Endocervical adenocarcinoma with non–block-type p16 staining mimicking an endometrial primary: a case report

Authors

Abstract

Introductionp16 immunohistochemistry is widely used as a surrogate marker for human papillomavirus (HPV)-associated cervical carcinoma. Non–block-type staining may complicate interpretation, particularly in resource-limited settings without molecular HPV testing.
Case PresentationA 51-year-old woman presented with abdominal pain, contact bleeding, and vaginal spotting. Cervical biopsy showed invasive adenocarcinoma with endometrioid-like morphology. Tumor cells were carcinoembryonic antigen (CEA) positive and estrogen receptor (ER), vimentin, and Napsin A negative, supporting cervical origin. Supplementary p16 showed weak, patchy, non–block-type staining, while Ki-67 showed a high proliferative index. Molecular HPV testing was unavailable.
ConclusionThis case highlights the importance of integrated morphologic and immunophenotypic assessment when interpreting non–block-type p16 staining to avoid misclassification as an endometrial primary.

Keywords

Introduction

Cervical carcinoma remains a major cause of cancer morbidity and mortality worldwide, particularly in low- and middle-income regions. Accurate histopathologic diagnosis is essential for appropriate classification and clinical management.¹ While evaluation of hematoxylin and eosin (H&E)-stained sections remains the diagnostic cornerstone, immunohistochemistry is widely used as an adjunct in morphologically challenging cases.
Current classification systems recognize both human papillomavirus (HPV)-associated and HPV-independent endocervical adenocarcinoma pathways; therefore, p16 immunostaining should be interpreted in that context. Among ancillary markers, p16 immunohistochemistry is routinely applied as a surrogate marker for high-risk HPV-associated cervical carcinoma, with diffuse block-type nuclear staining regarded as characteristic. However, reduced or non–block-type p16 expression may occur in invasive cervical carcinomas and represents a recognized diagnostic challenge when interpreted in isolation.^2,3 This report describes an invasive cervical adenocarcinoma with non–block-type p16 expression, emphasizing a practical diagnostic approach and the importance of integrated morphologic and immunophenotypic assessment in routine pathology practice.

Case Presentation

A 51-year-old woman presented with abdominal pain, contact bleeding, and vaginal spotting. She was initially referred with a clinical impression of a 3 × 3 cm uterine fibroid. Pelvic imaging showed a thin endometrium measuring approximately 3 mm and a posterior intramural uterine fibroid, with no findings suggestive of an endometrial primary malignancy. However, subsequent clinical evaluation revealed a cervical mass. A cervical biopsy was obtained and submitted for histopathologic evaluation.
Histological examination of H&E-stained sections revealed an invasive malignant glandular neoplasm composed of irregular infiltrative glands with an endometrioid-like architectural pattern (Figure 1). The glands were lined by atypical columnar cells with eosinophilic cytoplasm and enlarged pleomorphic hyperchromatic nuclei, along with increased mitotic activity. A focal solid growth pattern raised concern for poor differentiation; however, definitive squamous differentiation was not identified. The tumor was associated with a prominent lymphocytic inflammatory infiltrate.
To distinguish a cervical primary from an endometrial mimic, an initial immunohistochemical panel was performed. The tumor cells were positive for carcinoembryonic antigen (CEA) and negative for estrogen receptor (ER), vimentin, and Napsin A, supporting a cervical primary. Based on the integrated histomorphologic findings and site-of-origin markers, a diagnosis of invasive cervical adenocarcinoma, grade II, was made. Following the diagnosis, the patient was referred to a specialized oncology service for staging and definitive management. Because our facility served only as the initial diagnostic center, long-term clinical follow-up and survival outcomes were unavailable.
To further characterize the case in a resource-limited setting, supplementary immunohistochemical evaluation using available surrogate markers was subsequently performed. Additional histopathological review was performed on formalin-fixed, paraffin-embedded cervical biopsy tissue stained with H&E. Immunohistochemistry for p16 and Ki-67 was performed according to routine laboratory protocols. These markers were available in our laboratory but were not included in the initial routine diagnostic workup. p16 showed a non–block-type pattern characterized by weak, patchy, predominantly cytoplasmic staining and absence of diffuse block-type nuclear positivity (Figure 2), findings not supportive of HPV-associated block-type staining. Ki-67 showed a high labeling index with numerous positively stained tumor nuclei, consistent with high proliferative activity (Figure 3). The detailed data are provided in Supplementary Table 1.
Molecular HPV testing was not performed because it was unavailable within the institutional diagnostic workflow; therefore, HPV status remained unconfirmed. These supplementary findings provided additional interpretive context; however, they were obtained after sign-out as part of an internal diagnostic evaluation, and no amended report was issued.
Ethical ApprovalThe study was approved by the Ethics Committee of King Faisal Medical Complex, Taif, Saudi Arabia (Date: 19.02.2024, Decision No: 2024-E-10).
Reporting GuidelinesThis case report is presented in accordance with the Case report guidelines (CARE) guidelines.

Discussion

The 2020 WHO classification of female genital tumors classifies endocervical adenocarcinomas into HPV-associated and HPV-independent pathways. Diffuse block-type p16 staining is widely accepted as a useful surrogate marker supporting HPV-associated lesions. In contrast, negative, patchy, or non–block-type p16 staining patterns may be encountered in HPV-independent tumors and can complicate interpretation when p16 is used in isolation.^2,4,5
Molecular HPV testing was not available, HPV status remains unconfirmed. However, the absence of diffuse block-type p16 staining, interpreted together with the morphology and the immunoprofile excluding an endometrial primary, raised consideration of an HPV-independent pathway in this case, particularly in a resource-limited setting. Similar discordant p16 staining patterns have been reported in HPV-independent cervical carcinomas, underscoring the limitations of p16 as a standalone diagnostic marker.^1,6
Navigating this atypical immunophenotype requires a structured diagnostic approach to avoid clinically significant misclassification. Because the tumor exhibited an endometrioid-like appearance and the patient had a documented intramural fibroid, distinguishing the lesion from an endometrial primary mimic was a critical first step. The immunohistochemical profile, showing CEA positivity and negativity for ER and vimentin, supported a cervical origin.
This case demonstrates the diagnostic value of expanding immunohistochemical assessment beyond basic site-of-origin markers in resource-limited workflows. In routine practice, diagnosis may conclude at a broad category such as grade II adenocarcinoma. In this case, supplementary use of p16 and Ki-67, both available in our facility but not included in the initial workup, provided additional interpretive context. The non–block-type p16 pattern was not supportive of HPV-associated block-type staining and raised consideration of an HPV-independent pathway in the differential diagnosis, while Ki-67 supported high proliferative activity. This distinction may be clinically relevant because HPV-independent cervical carcinomas have been associated with less favorable outcomes and more aggressive behavior in published studies, although definitive pathway assignment requires molecular confirmation.⁷
Reduced p16 expression may reflect true biological mechanisms, including HPV-independent oncogenic pathways, partial disruption of the retinoblastoma pathway, tumor heterogeneity, or tumor dedifferentiation.6 In this case, Ki-67 immunohistochemistry confirmed high proliferative activity, supporting the malignant nature of the lesion, although it was not used as a surrogate marker for HPV status.⁸

Limitations

This case report has several limitations. First, the unavailability of molecular HPV DNA or RNA testing precluded definitive confirmation of the tumor’s biologic pathway. Additional markers, including p53 and gastric differentiation markers, were also unavailable in our laboratory workflow. Second, because our institution functioned only as the primary diagnostic center, long-term clinical follow-up and details of the patient’s oncologic management were not available.

Conclusion

Despite these limitations, this case highlights a practical diagnostic approach for navigating complex cervical pathology in a resource-limited setting. Awareness of atypical non–block-type p16 staining patterns and their potential association with HPV-independent pathways is important to avoid diagnostic misclassification, particularly confusion with endometrial mimics, in routine pathology practice.

Declarations

Abbreviations

CARE: Case report guidelines
CEA: Carcinoembryonic antigen
ER: Estrogen receptor
H&E: Hematoxylin and eosin
HPV: Human papillomavirus

References

1. Nicolás I, Marimon L, Barnadas E, et al. HPV-negative tumors of the uterine cervix. Mod Pathol. 2019;32(8):1189-1196.
   PubMed Google Scholar
2. Kulhan M, Bilgi A, Avci F, et al. Is HPV-negative cervical carcinoma a different type of cervical cancer? Eur Rev Med Pharmacol Sci. 2023;27(19):9205-9212.
   PubMed Google Scholar
3. Ribeiro EA, Maleki Z. p16 immunostaining in cytology specimens: its application, expression, interpretation, and challenges. J Am Soc Cytopathol. 2021;10(4):414-422.
   PubMed Google Scholar
4. Rokutan-Kurata M, Minamiguchi S, Kataoka TR, Abiko K, Mandai M, Haga H. Uterine cervical squamous cell carcinoma without p16 (CDKN2A) expression: heterogeneous causes of an unusual immunophenotype. Pathol Int. 2020;70(7):413-421.
   PubMed Google Scholar
5. International Agency for Research on Cancer. Female Genital Tumours. WHO Classification of Tumours. Published 2020. Accessed February 21, 2026.
   PubMed Google Scholar
6. Arezzo F, Cormio G, Loizzi V, et al. HPV-negative cervical cancer: a narrative review. Diagnostics (Basel). 2021;11(6):952.
   PubMed Google Scholar
7. Stolnicu S, Rakislova N, Morató A, et al. Cervical human papillomavirus-independent squamous cell carcinoma: a clinicopathological review and outcomes analysis compared with human papillomavirus-associated squamous cell carcinoma. Mod Pathol. 2025;38(6):100742.
   PubMed Google Scholar
8. Popiel-Kopaczyk A, Grzegrzolka J, Piotrowska A, et al. The expression of Testin, Ki-67 and p16 in cervical cancer diagnostics. Curr Issues Mol Biol. 2023;45(1):490-500.
   PubMed Google Scholar

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About This Article

Received:

March 8, 2026

Accepted:

May 17, 2026

Published Online:

May 17, 2026