# Cervical Pathology: HSIL, Adenocarcinoma In Situ, and Invasive Carcinoma

## Introduction

Cervical neoplasia remains a leading cause of cancer mortality worldwide despite effective screening and HPV vaccination programs. The pathologist must accurately diagnose squamous and glandular precursor lesions, assess invasion, and apply the updated WHO classification. **High-risk HPV** (hrHPV), particularly types 16 and 18, drives the vast majority of cervical neoplasms.

## HPV Biology and Carcinogenesis

The **E6 oncoprotein** degrades p53, preventing apoptosis, while the **E7 oncoprotein** inactivates Rb, driving uncontrolled cell proliferation. E7-mediated Rb inactivation causes **p16 overexpression**, which forms the basis for p16 immunohistochemistry in diagnostic practice. Integration of HPV DNA into the host genome is a critical step in the transition to malignant transformation.

## Squamous Intraepithelial Lesions

### Low-Grade Squamous Intraepithelial Lesion (LSIL / CIN 1)

LSIL is characterized by koilocytic change with perinuclear halos, nuclear enlargement, and binucleation. Dysplastic changes are confined to the **lower third** of the epithelium. Most LSILs regress spontaneously and are managed with surveillance alone.

### High-Grade Squamous Intraepithelial Lesion (HSIL / CIN 2-3)

In HSIL, dysplastic cells extend into the **upper two-thirds (CIN 2)** or involve the **full thickness (CIN 3)** of the epithelium. There is loss of maturation, increased mitoses including abnormal forms, and a high nuclear-to-cytoplasmic ratio. **p16 immunohistochemistry** showing strong, diffuse, block-positive staining supports the diagnosis of HSIL. Notably, CIN 2 with negative or patchy p16 may represent an LSIL mimic, and p16 use is recommended per LAST guidelines in such cases.

![HSIL (CIN 3) with full-thickness dysplasia and block-positive p16](images/hsil-p16.jpg)

## The LAST Project and p16

The **Lower Anogenital Squamous Terminology (LAST)** project standardized a two-tier nomenclature for squamous lesions: LSIL and HSIL. p16 immunohistochemistry is recommended when morphology is ambiguous between LSIL and HSIL (such as a CIN 2 equivalent) and when distinguishing HSIL from mimics like immature squamous metaplasia, atrophy, or tangential sectioning. Block-positive p16 is defined as continuous, strong nuclear and cytoplasmic staining.

## Adenocarcinoma In Situ (AIS)

AIS is the precursor to invasive **endocervical adenocarcinoma**. The glands are lined by pseudostratified, hyperchromatic cells with **apical mitoses and apoptotic debris**, but architecture is preserved without stromal invasion or desmoplasia. AIS is **p16 block-positive** and HPV-associated in the vast majority of cases. Margin status on cone biopsy is critical because positive margins confer significant risk of residual AIS or progression to invasive carcinoma.

## Invasive Squamous Cell Carcinoma

Squamous cell carcinoma is the most common cervical malignancy. It features irregular nests and tongues of squamous cells invading the stroma with a **desmoplastic reaction**. Depth and horizontal extent of invasion determine **FIGO staging**. **Superficially invasive carcinoma (FIGO Stage IA)** measures 5 mm or less in depth and is often amenable to conservative management. The pathology report should document depth of invasion in millimeters, horizontal extent, lymphovascular invasion (LVI), and margin status. Variants include keratinizing and non-keratinizing squamous cell carcinoma, as well as basaloid, verrucous, and papillary forms.

![Invasive squamous cell carcinoma of the cervix with stromal desmoplasia](images/cervical-scc.jpg)

## Invasive Endocervical Adenocarcinoma

### HPV-Associated (Usual Type)

The usual type is the most common endocervical adenocarcinoma and shows strong **p16 block-positive** staining. Apical mitoses and mucinous or endometrioid differentiation are typical. The Silva pattern classification provides prognostic stratification: **Pattern A** has well-demarcated glands without destructive invasion, **Pattern B** shows early or localized destructive invasion, and **Pattern C** demonstrates diffuse destructive invasion.

| Silva Pattern | Invasion Type | LN Metastasis Risk | Management Implications |
|---|---|---|---|
| A | Well-demarcated, no destructive invasion | Near 0% | May allow conservative management |
| B | Early/localized destructive invasion | Low (~5%) | Standard treatment |
| C | Diffuse destructive invasion | Higher (~25%) | Aggressive treatment |

### HPV-Independent Types

**Gastric type** adenocarcinoma features mucinous cells with voluminous cytoplasm and is p16 negative with aggressive behavior. It is often associated with **Peutz-Jeghers syndrome** or lobular endocervical glandular hyperplasia (LEGH). Clear cell and mesonephric types are also HPV-independent.

## Staging and Reporting

FIGO 2018 staging now incorporates **lymph node status** as Stage IIIC. Synoptic reporting includes tumor type, size, depth of invasion, LVI, margin status, and lymph node assessment. **Sentinel lymph node** evaluation with ultrastaging is increasingly used in clinical practice.

![Silva pattern classification for endocervical adenocarcinoma](images/silva-pattern.jpg)

## Clinical Pearls

Block-positive p16 is required to diagnose HSIL in morphologically ambiguous cases per LAST guidelines. AIS on cone biopsy with positive endocervical margins warrants re-excision or hysterectomy. The Silva pattern system for endocervical adenocarcinoma provides meaningful prediction of lymph node metastasis risk. HPV-independent adenocarcinomas, especially gastric type, carry a worse prognosis and require distinct clinical management strategies.

## References

1. Darragh TM, et al. The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions. *Arch Pathol Lab Med*. 2012;136(10):1266-1297.
2. WHO Classification of Tumours Editorial Board. Female Genital Tumours. 5th ed. Lyon: IARC Press; 2020.
3. Silva EG, et al. Invasive endocervical adenocarcinoma: a new pattern-based classification. *Am J Surg Pathol*. 2013;37(7):1051-1060.
4. Bhatla N, et al. Revised FIGO staging for carcinoma of the cervix uteri. *Int J Gynaecol Obstet*. 2019;145(1):129-135.