correlation confirmed ductal carcinoma in situ (DCIS). The patient was referred to breast oncology for further therapy. We would not recommend deviating from standard management for DCIS following the diagnosis of the inflammatory myofibroblastic tumor.

Dr Ramirez: what would be your discussion with the patient regarding routine surveillance?

No data supporting evidence-based recommendations on routine oncologic follow-up visits is available to date. However, relapses appear to occur frequently, as reported by Ladwig et al, with recurrence observed in seven out of eight cases available in the literature. The eighth case was lost to follow-up after primary therapy. 4 In the present case, both osseous metastases and positive margins in the area of the left inguinal canal suggest close post-therapeutic follow-up visits and imaging studies are reasonable. Intervals may be extrapolated from practices of other smooth muscle tumors, with follow-up visits every 3 months for the first 3 years and periodic pelvic MRIs.10

Discussant closing summary

Primary metastatic inflammatory myofibroblastic tumors in adults are exceedingly rare mesenchymal neoplasms. To our knowledge, clinical evidence of primary metastatic disease is currently limited to a review of eight previously reported cases; however, under-recognition may contribute to the assumed low incidence of these tumors. It was previously hypothesized that uterine inflammatory myofibroblastic tumors may have been frequently misclassified as smooth muscle tumors of uncertain malignant potential or leiomyosarcomas. The increasing availability of specific immunohistochemistry and molecular profiling may contribute to more accurate diagnoses in the future and is therefore strongly encouraged during the diagnostic work-up of all mesenchymal tumors. Histologic findings of inflammatory myofibroblastic tumors are characterized by cytologically bland spindle cells, low mitotic activity, and lymphoplasmacytic inflammatory infiltrate of varying intensity. The vast majority of uterine inflammatory myofibroblastic tumors appears to harbor ALK fusions. 4

Following diagnosis, referral to a tertiary care center specializing in gynecologic oncology is strongly encouraged. First-line treatment is surgical and should include radical tumor resection with the goal of achieving no macroscopic residual disease, as tumor recurrences are frequent and evidence on both effective adjuvant and recurrence therapy strategies is limited. Tyrosine kinase inhibitors targeting ALK mutations are currently the most promising approach; however, in case ALK inhibitors are unavailable, anecdotal evidence on responses to doxorubicin-based chemotherapies and external beam radiotherapy is available. 5 7 As data on the efficacy of systemic options for recurrence therapy is equally limited, surgery should be considered in case of relapse. Given a high risk of recurrence, clinical and radiologic surveillance are recommended after completion of therapy. Interval and duration are extrapolated from customary practices associated with other smooth muscle uterine neoplasms; follow-up visits every 3–6 months for 5 years appear reasonable. 10 11