Ovarian Serous Carcinoma With a Novel HSP90AB1 Mutation in a Patient With Synchronous Primary Fallopian Tube Serous Carcinoma

Discussion

This is an unusual case of primary high-grade ovarian serous carcinoma with synchronous primary fallopian tube serous carcinoma with a novel HSP90AB1 mutation of tumor mutational burden (TMB) identified from the ovarian serous carcinoma. Synchronous multiple uterus leiomyomas and adenomyosis were also present. The primary ovarian tumor showed solid and cystic changes with numerous psammoma bodies. Serous carcinoma in situ with invasion was morphologically identified in both origins. The patient with clinical stage 4 disease received regular neoadjuvant therapy followed by debulking surgery and her serum CA125 decreased from 3,238 to 96 U/ml. Although her overall survival 49 months after diagnosis through our treatments was longer than that reported in the literature (33 months) with similar treatment (5), NGS was performed to explore the possible targeted therapy for the patients with stage 4 disease. Interestingly mutations including novel mutation of HSP90AB1 (p.R456C) and common mutations of TP53 (c.524G>A at p.R175H), BRCA1 and BRCA2 were identified in this case. In addition, there were increased tumor infiltrating lymphocytes (TIL) seen in our case, consistent with a recent study that mutated TP53 at p.R175H is shared among a subset of patients with metastatic colorectal cancer (6). To the best of our knowledge, this has not been documented in ovarian carcinoma.

Although NGS in ovarian cancer has been reported in many cases, the exact tumor molecular pathogenesis remains to be elucidated for further targeted therapy. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases (7). Among patients with invasive ovarian carcinoma, family history is not sufficiently accurate to predict mutation status. In this case, although the patient’s parents died of colon cancer and prostate cancer at old age, respectively, and there was a cousin died at age 30 with unknown cancer, no family history of cancers arising from gynecologic organs and breast was identified. Recent studies showed that somatic mutation of tumor protein TP53 is a hallmark of tubo-ovarian high-grade serous carcinoma and is observed in almost all such cases and TP53 remains as the most frequently altered gene in high-grade serous ovarian cancer (2, 8). AB Mutalib et al. compared high-grade serous ovarian carcinoma to normal ovarian tissue by NGS and found that eight genes were altered in both the tumor and normal groups (APC, EGFR, FGFR3, KDR, MET, PDGFRA, RET and SMO) while four genes (TP53, PIK3CA, STK11 and KIT) were exclusively altered in the tumor group. TP53 alterations were present in all the tumors but not in the normal group. Six deleterious mutations in TP53 (p.R175H, p.H193R, p.Y220C, p.Y163C, p.R282G and p.Y234H) were identified in eight serous ovarian carcinoma samples and none in the normal group (8). In our case, despite the mutations of BRCA1 and BRCA2, we also found the mutation of TP53 (c.524G>A at p.R175H) that was recently reported as a novel TP53 mutation in some breast carcinoma cases (9) and two ovarian serous carcinoma cases (8).

The TMB refers to the total number of replacement and insertion/deletion (indel) mutations per basic group in the exon coding region of the assessed gene in the genome of a tumor cell. TMB may play an important role in the prognosis and guiding immunotherapy of ovarian carcinoma (10). By detecting the TMB of ovarian carcinoma, clinicians can more accurately treat patients with immunotherapy, thereby improving their survival rate (10). Per our protocol, qualitative TMB results include: Low: <10 mutations per Mb; Intermediate: 10-15 mutations per Mb; and High: >15 mutations per Mb. Therefore, searching for new treatment methods plays an important role in improving the prognosis of patients with ovarian carcinoma. In our case, a novel pathogenic mutation of HSP90AB1 (p.R456C) was identified through TMB analysis and this is the first documented case of ovarian serous carcinoma with HSP90AB1 (p.R456C) mutation. Although HSP90AB1 mutation is pathogenic, its significance among other mutated genes remains to be further elucidated through more case studies.

In recent years, immunotherapy, as a new treatment of ovarian cancer, has gradually attracted attention and achieved some results in the treatment of ovarian carcinoma, especially the inhibitors for immune checkpoint of PD1/PDL1. Unfortunately, the overall response rate of patients to these inhibitors is still low (11). Per our protocol, PD-L1 expression (normalized to multiple housekeeping genes and a common control) is reported as RNA expression score (RES, range=0-100) with a RES threshold >20.3 at least 50% of tumor content to define PD-L1 RNA high. This threshold was validated as 100% sensitive and 70% specific for predicting PD-L1 tumor proportion score (TPS) more than 50%. In our case, PD-L1 status was reported as low RES and anti-PD-L1 or PD-1 therapy was not offered to this patient. However, a recent study showed the prevalence of PD-L1 expression is variable in different types of tubo-ovarian carcinoma and is highest in high-grade serous carcinoma (HGSC). In high-stage HGSC, PD-L1 positivity in tumor cells is associated with an increased immune response and improved survival (12).

In addition, simultaneous germline and tumor sequencing is an efficient way to provide enhanced information to guide the care of patients with ovarian cancer. This approach can identify somatic BRCA mutations at diagnosis, allowing physicians to provide Poly (ADP-ribose) polymerase (PARP) inhibitor maintenance and improve outcomes for those patients (13).

In summary, our unusual case of high-grade ovarian serous carcinoma demonstrated molecular characteristics of the common mutations of BRCA1 and BRCA2, and TP53 (c.524G>A at pR175H), novel mutation of HSP90AB1 (p.R456C), as well as low RNA expression score of PD-L1. Identification of these mutations and PD-L1 abnormality at the diagnosis of ovarian carcinoma may shed light for clinicians to provide targeted therapy with PARP inhibitors and immune checkpoint inhibitors for ovarian serous carcinoma. The significance of novel HSP90AB1 (p.R456C) mutation in this entity remains to be further investigated through more case studies.