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Pathology of cervix

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Pathology of cervix

  1. 1. Pathology of Cervix Dr.CSBR.Prasad, M.D.
  2. 2. Inflammations - Cervicitis • Acute and Chronic cervicitis • Inflammatory infiltrate composed of polys, lymphocytes and macrophages • Papillae formation • Erosion & ulceration of the lining epithelium • Reparative atypia • Squamous metaplasia • Nabothian cyst formation
  3. 3. Specific inflammations: 1. Gonococci 2. Chlamydia 3. Mycoplasma 4. HSV They should be identified for their clinical relevance (Pregnancy complicaations, Sexual transmission et.c.) Inflammations - Cervicitis
  4. 4. Microscopy: Epithelial spongiosis Submucosal edema Inflammatory cell infiltration Reparative epithelial changes Granulation tissue formation Intranuclear inclusions in the case of HSV Follicular cervicitis + Plasma cells, with Chamydia infection Epithelial spongiosis with Trichomonas infection Inflammations - Cervicitis
  5. 5. Endocervical polyps • Inflammatory tumors that occur in 2-5% of adult women • They present with irregular spotting / bleeding (may be mistaken for Carcinoma) • Most polyps lie in the endocervical canal • Adenomatous / leiomyomatous nature • Simple curettage or excision is curative
  6. 6. Cervical intraepithelial neoplasia (CIN) and Carcinoma of cervix
  7. 7. CIN and Carcinoma of cervix • One of the leading causes of cancer deaths in women • There is a gradual decline in the incidence of Cx Ca because of availability of simple cheap screening method – PAP smear • Increased awareness also contributed to its decline • PAP smears can detect the lesions in an early stage when still it’s curable
  8. 8. Risk factors – Ca Cx A wealth of molecular epidemiological evidence has established the following risk factors 1. Early age at first intercourse 2. Multiple sexual partners 3. Increased parity 4. A male partner with multiple sexual partners 5. Presence of cancer associated HPV 6. Persistent detection of high risk HPV 7. Certain HLA and viral subtypes 8. Exposure to OCs and Nicotine 9. Genital infections (Chlamydia)
  9. 9. There is mounting molecular evidence linking HPV to cancer: 1. HPV DNA is detected in >95% of Cx Ca 2. Specific subtypes: ----High risk (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 & 68) ----Low risk (types 6, 11, 42, 44, 53, 54, 62 & 66) 3. HPV genes (E6, E7) can: ---disrupt the cell cycle by binding to RB with upregulation of Cyclin E ---interupt cell death pathway by binding to p53 ---induce centromere dupliction and genomic instability ---induce rapid degradation of p53 ---can form compelxes with active RB gene product and promote its proteolysis 4. Physical state of the virus differs in different lesions, being integrated into the host DNA in cancers and present as free particles in condylomata 5. Deletions of 3p and amplifications of 3q are associated with HPV-16 6. Most compelling recent data shows that vaccines against HPV can prevent infection and development of precancerous disorders However, HPV is not the sole agent in Cx. Ca. there are other factors like, immune status of the individual, cocarcinogens, nutrition et.c. Risk factors – Ca Cx
  10. 10. Normal anatomy of cervix • The cervix is the lower end of the uterus. • In the adult, the cervical and endocervical region comprises 1/3 of the length of the uterus. • The outer cervix is lined by a stratified squamous mucosa containing abundant glycogen. • The underlying fibrovascular connective tissue of the lamina propria merges with smooth muscle bundles • At the cervical os, the squamous epithelium changes to a tall columnar mucinous epithelium.
  11. 11. Normal and abnormal growth processes in the cervical epithelium
  12. 12. In this frontal section of the internal female genital tract, you see • Transverse section through the lower pelvis. The position of the uterus relative to the urinary bladder and the rectum is clearly outlined • The uterine cavity is lined with endometrium.
  13. 13. • the uterus • the cervix • the vagina The endocervical canal or endocervix, is lined with a single layer of tall columnar mucus-producing epithelium. The ectocervix and the vagina are lined with multiple layers of non-keratinizing squamous epithelium.
  14. 14. • Colposcopy: Normal Aspect of the Uterine cervix
  15. 15. • The border at which the columnar epithelium changes abruptly into the squamous epithelium is called the squamo- columnar junction. • Just above the squamo- columnar junction lies the 'transition zone', a zone of columnar epithelium that is undergoing a gradual change into squamous epithelium. • This 'transition zone' is the place where most cervical abnormalities occur, both malignant and non-malignant. It is for this reason that it is critical to make sure that both squamous and columnar cells are gathered from the transformation zone when making a Pap smear. •
  16. 16. The position of the transformation zone changes throughout each woman's lifetime. • Before the onset of puberty, the transition zone lies inside the endocervical canal.
  17. 17. The position of the transformation zone changes throughout each woman's lifetime. • After puberty, during the fertile years, the transition zone moves more in the direction of the ectocervix.
  18. 18. The position of the transformation zone changes throughout each woman's lifetime. • In the post- meno pausal years, the transition zone often recedes back into the endocervical canal.
  19. 19. Let us now look at how abnormalities develop in the columnar epithelium of the cervix, with emphasis on the intraepithelial lesions which may develop, - when not treated - into a squamous cell carcinoma or an adenocarcinoma. • In the zone of exposed columnar epithelium, the first indication of an irritation to the mucous membrane is the replacement of the columnar epithelial cells by primitive, cytoplasm-poor cells. • This process is called reserve cell hyperplasia.
  20. 20. • When the irritation continues, these reserve cells can change into abnormal cells, either of the squamous metaplastic type or of the columnar type. • Squamous cell carcinoma can develop from squamous and squamous metaplastic epithelium and adenocarcinoma can develop from columnar epithelium.
  21. 21. Normal cervix is seen at high power, with non-keratinizing squamous epithelium. The basal cells are seen at the right, and there is progressive maturation to the surface, where the flattened squamous cells have a low nuclear/cytoplasmic ratio with abundant pale-staining cytoplasm containing glycogen. The epithelium lies above the basement membrane. The submucosa is at the far right.
  22. 22. Normal cervix with stratified non-keratinizing squamous epithelium merges at the transformation zone (squamocolumnar junction) to endocervix lined by tall mucinous columnar cells as seen here at low power. The endocervix has underlying endocervical glands that are also lined by tall mucinous columnar cells.
  23. 23. The same area showing neoplastic transformation.
  24. 24. CIN and Ca. Cx. • Majority of cancers are preceeded by precancerous lesion • These precancerous lesions may exist for 20yrs before invasive carcinoma develops • During this period PAP smear shows abnormal cells • Most of the cancers are associated with HPV (high risk type) • Note: not all precrssor lesions proceed to malignancy. Some may regress.
  25. 25. Classification of CIN • British CIN I, II, III. • Bethesda LSIL, HSIL.
  26. 26. Early lesion CIN I • Nuclear enlargement and hyperchromasia in the superficial cells • This indicates active viral replication in the superficial mature squamous cells (Viral cytopathic effect) • Koilocytotic atypia (cytoplasmic changes) • Lesions can be raised (low risk) or flat (high risk HPV) • This stage is reversible
  27. 27. Koilocytosis
  28. 28. The koilocytosis is seen at high power in the cervical squamous epithelium. This type of change is usually produced with human papillomavirus (HPV) infection. HPV infection leads to changes in the cervical epithelium that start down the road toward dysplasia and neoplasia.
  29. 29. In this cervical biopsy, the dysplastic, disordered cells occupy less than 1/3 of the thickness of the epithelium, and the basal lamina is intact, so this is cervical intraepithelial neoplasia (CIN) I. Note the koilocytotic change in some cells, consistent with human papillomavirus (HPV) effect. CIN ICIN I
  30. 30. CIN II • Two thirds of the epithelium shows nuclear changes, mitotic activity • They are highly associated with high risk HPV • They exhibit aneuploid cell population • E6 / E7 induce genomic instability and inactivation of p16
  31. 31. In this cervical biopsy, the dysplastic, disordered cells occupy about 1/3 to 1/2 the thickness of the epithelium, and the basal lamina is intact, so this is cervical intraepithelial neoplasia (CIN) II.
  32. 32. CIN III • Progressive loss of differentiation • Atypia in all the layers • No surface epithelial differentiation
  33. 33. This is cervical squamous dysplasia at high magnification extending from the center to the right. The epithelium is normal at the left. Note how the dysplastic cell nuclei at the right are larger and darker, and the dysplastic cells have a disorderly arrangement. This dysplastic process involves the full thickness of the epithelium, but the basal lamina is intact, so this is cervical intraepithelial neoplasia (CIN) III.
  34. 34. This is a Pap smear. The cytologic features of normal squamous epithelial cells can be seen at the center top and bottom, with orange to pale blue plate-like squamous cells that have small pyknotic nuclei. The dysplastic cells in the center extending to upper right are smaller overall with darker, more irregular nuclei.
  35. 35. Pap smear, named for its developer, Dr. George Papanicolaou, is still one of the few tests we have available which can detect the presence of a premalignant lesion allowing for the prevention of cancer. The vast majority of tests utilized in cancer diagnostics detect cancer after it has already developed, and in most instances, do not prevent ultimate cancer death
  36. 36. • Note: progression is not always simple from CIN I to cancer • Low grade lesions and condyloma may not progress to cancer • High grade lesions my progress to carcinoma • However, it’s not possible to predict the progression in a given patient • in situin situ to invasion may take months toto invasion may take months to 20yrs20yrs
  37. 37. SCC • Peaks around 40-45yrs but can occur at any age from 2nd decade to senility. • It depends on exposure to HPV • Morphology: fungating (exophytic), ulcerating, infiltrative. • Spreads by contiguity (peritoneum, bladder, ureter, rectum, vagina) • Local & distant LN involvement • Distant mets (liver, lung, BM)
  38. 38. This is the gross appearance of a cervical squamous cell carcinoma that is still limited to the cervix (stage I). The tumor is a fungating red to tan to yellow mass.
  39. 39. This is a larger cervical squamous cell carcinoma which spread to the vagina. A total abdominal hysterectomy with bilateral salpingo-oopherectomy (TAH-BSO) was performed.
  40. 40. This large squamous carcinoma (yellow square) has obliterated the cervix and invaded the lower uterine segment. The uterus also has a round leiomyoma up higher (Red arrow).
  41. 41. This is a pelvic exenteration done for stage IV cervical carcinoma. At the left, dark vulvar skin leads to vagina and to cervix in the center, where an irregular tan tumor mass is seen infiltrating upward to the bladder. A slit-like endometrial cavity is surrounded by myometrium at the mid-right. The rectum and sigmoid colon are at the bottom extending to the right Vulvar skin Tumor Rectum Bladder
  42. 42. This is another pelvic exenteration for cervical squamous cell carcinoma. The irregular grey-brown tumor extends toward bladder and up into the uterus.
  43. 43. These abdominal CT scan views of the pelvis demonstrate a large mass with necrosis and air-filled spaces arising in the cervix and extending anteriorly to the bladder and posteriorly to the rectum. This is a squamous cell carcinoma of the cervix that has invaded both rectum and bladder--stage IV mass Bladder Rectum
  44. 44. Ca. Cx. Microscopy: 1. 95% are squamous cell carcinoma (keratinizing / non keratinizing / poorly differentiated) 2. Rarely neuroendocrine carcinoma may develop (very poor prognosis due to early spread. HPV 18HPV 18 is frequently associated with this) 3. 10-25% are adenocarcinoma, adenosquamous, undifferntiated carcinoma 4. Adenocarcinoma presumably arise from the endocervical glands and is preceeded by intraepithelial glandular neoplasia (AIS) 5. Clear cell carcinoma is associated with DES use by the mother
  45. 45. If abnormal cells break through the basal membrane, the disease is classified as (micro-)invasive squamous cell carcinoma. • As the cancer progresses, the highly abnormal cells grow into the underlying tissue and multiply there. Through contact with the lymph and blood vessels, the cancer can metastasize to other body sites. • The progression of cervical disease from stage to stage is very gradual. The development from a slightly atypical epithelium to an invasive carcinoma usually takes from 10 to 20 years.
  46. 46. This is why you do Pap smears--to prevent invasive squamous cell carcinomas from occurring. With Pap smears, pre-neoplastic and neoplastic cervical lesions can be detected when small and treated. Nests of squamous cell carcinoma have invaded underlying stroma at the center and left
  47. 47. At high magnification, nests of neoplastic squamous cells are invaded through a chronically inflammed stroma. This cancer is well- differentiated, as evidenced by keratin pearls. However, most cervical squamous carcinomas are non-keratinizing.
  48. 48. Ca. Cx. This is a clear cell carcinoma of the cervix in a young woman whose mother was given diethylstilbesterol (DES) during pregnancy. Red, granular foci on the vaginal mucosa called "adenosis" may precede clear cell carcinoma. These cancers are rare, even in women with this history. DES exposure increases the risk for clear cell carcinoma arising in upper vagina and cervix of adolescents and young adults.
  49. 49. Ca. Cx. – clinical course and Mx Prevention of ca cx: • Cytological screening (Mx of cytological abnormality) • Histological diagnosis (removal of precancerous lesion) • Use of vaccines against HPV
  50. 50. Ca. Cx. 5yr survival: • Stage-Ia 95% • Stage-1b 80-90% • Stage-II 75% • Stage-III <50%
  51. 51. Ca. Cx. Complications of spread: • Obstruction to bladder & ureter, pyelonephritis, uremia.
  52. 52. UterusUterus
  53. 53. Uterus • Myometrium (smooth muscle) • Endometrium (glands & stroma) • Hormonally responsive (EM is shed every month)
  54. 54. EM histology in menstrual cycle • It is helpful to assess: 1. Hormonal status 2. Ovulation 3. Infertility 4. To determine the cause of bleeding
  55. 55. The endometrial hormonal cycle is diagrammed here. The "average" cycle is 28 days. The time from ovulation to menstruation in the secretory portion of the cycle is a constant 14 day period. The menstrual portion of the cycle averages 3 to 7 days. The proliferative portion of the cycle is variable among women, but tends to remain the same for any one person.
  56. 56. EM • Upper half to one third is shed and lower one third is not responsive to hormones • Proliferative phase • Secretory phase (indicates post ovulation)
  57. 57. This is the microscopic appearance of normal proliferative endometrium in the menstrual cycle. The proliferative phase is the variable part of the cycle. In this phase, tubular glands with columnar cells and surrounding dense stroma are proliferating to build up the endometrium following shedding with previous menstruation.
  58. 58. Here is early secretory endometrium. The appearance with prominent subnuclear vacuoles in cells forming the glands is consistent with post-ovulatory day 2. The histologic changes following ovulation are quite constant over the 14 days to menstruation and can be utilized to date the endometrium.
  59. 59. Here is mid secretory endometrium with prominent stromal edema. The glands are becoming more tortuous as well
  60. 60. This is mid secretory endometrium with prominent predecidual reaction around prominent spiral arterioles.
  61. 61. The tortuosity of the endometrial glands is apparent in this late secretory endometrium. Such an endometrium is able to support implantation of a fertilized ovum
  62. 62. The late secretory endometrium has prominent pink secretions in the glands. Implantation has not occurred, and there is beginning stromal hemorrhage and increasing leukocyte infiltration just prior to menstruation
  63. 63. DUB • EM is controlled by rise and fall of pituitary and ovarian hormones • Alterations in this cycle leads to atrophy, abnormal proliferation and secretory pattern and also hyperplasia • Most common problem is bleeding PV occuring between menstrual period
  64. 64. DUB Causes: may vary depending upon the age. Pre-pubertal: precausious puberty Adolescent: anovulatory cycles Reproductive: complications of pregnancy, leiomyoma, adenomyosis, polyps, EM hyperplasia, anovulatory cycle Perimenopausal: anovulatory cycle, irregular shedding, carcinoma, hyperplasia Post menopausal: carcinoma hyperplasia, EM atrophy
  65. 65. Anovulatory cycle • Most common cause of DUB • Excessive prolonged action of estrogen • No lutela phase due to absence of ovulation • Excessive proliferation of EM • Unscheduled breaskdown of the stroma
  66. 66. Causes of anovulation: 1. Hypo / hyperthyroidism 2. Adrenal disease 3. Pituitary tumor 4. Functioning ovarian tumor 5. PCOD 6. Marked obesity 7. Note: anovulatory cycles are common at menarche and perimenopausal period Anovulatory cycle 1. Granulosa and 2. Theca cell tumors
  67. 67. Inflammations - Endometritis • Acute endometritis is uncommon --retained products • Chronic endometritis: 1-PID 2-retained gestational tissue 3-IUCD 4-TB 5- in 15% No cause is found Microscopy: Plasma cells and macrophages
  68. 68. • There are scattered neutrophils in glands and stroma, indicative of acute endometritis, a condition that most often is a complication of childbirth ("puerperal sepsis" or "post-partum fever"), with organisms such as group B streptococcus and Staphylococcus aureus. With good obstetrical care, this condition is uncommon, but throughout human history it has accounted for significant maternal mortality.
  69. 69. Endometritis Historical note: One of the earliest examples of the control of infection through proper hand washing was instigated by Ignác Semmelweis, a Hungarian obstetrician working in the Vienna General Hospital in the 1840's. He was puzzled by the high mortality of women due to "post-partum fever". Semmelweis noted that physicians and students would often come straight from the anatomy dissecting rooms and examine patients directly without washing their hands. He instigated a hand washing procedure, and statistics fully justified his hygenic reform: mortality due to post-partum fever dropped drastically. Hand washing continues to be an important means of infection control.
  70. 70. Chronic endometritis can occur in patients with chronic pelvic inflammatory disease, as a postpartum or postabortion complication, in association with intrauterine devices (IUD's), or with tuberculosis. In a sixth of patients there is no definable cause for chronic endometritis. The granulomatous form of chronic endometritis shown here is due to drainage of tuberculous salpingitis into endometrial cavity. This occurred in a patient with disseminated tuberculosis.
  71. 71. Endometriosis
  72. 72. Terms: Endometriosis Adenomyosis Endometriosis
  73. 73. • Def: Presence of endometrial glands or stroma in abnormal locations outside the uterus. • Sites: in descending order of frequency 1-Ovaries, 2-uterine ligaments, 3- rectovaginal septum, 4-pelvic peritoneum, 5-laparotomy scar, 5-umbilicus, vagina or appendix. Endometriosis
  74. 74. Sister Mary Joseph’s nodule? • Umbilical nodule – mets from pancreatic carcinoma, endometriosis
  75. 75. Adenomyosis • Def: presence of endometrial tissue in the uterine wall (myometrium) • Adenomyotic element is in continuity with the overlying EM (it signifies downgrowths fo EM into and between the smooth muscle) • Ocuurs in 20% of uteri.
  76. 76. Adenomyosis • Microscopy: Irregular nests of endometrial stroma with or without glands – present within the myometrium (2-3mm away from basalis)
  77. 77. Adenomyosis • Clinical features: 1-dysmenorrhea, menorrhagia, dyspareunia, pelvic pain. 2-seen in 3rd and 4th decades of life 3-10% of women suffer from this.
  78. 78. The thickened and spongy appearing myometrial wall of this sectioned uterus is typical of adenomyosis, a condition in which endometrial glands with stroma are located within the myometrium. There is also a small white leiomyoma at the lower left.
  79. 79. Adenomyosis occurs when endometrial glands and stroma are found in the myometrium, not just in the endometrium where they belong. This condition leads to uterine enlargement and irregular bleeding.
  80. 80. Endometriosis • Theories: 1-Regurgitation / implatation thru F.tube 2-Metaplastic theory 3-Vascular / Lymphatic dissemination theory
  81. 81. Endometriosis
  82. 82. Endometriosis • Clonality of endometriotic tissue: 1-aromatase cytochrome p450 is only seen in endometriotic EM but not in normal EM. 2-this indicates that EM is clonal in origin. 3-they can synthesize their own estrogens.
  83. 83. • Morphology: 1-Red blue to yellow brown nodules just beneath the serosa 2-Organizing hemorrhages causes extensive fibrous adhesions between tubes, ovaries and other structures and obliteration of Pouch of Douglas. 3-Ovaries – large cystic mass filled with brownish blood and debri (Chacolate cysts) Endometriosis
  84. 84. Grossly, in areas of endometriosis the blood is darker and gives the small foci of endometriosis the gross appearance of "powder burns". Small foci are seen here just under the serosa of the posterior uterus in the pouch of Douglas. Such areas of endometriosis can be seen and obliterated by cauterization via laparoscopy.
  85. 85. Upon closer view, these five small areas of endometriosis have a reddish-brown to bluish appearance. Typical locations for endometriosis may include: ovaries, uterine ligaments, rectovaginal septum, pelvic peritoneum, and laparotomy scars. Endometriosis may even be found at more distant locations such as appendix and vagina.
  86. 86. Scar endometriosis
  87. 87. Chacolate cyst - ovary
  88. 88. Ovarian endometriosis
  89. 89. • Microscopy: 1-Endometrial glands 2-Endometrial stroma 3-Hemorrhages & fibrosis 4-Hemosiderin laden macrophages Endometriosis
  90. 90. Ovarian endometriosis
  91. 91. Ovarian endometriosis
  92. 92. Here, a small cluster of endometrial glands and stroma with hemorrhage are seen at the left near the surface of the fallopian tube. The lumen of the tube is at the right. This is a focus of endometriosis.
  93. 93. Sister Mary Joseph’s nodule? • Umbilical nodule – mets from pancreatic carcinoma, GIT ca, endometriosis.

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