Reproductive Module - Cellular and Systematic Pathology - PDF

🧪 Reproductive Module Cellular and Systematic Pathology Date @November 21, 2024 Lecturer Sandra Cameron Week Week9-10 MALE REPRODUCTIVE SYSTEM - PATHOLOGY & HISTOPATHOLOGY...

🧪 Reproductive Module Cellular and Systematic Pathology Date @November 21, 2024 Lecturer Sandra Cameron Week Week9-10 MALE REPRODUCTIVE SYSTEM - PATHOLOGY & HISTOPATHOLOGY Learning Outcomes Brief recap of anatomy of the male reproductive system Testes - Common Disorders Congenital Conditions Inflammatory Conditions Common Disorders Testicular Cancer Hormone recap Prostate Benign conditions Prostate Carcinoma Reproductive 1  Male reproductive anatomy Lateral view of male reproductive system: Sagittal view of testes: Reproductive 2  Recap - The male reproductive system is made up of the penis, testes, epididymis, and the ducts and glands that produce and carry semen. The Sperm exit the scrotum through the ductus deferens, which is bundled in the spermatic cord. The seminal vesicles and prostate gland add fluids to the sperm to create semen. Sagittal view shows the seminiferous tubules, the site of sperm production. Formed sperm are transferred to the epididymis, where they mature. They leave the epididymis during an ejaculation via the vas deferens. Testes recap Paired ovals 4-5cm in length Source of gametes and androgens Active throughout reproductive lifespan Held in scrotum (temperature control) Testes cross section (H and E stain): Reproductive 3  Spermatozoa are produced in the germinal epithelium of the seminiferous tubules and released into the lumina of these ducts. The germinal epithelium contains both Sertoli cells and the developing spermatocytes. Sertoli cells extend from the basement membrane of the germinal epithelium to the lumen of the tubule. These cells envelope the developing sperm cells. They are joined to one another by junctional complexes and form the blood-testis barrier. The interstitial space contains clumps of darker, eosinophilic cells. These are the Leydig cells, which produce and release testosterone. Myoid cells surround the tubules and generate rhythmic contractions to propel spermatozoa and fluid. They also synthesize collagen and other fibers of connective Testes structure The bulk of the gland is composed of the seminiferous tubules, in which sperm develop Seminiferous tubules are lined with germinal epithelium Tubules surrounded by interstitial (connective) tissue Reproductive 4  Spermatozoa are produced in the germinal epithelium of the seminiferous tubules and released into the lumina of these ducts. The germinal epithelium contains both Sertoli cells and the developing spermatocytes. Sertoli cells extend from the basement membrane of the germinal epithelium to the lumen of the tubule. These cells envelope the developing sperm cells. They are joined to one another by junctional complexes and form the blood-testis barrier. The interstitial space contains clumps of darker, eosinophilic cells. These are the Leydig cells, which produce and release testosterone. Myoid cells surround the tubules and generate rhythmic contractions to propel spermatozoa and fluid. They also synthesize collagen and other fibers of connective Reproductive 5  Layer of smooth muscle around tubule –Myoid cells for contraction Germinal epithelium contains both Sertoli cells and the developing spermatocytes Leydig cells are located in the interstitial space between the tubules Leydig cells produce testosterone Sertoli cells are located in the germinal epithelium and play a supportive role in the development of spermatozoa. Interstitial or Leydig cells are located in the connective tissue surrounding the seminiferous tubules, they are responsible for producing testosterone Reproductive 6  Chryptorchidism Partial or abnormal descent of one or both testes Affects 30% of premature males and 3% of term infants Possible risk factors include: a family history of undescended testes; low birth weight and small for gestational age; preterm delivery; endocrine disorders, such as congenital adrenal hyperplasia; disorders of sexual development; and maternal smoking Complications include impaired fertility, increased risk of testicular cancer in the undescended testis, and increased risk of testicular torsion and inguinal hernia. A congenital condition that is painless. Screened for at birth then again at 6 – 8 weeks. Can be treated- an operation called an orchidopexy to move the testicles into the correct position inside the scrotum. Reproductive 7  Orchitis and epididymitis Orchitis: Inflammation of testes caused by urinary infection or systemic infection e.g. mumps Epididymitis: Inflammation of epididymis, usually secondary to orchitis Can result in fibrosis of tubules and atrophy of testes Spermatogenesis irreversibly impaired in 30% cases caused by mumps Sterility can occur if chronic and if both testes affected Can be a combined Epididymo-orchitis Symptoms include dysuria, pain and swelling in the groin area, fever and chills. In sexually active men, often caused by an STI –treated with antibiotics Varicocele Dilated veins of the pampiniform plexus in the spermatic cord Affects left side more often (90%) due to arrangement of veins Incompetent valves cause reflux of blood into veins of plexus Gravity increases venous dilation Reproductive 8  Can be linked to infertility Surgery to remove varicosities and improve blood flow usually improves fertility Debate over the link to infertility, but the increased blood flow to the area, will increase the temperature within the scrotum. Temperature has a negative effect on sperm motility. Testicular cancer Testicular cancer accounts for 1% of all new cancer cases in males in the UK (2017-2019) Incidence rates for testicular cancer in the UK are highest in males aged 30 to 34 (2017-2019) Around 9 in 10 (91.3%) men diagnosed with testicular cancer in England survive their disease for ten years or more, it is predicted (2013-2017) Usually only found in one testes Cause is unknown, but may have some link (10%) with Chryptorchidism Most testicular cancers are germ cell tumours. The 2 main types are: seminomas Reproductive 9  non-seminomas Survival rates are for all stages of cancer diagnosed – better survival rates associated with early diagnosis. CAUSES The cause of testicular germ cell cancer has not been identified but is associated with the following risk factors: Chryptorchidism – 10% of cases Caucasian Ethnicity – More prevelant in European and American white men than Asian or afro-Caribbean men. Hereditary - Links within families are being researched to look for a possible genetic component. However it is rare for testicular cancer to affect more than 1 member of the family. Lifestyle / Environmental Factors – various theories have been suggested including sedentary lifestyles (low levels of physical activity), infections, trauma, although none of these theories have been confirmed through research. Seminoma Most common testicular neoplasm Originates in the germinal epithelium of the seminiferous tubules Slow growing The blood-testis barrier formed by Sertoli cells, which physiologically aims to protect spermatozoa, may also play an indirect role in the prevention of testicular metastasis Reproductive 10  HISTOPATHOLOGY Normal testis appears at the left, and seminoma is present at the right. Note the difference in size and staining quality of the neoplastic nests of cells compared to normal germ cells. Note the lymphoid stroma between the nests of seminoma. DIAGNOSIS AND TREATMENT Earliest detection is best Reproductive 11  Many detected by regular self examination (recommended) Slight enlargement of testicle with some discomfort or heaviness Palpation and transillumination Testicular ultrasonography Immunoassay for tumour markers e.g. α-fetoprotein, hCG, CEA CT and MRI scan for metastasis Biopsy not undertaken due to risk of spreading Treatment begins with orchiectomy Seminomas respond well to radiotherapy Metastases treated with multi-agent chemotherapy and hormonal therapy 5-year survival stage 1 = 98%, with distant metastasis = 75% Can be offered a testicular prothesis after surgery AFP- Alpha Fetoprotein HCG – Human Chorionic Gonadotrophin LDH – Lactate Dehyrdrogenase Hormones recap Reproductive 12  Structures in male reproductive system are influenced by hormones Main hormone associated with males is testosterone Some is then converted to a more active form, dihydrotestosterone, by 5-α- reductase Males also produce small amounts of oestrogen which enhances the actions of dihydrotestosterone As males age testosterone levels decrease so proportionally higher levels of oestrogen Prostatic enlargement Benign Prostatic Enlargement/Hyperplasia (BPH) Reproductive 13  25% of men have some degree of hyperplasia by age 50, increases to 90% by aged 80 Increased levels of dihydrotestosterone (DHT) may stimulate hyperplasia Smooth muscle hypertrophy also a factor, activity mediated by α- adrenoceptors Enlargement is due to hyperplasia. Normal prostate should be 3 – 4 cms. This one is 5-6 cms. Below we can see prostate chips The prostate "chips" seen here are the firm, rubbery fragments obtained from transurethral resection of prostate (TURP) performed for symptomatic nodular hyperplasia. SYMPTOMS OF BPH Pathophysiology due mainly to location of prostate Enlargement blocks normal flow of urine Poor flow, post-voidal dribbling, increased frequency and nocturia Obstruction can lead to retention and backflow Can cause frequent UTI infection and, untreated, may lead to eventual kidney failure DIAGNOSIS OF BPH Patient history – symptoms index Digital rectal exam - signs show enlarged prostate with smooth, rubbery surface (hard nodules would suggest cancer rather than BPH) Urinary flow analysis (check for blockages) Urinalysis (check for infection) Serum creatinine (check kidney function) Prostate specific antigen (PSA – an enzyme produced by the prostate gland, elevated in conditions where prostate is enlarged) Reproductive 14  Abdominal radiographs TREATMENT FOR BPH Pharmacological options: 5α-reductase inhibitors e.g. finesteride α-adrenergic antagonist e.g. prozasin Surgical options: Transurethral prostatectomy (TURP) Transurethral incision of prostate (TUIP) Transurethral – vaporisation, ablation, ultrasound guided laser induced prostatectomy Stents – useful where surgery is inadvisable, tubular mesh inserted to hold urethra open Finasteride inhibits the enzyme 5-alpha reductase, responsible for converting testosterone to dihydrotestosterone within cells. This blocks the growth-promoting androgenic effect and diminishes prostatic enlargement Below we can see prostate chips The prostate "chips" seen here are the firm, rubbery fragments obtained from transurethral resection of prostate (TURP) performed for symptomatic nodular hyperplasia. Prostate cancer 98% prostate cancers are prostatic adenocarcinomas With exception of skin, most common cancer in men Affects 1 in 10 (Scotland) men during lifetime, only 1 in 30 die But ranks just below lung cancer as cause of death Peak incidence 60 – 70 years Reproductive 15  Insidious, unlike BHP usually confined to periphery of prostate so often no pressure on urethra until advanced Many cases diagnosed accidentally during investigation of BPH Hard, fixed nodules on rectal exam May present a low back pain due to bone metastasis Metastasis can also show as shortness of breath, weight loss or anaemia Clinical presentations can include urinary retention, frequency, hesitancy and nocturia. Also, back or hip pain. RISK FACTORS Ethnicity, more common in Black men than Asian men Family history, direct male relative who developed prostate cancer a possible link to BRCA1 and BRCA2 genes through familial female breast cancer and Obesity Diet Hormone status SCREENING AND DIAGNOSOS No definitive screening process urine sample to check for infection prostate-specific antigen (PSA) – blood test Digital rectal examination Transrectal MRI of prostate Trans perineal biopsy Transrectal biopsy using ultrasound Reproductive 16  an MRI scan, CT scanor PET scan– more detailed picture An isotope bone scan, for metastasis An isotope bone scan, for metastasis – a small amount of radiation dye is injected into the vein and then collects in parts of the bone where there are any abnormalities ~ PSA SCREENING ~ PSA screening good but not specific (3 neg:1 pos) PSA levels can be increased due to BPH, infection, after sex, during normal ageing Usually measured in nanograms per millilitre of blood (ng/ml) but no one normal PSA reading; the following values are a rough guide 3 ng/ml or less is considered to be in the normal range for a man under 60 years old 4 ng/ml or less is normal for a man aged 60 to 69 5 ng/ml or less is normal if you are aged over 70. A reading higher than these values but less than 10 ng/ml is usually due to a non cancerous (benign) enlargement of the prostate gland. A reading higher than 10 ng/ml may also be caused by benign prostate disease But the higher the level of PSA, the more likely it is to be cancer. Ongoing search for more sensitive marker for prostate cancer PROSTATE CANCER The gross appearance of adenocarcinoma of the prostate is shown here in cross section. The entire prostate is involved. The yellowish nodules represent larger foci of carcinoma. Reproductive 17  GRADING PROSTATE ADENOCARCINOMAS Reproductive 18  The Gleason score is the sum of the two worst areas of the histological slide. Summative assessment The higher the score or grade the poorer the prognosis. HISTOLOGY OF PROSTATE ADENOCARCINOMA Histological slide (H & E stain at x300) showing prostate cancer. On the right is a somewhat normal Gleason Value of 3 (out of 5) with moderately differentiated cancer. On the left is less normal tissue with a Gleason Value of 4 (out of 5) that is highly undifferentiated TNM STAGING Reproductive 19  Tumour, Nodes and Metastasis stage 1 and stage 2 cancer is called early (localised) prostate cancer stage 3 and stage 4 cancer that has not spread to other parts of the body is called locally advanced prostate cancer stage 4 cancer which has spread to other parts of the body usually the bones is called advanced (metastatic) prostate cancer Staging using the TNM system T1 = asymptomatic but found histologically T2 = palpable but confined to prostate T3 = extend beyond prostate T4 = involve adjacent structures N = nodular involvement, M = distant metastasis, both either 0 or 1 TREATMENT Dependent on many factors “Watchful waiting” – for elderly patients in early stages Radical prostatectomy – removal of prostate, seminal vesicles and ampullae Reproductive 20  Radiation – external beam or transperitoneal implantation of radioisotopes (seeding) Brachytherapy is a form of radiotherapy where the radiation dose is delivered inside the prostate gland. It's also known as internal or interstitial radiotherapy. Does not respond well to chemotherapy Hormonal manipulation: Anti-androgen therapy – blocks actions of testosterone (e.g. bicalutamide) Also, similar to that used in breast cancer, block LH hormone from pituitary- gonadal axis (e.g. goserelin) Or block release of GnRH from hypothalamus (e.g. degarelix) Often used in combination to achieve maximum blockade Hormone therapy can cause reduced sex drive and erectile dysfunction, also hot flushes, weight gain and breast tenderness. An alternative to hormone therapy is to surgically remove the testicles (orchidectomy). This does not cure prostate cancer, but by removing the testosterone it controls the growth of the cancer and its symptoms. FEMALE REPRODUCTIVE SYSTEM - PATHOLOGY AND HISTOPATHOLOGY Learning Outcomes Anatomy recap Normal pathology of the cervix Cervical screening Cervical Cancer Salpingitis and PID Ectopic pregnancy Reproductive 21  Endometriosis Endometrial cancer (uterine) Ovarian Cancer Normal Breast Physiology Hormones and the breast Benign conditions Breast Cancer Screening Diagnosis and treatment Anatomy of the female reproductive system Reproductive 22  The female reproductive system consists of 5 main parts. The uterus, the ovaries, the fallopian tubes, the cervix and the vagina. The cervix Lets start by looking at the cervix which makes up the neck area of the uterus. This area is composed of muscle tissue, connective tissue and glands. It forms a pathway between the vagina and the uterus. In this diagram there is an opening or orifice know as the Ostium internum uteri or OS for short. The space between the external os (vagina) and internal os (uterus) is the endocervical canal. Epithelium in the cervix Reproductive 23  The cervix has several different types of epithelial linings. The endocervix is lined with mucous secreting glandular epithelium, and the ectocervix is lined with stratified squamous epithelium. Where this squamous epithelium meets the glandular epithelium is known as the squamocolumnar junction (SCJ). Histology of the cervical squamo‐columnar junction (Hematoxylin‐Eosin stain). SSE: stratified squamous epithelium; SCE: simple columnar epithelium. The cervical squamo‐columnar junction consists of the stratified squamous epithelium and simple columnar epithelium. The simple columnar epithelial cells have clear mucus‐rich cytoplasm, and the cell nuclei formed close to the basal lamina. In the stratified squamous epithelium, cell shape is cuboidal in the basal layer, gradually becoming flatter toward the superficial layer. Stratified squamous epithelial cells Reproductive 24  have eosinophilic cytoplasm and no mucus. The cervical squamo‐columnar junction has no transitional area, and the boundary between the stratified squamous epithelium and the single columnar epithelium is clearly defined. SQUAMNOCOLUMNAR JUNCTION MOVEMENT The SCJ is dynamic, it moves! Age and hormonal status are the most important factors influencing location of SCJ. At birth and during premenarchal years, the SCJ is located at or very close to the external os (original SCJ). During reproductive age, the SCJ is located at variable distances from the external os. In a postmenopausal woman, the new SCJ is not visible and has receded into the endocervix. This movement of the SCJ along with large portions of columnar epithelium is called ectropian Over time through a process called metaplasia, the ectropian is replaced by metaplastic squamous epithelium Metaplasia is a reaction of the exposed everted columnar epithelium (ectropian) to irrigation by acidic vaginal environment This process is accelerated by trauma and infection TRANSFORMATION ZONE Area between the original SCJ and the new SCJ where the columnar epithelium (ectropion) has been replaced and/or is being replaced by the new metaplastic squamous epithelium. The TZ may be either wide or narrow depending on age, parity, prior infections and exposure to female hormones Reproductive 25  During transformation the metaplastic cells are highly sensitive to carcinogenic substances Genetic changes can lead to dysplasia (abnormal cells) Critical area for the development of cervical cancer Area sampled during cervical screening normal squamous epithelium (red star), squamous metaplasia (green star) with some remaining endocervical cells (blue arrow). Cervical screening programme The NHS cervical screening programme invites women from age 25 to 64 for cervical screening. You get an invite every 3 to 5 years depending on where you live and your age. You need to be registered with a GP to get your screening invitations. For England and Northern Ireland – you get an invite every 3 years if you are aged 25 to 49. After that, you get an invite every 5 years until age 64. Reproductive 26  For Wales and Scotland– you get an invite every 5 years if you are aged 25 to 64. If you are over 65 and have never had cervical screening, you can ask your GP for a test if you want one. Applies to anyone born with a cervix SAMPLE TAKING PROCESS Cells from the transformation zone of the cervix are retrieved during this sampling process. Speculum examination of the cervix by the health professional Cervix is sampled by inserting a small cervix broom into the cervical os and rotating 360o clockwise rotation, 5 times Cervix broom is then rinsed in Preservcyt solution (fixative solution) Reproductive 27  PATIENT PATHWAY / RESULTS HPV primary analysis, Pathways are complicated. But it is essential that we do not send patients to Colposcopy too soon as HPV can naturally regress. NORMAL SQUAMOUS EPITHELIUM PATTERN Reproductive 28  For cytology triage – this image displays a normal squamous epithelial pattern. LOW GRADE DYSKARYOSIS (KOILOCYTOSIS) AND MULTI- NUCLEATION Nuclear halos indicating HPV infection (koilocytes) Cytology sample Large, dark nuclei indicating DNA damage, increased incidence of mitotic events (dyskaryosis) HIGH GRADE DYSKARYOSIS (SEVERE) WITH HYPERCHROMATIC CROWDED GROUPS Reproductive 29  Overcrowded dense groups of cells – hyperchromatic, due to increased activity within the nucleus. Cytology sample HIGH GRADE DYSKARYOSIS ?INVASIVE Reproductive 30  Lots of dyskaryotic cells present, bizarre shapes, fibre and tadpole. Marked variation in size and shape with the nuclei. Tumour diathesis/debris Cytoplasmic Keratinisation. NC ratio can be low to high Increased mitotic rate. Cytology sample COLPOSCOPY Reproductive 31  If we see any of the changes shown in the last few slides, combined with a positive HPV test, the patient is sent to Colposcopy. A colposcope allows the clinician to take a magnified look at the cervix. The bottom images show how various grades of abnormalities show up as acetowhite after treatment with acetic acid wash. Further samples for histology can be taken at this point. Based on the view of the cervix; Acetic acid wash Punch biopsy LLETZ- large loop excision of the transformation zone Cone Biopsy These specimens can be diagnostic or a form of treatment! LLETZ uses a loop diathermy to take a small sample of tissue – about the size of a finger nail. Cone biopsy is cold knife under general anaesthesia – takes a larger piece of tissue. Reproductive 32  LLETZ: CONE BX: Reproductive 33  Histology of CIN I to CIN III Histology images from cervical bx’s. This is still pre cancerous changes Grading of cervical dysplasia / dyskaryosis Reproductive 34  Histology Grade (Cervical Intraepithelial Cytology Grade Neoplasia) CIN (Dysplasia/Dyskaryosis) CIN I Borderline/Mild CIN II Moderate CIN III Severe/Carcinoma in situ This slide shows the disease progression and the associated gradings for both Cytology and Histology. Cervical squamous cell carcinoma This is the gross appearance of a cervical squamous cell carcinoma that is still limited to the cervix (stage I). The tumour seen here is a fungating red to tan to yellow mass that obscures the cervical os. Treatment can also include surgical removal of the cervix and uterus. Cervical cancer staging Reproductive 35  FIGO staging international federation of gynaecology and obstetrics. Cervical cancer symptoms Unusual vaginal bleeding, post coital, intermenstrual, postmenopausal and menorrhagia Increased abnormal vaginal discharge with foul smell Pain during intercourse Pelvic pain Risk factors for cervical carcinoma Early first sexual intercourse Multiple sexual partners Male partner with multiple previous partners Smoking Reproductive 36  Long term oral contraceptive use DES exposure in-utero (synthetic oestrogen) Genetic predisposition Immunodeficiency All above linked with HPV infection (types 16 and 18 cause most cases, 70%) Almost unknown in celibate women Screening, diagnosis and treatment of cervical carcinomas Screening for Primary HPV Investigation of all abnormal bleeding Colposcopy Punch biopsy LLETZ* Cone* can be used to treat very early stages (1A1) of cervical cancer Surgery Trachelectomy Hysterectomy Chemotherapy Radiotherapy Immunotherapy for advanced (4B) carcinoma Prevention – HPV vaccination (Gardasil) protect against HPV types 16, 18, 6, 11, 31, 33, 45, 52, 58 Trachelectomy removes the cervix to try and maintain fertility. Reproductive 37  Salpingitis and pelvic inflammatory disease Salpingitis- inflammation of the fallopian tubes, Type of pelvic inflammatory disease (PID) Caused mainly by STD bacterial infection by can be a result of intrauterine procedures Symptoms can include foul discharge, pelvic pain, fever and nausea Can lead to tubal scarring, adhesions and blockages resulting in ectopic pregnancy and infertility Gross appearance of fallopian tube containing acute salpingitis. The tube is enlarged with a dilated lumen and erythematous mucosa. The wall is oedematous and thickened. Ectopic pregnancy External view of dilated fallopian tube containing an ectopic pregnancy Reproductive 38  88% of ectopic pregnancies associated with salpingitis Mainly in the ampulla region of the fallopian tube Endometriosis Ectopic (out of place) endometrium Endometrium can break off and travel in blood or lymph to lodge in distant sites Still responds to reproductive hormones Causes pain, bleeding, inflammation and scarring Found in 25-35% of infertile females Treatment can include surgery or hormone control Reproductive 39  Endometriosis has a highly varied presentation. Thought to affect 1.5 million women in the UK Endometrial (uterine) cancer Most common gynaecological cancer, 6% all female cancers Most people (95%) with endometrial cancer present with postmenopausal bleeding Approximately 690 new cases are diagnosed in Scotland each year Risk factors for endometrial cancer include: tamoxifen, obesity, age over 45 years, nulliparity, family history of colon or endometrial cancer and exposure to unopposed oestrogens Reproductive 40  Treatment depends on grade and type but surgery (e.g. total hysterectomy) radiotherapy and chemotherapy 5 year survival with early diagnosis is >90% Carcinoma occupying most of the endometrial cavity Staging of this cancer also uses the FIGO system, or the TNM system. Ovarian tumours Ovaries contain 3 cell types: 1. germ cells 2. hormone-producing stromal cells 3. surface epithelial cells Each cell type produces different neoplasms General rules: Most ovarian masses are benign cysts Reproductive 41  65% neoplasms from surface epithelium 50% bilateral 90% of malignant tumours carcinomas of surface epithelium OVARIAN TUMOUR CLASSIFICATION OVARIAN TERATOMA Germ cell tumour (teratomas in testes in males are similar) 20% all ovarian tumours Usually benign, affect mainly girls and young women Because of tissue origin teratomas generally contain materials not normally found in the organ Most are cysts containing skin and hair – “dermoid cysts” Sometimes discovered accidentally on x-rays or during pelvic exams Reproductive 42  Ovarian cancer A silent killer Usually asymptomatic until widespread invasion 5% of all female cancers Symptoms can be vague and mimic gastrointestinal disorder May sometimes cause vaginal bleeding Risks include high fat diet, exposure to talc applied to genitals, infertility, no children, post menopause, family history Some association with hereditary breast cancer (BRCA1 and BRCA2) https://www.nice.org.uk/guidance/ta528 OVARIAN CANCER TREATMENT Reproductive 43  Surgery – depends on spread. May involve removal of ovaries, uterus, tubes, cervix and omentum Chemotherapy – either IV or directly into abdomen Radiation – can be used after treatment to reduce tumour size and control pain Targeted therapy – target specific pathways unique to particular tumour Morality in female reproductive Reproductive 44  Despite recent advances in treatment ovarian cancer still has the poorest survival rate for advanced cases Behind that is cervical cancer Both produce vague symptoms that may not be considered serious until tumour has spread Breast anatomy Reproductive 45  The structure (a) and fascia (b) of the breast and changes in breast structure during lactation (b). Paired mammary glands, more prominent in females after puberty. The breast is composed of mammary glands surrounded by connective tissue stroma. These mammary glands consist of a series of modified ducts and secretory lobules (15- 20) Each lobule consist of many alveoli drained by a single lactiferous duct. These ducts converge at the nipple like the spokes of a wheel. We also have fat, vasculature, lymphatics and nerves all over the pectoris major. The breast change throughout lifespan. Hormones and normal breast histology Puberty: oestrogen stimulates the growth of breast ducts whilst progesterone stimulates the growth of ductile tissue and secretory lobules. Stroma of loose connective and adipose tissue Reproductive 46  Pregnancy and lactation: initially oestrogen stimulates proliferation of ducts and then progesterone stimulates proliferation of secretory alveoli (Posterior pituitary hormones: prolactin stimulates milk production in lobules and oxytocin triggers ejection into ducts) Post-menopause: hormone levels fall, breast glands atrophy (involution), replaced with adipose and dense connective tissue Reproductive 47  Breast pathology Many conditions that can affect the breast Some of these can cause redness and swelling of the breast Some also cause breast lumps Important - Most breast lumps are benign! Any breast changes should be checked right away, male and female The sooner they are investigated, even if they are cancer, the better the outlook We’ll start with a couple of common conditions that are not cancerous Fibrocystic change Most common breast lesion Affects pre-menopausal woman Enlargement of ducts to form cysts Metaplasia of ductal epithelium (Apocrine – similar to that seen during lactation) not shown here Reproductive 48  Stromal fibrosis Appears as nodular lesions, more prominent before menstruation Should be checked to eliminate possibility of breast cancer Can affect up to 50% of women, causing breast pain and lumpiness, it is cyclic and can be associated with polycystic ovarian syndrome More prominent before menstruation, that’s why you are advised to check your breasts just after your period. Diagnosed through needle aspirate Fat necrosis Mainly trauma associated Injured adipose cells dies Inflammatory cells infiltrate the area Proliferation of fibrous tissue around the injured area produce a hard lump Breast area might also look inflamed or dimpled Harmless, self-limiting, should self resolve Reproductive 49  Associated with trauma or injury, mainly in peri menopausal women. Typically present with a painless superficial solitary mass which may mimic cancer. Breast cancer The great majority of malignant breast tumours are carcinomas – i.e. of epithelial origin 2 main categories 1. ductal carcinoma – epithelium lining ducts 2. lobular carcinoma – epithelium of smallest ducts or milk gland Uncommon (but not unknown) in under 30’s, risk increases with age Additional risks: early menarche (onset of periods), nulliparity (no pregnancies), late childbearing, late menopause, increased height, obesity, alcohol intake, smoking, HPV infection? 5-year survival varies from 100% to 10% depending on a variety of factors Reproductive 50  Ductal epithelium and lobular epithelium This is a terminal duct lobular unit. Origin site for all breast cancers Genetics and breast cancer 1886 – Paul Broca reported importance of family history in breast cancer 1913 – Alvin Scott Warthin produced first comprehensive study of familial breast cancer 1990 – Marie-Clare King mapped first breast cancer susceptibility gene, BRCA1 at chromosome locus 17q21, 87% risk of breast cancer and 63% risk of ovarian cancer by age 70, also associated with colon and prostate cancer BRCA2 mapped to locus 13q12, 87% risk of breast cancer in females and 6% risk in males by age 70, also slight risk of ovarian cancer Both tumour suppressor genes Reproductive 51  (Other oncogenes and tumour suppressors now identified in sporadic mutations causing breast cancer e.g. p53 on 17q12) Earlier age of onset, mutation can be detected by genetic testing However, hereditary breast cancer only accounts for 5 – 10% all cases (but approx. 80% of cases in younger females) Signs and symptoms of breast cancer Many breast cancers are detected by self-examination Variable symptoms New lump in the breast or underarm Redness and or swelling Orange peel effect Dimpling of skin Puckering of skin Or changes to the nipple Discharge Retraction Change in direction Ulcer Scaliness Reproductive 52  This diagram shows a breakdown of the histological and molecular subtypes for breast cancer. On the left hand side you can see the histological component of the cancer, ductal or lobular. We know that all cancer originates in a terminal duct lobular unit. Cancer cells have a similar phenotype to the normal basal and luminal cells of this ductal structure. We can see this further broken down in the diagram. Finally we can look at the molecular subtypes of the cancer. Starting from the RHS or Luminal A. This cancer is ER/PR + so the cancer cells have ER/PR receptors. They tend to be low grade with a good prognosis. They have a low Ki67 index ( Ki67 is a protein found in cells that are differentiating, so proliferating) They respond well to endocrine therapy ie hormone therapy namely Tamoxifen. Luminal B cancer can be either ER or PR positive. This can also be Her2 positive or negative. Her2 human epidermal growth factor receptor2. Higher Ki67 index than Luminal A, so slightly faster growing with poorer prognosis. It can respond to targeted therapy if her 2 positive. Monoclonal antibody, trastuzamad. But less likely to respond to hormone therapy. HER2+ may be ER/PR + or neg. faster growing poorer prognosis cancers that tend to be diagnosed later. They have a high Ki67 index. Treated by trastuzumad. Finally we have the triple negs. Most common in the BRCA1 mutation. Seen in Reproductive 53  younger women and women of colour. Fastest growing, highest grade, poorest prognosis, Highest Ki67 index. Needs surgery, chemo/radiotherapy. Ductal carcinoma Most common from of breast carcinoma (75-80% of cases) Easiest to detect with mammography Usually confined to one breast Forms distinct mass Most aggressive type Reproductive 54 Reproductive 55  This is a grade 2 tumour with moderately differentiation. Mitotic figures are present. Pagets disease of the nipple Red, weeping, scaly lesion of the nipple and surrounding areola Thought to be due to breast carcinoma cells spreading to the surface along the epithelium of the ducts Usually associated with underlying ductal carcinoma Lobular carcinoma Less common than ductal carcinoma (10 -15% of cases) Less easy to detect More diffuse growth pattern, fewer distinct palpable masses Can infiltrate as rows of cells - “Indian files” Better prognosis than ductal form But can affect both breasts simultaneously Reproductive 56  Less common than ductal carcinoma (10 -15% of cases) Less easy to detect More diffuse growth pattern, fewer distinct palpable masses Can infiltrate as rows of cells - “Indian files” Better prognosis than ductal form But can affect both breasts simultaneously Reproductive 57 Reproductive 58  The top image shows the Indian files of lobular carcinoma. The bottom image is ICC ER/PR + Breast cancer metastasis This shows the most common sites for metastasis. You can see that for brain, lungs, and liver the primary is most likely HER 2 + and the spread is through the haematogenous system, so through the blood. Breast screening The NHS Breast Screening Programme invites all women from the age of 50 to 70 registered with a GP for screening every 3 years. This means that some people may not have their first screening mammogram until they are 52 or 53 years. Reproductive 59  Carcinoma of the breast. (A) Mammogram. An irregularly shaped, dense mass (arrows) is seen in this otherwise fatty breast. (B) Mastectomy specimen. The irregular white, firm mass in the center is surrounded by fatty tissue. (From Strayer D. S., Rubin R. (Eds.) (2015). Rubin’s pathology: Clinicopathologic foundations of medicine (7th ed., Fig. 25-35A and B, p. 1071). Philadelphia, PA: Lippincott Williams & Wilkins.) Ultrasound investigation of breast lump In younger females the breast tissue is too dense and so mammography is less suitable. Lumps usually investigated via ultrasound. Core biopsy Reproductive 60  Immunohistochemistry in diagnosis and treatment of breast cancer The use of enzyme or fluorescently labelled antibodies to detect specific protein markers in tissues Use in breast cancer to detect proteins such as oestrogen and progesterone receptors and also Her2/neu receptors This technique could help identify treatment options and provide prognostic indicators Reproductive 61  Hormone receptor status and hormone-blocking therapy Oestrogen and progesterone both involved in growth of breast tissue Many breast tumours are hormone dependent – but not all Presence/absence of receptors prognostic indictor Both receptors present – 70% chance of responding to hormone blocking therapy Only 1 type present – 33% chance Status unknown – 10% chance Reproductive 62  Surgical options Hormone-blocking therapy Oestrogen receptor antagonist – e.g. Tamoxifen, blocks actions of oestrogen on tissues. Usually used after surgery and chemotherapy. Treatment for 5 years after diagnosis. Reproductive 63  Aromatase inhibitors – e.g. Anastrozole (Arimidex), block action of enzyme that synthesises oestrogen in the adrenal glands. Used mainly in post- menopausal women after tamoxifen. Pituitary downregulators – e.g. Goserelin (Zoladex), blocks release of luteinising hormone from anterior pituitary, thereby preventing ovarian synthesis of oestrogen Her2/neu receptors Her2/neu receptor An epidermal growth factor receptor Cell-surface receptor tyrosine kinase Involved in signal transduction pathways for normal growth and differentiation Greatly over-expressed in some types of breast cancer Immunotherapy in Her2/neu+ breast cancer Trastuzumab Better known as Herceptin Recombinant monoclonal antibody Binds to over-expressed Her2/neu receptors on tumour cells Prevent binding of epidermal growth factors by down-regulating receptors hence prevents proliferation Only effective in Her2/neu + cancers Association with increased risk of heart disease, must be used with care Reproductive 64