Gynaecological Malignancy - Comprehensive Notes

Gynaecological Malignancy

Cancer: The Science & The Person

  • The Science: Genetics, pathophysiology, immunology, histopathology, medical management, incidence, aetiology, diagnosis, staging, management, prognosis.
  • The Person: Quality of life, beliefs, wishes, family, work/social life.

Cancer: Invasion and Metastasis

  • Cancer's ability to invade surrounding tissues and metastasize involves:
    • Loss of adhesion.
    • Invasion.
    • Angiogenesis.
  • Process:
    • a) In situ cancer.
    • b) Invasion of the tumor border.
    • c) Lymphatic spread.
    • d) Intravasion of the circulatory system.
    • e) Arrest, extravasion.
    • f) Solitary dormant cells, occult micrometastases.
    • g) Progressive colonization, angiogenesis.

Genetic Alterations and Cellular Function

  • Genetic alterations disrupt cellular functions, such as:
    • Proliferation.
    • Senescence.
    • Apoptosis.
  • These processes control the cell population.

Cellular Senescence

  • Normal cells limit the number of divisions via telomere shortening.
  • Malignant cells lengthen telomeres.

Apoptosis: Programmed Cell Death

  • Apoptosis is a 'suicide pathway' that maintains cell population and prevents malignant transformation.
  • Process:
    • Cell shrinkage.
    • Chromatin condensation.
    • Membrane blebbing.
    • Apoptotic body formation.
    • Nuclear collapse.
    • Lysis of apoptotic bodies.

Cell Cycle

  • G1 Phase: Cellular contents are duplicated (excluding chromosomes).
  • S Phase: Each of the 46 chromosomes is duplicated.
  • G2 Phase: The cell double-checks duplicated chromosomes for errors and makes necessary repairs.
  • Mitosis: Cell division occurs.
  • Cytokinesis: Cytoplasmic division occurs.
  • G0 Phase: Cell cycle arrest.

Tumour-Suppressor Genes

  • Act as ‘braking signals’ during the G1 phase to stop or slow the cycle before the S phase.
  • Examples:
    • p53: A transcription factor that regulates cell division and cell death.
    • Rb: Alters the activity of transcription factors, controlling cell division.
  • Mutation disables the normal ‘brake’ mechanism, leading to uncontrolled growth (cancer).

Oncogenes

  • Mutated genes whose presence can stimulate the development of cancer.
  • Instruct cells to make proteins that stimulate excessive cell growth and division.
  • Examples: HER-2/neu, RAS, SRC.

Oncogenes vs. Tumour Suppressor Genes

  • Oncogenes
    • Most often autosomal dominant (one copy mutation elevates risk).
    • Turned on by a mutation (gain of function).
  • Tumour Suppressor Genes
    • Most often autosomal recessive (both copies must be mutated).
    • Turned off by a mutation.

Gynaecological Cancers: UK Statistics (2017)

  • Most common gynaecological cancer in the UK: Endometrial cancer.
  • Ten Most Common Cancers in Females, UK, 2017 (New Cases):
    • Breast
    • Lung
    • Bowel
    • Uterus
    • Melanoma Skin Cancer
    • Ovary
    • Non-Hodgkin Lymphoma
    • Brain, Other CNS & Intracranial Tumours
    • Pancreas
    • Kidney

Cancer Incidence Trends (UK: 2005-2007 vs. 2015-2017)

  • Increasing:
    • All Cancers: 6%
    • Breast Cancer: 5%
    • Lung Cancer: 15%
    • Uterine Cancer: 13%
    • Melanoma Skin Cancer: 30%
    • Non-Hodgkin Lymphoma: 11%
    • Brain, Other CNS and Intracranial Tumours: 22%
    • Pancreatic Cancer: 9%
    • Kidney Cancer: 10%
    • Oesophageal Cancer: 24%
    • Thyroid Cancer: 38%
    • Liver Cancer: 46%
  • Decreasing:
    • Bowel Cancer: -2%
    • Ovarian Cancer: -5%
    • Cancer of Unknown Primary: -35%
    • Leukaemia: -9%
    • Head and Neck Cancer: -15%
    • Cervical Cancer: 8%
    • Myeloma: 69%
    • Stomach Cancer: -28%

Endometrial Cancer: Aetiology

  • Obesity
  • Type 2 Diabetes
  • Nulliparity
  • Late menopause
  • Ovarian Tumours (granulosa)
  • Unopposed oestrogen
  • Oestrogen-only HRT
  • Pelvic irradiation
  • Tamoxifen
  • PCOS
  • Lynch syndrome
  • Incidence: Over 9000 cases in the UK per year and rising.

Endometrial Cancer: Clinical Presentation & Investigations

  • Postmenopausal bleeding.
  • In Clinic:
    • History.
    • Examination.
    • Investigations:
      • Transvaginal ultrasound.
      • Endometrial biopsy.
      • Hysteroscopy.

Endometrial Cancer: Pathology & Staging

  • Pathology:
    • Adenocarcinoma.
    • Adenosquamous.
    • Squamous.
    • Papillary serous.
    • Clear cell.
    • Uterine sarcomas.
  • Staging: FIGO I/II/III/IV.

Endometrial Cancer: Staging Details

  • Stage 1:
    • IA - Cancer is in the endometrium (inner lining of the uterus) only, or has grown less than halfway into the myometrium (muscular outer layer of the uterus).
    • IB - Cancer has grown halfway or more into the myometrium.
  • Stage 2: Cancer has spread from the uterus to the cervix.
  • Stage 3:
    • 3A - Cancer has spread into the ovary.
    • 3B - Cancer has spread into the vagina.
    • 3C - Cancer has spread into the lymph nodes.
  • Stage 4:
    • 4A - Cancer is in the bladder or bowel.
    • 4B - Cancer is in other organs.

Endometrial Cancer: Treatment

  • Surgery: Hysterectomy +/- pelvic lymph nodes
  • Radiotherapy: Adjuvant (brachytherapy/external beam)
  • 5-year survival for Stage 1 disease: 92%
  • Progesterone therapy

Cervical Cancer: Aetiology

  • High-risk HPV
  • Immunosuppression
  • OCP usage
  • Cigarette smoking (more persistent HPV)
  • Missed vaccination
  • Early age intercourse
  • Multiple sexual partners
  • STDs
  • Previous CIN

HPV Infection

  • 75% of the population will come into contact with HPV at some time in their life without vaccination.
  • Most infections are transient.
  • Age 20-25 (pre-vaccination era): 20% HPV 16 positive
  • Age 50: 5% HPV 16 positive

High-Risk HPV

  • Over 130 double-stranded DNA viruses.
  • Oncogenic types: 16, 18, 31, 33, 45, 51, 53, etc.
  • E6 and E7 oncoproteins are the main transforming gene products.

HPV Oncogenesis

  • E6 and E7 regions of the HPV genome cause growth stimulation.
  • E6 p53 -ve
  • E7 pRb-E2F
  • Low levels of E2F -ve transcription factor

Persistent HPV Infection

  • Associated with increased risk of high-grade cervical intraepithelial neoplasia (CIN 2, 3/HSIL).
  • Immunological competence required to clear the virus.
  • Of particular concern in HIV and transplant patients.

Cervical Cancer Prevention

  • Use of the GARDASIL vaccine.
  • Approximate percentage of cervical cancer cases preventable: 94.6% (mentioned 70.7%, 85.1%, 99.8% as other options in a poll question).

Cervical Cancer in the UK

  • Incidence: Around 3000 women/year.
  • Social deprivation is a factor.
  • Peak age of incidence: 30-34 years.
  • 25% reduction in cases since the early 1990s.
  • Majority diagnosed at stage 1.
  • Around 900 deaths/year.
  • Pathology: Squamous (90%) / adenocarcinoma.
  • Staging: FIGO I/II/III/IV.
  • Prognosis: stage I > 90% 5-year survival (1a1 = 98-99%, 1b2 = 82%).
  • Best method of reducing risk: combination of vaccination and screening.

Cervical Cancer Worldwide (2015)

  • 561,000 new cases and 285,000 deaths.
  • 479,000 new cases and 251,000 deaths (88%) in less developed countries.
  • 810 cervical cancer deaths/day (compared to 830 maternal deaths/day).
  • Projected increase to 349,000 deaths in 2025 if no changes occur.

Cervical Cancer: Staging Details

  • Stage 1:
    • IA1 - Cancer has grown into the top part of the vagina.
    • IA2 - 2cm or smaller
    • 1B - Larger than 4cm
  • Stage 2: --wing stage.
  • Stage 3: The cancer has spread to the lungs.

Cervical Cancer: Treatment - Stage 1

  • Stage 1a1 Treatment: LLETZ (loop electrosurgical excision procedure) to remove abnormal cells.
  • May also include:
    • Vaginal cuff.
    • Margins for standard hysterectomy.
    • Parametrial tissue.

Cervical Cancer: Treatment - Stages 2+

  • Radiotherapy.
  • Chemotherapy.
  • Palliative care.

Vulval Cancer

  • Incidence: Uncommon (around 1300 new cases/year).
  • 20th most common cancer in women.
  • Incidence highest in women > 90 years old.
  • Aetiology: High-risk HPV / Lichen Sclerosis
  • Pathology:
    • Squamous (90%)
    • Malignant melanoma
    • Bartholin’s gland
    • Paget’s Disease

Vulval Cancer: Symptoms

  • Vulval itching
  • Vulval soreness
  • Persistent ‘lump’
  • Bleeding
  • Pain on passing urine
  • Past history of VIN or Lichen Sclerosis

Vulval Cancer: Staging & Survival

  • I: <2cm (79% 5-year survival)
  • II: >2cm (59% 5-year survival)
  • III: Adjacent organs / Unilateral Nodes (43% 5-year survival)
  • IV: Bilateral nodes / Distant mets (13% 5-year survival)

Vulval Cancer: Treatment

  • Surgery: Conservative or Radical
  • Radiotherapy
  • +/- chemotherapy

Ovarian/Fallopian Tube/Primary Peritoneal Cancer

*Presentation:

  • No symptoms
  • Bloating / ‘IBS’ like symptoms
  • Abdominal pain/discomfort
  • Change in bowel habit
  • Urinary frequency
  • Bowel obstruction

Ovarian/Fallopian Tube/Primary Peritoneal Cancer: Incidence & Aetiology

  • Incidence: > 7000 cases UK/year.
  • Incidence highest in women 75 – 79 years old.
  • Aetiology
    • Ovulation (menarche, menopause, parity, breast feeding, OCP, hysterectomy, ovulation induction).
    • Gene mutation (BRCA 1/2, HNPCC).
  • Almost 6 in 10 present with advanced (stage 3 + disease).
  • Stage 3 disease has 40% 5 year survival rate.

Ovarian Cancer: Pathology

  • Epithelial (serous, clear cell, endometroid) 85%
  • Sex cord (e.g. Granulosa)
  • Germ cell (e.g. dysgerminoma, teratomas)
  • Secondary (e.g. Krukenberg)
  • Many ovarian tumours may arise from the fallopian tube.
  • Primary peritoneal carcinoma

Suspected Ovarian Cancer

  • CA125
  • Ultrasound (USS)
  • Symptoms and age
  • Calculating the 'Risk of Malignancy' Index

Ovarian Cancer: Staging Details

  • Stage 1:
    • 1A - Cancer in one ovary.
    • 1B - Cancer in both ovaries.
    • 1C - Cancer in the ovary and on the surface of one ovary.
  • Stage 2:
    • 2A-
    • 2B - Cancer has spread to the bowel or bladder.
    • 2C - Cancer cells also in the fluid of the abdomen.
  • Stage 3:
    • 3A - Cancer cells are in the lining of the abdomen (only seen under a microscope).
    • 3B - Tumours of 2cm or smaller are in the lining of the abdomen.
    • 3C - Cancer is in the lymph nodes.
  • Stage 4: Cancer has spread to other organs.

Ovarian Cancer: Management

  • Surgery.
  • Chemotherapy.

Other Gynaecological Cancers

  • Vaginal: Squamous cell, adenocarcinoma, clear cell
  • GTD (Gestational Trophoblastic Disease): Hydatidiform moles, Choriocarcinoma, PSTT (Placental Site Trophoblastic Tumor).

Clinical Scenarios & Differential Diagnoses

  • Several clinical scenarios with questions about what to do next, potential differential diagnoses, and other relevant questions.

Summary

  • Holistic management is crucial.
  • Endometrial cancer is the most common gynaecological cancer.
  • Ovarian/Fallopian Tube/Primary Peritoneal Cancer often presents at an advanced stage.
  • Cervical Cancer is linked to HPV, screening, and specific statistics.
  • Vulval cancer has its unique characteristics and considerations.