Cervical Carcinoma

Slide 1 · Cervical carcinoma

Etiology · Pathogenesis · Morphology · Spread · Clinicopathologic staging

Histopathology and clinicopathologic correlation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain how high-risk HPV disrupts cell-cycle control and predisposes to malignancy.

Differentiate major cervical carcinoma subtypes by their morphology and pathogenetic associations.

Relate routes of tumor spread to stage, clinical morbidity, and prognosis.

Apply invasion and staging concepts to short diagnostic scenarios.

Slide 3 · The cervix contains two epithelial compartments

Ectocervix: Stratified squamous epithelium.

Endocervical canal: Mucus-secreting columnar epithelium and glands.

Their interface is the squamocolumnar junction; Adjacent immature metaplastic cells are HPV-susceptible.

SQUAMOUS EPITHELIUM

ENDOCERVICAL GLANDS

Stroma

Squamocolumnar junction

Schematic — not histology

Slide 4 · Why the transformation zone matters

Persistent high-risk HPV infection develops in susceptible immature epithelial cells.

Squamous and glandular malignancies arise in a cervix where epithelial differentiation changes across a narrow zone.

The cellular site of infection helps connect HPV biology to the distribution of cervical precursor lesions.

SQUAMOUS EPITHELIUM

ENDOCERVICAL GLANDS

Stroma

Squamocolumnar junction

Schematic — not histology

Slide 5 · Cervical cancer has a major worldwide burden

Cervical carcinoma as the fourth most common cancer in females worldwide.

The text cites an estimated 604,127 new cases in 2020, with more than half proving fatal.

These are textbook-reported, year-specific estimates—not a current annual incidence update.

604,127

Estimated global new cases in 2020 (Robbins)

Slide 6 · Invasive disease typically presents in mid-adulthood

Mean patient age is reported by Robbins as approximately 45–50 years.

This reflects the interval between acquisition or persistence of carcinogenic HPV and the development of invasive disease.

Individual trajectories vary; HPV acquisition alone does not imply inevitable progression.

HPV exposure

Persistent infection

Precursor lesion

Invasive cancer

Slide 7 · Histologic distribution

Squamous cell carcinoma accounts for approximately 80% of cervical cancer.

Adenocarcinoma accounts for approximately 15%.

Adenosquamous and neuroendocrine carcinomas together comprise the remaining approximately 5%.

Squamous carcinoma: ≈80%

Adenocarcinoma: ≈15%

Other: ≈5%

Slide 8 · Most cervical carcinomas are HPV-associated

HPV-associated

HPV-independent

Squamous carcinoma (majority)

Usual-type endocervical adenocarcinoma

Most adenosquamous / neuroendocrine carcinoma

Gastric-type adenocarcinoma

Distinct molecular and clinical behavior

Not prevented by HPV-directed immune responses

Slide 9 · Immature basal and metaplastic cells are susceptible

Mature superficial squamous cells are not the principal target of productive HPV infection.

HPV accesses basal cells where epithelium is injured or undergoing repair.

Immature squamous metaplasia at the squamocolumnar junction creates an important vulnerable field.

Basement membrane — intact

Basal proliferative compartment

Schematic (not a micrograph)

Slide 10 · Viral replication depends on host-cell division

HPV infection begins in immature epithelial cells.

Viral replication becomes prominent in maturing squamous cells.

HPV oncogenic proteins sustain cellular-cycle progression in cells that would ordinarily arrest during maturation.

Basal cell infection

Maturing squamous cell

Viral genome replication

Altered cell-cycle control

Slide 11 · High-risk HPV E7 disables the RB pathway

E7 promotes proteasomal degradation of the RB tumor suppressor.

E7 also inhibits the CDK inhibitors p21 and p27.

Reduced G1 restriction promotes proliferation and contributes to genomic instability.

High-risk HPV E7

RB degradation + p21/p27 inhibition

G1 checkpoint escape

Abnormal proliferation

Slide 12 · High-risk HPV E6 disables p53 protection

E6 binds p53 and promotes its proteasomal degradation.

Compromised p53 signaling weakens responses to DNA damage.

Unrepaired lesions may accumulate while infected epithelial cells continue cycling.

High-risk HPV E6

P53 degradation

Weakened DNA-damage response

Mutation accumulation

Slide 13 · E6 also supports cellular immortalization

High-risk HPV E6 up-regulates telomerase expression.

Telomere maintenance extends proliferative capacity.

Immortalization cooperates with loss of checkpoint surveillance but is not sufficient alone to explain cancer.

High-risk HPV E6

Telomerase up-regulation

Extended proliferative potential

Selection of altered clones

Slide 14 · E6 and E7 cooperate in carcinogenesis

E7 releases cell-cycle restrictions through RB pathway dysfunction.

E6 reduces p53-mediated genome protection and supports telomerase activity.

The combined effect favors persistence and expansion of cells that acquire further oncogenic alterations.

E7

RB / CDK inhibitor disruption

Sustained proliferation

E6

P53 loss + telomerase

Genomic vulnerability

Slide 15 · Viral integration can intensify oncogene expression

Episomal HPV DNA

Integrated HPV DNA

Extrachromosomal viral genome

Typical in productive infection

Often identified in precursor lesions

Viral DNA inserted into host genome

E6/E7 expression may increase

Potential effects on nearby host genes

Slide 16 · Persistence—not exposure alone—drives cancer risk

HPV infection is common, but only a small fraction of infected individuals develop invasive cancer.

Host immune status and additional co-carcinogenic exposures influence regression versus persistence.

Type-specific viral risk is important but cannot reliably predict an individual outcome.

High-risk HPV infection

Immune control / clearance

Persistent infection

Increased risk of HSIL / carcinoma

Alternative outcomes — schematic

Slide 17 · Low-risk and high-risk HPV differ mechanistically

Lower-risk HPV

High-risk HPV

Less effective RB disruption

No high-risk-type p53 degradation

Commonly productive benign lesions

E7 drives RB pathway disruption

E6 drives p53 degradation

Persistent infection may transform cells

Slide 18 · Squamous precursor lesions use a two-tier system

LSIL (CIN 1)

HSIL (CIN 2/3)

Productive HPV infection

Maturation largely preserved

Frequent spontaneous regression

More pronounced cell-cycle dysregulation

Immature cells occupy greater thickness

Substantial malignant potential

Slide 19 · LSIL reflects a productive HPV infection

Viral replication is high in differentiating epithelial cells.

The basal proliferative compartment is modestly expanded.

Koilocytic changes and largely retained maturation distinguish many LSILs from HSILs.

Basement membrane — intact

LSIL: Productive HPV changes

Schematic (not a micrograph)

Slide 20 · HSIL reflects a transforming epithelial lesion

Epithelial maturation becomes progressively reduced.

Immature atypical cells expand into the middle or upper epithelial layers.

The lesion remains intraepithelial until malignant cells breach the basement membrane.

Basement membrane — intact

HSIL: Expanded immature cells

Schematic (not a micrograph)

Slide 21 · The invasion threshold is the key diagnostic boundary

HSIL shows dysplastic full-thickness or partial-thickness epithelial changes with an intact epithelial–stromal interface.

Invasive carcinoma is defined by malignant epithelium infiltrating cervical stroma.

Surface severity alone does not establish stromal invasion.

Malignant nest in stroma

Schematic — epithelial–stromal boundary

Slide 22 · Koilocytic atypia signals HPV-related cytopathic change

Characteristic findings include nuclear enlargement and irregularity.

Hyperchromatic nuclei and perinuclear cytoplasmic halos occur in affected squamous cells.

The morphologic context and epithelial maturation pattern determine LSIL versus HSIL classification.

Slide 23 · P16 and Ki-67 provide supportive information

P16

Ki-67

Cell-cycle dysregulation surrogate

Often increased in high-risk HPV lesions

Interpret with morphology

Proliferation marker

Expansion beyond basal layer

Supports abnormal proliferation

Slide 24 · A precursor is not yet a carcinoma

LSIL is usually managed as a productive viral lesion, not as established malignancy.

HSIL is a premalignant lesion with potential to progress.

Invasive carcinoma adds the ability to infiltrate stroma and access lymphovascular channels.

LSIL

HSIL

Basement membrane breach

Invasive carcinoma

Slide 25 · Squamous and glandular routes differ

Squamous lesions commonly progress through LSIL and HSIL states.

Most HPV-associated endocervical adenocarcinomas develop from adenocarcinoma in situ (AIS).

The relevant epithelial architecture differs, but invasion remains a defining event for both pathways.

Squamous epithelium

HSIL

Squamous carcinoma

Endocervical glands

Adenocarcinoma in situ

Glandular carcinoma

Slide 26 · Cervical carcinoma: Principal histotypes

Squamous carcinoma forms invasive nests and tongues of malignant squamous cells.

Adenocarcinoma forms malignant glandular epithelial structures.

Adenosquamous carcinoma combines both; Neuroendocrine carcinoma is characterized by small- or large-cell morphology.

Squamous

Keratinizing

Nonkeratinizing

Glandular

Adenocarcinoma

Gastric-type exception

Other

Adenosquamous

Neuroendocrine

Slide 27 · Gross growth may be exophytic or infiltrative

Exophytic tumors may form fungating lesions that project from the cervix.

Infiltrative tumors extend into cervical tissue with a less surface-dominant configuration.

Gross configuration does not replace microscopic assessment of type and depth.

Exophytic projection

Infiltrative growth

Gross-form schematic — not a specimen

Slide 28 · Exophytic growth does not determine histologic subtype

Gross descriptor

Microscopic descriptor

Visible mass configuration

Exophytic / fungating

Infiltrative extension

Squamous / glandular differentiation

Tumor–stroma relationship

Pattern of invasion

Slide 29 · Squamous carcinoma invades as nests and tongues

Cohesive malignant squamous epithelial cells form irregular nests or tongues in cervical stroma.

The tumor may be keratinizing or nonkeratinizing.

Stromal location, rather than mere cytologic atypia, establishes invasive behavior.

Separate malignant squamous nests infiltrating stroma

Original schematic — not observed histology

Slide 30 · Keratinizing and nonkeratinizing patterns coexist

Keratinizing SCC

Nonkeratinizing SCC

Squamous differentiation

Conspicuous keratin production

May form keratin pearls

Malignant squamous cells

Keratin less apparent

Invasive nests remain diagnostic

Slide 31 · The basement membrane separates in situ from invasion

Preinvasive cells remain on the epithelial side of the basement membrane.

Tumor cells penetrating the interface enter the cervical stromal compartment.

Measured invasion depth becomes important in superficially invasive carcinoma.

Malignant nest in stroma

Schematic — epithelial–stromal boundary

Slide 32 · Adenocarcinoma creates abnormal malignant glands

Invasive glandular tumors comprise malignant endocervical cells with enlarged hyperchromatic nuclei.

Cytoplasm is relatively mucin depleted in typical HPV-associated lesions.

Darkly staining neoplastic glands contrast with normal paler endocervical epithelium.

Irregular malignant gland profiles in stroma

Original schematic — not observed histology

Slide 33 · Mucin depletion explains the “dark gland” appearance

Normal endocervical glands contain mucin-rich, relatively pale columnar cells.

Neoplastic glands in typical cervical adenocarcinoma show greater nuclear crowding and less cytoplasmic mucin.

The visual contrast reflects altered differentiation and nuclear-to-cytoplasmic balance.

Irregular malignant gland profiles in stroma

Original schematic — not observed histology

Slide 34 · AIS differs from invasive adenocarcinoma

Adenocarcinoma in situ

Invasive adenocarcinoma

Atypical endocervical glands

No destructive stromal invasion

Glandular precursor

Malignant glands in cervical stroma

Invasive growth established

Potential local and metastatic spread

Slide 35 · Adenosquamous carcinoma shows dual differentiation

Tumor contains admixed malignant squamous epithelium and malignant glandular epithelium.

Both components should be recognized within the malignant lesion.

Robbins groups it among rare cervical epithelial malignancies.

Malignant squamous nests

Squamous phenotype

Invasive component

Malignant glands

Glandular phenotype

Invasive component

Slide 36 · Neuroendocrine carcinomas: Small- and large-cell types

Small-cell morphology

Large-cell morphology

Small malignant tumor cells

Neuroendocrine carcinoma category

High-risk HPV association

Larger malignant tumor cells

Neuroendocrine carcinoma category

High-risk HPV association

Slide 37 · A shorter preinvasive interval changes presentation

More rapid progression for adenosquamous and neuroendocrine carcinomas than for typical SCC.

These tumors may be detected at a more advanced stage.

Shorter evolution and advanced presentation contribute to unfavorable clinical behavior.

In situ lesion

Shorter progression interval

Invasive disease

Often advanced presentation

Slide 38 · Gastric-type adenocarcinoma is HPV-independent

HPV-associated adenocarcinoma

Gastric-type adenocarcinoma

Usual type is common

Often AIS precursor

HPV-driven cell-cycle changes

HPV-independent

Gastric-type differentiation

Often aggressive behavior

Slide 39 · STK11 and TP53 in gastric-type adenocarcinoma

Frequent somatic alterations involving STK11 and TP53.

Some tumors occur with Peutz–Jeghers syndrome, associated with germline STK11 alteration.

Somatic tumor changes and inherited susceptibility are distinct genetic contexts.

Somatic tumor pathway

STK11 / TP53 changes

Gastric-type tumor

Hereditary context

Germline STK11

Peutz–Jeghers syndrome

Slide 40 · WHO 2020 emphasizes HPV etiologic classification

The WHO 2020 classification distinguishes HPV-associated and HPV-independent cervical carcinomas.

Gastric-type adenocarcinoma is included among HPV-independent glandular malignancies.

This classification is a contemporary supplement to the Robbins tumor descriptions.

HPV-associated

Squamous carcinoma

Usual-type adenocarcinoma

HPV-independent

Gastric-type adenocarcinoma

Other defined glandular types

Slide 41 · Histotype provides information beyond anatomic stage

Stage

Histotype

Local extension

Regional lymph nodes

Distant dissemination

Cell lineage / morphology

HPV association

Subtype-associated prognosis

Slide 42 · Locoregional extension is a major route of spread

Advanced lesions may extend into paracervical soft tissue.

Contiguous spread can involve vagina, urinary bladder, ureters, and rectum.

Local invasion itself is a major driver of late complications.

Cervix

Paracervical soft tissue

Bladder / ureters

Rectum / vagina

Regional lymph nodes

Distant sites

Routes of spread — schematic

Slide 43 · Paracervical extension reflects loss of confinement

Cervix-confined disease differs from tumors extending beyond the cervix.

Tumor infiltration of adjacent soft tissue expands the anatomic field requiring treatment.

Regional extent is central to clinical staging.

Cervix

Paracervical soft tissue

Bladder / ureters

Rectum / vagina

Regional lymph nodes

Distant sites

Routes of spread — schematic

Slide 44 · Ureteral obstruction can cause hydronephrosis

Tumor encroachment on a ureter can impede urinary drainage.

Urine pressure backs up into the collecting system, producing hydronephrosis.

Advanced obstruction may lead to infection and renal dysfunction.

Cervical tumor extension

Ureter compression / involvement

Hydronephrosis

Renal complications

Slide 45 · Bladder and rectal involvement signal advanced spread

Direct growth into adjacent pelvic organs may occur with advanced disease.

Mucosal invasion of bladder or rectum is a major staging distinction.

Symptoms and morbidity may arise from local organ invasion rather than distant tumor deposits.

Cervix

Paracervical soft tissue

Bladder / ureters

Rectum / vagina

Regional lymph nodes

Distant sites

Routes of spread — schematic

Slide 46 · Lymphovascular invasion enables nodal metastasis

Malignant cells entering lymphovascular channels can disseminate beyond the primary cervical lesion.

Pelvic and para-aortic nodes are clinically important regional sites.

Nodal status affects modern cervical-cancer stage assignment.

Primary cervical tumor

Lymphovascular invasion

Pelvic / para-aortic nodes

Staging and prognosis

Slide 47 · Distant metastasis can involve several organs

Regional disease

Distant disease

Paracervical tissue

Pelvic structures

Regional lymph nodes

Lung

Liver

Bone marrow / other organs

Slide 48 · Extent of disease underlies staging

Localized invasive carcinoma remains confined to cervix.

Higher stages describe progressively wider local extension, nodal involvement, or distant dissemination.

Stage is a structural description, not a proxy for tumor histology.

I: Cervix

II: Beyond cervix

III: Pelvic wall / lower vagina / nodes

IV: Adjacent mucosa / distant

Slide 49 · FIGO 2018 stage I: Disease confined to cervix

Stage IA is diagnosed only microscopically; The maximum depth of stromal invasion is 5 mm.

IA1: Invasion ≤3 mm; IA2: Invasion >3 mm and ≤5 mm.

Stage IB represents invasive carcinoma confined to cervix beyond IA; Size subdivisions apply.

I

Confined to cervix

II

Beyond cervix, not pelvic wall / lower vagina

III

Lower vagina, pelvic wall, obstruction and/or nodes

IV

Bladder/rectal mucosa, beyond pelvis or distant

Slide 50 · Invasion depth distinguishes IA1 and IA2

Stage IA1 includes stromal invasion of at most 3 mm.

Stage IA2 includes invasion deeper than 3 mm but not deeper than 5 mm.

Measurement refers to the maximum depth of stromal invasion, not the size of an exophytic surface mass.

IA1 ≤3 mm

IA2 >3 to ≤5 mm

Slide 51 · FIGO 2018 stage II: Beyond cervix, not pelvic wall

Disease extends beyond uterus/cervix without reaching the pelvic wall or lower vaginal third.

IIA involves the upper two-thirds of vagina without parametrial involvement.

IIB denotes parametrial involvement short of the pelvic wall.

I

Confined to cervix

II

Beyond cervix, not pelvic wall / lower vagina

III

Lower vagina, pelvic wall, obstruction and/or nodes

IV

Bladder/rectal mucosa, beyond pelvis or distant

Slide 52 · FIGO 2018 stage III includes nodes and obstruction

Extent to lower vaginal third or pelvic wall is included.

Tumor-related hydronephrosis or nonfunctioning kidney qualifies (unless due to another cause).

IIIC captures pelvic or para-aortic lymph node metastases, regardless of primary tumor size.

I

Confined to cervix

II

Beyond cervix, not pelvic wall / lower vagina

III

Lower vagina, pelvic wall, obstruction and/or nodes

IV

Bladder/rectal mucosa, beyond pelvis or distant

Slide 53 · FIGO 2018 distinguishes pelvic from para-aortic nodes

IIIC1

IIIC2

Pelvic nodal metastasis

Any primary tumor size

FIGO 2018

Para-aortic nodal metastasis

Any primary tumor size

FIGO 2018

Slide 54 · FIGO 2018 stage IV: Adjacent mucosa or distant spread

IVA: Extension to the mucosa of bladder or rectum or beyond the true pelvis (without distant spread).

IVB: Distant metastasis.

Superficial adjacency to an organ is not automatically equivalent to mucosal invasion.

I

Confined to cervix

II

Beyond cervix, not pelvic wall / lower vagina

III

Lower vagina, pelvic wall, obstruction and/or nodes

IV

Bladder/rectal mucosa, beyond pelvis or distant

Slide 55 · Why “stage 0” needs careful terminology

Noninvasive precursor

Invasive staged cancer

CIN 3 / HSIL

Adenocarcinoma in situ

No stromal infiltration

FIGO stage I–IV

Stromal invasion or greater extent

Extent determines stage

Slide 56 · Staging integrates morphology and anatomic extent

Histology establishes the malignant subtype and confirms invasion.

Local extent, ureteral obstruction, regional nodes, and distant spread refine stage.

Staging cannot be inferred from grade, p16 staining, or tumor type alone.

Histologic diagnosis

Invasion assessment

Local / nodal assessment

FIGO stage assignment

Slide 57 · Screening participation changes detection patterns

More than half of invasive cases occur in people not participating in regular screening.

Cervical precursors often persist for years before invasion, enabling detection.

Screening and prevention are the subject of the adjacent Robbins topic; This lecture emphasizes invasive disease.

>50%

Invasive cancers detected in persons without regular screening (Robbins)

Slide 58 · Diagnosis requires tissue assessment

An abnormal screening or examination result may prompt colposcopy and targeted biopsy.

Histologic review determines whether the lesion is intraepithelial or invasive.

When invasion is identified, depth and subtype influence further assessment and planning.

Abnormal finding

Colposcopy / biopsy

Morphology + invasion

Extent / staging work-up

Slide 59 · Superficially invasive SCC may permit local excision

Excision pathology

Clinical decision

Depth of invasion

Margins and lesion extent

Tumor morphology

Stage and risk features

Individual circumstances

Specialist-directed management

Slide 60 · Treatment intensity generally rises with extent

Hysterectomy with lymph-node dissection for many invasive tumors.

Advanced disease may require radiation and chemotherapy.

Specific contemporary treatment protocols are beyond the scope of this source-anchored pathology lecture.

Selected superficial lesion

Local surgical approach

More extensive disease

Multimodal treatment

Slide 61 · Stage is the strongest prognostic determinant

Superficially invasive SCC

Beyond-pelvis extension

Robbins: 100% five-year survival

Favorable when appropriately treated

Localized disease

Robbins: <20% five-year survival

Very advanced extent

Poor outcome

Slide 62 · Aggressive histotypes modify prognosis

Neuroendocrine carcinoma is associated with particularly unfavorable clinical behavior.

Gastric-type HPV-independent adenocarcinoma has a poor prognosis.

Stage and histologic subtype provide complementary prognostic information.

Anatomic stage

Burden and extent

Major prognosis driver

Histologic subtype

Aggressive biology

Additional prognostic information

Slide 63 · Local complications often cause late mortality

Ureteral obstruction, pyelonephritis, and uremia in advanced cervical cancer.

Local extension can severely disrupt pelvic-organ function.

Distant metastasis is not the only, or necessarily the dominant, cause of death in advanced cases.

Advanced local tumor

Ureteral obstruction

Pyelonephritis / uremia

Severe morbidity

Slide 64 · Case: Dysplasia versus invasion

A biopsy shows a high-grade atypical squamous epithelium with loss of maturation.

An irregular malignant nest is identified beyond the epithelial basement membrane in cervical stroma.

Question: Is the correct diagnostic category HSIL alone, or invasive squamous carcinoma?

Slide 65 · Case analysis: Stromal invasion changes diagnosis

HSIL describes atypia confined above the basement membrane.

A malignant squamous nest in cervical stroma establishes invasion.

Correct conclusion: Invasive squamous cell carcinoma; Further extent assessment is required.

Malignant nest in stroma

Schematic — epithelial–stromal boundary

Slide 66 · Case: Ureteral obstruction and nodal spread

A cervical tumor extends toward the pelvic wall and causes tumor-related hydronephrosis.

Imaging also identifies metastatic pelvic lymph nodes.

Question: Which category of FIGO 2018 stage is relevant, and why?

Slide 67 · Case analysis: The stage III mechanisms

Tumor-related hydronephrosis qualifies as FIGO 2018 stage IIIB.

Pelvic lymph node metastasis qualifies as IIIC1 under FIGO 2018.

The final stage designation integrates the nodal information; Identify the basis of nodal detection.

I

Confined to cervix

II

Beyond cervix, not pelvic wall / lower vagina

III

Lower vagina, pelvic wall, obstruction and/or nodes

IV

Bladder/rectal mucosa, beyond pelvis or distant

Slide 68 · Cervical carcinoma: Pathology synthesis

Most cases involve high-risk HPV-driven disruption of RB and p53 pathways.

Invasion distinguishes carcinoma from LSIL, HSIL, and AIS.

Squamous, glandular, mixed, neuroendocrine, and gastric-type tumors have different morphology and biology.

Disease extent, nodal involvement, and local complications dominate staging and much of prognosis.

Slide 69 · Primary textbook and verified supplements

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. 2026. Female genital tract: cervical carcinoma section.

WHO Classification of Tumours: Female Genital Tumours. 5th ed. 2020 (HPV-associated versus HPV-independent categories).

FIGO 2018 revised cervical cancer staging; IARC/WHO World Cancer Report staging table (2018 schema).

Historical and source-specific epidemiology and survival values are identified on relevant slides.