A woman in her 60s with a body mass index (BMI) of 22.7 visited her local doctor with complaints of abdominal distension and loss of appetite. She had undergone total hysterectomy and adnexectomy for uterine leiomyoma at another hospital 6 years prior. Her family history included a father who had suffered from stomach cancer and a sister who had been diagnosed with uterine leiomyoma.
Upper endoscopy revealed an extramural gastric mass, and computed tomography (CT) demonstrated a left upper abdominal mass. She was referred to the Kanagawa Cancer Center for further evaluation and treatment. The differential diagnoses included gastrointestinal stromal tumor (GIST), lymphoma, and peritoneal cancer, and repeat CT scans were performed for confirmation. A large mass with a longitudinal diameter of approximately 180 mm was observed on the midline, with a slight deviation towards the left abdomen (Fig. 1a). The tumor was contiguous with the transverse colon, without luminal lesions. Positron emission tomography demonstrated 18F-fluorodeoxyglucose (FDG) accumulation in the mass, with a maximum standardized uptake value (SUVmax) of 9.42. No evidence of space-occupying lesions was found in any other part of the abdomen or in other organs (Fig. 1b).
A transverse colon biopsy was performed via colonoscopy. Histologically, the tumor was abundant in spindle-shaped cells, which were negative for c-kit, DOG-1, CD31, CD34, desmin, myogenin, S100 protein, MDM2, and CDK4, with a Ki-67 index of 20% as seen via immunohistochemical analysis. The pathological diagnosis was limited to a descriptive spindle cell tumor, which led to an open lumpectomy being performed.
The resected tumor was 260 × 250 × 120 mm in size, weighed approximately 3.5 kg, and was grossly located in the submucosa of the transverse colon (Fig. 1c). The tumor was solid, well-demarcated, grayish-white, and partially hemorrhagic with some degree of mucinous degeneration (Fig. 1d). The mass was located outside the bowel wall (Fig. 2a), and histologically comprised uniform spindle-shaped tumor cells that proliferated in bundles or herringbone patterns (Fig. 2b). Sparse and dense cell areas intermingled with edematous stroma to some extent (Fig. 2c). Mitotic figures were abundant with a frequency of 39/10 HPFs (High Power Fields) (Fig. 2d), and necrosis was commonly observed. The spindle-shaped tumor cells stained positive for CD99 and were weakly positive for CyclinD1 and CD10 as observed via immunohistochemical analysis. Further, the cells stained negative for cytokeratin AE1/AE3, CAM5.2, EMA, CDK4, MDM2, DOG-1, CD31, CD34, SMA, desmin, myogenin, S100 protein, synaptophysin, STAT6, MUC4, ER, and PgR. Additionally, INI1 expression was confirmed and the Ki-67 index was found to be approximately 30%. These findings resulted in the tumor being diagnosed as a spindle cell sarcoma that was highly suggestive of adult fibrosarcoma.
CT revealed recurrence of the tumor as evidenced by the presence of multiple masses in the abdominal cavity four months post tumor removal. Give the challenge associated with radical surgical removal of the tumors, chemotherapy with doxorubicin and ifosfamide was selected as the treatment of choice based on the histological diagnosis of fibrosarcoma. The recurrent masses were remarkably smaller, and chemotherapeutic protocol was adjudged to have resulted in a complete response post administration of the fifth course (14 months postoperative). Consequently, chemotherapy was temporarily halted; however, CT indicated re-expansion of the intra-abdominal mass 4 months later (18 months postoperative). Although monotherapy with doxorubicin was initiated, the response was unsatisfactory and the cancer was categorized as progressive disease (PD). Chemotherapy was subsequently switched to ifosfamide and etoposide, which initially achieved a partial response (PR). However, on account of enlargement of the pelvic mass after the 7th course, the cancer remained a PD. A CGP test was ultimately performed to explore possible treatment options.
Formalin-fixed and paraffin-embedded tissue from the initially excised abdominal tumor was subjected to the CGP test, Foundation One®ฎ CDx (Chugai Pharmaceutical Co. Ltd., Japan) which interrogates the entire coding sequence of 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer. The test was performed successfully using the 96.7% pure sample comprising 80% tumor nuclei. The tumor mutational burden (TMB) was estimated to be 1.26 mutations/Mb, and microsatellite status was stable (MSS). The CGP test identified four small variants, including three single-nucleotide polymorphisms (SNPs) and a variant of uncertain significance (VUS). A single copy number loss, corresponding to exons 3 to 5 of CDKN2A, was identified as a pathogenic alteration that resulted in loss of function of the tumor suppressor. Additionally, a high confidence rearrangement between JAZF1 and BCORL1 with 276 supporting-read pairs was identified. This rearrangement was deduced to produce truncated BCORL1, albeit, with a degree of uncertainty on account of the lack of RNA-based analysis. In view of the fact that JAZF1-BCORL1 rearrangements have been previously reported in uterine stromal sarcoma, we decided to re-evaluate surgical specimens obtained post the radical hysterectomy performed at other hospital for the preceding uterine leiomyoma in this patient.
The hysterectomy specimen showed dense proliferation of uniform spindle cells in the stroma just below the glandular epithelium, without nuclear atypia in addition to the leiomyoma (Fig. 3a, b). Leaflike architecture of growth with intraglandular polypoid projections of the stroma was observed in certain areas. The atypical stromal cells had irregular oval to spiniform nuclei with mitotic figures at a frequency of approximately 5/10 HPFs (Fig. 3c). The proliferating stromal spindle cells were densely packed just below the benign glandular epithelium with an edematous stroma (Fig. 3d), and were positive for PgR as well as partially positive for desmin, CyclinD1, ER, WT-1, and CD10. Further, these cells were generally SMA negative, and had a Ki-67 index of 20%. These findings were consistent with a diagnosis of uterine adenosarcoma. Since BCOR was shown to be strongly expressed in adenosarcoma carrying JAZF1-BCORL1 fusion gene, we examined expression of BCOR in our case by immnohistochemistry using anti-BCOR monoclonal antibody (clone C-10, Santa Cruz Biotechnology, Dallas, TX) [6]. Both spindle cells in the corpus uteri and the intra-abdominal mass demonstrated showed partial nuclear positivity for BCOR (Fig. 4a, b), suggesting that the intra-abdominal mass was a metastatic tumor derived from the preceding uterine adenosarcoma that may carry the JAZF1-BCORL1 fusion gene. Given that uterine stromal sarcomas often harbor a JAZF1-BCORL1 rearrangement, platinum-based chemotherapy that is used for the treatment of the sarcoma was considered for this patient [7]. However, the same could not be implemented on account of recurrent enlarged abdominal tumors with pulmonary metastasis, which resulted in rapid deterioration of the patient's general condition, and adoption of a non-aggressive treatment approach.