Abstract
Objective:
To evaluate the clinical significance and genomic associations of concurrent serous tubal intraepithelial carcinoma (STIC) with high-grade serous carcinoma (HGSC) of the ovary in women undergoing primary debulking surgery (PDS).
Methods:
All patients who underwent PDS for HGSC between 01/2015 and 12/2018 were captured in a prospectively maintained institutional database. Patients were categorized based on the presence or absence of concurrent STIC noted on final pathology. Demographic, perioperative, and outcomes data were collected, and groups were compared using standard statistical tests. Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan-Meier method. For comparison of differences in somatic alterations between the two cohorts, specimens were sequenced using MSK-IMPACT.
Results:
Of 306 eligible patients, 87 (28%) had a concurrent STIC lesion (+STIC) and 219 (72%) did not (no-STIC). Demographics and clinicopathological factors were similar between the two cohorts, except for a significantly higher median preoperative CA-125 level in the no-STIC group (423 U/mL vs. 321 U/mL; p=0.029). There were no significant differences in median PFS (22.7 months [95%CI: 18.9-28.4] vs. 27.7 months [95%CI: 25.5-30.5]; p=0.126) and 3- year OS rate (81% [95%CI: 70-88%] vs. 85% [95%CI: 78-90%]; p=0.392) between +STIC and no-STIC patients, respectively. Targeted DNA-sequencing via MSK-IMPACT showed a similar distribution of driver mutations or structural genetic alterations, and affected genetic signaling pathways were similar between the cohorts.
Conclusions:
There were no identifiable clinical and genetic differences in patients with HGSC and concurrent STIC. These data suggest a comparable, if not identical, disease process.
Keywords: high-grade serous ovarian cancer, serous tubal intraepithelial carcinoma, primary debulking surgery, mutation profiling, MSK-IMPACT
Introduction
High-grade serous carcinoma (HGSC) is the most common, and most lethal, ovarian malignancy and is largely responsible for the poor outcomes associated with the disease [1]. Initially, this subtype of epithelial ovarian cancer was thought to arise from the ovarian surface epithelium or cortical inclusion cysts; however, improved pathologic assessment and broader genetic analysis in recent years have provided accumulating evidence showing precursors of HGSC originate from secretory epithelial cells within the fimbriated end of the fallopian tube, in the form of serous tubal intraepithelial carcinoma (STIC).
STIC lesions were originally identified in the fallopian tubes of patients undergoing risk-reducing bilateral salpingo-oophorectomy for inherited ovarian cancer susceptibility syndromes and were thought to be closely associated with mutations in the BRCA genes [2]. In patients with early-stage HGSC, STIC lesions can almost always be detected in the fallopian tubes, whereas in advanced disease, concurrent STIC lesions are found at a much lower frequency [3, 4]. As more sophisticated models of HGSC pathogenesis emerge, such as early “precursor escape” in which early non-malignant precursor cells from the fallopian tube are shed and subsequently undergo malignant transformation to peritoneal carcinomatosis in the peritoneal cavity [5], the significance of fallopian tube STIC lesions has become even less clear. Moreover, the relevance of a STIC lesion identified at the time of surgical resection for advanced HGSC is unknown. This study aimed to evaluate the clinical significance and genomic associations of concurrent STIC with HGSC in women undergoing primary debulking surgery (PDS).
Methods
This study was approved by the Institutional Review Board of Memorial Sloan Kettering Cancer Center (MSK). All patients who underwent PDS for HGSC between January 2015 and December 2018 were captured in a prospectively maintained institutional database. During the study period, our pathologists routinely used a protocol for sectioning and extensively examining the fimbriated end (SEE-FIM) of the fallopian tubes. All cases were reviewed by a specialty gynecologic pathologist to confirm the presence (+STIC) or absence (no-STIC) of STIC lesions using generally accepted criteria [6, 7]. Patients with mixed-type histology (n=2), a history of salpingectomy (n=13) prior to PDS, and those who did not undergo tubal resection at PDS (n=13) were excluded from this analysis. Two patients included in the analysis underwent a unilateral fallopian tube resection at PDS; one patient had a fallopian tube removed due to ectopic pregnancy and the other patient had a fallopian tube removed due to cervical cancer, both more than 30 years before PDS.
Electronic medical records were reviewed to abstract patient demographics, clinicopathological characteristics, and survival data. Complete gross resection (CGR) was defined as no visible disease after surgery. Optimal and suboptimal surgical debulking were defined as residual disease of 0.1-1 cm and >1 cm in maximal tumor diameter, respectively. Peritoneal carcinomatosis (PC) was defined as the presence of >20 tumor nodules within the abdominal cavity, and bulky upper abdominal disease (UAB) as tumor implants >1 cm cephalad to the greater omentum. PC and bulky UAB are both specifically addressed in the operative note at MSK. OR Tumor Index, a scoring system that reflects the extent of disease based on a 2-point scale (PC and bulky UAB disease account for 1 point each), was used to quantify disease burden [8]. Disease stage was based on the 2014 International Federation of Gynecology and Obstetrics (FIGO) staging criteria [9].
Descriptive statistics were provided. The differences between the two treatment groups (+STIC vs. no-STIC) were tested using the Fisher exact test for categorical variables and the Wilcoxon rank sum test for continuous variables. Progression-free survival (PFS) and overall survival (OS) were calculated from the date of PDS until the first relapse or death, whichever came first (for PFS) or until the time of death (for OS). Patients who did not experience the event of interest by the end of the study were censored at the time of the last follow-up. Median PFS and OS and 3-year PFS and OS rates were estimated using the Kaplan-Meier method. Different levels of a categorical variable were compared using a log-rank test for survival outcome. All patients were included in the survival analysis. P values for continuous variables were obtained using the Wald test based on the Cox proportional hazards model in survival analysis. Statistical analyses were performed using SAS 9.4 and R version 3.5.2.
Genomic profiling
For comparison of differences in somatic alterations between the two cohorts (+STIC vs. no-STIC), available specimens were sequenced using the MSK-IMPACT (MSK-Integrated Mutation Profiling of Actionable Cancer Targets) assay, as previously described [10]. MSK-IMPACT is a hybridization capture-based targeted next-generation sequencing array that can detect mutations and copy-number alterations (CNAs), and select rearrangements in 468 cancer-associated genes [10]. All classes of genomic alterations, including substitution, indels, CNAs, and rearrangements, were determined and called against the patient’s matched normal blood sample. Genomic alterations were filtered for oncogenic variants using OncoKB, a precision oncology database with annotations of more than 1000 cancer genes and their potential clinical actionability [11].
The fraction of genome altered (FGA) was defined as the fraction of log2 copy number variation (gain or loss) >0.2 relative to the size of the genome whose copy number was profiled. Tumor mutation burden (TMB) was calculated by dividing the total number of somatic non-silent protein-coding mutations by the number of Mbs in the coding region captured by the MSK-IMPACT panel (468 genes, 1.22 Mb). Previous studies have demonstrated that TMB derived from the MSK-IMPACT platform allows for an accurate estimate of TMB, similar to whole-exome sequencing [12]. MSK-IMPACT is a clinically validated assay performed in Clinical Laboratory Improvement Amendments (CLIA)-accredited laboratories.
Results
Patient clinical and pathologic characteristics
We identified 306 patients who underwent PDS for HGSC between January 2015 and December 2018 at MSK. Patient demographics and clinicopathologic characteristics are detailed in Table 1. A concurrent STIC was identified in the resected fallopian tubes (+STIC group) of 87 patients (28%). No STIC was found in the other 219 patients (72%; no-STIC group). Interestingly, STIC was more commonly detected in the right (66/87, 76%) than in the left fallopian tube (43/87, 49%). Within the no-STIC group, 185 (84%) of 219 patients had documented serosal or mucosal involvement of at least one fallopian tube by HGSC. Demographic and clinicopathologic characteristics were similar between the two cohorts, except for significantly higher preoperative CA-125 levels in the no-STIC group (median CA-125: 423 U/mL vs. 321 U/mL; p=0.029).
Table 1.
Demographics and clinicopathological findings
| Variable | All patients (N=306) |
No-STIC (n=219) |
+STIC (n=87) |
p* |
|---|---|---|---|---|
| Age at diagnosis, years | ||||
| Median (range) | 62.5 (33.1-88.4) | 62.6 (36.2-88.4) | 62.4 (33.1-86.3) | 0.422 |
| Race | ||||
| White | 239 (78.1%) | 163 (74.4%) | 76 (87.4%) | 0.082 |
| Black | 14 (4.6%) | 12 (5.5%) | 2 (2.3%) | |
| Asian | 33 (10.8%) | 26 (11.9%) | 7 (8%) | |
| Other/Unknown | 20 (6.5%) | 18 (8.2%) | 2 (2.3%) | |
| ASA status | ||||
| 1-2 | 64 (20.9%) | 41 (18.7%) | 23 (26.4%) | 0.161 |
| 3-4 | 242 (79.1%) | 178 (81.3%) | 64 (73.6%) | |
| BMI, kg/m2 | ||||
| Median (range) | 25.5 (18-48.8) | 25.4 (18-48.8) | 26 (18-47.9) | 0.419 |
| Preoperative albumin, g/dL | ||||
| Median (range) | 4.1 (2.3-4.9) | 4.1 (2.3-4.9) | 4.1 (2.8-4.7) | 0.902 |
| Preoperative CA-125, U/mL | ||||
| Median (range) | 376.5 (3-17560) | 423 (18-17560) | 321 (3-7742) | 0.029 |
| ≥500 U/mL | 121 (40.3%) | 96 (44.4%) | 25 (29.8%) | 0.026 |
| <500 U/mL | 179 (59.7%) | 120 (55.6%) | 59 (70.2%) | |
| Residual disease status | ||||
| CGR | 236 (77.1%) | 170 (77.6%) | 66 (75.9%) | 0.864 |
| 0.1-1 cm | 61 (19.9%) | 43 (19.6%) | 18 (20.7%) | |
| >1 cm | 9 (2.9%) | 6 (2.7%) | 3 (3.4%) | |
| FIGO tumor stage | ||||
| I/II | 15 (4.9%) | 11 (5%) | 4 (4.6%) | 0.925 |
| III | 201 (65.7%) | 142 (64.8%) | 59 (67.8%) | |
| IV | 90 (29.4%) | 66 (30.1%) | 24 (27.6%) | |
| BRCA status, germline | ||||
| Negative | 230 (75.2%) | 165 (75.3%) | 65 (74.7%) | 0.975 |
| BRCA1 | 51 (16.7%) | 36 (16.4%) | 15 (17.2%) | |
| BRCA2 | 25 (8.2%) | 18 (8.2%) | 7 (8%) | |
| BRCA status, somatic | ||||
| Negative | 132 (43.1%) | 98 (44.7%) | 34 (39.1%) | 0.628 |
| BRCA1/BRCA2 | 16 (5.2%) | 11 (5%) | 5 (5.7%) | |
| Unknown/Not Tested | 158 (51.6%) | 110 (50.2%) | 48 (55.2%) | |
| mBRCA | ||||
| Negative | 216 (70.6%) | 156 (71.2%) | 60 (69%) | 0.889 |
| BRCA1/BRCA2 | 67 (21.9%) | 47 (21.5%) | 20 (23%) | |
| Unknown/Not Tested | 23 (7.5%) | 16 (7.3%) | 7 (8%) | |
| Ascites, mL | ||||
| Median (range) | 200 (0-13500) | 200 (0-8000) | 300 (0-13500) | 0.801 |
| ≥500 mL | 133 (43.5%) | 92 (42%) | 41 (47.1%) | 0.444 |
| <500 mL | 173 (56.5%) | 127 (58%) | 46 (52.9%) | |
| Bulky upper abdominal disease | ||||
| Negative | 98 (32%) | 72 (32.9%) | 26 (29.9%) | 0.684 |
| Positive | 208 (68%) | 147 (67.1%) | 61 (70.1%) | |
| Carcinomatosis | ||||
| Negative | 93 (30.4%) | 71 (32.4%) | 22 (25.3%) | 0.27 |
| Positive | 213 (69.6%) | 148 (67.6%) | 65 (74.7%) | |
| Tumor Burden Index | ||||
| 0 | 74 (24.2%) | 56 (25.6%) | 18 (20.7%) | 0.634 |
| 1 | 43 (14.1%) | 31 (14.2%) | 12 (13.8%) | |
| 2 | 189 (61.8%) | 132 (60.3%) | 57 (65.5%) | |
| Site of STIC lesion | ||||
| Left | 21 (24.1%) | |||
| Right | 44 (50.6%) | |||
| Bilateral | 22 (25.3%) |
p values obtained using the Fisher exact test for categorical variables and Wilcoxon rank sum test for continuous variables; p value not provided if certain level has counts <5.
ASA = American Society of Anesthesiologists; STIC = serous tubal intraepithelial carcinoma; BMI = body mass index; CGR = complete gross resection; FIGO = International Federation of Gynecology and Obstetrics; mBRCA = mutated BRCA1/2 status
Survival outcomes
The median follow-up for all survivors was 34 months (range, 0.9-65.3); the median follow-up was 38.1 months (range, 2.5-64.8) for those with concurrent STIC and 32.4 months (range, 0.9-65.3) for those without STIC. At the time of analysis, 174 patients had recurred. The median PFS was 26.6 months (95% CI, 24.4-28.5) for the entire cohort, with a 3-year PFS rate of 36% (95% CI, 29-42%). PFS was similar between the +STIC and no-STIC groups (22.7 months [95% CI, 18.9-28.4] vs. 27.7 months [95% CI, 25.5-30.5], respectively; p=0.126) (Table 2 and Figure 1).
Table 2:
Univariate analysis of progression-free and overall survival
| Progression-free survival | Overall survival | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Variable | Total (#) |
events (#) |
3-yr PFS rate (95%CI) |
HR (95% CI) | p* | Total (#) |
events (#) |
3-yr OS rate (95% CI) |
HR (95% CI) | p* |
| All patients | 306 | 174 | 35.6% (29.4-41.9%) | 306 | 53 | 83.6% (77.8-87.9%) | ||||
| Age at diagnosis (1-yr increase) | 1 (0.99-1.01) | 0.972 | 1 (0.98-1.03) | 0.96 | ||||||
| STIC | ||||||||||
| No | 219 | 119 | 37% (29.4-44.6%) | 1 | 0.126 | 219 | 34 | 84.7% (77.6-89.7%) | 1 | 0.392 |
| Yes | 87 | 55 | 31.7% (21.4-42.6%) | 1.28 (0.93-1.77) | 87 | 19 | 80.9% (69.6-88.3%) | 1.28 (0.73-2.24) | ||
| Race | ||||||||||
| White | 239 | 140 | 33.8% (26.9-40.9%) | 1 | 0.163 | 239 | 46 | 82.1% (75.4-87.1%) | 1 | 0.059 |
| Black/Asian/Other/Unknown | 67 | 34 | 41.7% (28.2-54.7%) | 0.77 (0.53-1.12) | 67 | 7 | 88.8% (74.8-95.3%) | 0.47 (0.21-1.05) | ||
| ASA status | ||||||||||
| ASA 1-2 | 64 | 31 | 40.6% (25.9-54.7%) | 1 | 0.154 | 64 | 8 | 87.9% (72.5-95%) | 1 | 0.303 |
| ASA 3-4 | 242 | 143 | 34.3% (27.5-41.2%) | 1.33 (0.9-1.95) | 242 | 45 | 82.4% (75.9-87.4%) | 1.48 (0.7-3.14) | ||
| BMI, kg/mL | ||||||||||
| BMI <25 (Normal) | 143 | 84 | 35.2% (26.4-44.2%) | 1 | 0.989 | 143 | 23 | 86.6% (78.1-92%) | 1 | 0.36 |
| BMI: 25-30 (Overweight) | 95 | 52 | 35.6% (24.3-47%) | 0.97 (0.69-1.38) | 95 | 19 | 75.7% (63.2-84.4%) | 1.54 (0.84-2.83) | ||
| BMI: ≥30 (Obese) | 68 | 38 | 37% (24.1-50%) | 1 (0.68-1.46) | 68 | 11 | 87.5% (74-94.3%) | 1.1 (0.53-2.25) | ||
| Preoperative albumin, g/dL (1 unit increase) | 0.74 (0.53-1.04) | 0.083 | 0.58 (0.33-1.02) | 0.057 | ||||||
| Preoperative CA-125 U/mL | ||||||||||
| ≥500 | 121 | 69 | 31.8% (22.2-41.7%) | 1 | 0.404 | 121 | 18 | 87.3% (77.9-92.9%) | 0.561 | |
| <500 | 179 | 101 | 38.7% (30.5-46.8%) | 0.88 (0.65-1.19) | 179 | 34 | 81.4% (73.4-87.1%) | 1.19 (0.67-2.1) | ||
| Residual disease status | ||||||||||
| CGR (0 cm) | 236 | 122 | 40.8% (33.3-48.2%) | 1 | 0.001 | 236 | 33 | 85.5% (78.7-90.3%) | 1 | 0.027 |
| Non-CGR (>0 cm) | 70 | 52 | 20.5% (11.5-31.2%) | 1.7 (1.22-2.35) | 70 | 20 | 77.3% (64.5-86%) | 1.85 (1.06-3.23) | ||
| FIGO tumor stage | ||||||||||
| I/II | 15 | 0 | 100% | - | - | 15 | 0 | 100% | - | - |
| III | 201 | 114 | 36.1% (28.5-43.7%) | - | 201 | 37 | 81% (73.2-86.8%) | - | ||
| IV | 90 | 60 | 28.1% (18.2-38.9%) | - | 90 | 16 | 86.2% (75.8-92.4%) | - | ||
| BRCA status, germline | ||||||||||
| Negative | 230 | 138 | 34.1% (27.2-41.1%) | 1 | 0.112 | 230 | 42 | 83% (76.2-88%) | 1 | 0.286 |
| BRCA1 | 51 | 29 | 30.3% (16.3-45.6%) | 0.97 (0.65-1.45) | 51 | 6 | 91.3% (75.3-97.1%) | 0.6 (0.25-1.4) | ||
| BRCA2 | 25 | 7 | 66.1% (35.3-84.8%) | 0.45 (0.21-0.97) | 25 | 5 | 71.4% (41.8-87.8%) | 1.51 (0.6-3.81) | ||
| BRCA status, somatic | ||||||||||
| Negative | 132 | 100 | 12.9% (6.8-20.9%) | 1 | <0.001 | 132 | 28 | 79.6% (69.3-86.8%) | - | - |
| BRCA1/BRCA2 | 16 | 9 | 16% (1-48.4%) | 0.61 (0.31-1.21) | 16 | 0 | 100% | - | ||
| Unknown/Not Tested | 158 | 65 | 54.8% (45.6-63%) | 0.35 (0.25-0.48) | 158 | 25 | 85% (77.3-90.3%) | - | ||
| mBRCA | ||||||||||
| Negative | 216 | 129 | 34.9% (27.8-42.2%) | 1 | 0.146 | 216 | 42 | 81.9% (74.7-87.2%) | 1 | 0.094 |
| BRCA1/BRCA2 | 67 | 38 | 28% (15.6-41.8%) | 0.97 (0.68-1.4) | 67 | 6 | 93.2% (80.3-97.8%) | 0.44 (0.19-1.04) | ||
| Unknown/Not Tested | 23 | 7 | 64.9% (34.3-83.9%) | 0.47 (0.22-1.02) | 23 | 5 | 70.4% (40.8-87.2%) | 1.44 (0.57-3.64) | ||
| Ascites, mL | ||||||||||
| ≥500 | 133 | 83 | 30.5% (21.8-39.6%) | 1 | 0.019 | 133 | 34 | 76.1% (66.3-83.3%) | 1 | 0.002 |
| <500 | 173 | 91 | 39.5% (30.9-48%) | 0.7 (0.52-0.94) | 173 | 19 | 90% (82.7-94.3%) | 0.42 (0.24-0.73) | ||
| Upper abdominal disease | ||||||||||
| Negative | 98 | 37 | 56.1% (43.8-66.6%) | 1 | <0.001 | 98 | 8 | 93% (82.1-97.4%) | 1 | 0.006 |
| Positive | 208 | 137 | 26.4% (19.7-33.6%) | 2.43 (1.69-3.49) | 208 | 45 | 79.6% (72.3-85.2%) | 2.74 (1.29-5.81) | ||
| Carcinomatosis | ||||||||||
| Negative | 93 | 35 | 53.9% (41.1-65.1%) | 1 | <0.001 | 93 | 4 | 96.9% (88-99.2%) | 1 | <0.001 |
| Positive | 213 | 139 | 28.2% (21.5-35.3%) | 2.26 (1.56-3.27) | 213 | 49 | 78.8% (71.5-84.4%) | 5.12 (1.85-14.2) | ||
| Tumor Burden Index | ||||||||||
| 0 | 74 | 25 | 58.1% (43.3-70.3%) | 1 | <0.001 | 74 | 3 | 95.9% (84.6-99%) | 1 | 0.003 |
| 1 | 43 | 22 | 45.1% (28.5-60.3%) | 1.65 (0.93-2.93) | 43 | 6 | 92.3% (72.6-98%) | 3.01 (0.75-12.05) | ||
| 2 | 189 | 127 | 25.3% (18.4-32.7%) | 2.82 (1.83-4.33) | 189 | 44 | 77.7% (69.8-83.7%) | 5.6 (1.74-18.06) | ||
p values were obtained using the log-rank test for categorical variables and Wald test based on Cox proportional hazards model for continuous variables; p value and HR are not provided if certain level event counts <3.
PFS = progression-free survival; OS = overall survival; STIC = serous tubal intraepithelial carcinoma; ASA = American Society of Anesthesiologists; NR = not reached; NE = not estimable; HR = hazard ratio; yr = year; BMI = body mass index; FIGO = International Federation of Gynecology and Obstetrics; CGR = complete gross resection
Figure 1.
Progression-free survival (PFS) and overall survival (OS) of patients who underwent primary debulking surgery for high-grade serous ovarian cancer stratified by the presence or absence of concurrent serous tubal intraepithelial carcinoma (STIC).
There were 53 deaths within the entire cohort at the time of analysis, and the median OS had not been reached for either cohort. Survival was similar between the two groups (p=0.392), with 3-year OS rates of 81% (95% CI, 70-88%) and 85% (95% CI, 78-90%) for patients with and without concurrent STIC, respectively (Table 2 and Figure 1).
In contrast to the presence of concurrent STIC, known prognostic factors such as residual disease after cytoreduction, presence of ascites, somatic BRCA mutations, and high tumor burden index were strongly associated with shorter PFS and OS in our analysis (Table 2).
Genetic analysis
Targeted DNA-sequencing was performed on the samples (primary or metastasis) of 147 patients (48%)—38 (44%) of the 87 +STIC patients and 109 (50%) of the 218 no-STIC patients—and identified 795 oncogenic alterations (mutations, CNAs, fusions). TMB and FGA were similar between both groups (TMB, p=0.67; FGA, p=0.30), and no patients in either group had an MSIsensor score ≥10 or a TMB ≥25 Mbs, a level consistent with microsatellite instability (Figure 2A). The most commonly altered genes were TP53 (97%), AGO2 (16%), MYC (15%), CCNE1 (12%), and NF1 (10%) (Figure 2C). Both MYC and AGO2 amplifications were encompassed within a broader amplification on the q arm of chromosome 8, while CCNE1 amplifications were part of a broader amplification on the q arm of chromosome 19. The majority of genes belonged to four key pathways; the most common were aberrations to TP53 (144/147, 98%), RTK/RAS signaling (51/147, 35%), the PI3K pathway (51/147, 35%), and cell cycle genes (37/147, 25%) (Figure 2B). Somatic BRCA1/2 alterations were found in 6% (n=5) of patients in the +STIC group and 5% (n=11) in the no-STIC group. Overall, the distribution of driver mutations or structural genetic alterations and affected genetic signaling pathways were similar between the two cohorts.
Figure 2:
(A) The distribution of tumor mutation burden (TMB) and fraction of genome altered (FGA) in patients with high-grade serous ovarian cancer and concurrent serous tubal intraepithelial carcinoma (+STIC) or without STIC (no-STIC). Box plots represent medians and interquartile ranges, and vertical lines extend to the 95th percentiles. Individual patient outliers of high TMB are represented with dots. (B) Distribution of driver mutations or structural genetic alterations occurring with a frequency of greater than 5% in tumors with or without concurrent STIC. (C) OncoPrint representation of the genetic alterations occurring in +STIC vs. no-STIC tumors, including a detailed breakdown of the cell cycle and PI3K/RAS pathway genes.
Discussion
As there is no effective screening test to identify premalignant or early-stage neoplasm, and early-stage disease is associated with minimal symptoms, most patients with epithelial ovarian cancer present with advanced disease, for whom prognosis is poor [1]. To address this unmet clinical need, the elucidation of the early pathogenesis of this disease to improve early detection and to develop new preventive strategies is highly warranted. There is now overwhelming evidence showing that the majority of HGSCs originate in epithelial cells of the distal fallopian tube in the form of STIC and not in the ovarian epithelium itself, as was initially proposed [2, 13-16].
Interestingly, in incidental HGSCs of asymptomatic women undergoing risk-reducing salpingo-oophorectomy (RRSO) for germline BRCA 1 or 2 mutations, an associated STIC lesion can be detected in nearly 100% of the resected fallopian tubes [14, 17]. In advanced tumors, however, they are found less frequently. This paradox of high rate in an early and low rate in an advanced HGSC has led to the emerging theory of early “precursor escape” [18, 19]. In this new model, proposed by Soong et al., early secretory cell proliferation (ESP) with non-malignant TP53 mutations are shed from the fallopian tube and undergo a subsequent malignant transformation in the peritoneal cavity. Based on this dualistic model of carcinogenesis, HGSC can arise either from a STIC in the distal fallopian tubes with later spread to the ovaries and peritoneum or as a consequence of malignant transformation of detached early precursor lesions in the peritoneum without concurrent STIC lesions in the fallopian tube. The clinical significance of coexisting STIC in advanced ovarian cancer at the time of initial cytoreductive surgery has not yet been fully explored in the literature.
In this analysis, we described the clinicopathological characteristics and genetic sequencing profiles of 306 women with or without concurrent STIC at the time of primary cytoreduction for advanced HGSC, representing one of the largest series to date, coupled with detailed clinical annotation of oncologic outcomes. We identified a concurrent STIC in 28% of our cases, a rate similar to those of previously published studies [3]. In a meta-analysis of 10 studies with 1643 patients with HGSC, Chen et al. reported concurrent STICs with HGSCs in 31% (95% CI, 17-46%) of the resected fallopian tubes [3], with frequencies ranging from 11% to 61% across studies. Interestingly, in the current study, the majority of patients in the no-STIC group nevertheless had evidence of fallopian tube involvement by HGSC, leaving only 34 patients in the entire cohort (11%) with benign unremarkable fallopian tubes. This suggests that the frequency of reported STICs in our study may underestimate the true number of HGSCs originating from the fallopian tube, since tumor overgrowth or metastatic colonization may obliterate focal STIC lesions in those cases of overt tubal involvement by HGSC. In such advanced-stage cases, pathologists may not explicitly mention the presence of STIC in the pathology report, since the morphologic distinction between STIC versus tumor overgrowth or mucosal involvement by metastatic HGSC is oftentimes subjective. Given the lack of any clinical significance in making this distinction, a designation of “positive for fallopian tube involvement” often suffices. n our series, there were no significant associations between the presence of a concurrent STIC lesion with specific clinicopathological characteristics or oncologic outcomes. Specifically, the presence of a STIC was not associated with compromised PFS or OS, in contrast to other known prognostic confounders assessed in our study, including residual disease status, presence of ascites, and tumor burden index. Of note, patients found to not have concurrent STIC had significantly higher preoperative CA-125 levels. As CA-125 is a surrogate for tumor burden, this finding might be partially explained by obliteration of STIC by tumor overgrowth in some of the advanced-stage patients in the no-STIC group.
The incidence of STIC has been studied primarily in patients with a genetic, elevated risk for the development of HGSC, such as BRCA 1 and 2 carriers who have undergone RRSO [20]. The rate of incidental STIC in the general population is still unknown. In our study, we could not detect a link between the presence of a somatic or germline alteration in the two BRCA susceptibility genes and the detection of a concurrent STIC lesion, as the incidence of BRCA mutations was nearly identical among both groups of patients.
In addition, targeted sequencing could not detect any specific genetic mutational profile for patients with a concurrent STIC lesion. This is consistent with the findings of Ducie et al. [21]. The authors showed via a comprehensive genomic analysis of advanced-stage HGSC that most somatic CNAs were identical between women with and without STIC lesions. Additionally, there were no observed differences between the two groups using messenger RNA-sequencing and micro-RNA profiling, indicating a common clonal origin. In their study, the authors also did not detect differences in PFS (p=0.56) and OS (p=0.08) between +STIC and no-STIC patients, without providing any further details on survival. These results are very difficult to interpret due to the small sample size (n=85) and the inclusion of patients from three different centers without predefined study periods, which consequently has a pronounced risk of selection bias. Furthermore, median follow-up time and known predictive clinical factors such as CGR rate, BRCA status, presence of ascites, and preoperative CA-125 levels were not reported, possibly representing unbalanced groups with misleading results and conclusions. Based on the currently available data, the finding of an STIC lesion in the fallopian tube of a patient with advanced-stage HGSC portends no clinical significance and therefore should not alter clinical care or decision to refer for genetic testing. Furthermore, the SEE-FIM protocol on these patient specimens can be safely omitted from routine care, offering a potential resource and cost savings. Moreover, rather than enforcing formalin fixation of fallopian tubes in their entirety as a clinical necessity, portions of fresh tubal tissue may be safely allocated for translational research in light of the high rate of both precursor and invasive tubal lesions in advanced-stage HGSC.
The limitations of our study include the inherent biases associated with a retrospective review and analysis of patients. Furthermore, a more precise and comprehensive genetic analysis with whole-exome or whole-genome sequencing may have identified additional unique molecular genetic profiles, but such an approach in this cohort was not feasible due to the higher costs and associated extended time for analysis. Finally, patients were categorized based on the presence or absence of a concurrent STIC fallopian tube lesion as documented in the diagnostic surgical pathology report. Even though a comprehensive assessment of STIC lesions using SEE-FIM was routinely performed, some of the tumors in the no-STIC group were likely derived from the fallopian tube, since subtle focal lesions may not have been identified during pathologic assessment. It has been recognized that the routine evaluation of a single H&E slide misses a proportion of small tubal precursor lesions that can emerge upon examination of additional deeper sections [22]. As previously discussed, the issue concerning obliteration of pre-existing STIC by tumor overgrowth or metastatic mucosal colonization presumably led to cases being misclassified into the no-STIC group, but conversely, it is also conceivable that some of the lesions designated as STIC may, in fact, be metastatic carcinoma mimicking STIC [23].
Regardless, our data continue to support the important role of the fallopian tube in the pathogenesis of HGSC, with 28% of patients having an STIC lesion and 89% of patients having either an STIC lesion or involvement of the tube by overt carcinoma. The natural history of HGSC associated with STIC is comparable, if not identical, to that of HGSC without associated STIC. Therefore, it can be theorized that the site of malignant transformation of precursor lesions, whether the fallopian tube, the ovarian surface, or the peritoneum, may not directly impact the overall course of the disease. Without question, further research is needed to elucidate the mechanism and associated factors of malignant transformation of HGSC precursor lesions.
Highlights.
Concurrent STIC lesion is common in patients with advanced HGSC of the ovary
There was no difference in germline genetics between patients with advanced ovarian HGCS with or without concurrent STIC
There was no difference in clinical outcomes between patients with advanced ovarian HGCS with or without concurrent STIC
Acknowledgments
Funding: This research was supported in part by the NIH/NCI Memorial Sloan Kettering Cancer Center support grant P30 CA008748
Footnotes
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Conflict of Interest Statement
Outside the submitted work, Dr. Iasonos reports personal fees from Mylan. Dr. Grisham reports personal fees from Clovis, Mateon, Regeneron, Verastem, Amgen, and Medscape, as well as a Conquer Cancer Foundation Career Development Grant (CDA) supported by Amgen; she has also received academic grants from Cycle for Survival, OCRFA, and Kaleidoscope of Hope. Dr. Aghajanian reports personal fees from Tesaro, Immunogen, Abbvie, Roche/Genentech, Eisai/Merck, Mersana Therapeutics, Clovis, and AstraZeneca, as well as grants from Genentech, AbbVie, and AstraZeneca. Dr. O'Cearbhaill reports personal fees from Tesaro, GlaxoSmithKline, Regeneron , and Genmab Therapeutics, as well as other (meal) from Genentech USA; she is also a non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK) and DUO-O (AstraZeneca) studies; she also reports funding to her institution for clinical research from Celgene/Juno, Tesaro/GSK, Ludwig Cancer Institute, Abbvie, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, and the Gynecologic Oncology Foundation. Dr. Chi reports personal fees from Bovie Medical Co., Verthermia Inc. (now Apyx Medical Corp.), C Surgeries, and Biom ‘Up. He also reports previous stock ownership in Intuitive Surgical, Inc. and TransEnterix, Inc. Dr. Abu-Rustum reports grants from Stryker/Novadaq, Olympus, and GRAIL. The other authors have nothing to disclose.
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