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. 2024 Apr 1;48(4):475-486.
doi: 10.1097/PAS.0000000000002187. Epub 2024 Feb 1.

Morphologic and Molecular Heterogeneity of High-grade Serous Carcinoma Precursor Lesions

Yen-Wei Chien  1   2 , Yeh Wang  3 , Peng Huang  2   3 , Barrett Craig Lawson  4 , David L Kolin  5 , M Herman Chui  6 , Russell Vang  3 , Tricia A Numan  3 , T Rinda Soong  7 , Brant G Wang  8   9   10 , Saron Ann Smith  11 , Chi-Long Chen  12 , Rebecca Stone  1 , Christopher Douville  2 , Tian-Li Wang  1   3 , Ie-Ming Shih  1   3
Affiliations

Morphologic and Molecular Heterogeneity of High-grade Serous Carcinoma Precursor Lesions

Yen-Wei Chien et al. Am J Surg Pathol. .

Abstract

Serous tubal intraepithelial carcinoma (STIC) is the fallopian tube precursor lesion for most cases of pelvic high-grade serous carcinoma (HGSC). To date, the morphologic, molecular, and clinical heterogeneity of STIC and a less atypical putative precursor lesion, termed serous tubal intraepithelial lesion, has not been well characterized. Better understanding of precursor heterogeneity could impact the clinical management of women with incidental STICs (without concurrent carcinoma) identified in cases of prophylactic or opportunistic salpingectomy. This study analyzed morphologic and molecular features of 171 STICs and 21 serous tubal intraepithelial lesions. We assessed their histologic features, Ki-67 and p53 staining patterns, and genome-wide DNA copy number alterations. We classified all precursor lesions into 2 morphologic subtypes, one with a flat surface (Flat) and the other characterized by budding, loosely adherent, or detached (BLAD) morphology. On the basis of pathology review by a panel of 8 gynecologic pathologists, we found 87 BLAD, 96 Flat, and 9 indeterminate lesions. As compared with Flat lesions, BLAD lesions were more frequently diagnostic of STIC ( P <0.0001) and were found concurrently with HGSC ( P <0.0001). BLAD morphology was also characterized by higher Ki-67 proliferation index ( P <0.0001), presence of epithelial stratification ( P <0.0001), and increased lymphocyte density ( P <0.0001). BLAD lesions also exhibited more frequent DNA copy number gain/amplification at the CCNE1 or CMYC loci canonical to HGSCs ( P <0.0001). Both BLAD morphology and STIC diagnoses are independent risk factors for an elevated Ki-67 proliferation index. No correlation was observed between BLAD and Flat lesions with respect to patient age, presence of germline BRCA1/2 mutation, or p53 staining pattern. These findings suggest that tubal precursor lesions are morphologically and molecularly heterogeneous, laying the foundation for further studies on the pathogenesis of HGSC initiation and identifying histologic features predictive of poor patient outcomes.

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Conflict of interest statement

Supported by the Break Through Cancer (BTC-IOC), the Richard W. TeLinde Endowment from the Johns Hopkins University, NIH/NCI (U2CCA271891, P50CA228991, R01CA260628, and R01CA215483). C.D. is a consultant to Exact Sciences and has been paid in equity and income. C.D. is a founder of Belay Diagnostics. C.D. is an inventor of some technologies. The companies named above as well as other companies have licensed previously described technologies related to the work described in this paper from Johns Hopkins University. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors as well as Johns Hopkins University. The terms of all of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Figures

FIGURE 1
FIGURE 1
Study design and case selection. A, Flowchart schematically showing sequential case selection, pathologic review, and data analysis. B, Diagnosis of the tubal precursor lesions selected in the cohort.
FIGURE 2
FIGURE 2
Representative photomicrographs of STICs and STILs. H&E (first row), p53 staining (second row), and Ki-67 staining (third row). H&E indicates hematoxylin and eosin staining.
FIGURE 3
FIGURE 3
Representative STICs with BLAD and Flat features. Flat lesions with smooth and intact surface outlined by red lines (left column); BLAD lesions with irregular surface outlined by red lines featuring budding or detached cells marked by green arrows (right column).
FIGURE 4
FIGURE 4
Results of classification of BLAD versus Flat morphological patterns. (A) Numbers and percentages of BLAD, Flat, and indeterminate lesions; (B) Bar graph shows diagnosis of the lesions in each group by percentage.
FIGURE 5
FIGURE 5
Clinicopathologic features in BLAD and Flat lesions. (A) A bar graph showing percentage of BLAD lesions with concurrent HGSC at the time of diagnosis of tubal precursor lesions; (B) A bar graph showing percentage of BLAD lesions with increased lymphocytic infiltrate compared with Flat lesions; (C) Representative lesions with increased lymphocytes (marked by star) compared with adjacent NFT tissue. NFT indicates normal-appearing fallopian tube.
FIGURE 6
FIGURE 6
Comparisons of proliferative activities between BLAD lesions and Flat lesions in the entire cohort (left) and within the subgroup without concurrent HGSC (right). A, Scatter plots showing proliferative status, represented by normalized Ki-67 proliferation index, in BLAD lesions and Flat lesions. B, Percentage in bar graphs showing the distribution of specific aneuploidy patterns in BLAD lesions and in Flat lesions. The BLAD lesions are exclusively associated with the Path 2 aneuploidy pattern characterized by CCNE1 amplification.
FIGURE 7
FIGURE 7
Multivariate analysis in predicting proliferative activity. A, Scatter plots showing synergy by combining BLAD pattern and Path 2 aneuploidy pattern to best predict elevation of Ki-67 index both in the complete cohort analysis (left) and in the subgroup lesions without concurrent HGSC (right). B, Representative lesions of each group with H&E staining (upper row) and with Ki-67 staining (lower row). C, Scatter plot depicting prediction of elevated Ki-67 index in 3 groups of tubal precursor lesions defined by the combination of BLAD versus Flat pattern, layering feature, and STIC diagnosis. H&E indicates hematoxylin and eosin staining.
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