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. 2023 Dec 1;47(12):1376-1389.
doi: 10.1097/PAS.0000000000002122. Epub 2023 Sep 13.

Incidence and Clinicopathologic Characteristics of Human Papillomavirus-independent Invasive Squamous Cell Carcinomas of the Cervix: A Morphologic, Immunohistochemical, and Human Papilloma-Virologic Study of 670 Cases

Simona Stolnicu  1 , Douglas Allison  2 , Aaron M Praiss  3 , Basile Tessier-Cloutier  2 , Amir Momeni Boroujeni  2 , Jessica Flynn  4 , Alexia Iasonos  4 , Rene Serrette  2 , Lien Hoang  5 , Andrei Patrichi  1 , Cristina Terinte  6 , Anna Pesci  7 , Claudia Mateoiu  8 , Ricardo R Lastra  9 , Takako Kiyokawa  10 , Rouba Ali-Fehmi  11 , Mira Kheil  11 , Esther Oliva  12 , Kyle M Devins  12 , Nadeem R Abu-Rustum  3   13 , Robert A Soslow  2
Affiliations

Incidence and Clinicopathologic Characteristics of Human Papillomavirus-independent Invasive Squamous Cell Carcinomas of the Cervix: A Morphologic, Immunohistochemical, and Human Papilloma-Virologic Study of 670 Cases

Simona Stolnicu et al. Am J Surg Pathol. .

Abstract

We aimed to determine the frequency of human papillomavirus-independent (HPVI) cervical squamous cell carcinoma (SCC) and to describe clinicopathologic characteristics. Among 670 patients with surgically treated SCCs in an established multi-institutional cohort, 447 had available tissue. Tissue microarrays were constructed and studied by in situ hybridization (ISH) for high-risk and low-risk human papillomavirus (HPV) mRNA and immunohistochemistry for p16 and p53. Tumors were HPVI if negative by HPV ISH and they failed to show diffuse p16 positivity by immunohistochemistry, and human papillomavirus-associated (HPVA) if positive by HPV ISH. Ten HPVI SCCs and 435 HPVA SCCs were identified; 2 cases were equivocal and excluded from analysis. The overall rate of HPVI SCC was low (2%) but was higher among older patients (7% in patients above 60 y of age and 17% in patients above 70 y of age). Compared with HPVA, patients with HPVI SCC were significantly older (median age, 72 vs. 49, P <0.001) and diagnosed at a higher stage (40% vs. 18% with stage III/IV disease, P =0.055). p53 expression was varied; 2 cases (20%) had null expression and 8 (80%) had wild-type expression. HPVI SCCs were heterogenous, with keratinizing, nonkeratinizing, and warty morphologies observed. Several cases had a precursor lesion reminiscent of differentiated vulvar intraepithelial neoplasia, with prominent basal atypia and hypereosinophilia or a basaloid-like morphology. Two patients (20%) had distant recurrences within 12 months, and 3 (30%) died of disease during follow-up. HPVI SCCs are rare tumors that are more common among older patients with higher stage disease and have important clinical and histologic differences from HPVA SCCs.

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Conflict of interest statement

Conflicts of Interest and Source of Funding: Funded in part by the National Institutes of Health (NIH)/National Cancer Institute (NCI) Cancer Center Support Grant P30 CA008748. Outside the submitted work, N.R.A.-R. reports research funding paid to the institution from GRAIL. A.I. reports consulting fees from Mylan. For the remaining authors none were declared.

Figures

Figure 1:
Figure 1:
HPVA SCC keratinizing growth pattern. Low power illustrating tumor cell nests (A) with numerous keratin pearls (B); p16 is block-type diffusely positive (C); p53 is wild type (D); HR-HPV is positive (E) HPVA, human papillomavirus-associated; SCC, squamous cell carcinoma; HR-HPV, high-risk human papillomavirus
Figure 2:
Figure 2:
HPVA SCC nonkeratinizing growth pattern. Low power illustrating tumor cell nests (A) without keratin pearls (B); p16 is block-type diffusely positive (C); p53 is wild type (D); HR-HPV is positive (E) HPVA, human papillomavirus-associated; SCC, squamous cell carcinoma; HR-HPV, high-risk human papillomavirus
Figure 3:
Figure 3:
HPVI SCC keratinizing growth pattern. Low power illustrating tumor cell nests (A) with numerous keratin pearls (B); p16 is patchy negative (C); p53 is wild type (D); HR-HPV is negative (E) HPVI, human papillomavirus-independent; SCC, squamous cell carcinoma; HR-HPV, high-risk human papillomavirus
Figure 4:
Figure 4:
High power illustrating tumor cell nests without keratin pearls (A); p16 is patchy negative (B); p53 is wild type (C); HR-HPV is negative (D) HR-HPV, high-risk human papillomavirus
Figure 5:
Figure 5:
Spectrum of HPVI precursor lesions. Basaloid-like morphology (A); dVIN-like morphology (B); precursor lesion on H&E staining (C) with p53 wild-type expression (D) and negative for HR-HPV (E) HPVI, human papillomavirus-independent; dVIN, differentiated vulvar intraepithelial neoplasia; H&E, hematoxylin-eosin; HR-HPV, high-risk human papillomavirus
See this image and copyright information in PMC

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