Anatomy of the uterine  cervix Ectocervix: squamous epithelium (non-  keratinizing, glycogen-rich) Endocervix: glandular...
Uterus                     Fundus                     Corpus       Endometrial         Cavum                              ...
Transformation zone Changes during life (Epithelial  transformation, moving of the squamo-  columnar junction) Prolifera...
Fertile period of life             Before puberty                                                          SquamousEndocer...
Pathology of the uterinecervix Reactive changes   Inflammation Neoplastic changes   Non-invasive (precursor lesions;  “p...
Benign Lesions of the   Cervix Endocervical and Cervical Polyps Secondary to inflammation or abnormal focal   responsive...
ENDOCERVICAL POLYP
Nabothian Cysts Retentions mucus cysts of endocervical    columnar cells mostly found at the    transformation zone   On...
Cervical Myoma Smooth, firm, solitary nodular masses mostly  arising from the isthmus Most are small and asymptomatic E...
Cervical Stenosis Often occurs at the internal os Congenital or acquired Management:Cervical dilatation under ultrasoun...
Cervical carcinoma andprecursor lesions  CIN                  AIS                HPVSquamous cell     Adenocarcinoma  carc...
Epidemiology of cervicalcarcinoma HPV Socio-economic status
Risk factors for cervicalcarcinoma HPV infection Cigarette smoking Multiparity Oral contraceptivs Other STD (Chlamydi...
HPV and Cervix Almost all cervical neoplasias HPV-related (99.7% of all  cervical carcinomas world wide) HPV-positivity ...
Precancerous lesions of theuterine cervix Squamous epithelium:  Cervical intraepithelial neoplasia (CIN 1-3)  Squamous in...
Uterine cervix: Pathology andclinic Early changes (CIN): cytology and  colposcopy Clinical tumours: contact bleeding,  h...
Terminology ofnon-invasive squamous lesions    Traditional            WHO        Bethesda• Mild dysplasia    • CIN 1      ...
Condyloma Considered among CIN 1 No distinction by cervical cytology from CIN 1
Dysplasia / IntraepithelialNeoplasia Architectural and cytological  abnormalities (atypia)
HPV and cervical neoplasia Almost all cervical neoplasia HPV-  associated (99.7% of all cervical  carcinomas world-wide)...
HPV StructureEpisomal HPV Genome            URR        E6                             E7  L1                             E...
Molecular mechanisms of HPV on the host cell                     DNA damage    HPV E6                p53                  ...
HPV 16 InfectionNormal basal cell          Intraepithelial Neoplasia        Invasive Carcinoma   polyclonal               ...
Cellular effects of HPV:    LSIL Infection of the basal- (reserve-) cells Suprabasal expression of E-proteins Further d...
Cellular effects of HPV:     HSIL Coordination between cellular differentiation and expression of    viral E- proteins lo...
Cell transformation in squamous intraepithelial lesions                            Terminally differentiated cells        ...
“Molecular markers” for CINdiagnosis   HPV   p16   “Proliferationsmarker” (Ki-67, PCNA)   pRb   Cytokeratine 13 und 1...
HPV in situ Hybridisation HPV in situ Hybridisation helpful for the differential  diagnosis between HPV associated cytopa...
Adenocarcinoma in situ(AIS/ACIS) Normal glandular or surface epithelium  replaced by neoplastic epithelium
Malignant Tumours Carcinoma  Squamous cell carcinoma (Keratinizing or non-  keratinizing)  Adenocarcinoma  Rare types (ad...
Invasive cervical carcinoma Any age; peak incidence at 40-45 years Cervix enlarged, ton-like, ulcerated tumor Spread: t...
Microinvasive squamous cellcarcinoma No palpable or visible tumour Diagnosed on cone or punch biopsy Pathological cytol...
Adenocarcinoma Less frequent compared to SCC Association with HPV Type 18 Same spread and behavior as squamous cell car...
Therapy of invasive cervicalcarcinoma Depends from stage Stage (FIGO) determined before therapy by  clinical examination...
Therapy of invasive cervicalcarcinoma                    (Ia2)   Ia1        Ia2                     IIb   III             ...
Conisation Cold knife cone;  LOOP, (LEEP, LEETZ) Diagnosis / Therapy of  intrepithelial neoplasia  (CIN), AIS,  microcar...
Clinico-pathologicalManagement of Cone Biopsies Processing Analysis of resection margins Consequences
Cone Bx: Analysis of resectionmargins Positive margins in up to 20% of cones in the  literature Recurrent CIN 2/3 after ...
Traditional Technique ofProcessing
Alternative Technique GH GrazWest: Serial sectioning of theopened cone
Persistence / Recurrence ofCIN 3 Free margins: recurrent CIN3 in about 1% Involved margins: recurrence in 22% (8% invasi...
Risk of cervical carcinomaafter CIN 3 Low, but 4-5 x higher compared to general  population Important: Follow up after c...
Clinical Cervical Carcinoma Exophytic, Ulcerative, fungating (contact-) Bleeding
Staging of Cervical Carcinoma Staging according to FIGO is always  performed pre-operatively based on clinical  examinati...
Adenocarcinoma of the Cervix:Invasion Depth of glands (Cave: Variability) Desmoplastic stromal response Extensive buddi...
Prognosis of cervicalcarcinoma Tumor stage is most important prognostic  factor  Parametrium involvement, Lymph node meta...
HPV Testing 2 methods: Hybrid capture (liquid based  assay), PCR PCR more sensitive
HPV vaccination 2 vaccines on the market (bivalent and  tetravalent) Further vaccines (pentavalent) in  development Goa...
Cervical cancer
Cervical cancer
Cervical cancer
Cervical cancer
Cervical cancer
Cervical cancer
Cervical cancer
Cervical cancer
Cervical cancer
Cervical cancer
Cervical cancer
Cervical cancer
Cervical cancer
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Cervical cancer

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Cervical cancer

  1. 1. Anatomy of the uterine cervix Ectocervix: squamous epithelium (non- keratinizing, glycogen-rich) Endocervix: glandular epithelium, „glands“ (clefts) Transformation zone: squamous metaplasia
  2. 2. Uterus Fundus Corpus Endometrial Cavum stroma Endometrium Glandular Perimetrium epithelium Isthmus Reserve cells Endocervix MucinousCervix epithelium Portio Squamous epithelium
  3. 3. Transformation zone Changes during life (Epithelial transformation, moving of the squamo- columnar junction) Proliferation of reserve cells : labile epithelium“ Predominant site of most pathological changes, in particular intraepithelial neoplasia
  4. 4. Fertile period of life Before puberty SquamousEndocervical mucosa Ectopy (Eversion) metaplasia New squamo- Squamous epithelium columnar junction
  5. 5. Pathology of the uterinecervix Reactive changes Inflammation Neoplastic changes Non-invasive (precursor lesions; “precancer”) Invasive (cancer)Central and crucial role of HPV!
  6. 6. Benign Lesions of the Cervix Endocervical and Cervical Polyps Secondary to inflammation or abnormal focal responsiveness to hormonal stimulation Histologic subtypes:-Adenomatous (80%) - Cystic-Fibrous - Vascular-Inflammatory - Fibromyomatous
  7. 7. ENDOCERVICAL POLYP
  8. 8. Nabothian Cysts Retentions mucus cysts of endocervical columnar cells mostly found at the transformation zone On Gross appearance: translucent or opaque whitish or yellow Vary from microscopic to macroscopic size Asymtomatic No treatment is required.
  9. 9. Cervical Myoma Smooth, firm, solitary nodular masses mostly arising from the isthmus Most are small and asymptomatic Expanding myomas can produce symptoms which are secondary to mechanical pressure on adjacent organs
  10. 10. Cervical Stenosis Often occurs at the internal os Congenital or acquired Management:Cervical dilatation under ultrasound guidance
  11. 11. Cervical carcinoma andprecursor lesions CIN AIS HPVSquamous cell Adenocarcinoma carcinoma
  12. 12. Epidemiology of cervicalcarcinoma HPV Socio-economic status
  13. 13. Risk factors for cervicalcarcinoma HPV infection Cigarette smoking Multiparity Oral contraceptivs Other STD (Chlamydia trachomatis) Poor nutritional status
  14. 14. HPV and Cervix Almost all cervical neoplasias HPV-related (99.7% of all cervical carcinomas world wide) HPV-positivity is strongest independent risk factor for the development of cervical carcinoma HPV Prevalence among 30-40 year-old women In USA newly diagnosed 13000 invasive cervical carcinomas and 1 000 000 SIL per anno
  15. 15. Precancerous lesions of theuterine cervix Squamous epithelium: Cervical intraepithelial neoplasia (CIN 1-3) Squamous intraepithelial lesion: low / high grade Columnar epithelium: (glandular dysplasia) Adenocarcinoma in situ (AIS) Association with HPV (up to 100%)!
  16. 16. Uterine cervix: Pathology andclinic Early changes (CIN): cytology and colposcopy Clinical tumours: contact bleeding, hemorrhagic discharge
  17. 17. Terminology ofnon-invasive squamous lesions Traditional WHO Bethesda• Mild dysplasia • CIN 1 • LSIL• Moderate dysplasia • CIN 2• Severe dysplasia • HSIL • CIN3• Carcinoma in situ
  18. 18. Condyloma Considered among CIN 1 No distinction by cervical cytology from CIN 1
  19. 19. Dysplasia / IntraepithelialNeoplasia Architectural and cytological abnormalities (atypia)
  20. 20. HPV and cervical neoplasia Almost all cervical neoplasia HPV- associated (99.7% of all cervical carcinomas world-wide) HPV-positivity strongest independent risk factor for development of cervical carcinoma HPV prevalence among 30-40 year old
  21. 21. HPV StructureEpisomal HPV Genome URR E6 E7 L1 E1 integrated HPV Genome L2 cellular L1 L2 URR E6 E7 E1 E2/4/5 cellular E2 E4 E5
  22. 22. Molecular mechanisms of HPV on the host cell DNA damage HPV E6 p53 Apoptosis Cyclin / cdk-complexes Telomerase p21 HPV E7 pRB E2F cdk4 Cyclin E p16 G1- cell cycle arrest DNA sythesis
  23. 23. HPV 16 InfectionNormal basal cell Intraepithelial Neoplasia Invasive Carcinoma polyclonal monoclonal different subclones diploid aneuploid Regulated cell cycle deregulated cell cycle (high proliferation rate) Increasing losses and gains of alleles Episomal Viral DNA Integrated Viral DNA regulated episomal E6/E7 expression constitutive E6/E7 expression 3q amplification
  24. 24. Cellular effects of HPV: LSIL Infection of the basal- (reserve-) cells Suprabasal expression of E-proteins Further differentiation: Induction of all viral genes, viral DNA synthesis, viral replication Nuclear enlargement, hyperchromasia: direct consequence of E6/E7 mediated activation of host DNA-synthesis (ineffective, because excessive) Koilocytes: Expression of keratin-binding protein E4
  25. 25. Cellular effects of HPV: HSIL Coordination between cellular differentiation and expression of viral E- proteins lost; Causes unclear Virus integration or mutation in E2? (subsequently E2- controlled regulation of E6/E7 expression) Cell proliferation predominates differentiation Supported by cofactors? (other viruses, smoking, spontaneous mutations etc.) Occurs less frequent than LSIL
  26. 26. Cell transformation in squamous intraepithelial lesions Terminally differentiated cells Committed cells Basal and stem cellsLSIL / Transformed terminally differentiated cellsCIN 1 Committed cells Basal and stem cells Lack of terminal differentiationHSIL /CIN 2&3 Transformed basal/stem and committed cells
  27. 27. “Molecular markers” for CINdiagnosis HPV p16 “Proliferationsmarker” (Ki-67, PCNA) pRb Cytokeratine 13 und 14 p63 Telomerase CEA
  28. 28. HPV in situ Hybridisation HPV in situ Hybridisation helpful for the differential diagnosis between HPV associated cytopathic changes (e.g. koilocytes) and reactive/ metaplastic changes Disadvantage: method more laborious and more expensive, but full automatisation available
  29. 29. Adenocarcinoma in situ(AIS/ACIS) Normal glandular or surface epithelium replaced by neoplastic epithelium
  30. 30. Malignant Tumours Carcinoma Squamous cell carcinoma (Keratinizing or non- keratinizing) Adenocarcinoma Rare types (adenosquamous, small cell carcinoma) Malignant lymphoma
  31. 31. Invasive cervical carcinoma Any age; peak incidence at 40-45 years Cervix enlarged, ton-like, ulcerated tumor Spread: to parametrium, vagina, rectum, bladder Metastases to pelvic and para-aortal lymph nodes, lungs, liver, bone Prognosis depends on stage: 95%-85%-75%- <50% (IA-IB-II-III and>)
  32. 32. Microinvasive squamous cellcarcinoma No palpable or visible tumour Diagnosed on cone or punch biopsy Pathological cytology (Pap IV/HSIL) Horizontal extension: 7 mm maximum Depth of infiltration: 3 and 5 mm, respectively Therapy: cone biopsy or vaginal hysterectomy (+/- lymphadenectomy) Prognosis excellent
  33. 33. Adenocarcinoma Less frequent compared to SCC Association with HPV Type 18 Same spread and behavior as squamous cell carcinoma Adenosquamous carcinoma: Poor behavior Microinvasive adenocarcinoma Rare tumour Excellent prognosis
  34. 34. Therapy of invasive cervicalcarcinoma Depends from stage Stage (FIGO) determined before therapy by clinical examination (remains unchanged after therapy)
  35. 35. Therapy of invasive cervicalcarcinoma (Ia2) Ia1 Ia2 IIb III Ib1-IIaCone biopsy (IIb) Hysterectomy Radical Hysterectomy +Lymphadenectomy Radiotherapy Combined Radio-Chemotherapy Therapy depends on clinical stage
  36. 36. Conisation Cold knife cone; LOOP, (LEEP, LEETZ) Diagnosis / Therapy of intrepithelial neoplasia (CIN), AIS, microcarcinoma Therapy of chronic ectopy with cervicitis
  37. 37. Clinico-pathologicalManagement of Cone Biopsies Processing Analysis of resection margins Consequences
  38. 38. Cone Bx: Analysis of resectionmargins Positive margins in up to 20% of cones in the literature Recurrent CIN 2/3 after conisation in 9-21% Recurrence also if margins are free of CIN Progression to invasive carcinoma in 0,9-1,6%
  39. 39. Traditional Technique ofProcessing
  40. 40. Alternative Technique GH GrazWest: Serial sectioning of theopened cone
  41. 41. Persistence / Recurrence ofCIN 3 Free margins: recurrent CIN3 in about 1% Involved margins: recurrence in 22% (8% invasive carcinoma) Most frequent if endo- and ectocervical margin involved 68% persistence in 1st year, 32% recurrence after 3 years (median) Involved margins either need re-excision or close follow up (cytology; HPV testing)
  42. 42. Risk of cervical carcinomaafter CIN 3 Low, but 4-5 x higher compared to general population Important: Follow up after conisation, Margins not a significant prognostic factor Importance of positivity for high risk HPV
  43. 43. Clinical Cervical Carcinoma Exophytic, Ulcerative, fungating (contact-) Bleeding
  44. 44. Staging of Cervical Carcinoma Staging according to FIGO is always performed pre-operatively based on clinical examination Exception: IA diagnosed histologically pTNM based on surgical staging, usually after surgical therapy
  45. 45. Adenocarcinoma of the Cervix:Invasion Depth of glands (Cave: Variability) Desmoplastic stromal response Extensive budding of the glands Irregularity of glands Extensive cribriform structures Relation to blood vessels Glands back to back Papillae on the surface
  46. 46. Prognosis of cervicalcarcinoma Tumor stage is most important prognostic factor Parametrium involvement, Lymph node metastases Tumor volume
  47. 47. HPV Testing 2 methods: Hybrid capture (liquid based assay), PCR PCR more sensitive
  48. 48. HPV vaccination 2 vaccines on the market (bivalent and tetravalent) Further vaccines (pentavalent) in development Goal: World-wide vaccination (would prevent 90% CC)

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