Reproductive System Pathology Part 1 PDF

Reproductive System Pathology Part 1– Male Urogenital and Breast Pathology Cases 1. Testes – Normal histology 2. Testis – Epididymo-orchitis 3. Testis – Torsion 4. Testis – Hydrocele 5. Testis – Seminoma 6. Prostate – Normal Histology 7. Prostate – Benign Nodular hyperp...

Reproductive System Pathology Part 1– Male Urogenital and Breast Pathology Cases 1. Testes – Normal histology 2. Testis – Epididymo-orchitis 3. Testis – Torsion 4. Testis – Hydrocele 5. Testis – Seminoma 6. Prostate – Normal Histology 7. Prostate – Benign Nodular hyperplasia (BPH) 8. Prostate – Adenocarcinoma 9. Bladder – Normal Histology 10. Bladder – Transitional Cell Carcinoma 11. Breast – Normal Histology 12. Breast – Fibroadenoma 13. Breast – Ductal Carcinoma Case 1: Testis – Normal Histology Role of the testes: production of spermatozoa and androgens. testosterone Organisation: subdivided by septa into ~250 lobules. Each lobule contains 1-4 seminiferous tubules embedded in surrounding stroma (each tubule is 30- 70cm long). tightly coiled The septa converge posteriorly at a thickened region called the mediastinum testis; this is where the seminiferous tubules also open into a network called the rete testis. where all converge and drain  tightest The thick capsule surrounding the testis is the tunica The lining of the albuginea; external to this is a double layer of mesothelium, seminiferous tubules is the tunica vaginalis. find some fluid composed of tall columnar cells called sustentacular cells (Sertoli cells) - the supporting cells for spermatogenesis – and 3-4 polygonal interstitial produce testosterone layers of smooth muscle with LH cells. supporting cells help favour sperm production The interstitial cells of faded purple Leydig are the endocrine cells of the testis, found between seminiferous outside - stem cells tubules. These synthesise lumen and secrete testosterone. spermatids second division, spermatids  stem cells closest Spermatogonia line by smooth muscle divide again Spermatids island of Leydig  Case 2: Epididymo-orchitis replaced by abscess, surgical removal Epididymitis = inflammation of the epididymis Orchitis = inflammation of the testicles spreads to testicle inflammation of testicle and epididymis Cause varies with age of the patient. - Children: uncommon but may be associated with congenital anomalies and Gram-negative urinary tract infections. improper development backflow of bacteria - Sexually active men under the age of 35: sexually transmitted infections with Gonorrhoea or Chlamydia should be suspected. - Men over the age of 35: urinary tract infections and prostatitis are more common with Pseudomonas and Acute epididymitis caused by gonococcal; E.coli being the main culprits. TB version in prac older males UTI granuloma, giant cell epididymis is replaced by an abscess (Robbins) inflame prostate, retention of urine UTI, sexually transmitted *the case you will be reviewing in practicals this week is a case of tuberculous epididymo-orchitis Epidiymo-orchitis Presentation: Management: - Symptoms develop over 24-48 hours If suspected sexually transmitted organism – Ceftriaxone and doxycycline or azithromycin - Swollen, red, tender testicle (antibiotic coverage for Chlamydia and - ++Pain painful urination, frequencty Gonorrhoea) - Systemic signs of fever, nausea, vomiting in severe cases - Symptoms of underlying cause also present (dysuria, discharge etc.) If suspected UTI – trimethoprim or ceflex for 2 weeks (as for prostatitis) - Positive Prehn’s sign (relief of pain on elevation of the testis) elevate testicle, relieve pain - epididymal-orchitis Tests: torsion, ischaemia - need untwisting - Urine MCS - STD panel urine - Standard bloods (FBC, Chem20, CRP) white cell count - Doppler ultrasound to exclude torsion make sure there is supply  Bacterial invasion induces non-specific acute inflammation characterised by congestion, oedema, and infiltration by neutrophils, eventually macrophages, and lymphocytes. May result in atrophy of the tubules (left) and may progress to abscess formation. With treatment, acute epididymo-orchitis heals with fibrous deposition and scarring that can lead to infertility; some cases persist and become chronic. *Leydig cells are spared (usually); androgen production is not affected pick up and treat early infertile due to scarring not well defined Sertoli cells, light pink with loss of chromatin distribution Case 3 - Testicular arteries typically patent Torsion swollen and painful Most important differential for presentations involving painful swelling of the testicles. Results from twisting of the spermatic cord, cutting off venous drainage. One of the few true urological emergencies. time-limited The arteries remain patent, producing intense vascular engorgement and eventual Testicular Torsion (Robbins) haemorrhagic infarction. twists and cuts off drainage  Occurs most commonly in adolescence. Usually results from a bilateral anatomic Testicular Torsion defect that leads to increased mobility of the testes (bell-clapper abnormality – high attachment of the tunica vaginalis leaving the testis to freely rotate), precipitated by increased growth of the testes during puberty. unusually high attachment of tunica vaginalis Presents with sudden onset extreme testicular pain, often without inciting injury or on waking. The affected testicle is swollen, tender, testicle pulled up high riding and high-riding. Nausea/vomiting and abdominal pain may be present. The testicle may be red and may contain blue/purple areas of infarction. Prehn’s sign is NEGATIVE. no amount of lifting will relieve pain Manual untwisting of the testicle must occur within 6 hours of symptom onset. Orchiopexy is also performed. both testicles saved 6 hours to save fix to scrotum  heterogenous - areas of necrosis 24 hrs to see hyperechoic - haemorrhage doppler for flow look at swelling normal surgery for clinical criteria remove gravity Case 4: Hydrocele all fluid impaired drainage, fluid accumulation Presents as a painless mass in the testicle, often “balloon-like”. Large hydroceles can cause discomfort due to their size. remove sac or fluid re-accumulate Definitive treatment is surgical excision of the hydrocele sac or recurrence rate is high. Congenital hydroceles: during testicular descent, as the testis descends through the inguinal canal, the peritoneum is also drawn into the scrotum (the processus vaginalis – future tunica vaginalis). If the connection between the peritoneum and the processus vaginalis remains, there is potential for peritoneal fluid to accumulate in the scrotum, forming a hydrocele. transillumination, impaired drainage  Case 5: Seminoma Testicular neoplasms are divided into two categories: germ cell tumours (95%) and sex cord-stromal tumours. from other cell types Sertoli, Leydig Germ cell tumours are further subdivided into seminomas and non- separate out seminomas. and other chemicals Germ-cell tumours are associated with in-utero exposure to pesticides and are more likely to develop in men with previous cryptorchidism or hypospadias. There is also a strong genetic predisposition. As such these tumours often arise from a precursor lesion called intra-tubular germ cell neoplasia (ITGCN) which is present in-utero and remains dormant until after puberty. present at birth Seminomas account for 50% of all testicular germ-cell tumours. present from birth accumulate  tunica albuginea - stop spread never direct needle biopsy Seminomas present as a painless testicular mass. Although they are malignant, the tunica albuginea acts as a natural barrier to spread and should not be compromised by direct needle biopsy. Treatment is via radical orchidectomy followed by radio or chemotherapy. Diagnostic markers include: lactate dehydrogenase - Elevated LDH (expressed on chromosome 12p which is often reduplicated and amplified in almost all seminomas) often mutated - Elevated HCG in 15% of patients whose seminomas contain syncytiotrophoblasts - On immunohistochemistry – positive for KIT Macroscopically: homogenous, lobulated, gray-white screen other markers appearance. Sometimes 10x the size of the normal testis sheet of large uniform cells, not have seminiferous tubules + fibrous septa with lymphocytes Microscopically, a seminoma appears as sheets of uniform cells divided into poorly demarcated lobules. Seminoma cells are large and round with a distinct cell membrane and a large central nucleus. The surrounding fibrous septa are infiltrated by lymphocytes  1. A 15-year-old male patient presents with sudden onset left scrotal pain of 2 hours duration. The left half of the scrotum is swollen, tender, and the testicle is palpable in the upper scrotum. What is the most appropriate next step in management? A. Pain relief and overnight observation testicular torsion B. Urgent scrotal exploration B C. External version of the left testis Practice D. E. Send for doppler USS of the testis Administer IV fluids Questions 2. Which of the following is incorrect regarding the histology of a normal testis: A. Fibrous septa separate the testes into multiple lobules’ B. Interstitial cells of Leydig produce testosterone under the influence of LH C. The seminiferous tubules are lined by a tall columnar epithelium known as sustentacular (Sertoli) cells D. Spermatids are located closest to the lumen of the seminiferous tubule E. Sustentacular cells produce testosterone under the influence of LH E Leydig produce testosterone with LH  3. Which of the following is true regarding acute epididymo-orchitis? A. Common causative organisms in males >35 years old include E.coli and Pseudomonas A B. Epididymo-orchitis is common in children due to congenital anomalies of the urogenital system C. Prehn’s sign is negative on clinical examination positive D. Neutrophilic infiltration is uncommon on histological examination do see Practice E. The testis is more commonly involved than the epididymis Questions 4. A 21-year-old male presents with a painless, firm mass in his right testicle. The mass is non-transilluminating. Which of the following is correct regarding this condition: A. Core biopsy is the most appropriate next step in investigating this lesion B. HCG would likely be elevated and LDH decreased in this patient C. Microscopically this lesion would appear as sheets of uniform cells with large nuclei C solid mass, never biopsy D. Microscopically this lesion would most likely demonstrate caseating granulomatous inflammation E. Antibiotics are the most appropriate management for this condition  at base of bladder seminal vesicles large portion of seminal fluid Prostate Pathology peripheral near rectum transition through periurethral region  papillary infold Case 6: Normal Prostate Histology gland to ducts The prostate consists of glands, ducts, and fibromuscular stroma. The mucosa of the secretory glands contains papillary projections into the lumen, giving the glands a distinct appearance. The epithelium is cuboidal or columnar. The secretory glands may also contain aggregates of prostatic secretions called corpora amylacea. The number of these deposits increases with age and is a normal pink regions characteristic of the prostate. normal hyperactive - normal deposits Prostatic secretions The secretions from the prostate account for 30% of total seminal fluid volume. travel through female repro system It contains citric acid, the enzyme fibrinolysin (liquifies the semen), acid phosphatase, and a number of other enzymes and lipids. Prostate-specific antigen (PSA) is also secreted by the secretory cells of the epithelium which functions to liquefy semen allowing sperm to travel freely. It also aids in dissolving cervical mucus, allowing the entry of sperm into the uterus. In prostatic adenocarcinoma, PSA levels rise in response to an increased number of dysplastic glands and increased glandular activity. PSA may also be elevated in non- cancerous conditions of the prostate including prostatitis, and benign prostatic hyperplasia. not perfect screening tool  Case 7: Benign Prostatic Hyperplasia The most common benign prostatic disease in men older than 50 years. Arises from hyperplasia of predominantly stromal tissue (as compared to glands in prostate cancer) under the influence of androgens. The main androgen formed in the prostate is dihydrotestosterone (DHT) through the enzyme 5-alpha-reductase. very active - growth and proliferate prostate dysplastic glands tissue Nodular enlargement predominantly occurs in the peri-urethral area which may result in urinary tract obstruction, hence symptoms often include poor stream, difficulty passing urine, nocturia, and overflow dribbling. obstruction Treatment includes lifestyle modifications (reducing alcohol and caffeine), pharmacological treatment (alpha blockers i.e. tamsulosin to relax prostate smooth muscle and 5-alpha-reductase inhibitors i.e. finasteride, dutasteride), and surgical intervention (TURP, HIFU, radiofrequency ablation etc.). HIFU - high frequency ultrasound resect out reduce testosterone available surgical later erectile dysfunction Investigations should include: BPH most commonly affects the inner periurethral zone of the prostate, producing nodules that compress the prostatic urethra. On microscopic - Urine MCS make sure not UTI, prostatitis examination, the nodules exhibit variable proportions of stroma and glands. - DRE change in peripheral zone e.g. cancer - PSA Hyperplastic glands are lined by tall columnar epithelium and retain their papillary infoldings. Stromal tissue is increased and corpora amylacea - Prostate USS evaluate size deposits may be prominent. more fibromuscular stroma cancer - lose papillary infold, lose stromal tissue increased glands Papillary infoldings Hyperplastic within hyperplastic stroma glands still normal prostate  significant BPH distended bladder prostate sitting below bladder Normal Case 8: Prostate adenocarcinoma glandular The most common form of cancer in men, linked to several factors including age, race, family history, hormone levels, and environmental influences. Survival and growth of prostate cancer is highly androgen driven. Growth is usually within the peripheral zone. cancer growth mainly here androgens how dysplastic and poorly differentiated Grading is via the Gleason Scale where tumour growth pattern is graded between 1 (well differentiated) and 5 (no differentiation); because most tumours contain two growth patterns, both patterns are graded and the numbers added to arrive at the final Gleason Score. score increases two common patterns 2+3 = 5  cells pleomorphic and dysplastic Microscopically, prostate adenocarcinoma presents with back-to-back glands and predominantly glandular hyperplasia as opposed to BPH which is predominantly stromal hyperplasia. These glands often lack the papillary infoldings as seen in the normal prostate. There may be invasion of these dysplastic glands into surrounding smooth muscle. hallmark of cancer Prostate Cancer Presentation: - Asymptomatic in early stages - Similar symptoms to BPH develop: frequent urination, nocturia, poor stream, dribbling, haematuria invasive and start to break down - Fatigue, weight loss, bone pain Metastasis often involves bones Investigations: image - glandular solid, no longer spongy - solid mass in prostate of the vertebra (through Batson’s - DRE initial workup osteoblastic lesions plexus) or pelvis. These are - PSA if significantly high spread in vertebral column osteoblastic lesions (bone - Prostate biopsy (Trans-rectal, US guided) - MRI/CT for staging usual forming) metastases, via venous plexus - Batson's Management: - Radical prostatectomy for localised disease like solid masses if local only - External beam radiation therapy - Interstitial radiation therapy (brachytherapy) - Androgen deprivation in advanced metastatic disease either through orchidectomy or synthetic LHRH which suppresses LH release. remove testicles  Bladder Pathology  top layer - dome cells Case 9: Normal stretch when full Bladder Histology The epithelium of the bladder is transitional epithelium (also called urothelium) – a type of tissue that changes shape in response to stretch. Consists of multiple layers of epithelial cells which contract and expand as required. The superficial layer of transitional epithelium appears dome-shaped (termed umbrella cells) when the bladder is not stretched, and these flatten to a squamous shape when stretched. The muscosal layer is highly folded in its relaxed state.  detrusor mucosa, highly folded very muscular wall - detrusor The muscle layer of the bladder is comprised of three layers: inner longitudinal, middle circular, and outer longitudinal (difficult to distinguish histologically). Note the highly folded mucosal layer. increase surface area Case 10: Bladder Carcinoma from transitional cells 95% of bladder tumours are epithelial in origin, mostly arising from the transitional cells and hence are called urothelial or transitional tumours. Although most commonly found in the bladder, urothelial carcinoma may also develop in the renal pelvis and ureters where urothelium is also present. Two precursor lesions: non-invasive papillary tumours (most common – originate from urothelial hyperplasia) and flat noninvasive papillary carcinoma (CIS) which are associated with smoking, older age, and occupational exposure to chemicals (i.e. arsenic, nitrosamines). genetic or environmental smoking most important - 3-7x increased Most common presentation is painless haematuria. why present One of the worst prognostic markers for urothelial carcinoma is invasion of the detrusor muscle as once this occurs, there is a 30% 5-year mortality rate. before into detrusor if possible both environmental and genetics more common increased thickness then invade  massive lesion with necrosis Diagnosis is assisted through urinalysis and urine cytology and confirmed through biopsy via cystoscopy. sheds Treatment requires resection of existing lesions with adjunct chemo/radiotherapy. camera through until surgically amenable flat, localised Microscopically, urothelial carcinoma appears as a thickened, highly dysplastic transitional epithelium with inflammatory infiltration and neo-vascularisation. Umbrella cells are absent and haemorrhage is common. no longer dome cells thick and dysplastic elongated and spindled neovascularisation haemorrhage common Practice Questions 1. A 65-year-old man presents with urinary frequency, nocturia, poor stream initiation, and dribbling post urination. Which of the following, if present, would suggest a diagnosis of benign prostatic hyperplasia over prostate cancer? A. The presence of corpora amylacea within glands B. An elevated PSA C. Histologically, the presence of hyperplastic stroma more-so than glandular tissue C D. The absence of papillary infoldings in glandular mucosa more stroma E. The presence of hyperplastic glands with minimal stroma on histological examination 2. Which of the following is FALSE regarding transitional cell carcinoma (TCC) of the bladder: A. These lesions often arise from urothelial cell hyperplasia B. Occupational exposure to nitrosamines has been attributed to development of TCC C. Microscopically, haemorrhage is common due to neo-vascularisation D. Umbrella cells are more prevalent within the mucosa of this lesion upon microscopic examination D absent in carcinoma E. The most common presenting complaint is painless haematuria Breast Pathology  The adult female breast is composed of branching ducts and acini, grouped together to form lobules. The ducts and acini are lined by a dual cell layer → Case 11 – Normal inner epithelial cell layer (cuboidal to columnar) and outer myoepithelial cell layer (flattened cells), resting on a basement membrane. Breast Pathology There are two types of stroma within breast tissue: denser interlobular stroma (between lobules) and loose intra-lobular stroma (within lobules, surrounding acini). into lots of lobules b/w lobules Interlobular stroma mosdt b/w intralobular stroma Lobule in lobules some within cells lining ducts  ducts and glands A lobule has been isolated here. A Note the intra-lobular stroma (A). b/w ducts An acinus has been magnified in the in-set image at the bottom left. The cells lining the lumen are cuboidal luminal epithelial cells (green arrow), surrounding this are flattered myoepithelial cells (red in lumen, secretory component arrow). form mammary gland Case 12 - Fibroadenoma A benign, solid tumour. Commonly found in young women of reproductive age, fluctuate with the menstrual cycle and may regress after menopause (likely hormonal relationship). Arise from hyperplasia of intra-lobular stroma (within lobules), which results in flattening of ducts and acini. rubbery from stromal tissue intralobular Presentation: discrete, mobile, non-tender strong hormonal relationship rubbery mass. move away discrete and homogenous mass Investigations: USS and fine needle aspiration Treatment: nil required, can excise if bothersome benign, not bother them  benign, homogenous breast lobule On US of the breast, these lesions present as well—circumscribed, hypo- echoic masses without disruption of normal breast architecture Hyperplasia of intra-lobular stroma (1) surrounded by a connective tissue capsule (2). On high power, note the huge space b/w, hyperplasia, squish acini and give slit-like appearance flattening of normal breast epithelium due to compression from the hyperplastic stroma. This is a benign lesion but requires histological diagnosis to exclude a similar lesion (Phyllodes tumour) which resembles a fibroadenoma both clinically and radiographically (differing histologically) but has malignant potential. potential to develop into cancer fibroadenoma  Case 13 – Breast The most common and deadly female malignancy. Each year, 1.7million women are diagnosed. Cancer Types: all breast cancers can be separated into three major groups defined by the expression of two proteins, ER and HER2 “Luminal” cancers are defined as being positive Risk factors: for ER and negative for HER2. This is the most increased exposure lifetime to oestrogen Gender (99% are female) common cancer in older women. epithelial oestrogen receptor +tve others luminal B HER2 cancers are defined as cancers over- HER2 Age mostly older expressing HER2 and can be ER positive or Lifetime exposure to oestrogen (nulliparity, early menarche, negative. *Cancers that are HER2 positive and ER late menopause) not having children - risk positive are also called luminal B cancers. hyperproliferative menopause late Triple negative breast cancers (TNBC) are negative Genetics (BRCA genes) increased risk for ER and HER2. The term “triple” negative arises Environmental and lifestyle factors (less important) as they are also negative for PR which is under the control of ER. don't express receptors also negative for progesterone, HER2, oestrogen TNBC and HER2 cancers peak and plateau in middle aged women and occur infrequently in older women.  BRCA more common Pathogenesis of familial breast cancer Pathogenesis of sporadic breast cancer ¼ to 1/3 rd of breast cancers occur due to inheritance of Luminal (ER+) cancers arise via the dominant pathway of breast susceptibility genes. cancer development, accounting for 50-65% of cases. Those with most common high ER expression usually have PR expression which is The most important high penetrance genes for familial breast upregulated by oestrogen. ER+ and PR+ tumours are often well cancer are tumour suppressor genes involved in genomic differentiated and slow-growing. well differentiated and slow growing stability. Inheritance is autosomal dominant. Biggest risk factor is oestrogen exposure which increases Mutations in BRCA1 and BRCA2 are responsible for 80-90% of local growth factor expression and regulates dozens of single gene familial breast cancers and 3-6% of all breast genes expressed in breast epithelium. cancers. Respond well to therapy; have more favourable outcome; BRCA1 cancers are usually poorly differentiated TNBC. risk of recurrence low; even when they metastasise can be This gene is also associated with ovarian cancer (20-40% held in check by anti-oestrogen therapy for years. unfavourable of carriers) Most commonly detected by mammogram screening (even BRCA2 cancers are also poorly differentiated but often when no mass is palpable) driven by oestrogen, not proliferate w/o oestrogen ER positive. This gene is also associated with male breast cancer increased risk of breast cancer HER2+ cancers (20% of cancers) arise via a pathway that leads to amplification of the HER2 gene which stimulates cell Both genes are associated with prostatic and pancreatic proliferation. Detectable by immunostaining. Has targeted cancer therapy TNBC arise through an oestrogen independent pathway, not associated with HER2 amplification and comprise 15% of breast cancers. Associated with TP53 mutations and BRCA mutations. More likely to present as a palpable mass, less readily detectable on screening. Survival with mets is unlikely. less detectable, less likely survival possible to survive long periods  Histology Almost all breast cancers are adenocarcinoma and arise from either the ducts (ductal carcinoma) or lobules (lobular carcinoma). If bound by the basement membrane, they are referred to as carcinoma in situ (i.e. ductal carcinoma in situ). ductal - no specific type The majority of invasive breast cancers are ductal carcinomas (now referred to as breast carcinoma of no specific type or NST) – these you will be expected to know in more detail. Most commonly, these present as a hard, irregular, radiodense mass associated with desmoplastic stromal reaction. Invasive carcinoma is classed into one of three types based on its luminal - HER2 receptor profile (discussed earlier) and is also graded based on the Nottingham Histologic Score (Grade 1 for well differentiated; grade 2 for moderately differentiated; and grade 3 for poorly differentiated). dysplastic ducts Histologically appears as pleomorphic, atypical ductal epithelium invading the stroma with surrounding desmoplasia  highly expressing overexpressed in hyperproliferative expansion, lots of ductal atypical tissue not well differentiated dysplastic Tumour composed of nests of atypical epithelial cells forming irregular gland-like structures with prominent bands of fibrous tissue (desmoplasia) moderately differentiated some desmoplastic stroma see some glands  Presentation Presenting features vary and may include a palpable mass, skin changes (puckering, skin dimpling, nipple inversion), and Paget’s disease of the nipple (seen in DCIS as unilateral erythematous scale over the nipple of the affected breast due to malignant cell extension along the duct system into the nipple skin). malignant extension scaly, red itching indicate ductal CIS  Stage DEGREE TNM T - SIZE N - NODES M - METASTASES  Duct Ectasia Commonly Assessed Differentials Mastitis: acute localised redness, swelling and tenderness of the breast often associated with breast- feeding Fat necrosis: painless palpable mass with a history of breast trauma trauma Mastitis Duct ectasia: dilation of the ducts post-menopause (due to secretory stasis), presenting with white nipple bacterial infection in milk ducts discharge and peri-areolar mass dilate ducts, discharge Fibrocystic change: lumpy breasts, may be tender, hormone dependent fluctuate Intraductal papilloma: most common cause of bloody nipple discharge benign growth Questions 1. What is the MOST likely diagnosis in a young woman presenting with a painless, rubbery, mobile breast lump which fluctuates throughout her menstrual cycle: a. Intraductal papilloma b. Duct ectasia c. Fat necrosis d. Fibroadenoma D painless, rubbery e. Ductal carcinoma Questions 2. Which of the following histopathological diagnoses of a breast mass would be associated with the least favourable prognosis? a. Ductal carcinoma in situ localised b. Phyllodes tumour benign with potential c. Well—differentiated ER positive ductal carcinoma fair d. ER+/PR+ ductal carcinoma with metastasis anti-oestrogen therapy e. Triple negative ductal carcinoma with metastasis E Questions 3. Which of the following receptor profiles constitutes “luminal” breast cancer? a. HER2 receptor positive b. ER receptor positive B ER positive is luminal c. HER2 receptor positive; ER receptor negative d. ER receptor positive; HER 2 receptor positive e. ER receptor negative; HER2 receptor negative  Thank you! 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