ATM mutation in aggressive uterine adenosarcoma in which systemic chemotherapies had remarkable effects

Abstract

Uterine adenosarcoma is a rare gynecologic malignancy, and 10–25% of the cases exhibit clinically aggressive behaviors. Although TP53 mutations are frequently identified in high-grade adenosarcomas of the uterus, definitive gene alterations have not been identified in uterine adenosarcomas. Specifically, no reports have described mutations in homologous recombination deficiency-related genes in uterine adenosarcomas. This study presents a case of uterine adenosarcoma without sarcomatous overgrowth but with TP53 mutation that exhibited clinically aggressive behaviors. The patient had an ATM mutation, which is a gene associated with homologous recombination deficiency, and exhibited a good response against platinum-based chemotherapy and possible therapeutic target by poly(ADP-ribose) polymerase inhibitors.

Introduction

Uterine adenosarcoma is an uncommon biphasic epithelial–mesenchymal tumor with benign or atypical epithelial elements and a malignant mesenchymal component ranging from low-grade to high-grade sarcomas. Although patients with adenosarcomas may have favorable clinical outcomes, approximately half of them had a recurrence [1, 2]. Poor pathological prognostic factors of adenosarcomas include vascular invasion and sarcomatous overgrowth, i.e., > 25% of the tumor volume comprise the sarcoma alone [1, 3, 4]. Although complete resection is the only treatment of choice for this patient population, advanced or recurrent disease is minimally responsive to current standard adjuvant treatments, including chemotherapy and radiation [2].

Among uterine sarcomas, several genomic features of leiomyosarcomas were assessed [5]; however, the molecular landscape of adenosarcomas has not been characterized yet, even though some cases exhibit aggressive biological behaviors. The identification of gene mutations in unknown primary and rare cancers, for which there is no standard treatment, is promising for finding molecular targeting therapies and alternative anticancer agents. Specifically, homologous recombination (HR) deficiency is a biomarker for the use of poly(ADP-ribose)polymerase inhibitors (PARPis) [6] and has frequent effects against platinum-based chemotherapy. HR deficiency occurs across malignancies arising from several organs [7, 8]. Moreover, 22% of primary uterine leiomyosarcomas showed alterations in HR deficiency-related genes [9], especially BRCA2 alterations [10]. However, a few studies have identified the HR deficiency-related genes in uterine adenosarcoma.

In this study, we report a case of uterine adenosarcoma that showed highly malignant clinical behaviors without sarcomatous overgrowth or vascular invasion. The patient harbored a mutation in the ATM gene, which is an HR deficiency-related gene. This case demonstrated the efficacy of platinum-based chemotherapy and a possible therapeutic target by PARPis.

Case report

The patient was a 58-year-old woman (gravida 2 and para 2). Her past histories included a thyroid tumor and left submandibular gland pleomorphic adenomectomy when she was 55 and 56 years old, respectively. Cervical cancer screening performed 2 months before she visited her previous doctor did not detect abnormalities. On her previous doctor, her chief complaint was abnormal genital bleeding. Magnetic resonance imaging identified irregularly shaped tumor with cystic changes occupying the uterine cavity, which exhibited high intensity on T2-weighted images and low intensity on T1-weighted images with contrasted components (Fig. 1). She was suspected of uterine malignancy, for which total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, and partial omentectomy were performed 2 months after her first visit. The postoperative pathological diagnosis was uterine sarcoma, pT1bN0. She was introduced to our hospital 1 month after the surgery for consultation on definitive diagnosis and postoperative treatment. Macroscopically, the resected tissues indicated an irregularly shaped tumor that protruded from the endometrium into the uterine cavity, but the tumor did not invade the uterine myometrium. Microscopically, multi-ridged and short-spindle-shaped cells with nuclear atypia were found (Fig. 2). No obvious atypical epithelial cells were observed. The sarcoma component was occupied by cells with CD10 positivity, estrogen receptor negativity, and p53 null pattern. The Ki-67 index was > 90% in the sarcomatous area. The final histopathological diagnosis was stage 1B adenosarcoma. Because no adenosarcoma with sarcomatous overgrowth, vascular invasion, or rhabdomyosarcoma components were identified, the patient did not receive any adjuvant therapies postoperatively.

Fig. 1.

Magnetic resonance imaging identified an irregularly shaped tumor with cystic changes occupying the uterine cavity (white arrows), which exhibited high intensity on T2-weighted images (a) and low intensity on T1-weighted images (b) with contrasted components (c)

Fig. 2.

Hematoxylin and eosin staining indicates multi-ridged and short spindle-shaped cells with nuclear atypia in stromal cells, 5 × magnification (a) and 40 × magnification (b and c). CD10 was positive for the sarcoma cells, 20 × magnification (d). Immunoreaction of p53 indicated null pattern, 20 × magnification (e). The Ki-67 index was > 90% in the sarcoma area, 20 × magnification (f)

Four months after the first surgery, computed tomography (CT) identified several peritoneal dissemination recurrences (Fig. 3, Rec1). Eight courses of doxorubicin and ifosfamide (AI) therapy (doxorubicin: 30 mg/m² days 1 and 2; ifosfamide: 2 mg/m² days 1, 2, and 3) were performed, because AI therapy was reported to be the most effective chemotherapy [11]. CT images obtained 10 months after the recurrence showed complete response (Fig. 3, CR1). On patient follow-up, CT images identified peritoneal dissemination and pelvic lymph-node swelling 7 months after the end of the AI therapy (Fig. 3, Rec2). Because we considered that the anticancer agents had limited effectiveness, the initial surgical specimen was submitted for cancer gene panel testing to explore the therapeutic targets. The candidates of chemotherapeutic regimens against Rec2 were ifosfamide and cisplatin (IP) therapy, and docetaxel and gemcitabine therapy [11]. As ifoshamide showed efficacy in the previous treatment, IP therapy (ifosfamide: 1.5 mg/m2 days 1, 2, 3, and 4; cisplatin: 20 mg/m2 days 1, 2, 3, and 4) was administered against the recurrence of peritoneal dissemination and pelvic lymph nodes. CT images after six courses of IP therapy showed complete response (Fig. 3, CR2), and no evidence of disease was observed in 12 months. A cancer gene panel test revealed ATM mutations, namely, F1774fs*8 and TP53 R213*. Other pathogenic findings were not observed. PARPis were recommended based on the ATM mutation.

Fig. 3.

Clinical history of this case with computed tomography images. Rec1, CR1, Rec2, and CR2 represent the first recurrence, complete response using the first-line chemotherapy, second recurrence, and complete response using the second-line chemotherapy, respectively. White circles indicate the sites of recurrence. AI doxorubicin and ifosfamide therapy, IP ifosfamide and cisplatin therapy, M months

Discussion

Several gene variants have been identified in uterine adenosarcoma. Target sequencing analysis revealed that uterine adenosarcomas harbored oncogenic alterations in genes encoding the subunits of the SWI/SNF complex including ARID1A and SMARCB1 in 43% and histone-modification genes in 36% of the cases [12, 13]. DICER1 mutations were identified in 42% of Müllerian adenosarcomas [14]. FGFR2, KMT2C, and DICER1 recurrently mutated in 19 adenosarcoma cases [13]. TP53 mutations frequently mutated in high-grade uterine adenosarcomas (81%) [15]. Their genetic mutations in uterine adenosarcomas included DNMT3A, DAXX, EPHA7, TRRAP, PRKDC, KAT6B, TSC2, PTEN, AKT1, CTNNB1, KRAS, MITF, PIK3CA, MED12, DIS3 AXIN1, PTCH1, FLT4, PIK3R1, ABL1 AXIN2, NKX3-1, SPOP, KDM5C, BBC2, GRIN2A, GNAS, and KEAP1 [13, 16, 17]. Benjamin et al. reported that 35% of uterine adenosarcomas had altered DNA damage repair genes [12]. The deletion and inactivation of BAP1 (BRCA-associated protein) were reported [13, 14]. ATRX whose inactivation results in increased DNA damage and HR repair defects and impaired replication fork processivity was reported in uterine adenosarcomas [18]. However, ATM mutations have not been reported in uterine adenosarcomas. On the contrary, leiomyosarcomas sometimes possess mutations in HR-related genes, especially BRCA2 [10]. Moreover, 16 of 73 (22%) primary uterine leiomyosarcomas showed alterations in HR deficiency-related genes [9], 3% of patients with uterine leiomyosarcomas had a loss of a non-BRCA HR gene, and 10% of the patients exhibited a pathogenic genomic sequence alteration in a non-BRCA HR gene [19]. In addition, 9–10% of uterine leiomyosarcoma tumors had a BRCA2 alteration [10, 19], and 16% of leiomyosarcomas arising from multiple sites including the uterus harbored ATM mutations [20]. HR defect and BRCA2 or ATM defect were independent significant factors associated with favorable progression-free survival to platinum-based chemotherapy in metastatic castration-resistant prostate cancer [21]. The presence of germline and somatic HR mutations including ATM was highly predictive of primary platinum sensitivity and improved overall survival in ovarian cancer [22]. All uterine serous carcinoma patients who are platinum-sensitive had HR germline mutations (RAD51, NBN, and ATM) [23]. Platinum agents and PARPis were suggested to be effective against cases with ATM gene mutations [24]. In the present case, IP therapy, which included a platinum agent, indicated a complete response, and ATM gene mutation was identified, suggesting the efficacy of PARPis. As a cancer gene panel test recommended, PARPis are possibly a candidate therapeutic strategy for further regression. However, PARPis monotherapy for HR-mutated ovarian cancer is controversial. Although PARPis monotherapy showed favorable efficacy in late-line treatment of ovarian cancer, the inclusion criterion was not HR repair-defected cases but BRCA-mutated ovarian cancer [25, 26]. The loss of ATM function in p53-deficient cells resulted in increasing sensitivity to topoisomerase I poisons, topoisomerase II poisons (doxorubicin), and antimetabolites [27]. ATM stabilizes p53 through phosphorylation of Mdm2 Ser394 in mice and MDM2 S386, and S429 in human fibroblast cell lines [11, 28]. DNA damaging agents, including doxorubicin, etoposide, and camptothecin, induce ATM-dependent phosphorylation of S386 and S429, which inhibits p53 polyubiquitination [28]. Despite the low evidence level, doxorubicin might contribute to the complete response in this case, because the patient harbored ATM and TP53 mutations.

TP53 exhibits the highest frequency of missense-type gene mutations in 48% of uterine sarcomas including leiomyosarcomas, endometrial stromal sarcomas, and carcinosarcomas [16]. Among uterine leiomyosarcomas, 52% of the tumors harbored TP53 mutations [9, 12]. TP53 alterations including mutations and copy loss most frequently occurred (60%) in uterine leiomyosarcomas [5]. Among uterine adenosarcomas, TP53 mutations were relatively rare and observed in aggressive phenotypes of uterine adenosarcomas. TP53 mutations were observed in 11–16% of adenosarcomas, whereas 73–88% of carcinosarcomas exhibited TP53 mutations [13, 14]. The immunoreactive analysis of TP53 identified mutant-type TP53 expression in 9 of 11 (81.8%) high-grade adenosarcomas and none in low-grade adenosarcomas [15]. The sequencing of high-grade adenosarcomas identified TP53 pathway alterations in 7 of 9 (78%) cases [17]. TP53 mutations were predominant in uterine adenosarcomas with sarcomatous overgrowth [17, 18]. The present case showed aggressive clinical behaviors even without sarcomatous overgrowth and vascular invasion. Moreover, adenosarcomas with TP53 mutations possibly exhibit aggressive clinical behaviors even without sarcomatous overgrowth and lymphovascular invasion.

Even uterine adenosarcomas without sarcomatous overgrowth or vascular invasion may have highly aggressive clinical behaviors, and TP53 gene mutations may be a poor prognostic factor. Mutations in HR deficiency-related genes including ATM occur in some uterine adenosarcoma cases. To search for promising therapeutic strategies, multi-cancer gene panel testing should be performed for uterine adenosarcomas in which standard treatments show limited efficacy.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from the patient for whom identifying information is included in this article.