Two principles: 1) The ENTIRE lower urinary tract reacts to inflammatory and neoplastic influences SIMILARLY, if not identically? Why? It is ALL the same type of mucosa, i.e., transitional. Or urothelial. Histologically, and embryologically, too. 2) The lower urinary tract is a classical example of how a neoplastic influence acting on ONE part of the urothelium, is also acting on OTHERS!. E.g., cut out a cancer in one place, the etiologic agents are STILL acting on other transitional mucosal places.
GENERAL scheme of the ENTIRE lower urinary tract = 1) transitional epithelium + 2) smooth muscle! Why is “transitional” epithelium called “transitional”?
Understanding the origins of the lower urinary, female, and male tracts, means understanding the simple embryology. Mullerian tissue behaves similarly, Wolffian tissue behaves similarly, and metanephric tissue behaves similarly also! Most of the lower urinary tract is METANEPHRIC tissue. KEY CONCEPT!!! In MALES, there is considerable overlap between the Wolffian system and the –nephric system. In females there is none.
What are the three most likely places to have ureteral constriction just from the gross anatomy alone? 1) UPJ 2) Pelvic brim 3) Bladder
Identify, mucosa, wall, detrusor muscle, prostate, prostatic urethra, seminal vesicles, perivesicle fat. Classically, the bladder submucosa is often called, interchangeably, the lamina propria because there is no clear cut differentiation between the two. Where would the membranous urethra be? Where would the “spongy” urethra be?
Ductus deferens may be grossly indistinguishable from the seminal vesicles, but are MEDIAL to them.
This is probably the most classical bladder you will ever see.
Classically the textbooks say urothelium ranges from, say, 4-8 layers thick normally from calyces to urethra, but this is highly variable, even with normal distension vs. relaxation. Can you COUNT the “layers” of transitional cells, This is important because it can help you determine sometimes if hyperplasia or neoplasia is present.
Typical real life bladder wall. What would be the difference between adventitia and serosa? Where are they?
How many layers? 4? 5? 6?
Once again, if we go back and try to classify diseases into DEG, INF, NEO, we find very few DEG diseases of the LUT, but many “anomalies”. In fact the urinary tract is the MOST LIKELY site for ANY congenital anomaly, having an anomaly rate classically quoted as being around 10% of all births, most of which are minor.
This is a real person with a GREAT CT reconscruction!
Please keep in mind the transitional mucosa/smooth muscle prototype.
UPJ obstruction, this is the KEY concept in all LUT obstruction, i.e., distention or dilatation proximal (upstream) to the obstruction. Doesn’t this seem to apply to just about all of the tubular structures in the body? YES And does inflammation go hand in hand with obstruction? YES
IVP UPJ obstruction. Can you see the renal pyramid’s tip (papilla)?
HYDROURETER, which side?
The ENTIRE lower urinary tract are generally infected by the same types of bacteria, generically lumped as enteric gram negatives, of which E. coli is always the most common on ANY study.
Ureteritis cystica is the ureteral counterpart ofd cystitis cystica, i.e., little mucosal cysts lined by COLUMNAR epiothelium, NOT transitional. Is this metaplasia? Sure it is!
You know the drill. Acute urothelial –itis = neutophils (POLYs), and chronic urothelial –itis = lymphs and macrophages (i.e., MONO-nucleated cells)
The disease means exactly what it is named! Why is it generally regarded as “auto-immune”?
As a general rule, ANY papillary tumor, lined by urothelium, is usually called carcinoma, no matter WHAT the cells like, in ANY part of the LUT
Why would you expect a URETERAL UROTHELIAL CA rather than a pelvic or bladder?
Fibroepithelial “polyp”. Why? Why would the distinction be made between polyp and papilloma?
Leiomyoma. Why? Is this smooth muscle? Could it be fibroblasts? How can you tell the difference? What is a cigar?
Transitional cell carcinoma, ureter, gross.
Transitional cell carcinoma, ureter, microscopic. Up until now all of the “Papillary” tumors we talked about were ADENOCARCINOMAS or SQUAMOUS. In the lower urinary tract however, all of the papillary tumors are TRANSITIONAL (UROTHELIAL) carcinomas, NOT adenocarcinomas.
Movin’ on down the LUT, let’s repeat the same way of thinking for the bladder, as we did for the ureter.
X-ray cystogram, bladder diverticulum. What proof do you have that this diverticulum communicates with the lumen of the bladder?
Diverticula, bladder, concept. Do they have to communicate with the main bladder lumen? Ans: No
Diverticula, bladder, real, these do not have to communicate with the main lumen..
EXTROPHY means EVERSION of an organ, but usually used in reference to the bladder, mostly males, 1/50,000 births.
Reflux has the same consequences as obstruction in that it is associated with chronic infection and proximal dilatation. Remember BACTERIA are normally in the bladder urine, the HIGHER this refluxes, the more likely it is to cause infection.
Bilateral vesicoureteral reflux. Which side is worse?
Hemmorhagic? Is hemorrhagic more likely to be acute or chronic?
More hemorrhagic? Would you expect neutrophils (POLYs) or lymphs and macrophages (MONOs) to infiltrate predominantly here?
Eosinophilic? Might you suspect an allergic or parasitic etiology, always, when you see eosinophils? Ans: YES
What is “URO-sepsis”?
Interstitial cystitis is still a mysterious disease with all kinds of “theories”. But remember, it is largely “interstitial” which means fibrosis of the muscular bladder wall itself, if common. Malacoplakia is also mysterious (soft yellow plaques filled with macrophages and calcium) but is associated with: Prolonged therapy with systemic corticosteroids Organ transplantation Diabetes mellitus Lymphoma Rheumatoid arthritis
Interstitial cystitis is still a mysterious disease with all kinds of “theories”. But remember, it is largely “interstitial” which means fibrosis of the muscular bladder wall itself, if common.
Why are they called “glomerulations”?
Malacoplakia is also mysterious (soft yellow plaques filled with macrophages and calcium) but is associated with: Prolonged therapy with systemic corticosteroids Organ transplantation Diabetes mellitus Lymphoma Rheumatoid arthritis
Where is the pigment? What is it? How would you prove what it is?
Brunn nests are clusters of urothelium which usually lie UNDER the surface mucosa. They can undergo glandular (i.e., columnar) metaplasia. SO, the transitional epithelium of the lower urinary tract can METAPLASE in two ways: Glandular Squamous
Is there anything here to suggest malignancy? Ans: NO Is cystitis cystica PRE-malignant? NO Do adenocarcinomas of the bladder usually arise in previously existing cystitis cystica (glandularis)? : YES
Columnar or transitional? Hard to say for sure, isn’t it?
Whereas squamous metaplasia of transitional mucosa can be nonspecific, it is almost universally found with shistosome infections of the bladder, i.e., bilharziasis. Squamous cell carcinoma of the bladder arises from squamous metaplasia and is VERY VERY common in Egypt, where bilharziasis is rampant.
The general rule is: ALL papillary tumors of the bladder are regarded as cancer or potentially cancer. You will ALMOST NEVER see a path report of a SQUAMOUS PAPILLOMA, especially in the USA.
Good rule of thumb: All papillary tumors of urothelium are carcinomas, not papillomas!
Ques: Why is this LOW grade? Ans: It looks like normal transitional mucosa.
How many “layers” of epithelial cells are here?
Ques: Why is this HIGH grade? Ans: It does NOT look like normal transitional mucosa, and its very pleomorphic and hyperchromatic. Can you see many mitoses? Ans: I’m having a hard time finding even one.
Can you tell this is HIGH or LOW grade just from the cystoscopists view? Ans: NO Can you tell if it is bleeding much? Ans: It is NOT bleeding much Can you tell if it is invading the wall? Ans: NO Does it look necrotic? Ans NO
NECROSIS, INVASION, HEMORRHAGE are present here. Find them.
“SKIP” areas. What are “skip” areas?
Urine cytology of normal patient and bladder cancer patient. Which is which?
An alternative route would be: PAPILLOMA CARCINOMA
Isn’t this totally explanatory of the biologic behavior? Ans: YES
What is the EXACT definition of cystocele (Wiki it please) A cystocele is a medical condition that occurs when the tough fibrous wall between a woman's bladder and her vagina (the pubocervical fascia) is torn by childbirth, allowing the bladder to herniate into the vagina. What is a rectocele? A rectocele results from a tear in the rectovaginal septum (which is normally a tough, fibrous, sheet-like divider between the rectum and vagina). Rectal tissue bulges through this tear and into the vagina as a hernia. There are two main causes of this tear: childbirth, and hysterectomy.
Urethral caruncles, which often originate from the posterior lip of the urethra, may be described as fleshy outgrowths of distal urethral mucosa. They are usually small but can grow to 1-2 cm in diameter. They are caused by distal urethral prolapse and related to estrogen withdrawal.
Caspar Friedrich Wolf
Excellent conceptual diagram to review gross anatomy. Recall the journey of Herm the sperm from the seminiferous tubule to the urethral meatus.
Remember the order of sperm transfer from seminiferous tubules to urethra.
Excellent conceptual diagram to review gross anatomy.
Main players of seminiferous tubules.
Straight tubules are 100% sertoli cells.
Testicular epididymeal junction
Cilia vs. stereocilia
Vas deferens. Is the inner smooth muscle layer circular or longitudinal?
Seminal vesicles, look for significant atypia. Almost every pathologist I know, including myself, has mistaken the NORMAL ATYPIA seen in the seminal vesicles for prostate cancer!
Paired ejaculatory duct leading from the seminal vesicles to the prostatic urethra. Nothing exciting here.
Q: What is the utricle analogous to in the female? A: Uterus and Vagina
Don’t forget the Cowper’s (bulbourethral) glands.
EXTREMELY slippery secretion, but very low volume, from the glands of Littré.
Urethral deviations and prepuce contractions.
Smegma (Greek smēgma, "soap"), sometimes described as a "cheesy substance", is a combination of exfoliated (shed) epithelial cells, transudated skin oils, and moisture. It occurs in both female and male mammalian genitalia. If the penis was a toe, smegma would be called toe jam.
Condyloma accuminata, EXACTLY the same appearance and etiology as on the female external genitalia.
Condyloma accuminata, EXACTLY the same appearance and etiology as on the female external genitalia.
Koilocytosis is perinuclear vacuolization, quite classical for HPV, this can be seen on cytology, as well as histology.
Bowen’s Disease of the penis also goes by the name Erythroplasia of Queyrat. BOWEN’S diseases can be thought of as squamous cell carcinoma-in-situ of not only the skin of the penis, but skin ANYWHERE!
Note the surface cells are not much different from the base cells, this is defined as a “loss of maturation” pattern, and is quite typical of squamous CIS everywhere.
Infiltrating SCC, penis.
Infiltrating SCC, penis. At this point EVERYBODY should immediately recognize this as: Malignant Epithelial Squamous Where are the intercellular bridges?
Do you think these are all logical? Of course you do!
Testicular atrophy, classical pattern, showing ghosting or fibrosis of tubules, NO spermatogenesis, INCREASED interstitial cells of Leydig. Are the Leydig cell hyperplastic because of the atrophy and endocrine feedback mechanisms? Ans: YES
Often, Inflammations in the testicle ALSO involve the epididymis, and vice versa. Commonly urinary tract gram negatives infect BOTH.
Infarcted, purple, testicle and epididymis due to “torsion”. Inflammatory vs. ischemic? Ans: Ultimately, ISCHEMIC
Most testicular tumors are malignant germ cell tumors. Most germ cell tumors of the testes are MALIGNANT. Most ovarian tumors are benign NON-germ cell tumors (cystic). Most germ cell tumors of the ovary are BENIGN (dermoid cysts)
The larger cells are GERM cells and they often DO look like spermatocytes, from normal histology. The smaller cells look like typical lymphocytes bacause they ARE typical lymphocytes. Ususlly, there are good numbers of BOTH kinds of cells. The GROSS appearance of a seminoma is usually the same gross appearance of a lymphoma. Why? Ans: Lymphs, very little fibrous tissue.
These cells are usually described as “primitive”, but usually show kind of a GLAMNDULAR pattern, which is why in the old days they were ofem call adenocarcinomas, but remember they are GERM cells, NOT glandular epithelial cells.
If you remember your placenta histology you might say this looks like a placental villus, with TROPHOBLAST. From a histology viewpoint alone, could this be from a female placenta or an ovary? Ans: YES
Most common testicular tumor in male CHILDREN
Most testicular teratomas are malignant. Most ovarian teratomas are benign (e.g., dermoid cyst) Why did I underline the first bullet? Because it is the MOST common thing found in ANY teratoma.
Wheras, most germ cell tumors are regarded as benign, most sex cord (NON germ cell) tumors are regarded as benign. Leydig cells make testosterone so you might guess that a Leydig cell tumor migh have a clinical syndrome of hypertestosteronism, or sometimes even feminizing features. Sertoli cells make a variety of hormonal and non-hormonal compounds which “nurse” the spermatocytes, hence the name “nurse” cells.
Testicular tumors do NOT metastasize to inguinal nodes but peri-aortic nodes. Why? Ans: Because that’s where they came from embryologically, so the RETROPERITONEUM is usually the first place to detect a metastatic testicular tumor.
CZ is nearest the urethra, PZ is nearest the capsule. TZ is between the two.
Acute prostatitis. Why? Ans: Neutrophils
Chronic prostatitis. Why? Lymphocytes
Granulomatous prostatitis. “TB or Not TB, that is the question”
Glandular hyperplasia, note ABSENCE of nucleoli. Also note nuclei are where they should be, i.e., basal. Also note glands are NOT back to back, but each one is separated by thin fibrous tissue. The above THREE conditions favor a BENIGN process.
PIN (Prostatic Intraepithelial Neoplasia) is the grey zone between BENIGN and MALIGNANT prostate glands. The can be LOW grade PIN, or HIGH grade PIN. Notice the secondary INFOLDING of epithelial “papillae” within the lumen.
NUCLEOLI separate benign from malignant prostate glands!!! Of course there are other differentiating features, but this is the MOST RELIABLE one. The presence of NUCLEOLI in most of these cells almost nails the diagnosis of malignancy.
Even if, theoretically, the prostate gland cells looked 100% benign, if they surround nerve spaces, they are malignant. Why?
TIP: Numerous bone metastases in males usually carcinoma of the prostate until proven otherwise.
Know this correct order of biologic behavior.
A Gleason’s final SCORE is the SUM of the predominant pattern (1-5) and the secondary pattern (1-5). So a Gleason GRADE ranges from 1-5, and a Gleason SCORE ranges from 2-10. Dr Gleason is certainly laughing at us today because he designed this numbering system just as a convenience, but so many people stake their LIFE on it, and it is SO subjective to boot!
Please don’t memorize this, but just think of the BIOLOGIC BEHAVIOR instead, and the anatomy!
Remember, the “S” stands for SPECIFIC for prostate, NOT SPECIFIC for cancer! Ask any urologist when has he seen the HIGHEST PSA ever, and he’ll probably tell you he saw it with massive hyperplasia!
2. LOWER URINARY TRACT
• YELLOW Mucosal “Plaques”
• Why Yellow?
• Chronic bacterial infection
• Michaelis-Gutmann bodies contain Fe
and Ca in macrophages
• Glandular(is) (Cystica),
from Von Brunn nests
• Squamous metaplasia
• 95% Epithelial (urothelial), 5%
mesenchymal, i.e., mesodermally
derived (mostly smooth muscle)
• Benign or Malignant
• Primarily urothelial or transitional, but
a few squamous, from antecedent
squamous metaplasia, and a few
adenocarcinomas, from antecedent
25. TCC TUMORS
• MULTIPLE, MULTIPLE, MULTIPLE, i.e.,
• Papillomas vs. Carcinomas
• Grading, I, II, III, or wellpoor
• Staging, TNM, based on biologic
behavior, really based on normal
26. TCC TUMORS
• Causes/Risk Factors
– Arylamines (aniline
– Longstanding analgesics, same as
analgesic nephropathy drugs, most
– ChemoRX, esp. cyclophosphamides
– Radiation RX
27. Papillomas vs. Carcinomas
• Very few pathologists will have enough
guts to diagnose a transitional papilloma.
• PUNLMP, Papillary Urothelial
Neoplasm of Low Malignant Potential
– LOW grade PUC (TCC)
– HIGH grade PUC (TCC)
28. LOW Grade
29. HIGH Grade
30. BIOLOGIC BEHAVIOR
NORMAL MUCOSADYSPLASIA, SEVERE
DYSPLASIA, CARCINOMA IN SITU,
MUCOSA MUSCULARIS PROPRIA
(i.e., WALL)SEROSA or ADVENTITIALYMPH
31. TNM example:
• Ta----noninvasive, papillary
• Tis---Carcinoma in situ, flat
• T1----Lamina Propria
T3a---Microscopic beyond the wall
T3b---Grossly beyond the bladder wall
T4----Invades adjacent structures
32. Bladder Neck OBSTRUCTION
• Cystocele, MOST common cause in
• Prostate, MOST common cause in
• Foreign Bodies, Calculi
51. Testicular Atrophy
• atherosclerotic narrowing of the blood supply in old age
• the end stage of an inflammatory orchitis, whatever the
• Cryptorchidism (undescended testes are sterile)
• generalized malnutrition or cachexia
• prolonged administration of female sex hormones, as in
treatment of patients with carcinoma of the prostate; and
57. Embryonal Carcinoma,
Formerly called “adeno”carcinoma,
so look for “glands” and AFP!!!)
look for “trophoblast”, and HCG!!
59. YOLK SAC TUMOR,
aka “endodermal sinus tumor”
clusters of squamous epithelium, hair, skin glands
islands of cartilage
structures reminiscent of thyroid gland
bronchial or bronchiolar epithelium
bits of intestinal wall or brain substance
61. SEX Cord Tumors
tumor cells look
like Leydig cells
tumor cells look
like sertoli cells
• Stage : Tumor confined to the testis,
epididymis, or spermatic cord
• Stage : Distant spread confined to
retroperitoneal nodes below the
: Metastases outside the
retroperitoneal nodes or above the
• ACUTE, usually same as
Urinary Tract Pathogens
• CHRONIC, usually A-bacterial,
but also often recurrent or
persistent from acute
• GRANULOMATOUS, TB or nonTB, that is the question!
67. “BENIGN” Enlargement
BPH (H= Hyperplasia)
Glandular and Stromal Hyperplasia
Associated with old age
Associated with urinary obstruction,
frequency, bladder hypertrophy and bladder
• By itself, it is NOT premalignant, however….
69. NUCLEOLI, NUCLEOLI, NUCLEOLI
70. PERINEURAL INVASION
71. BIOLOGIC BEHAVIOR
• NORMAL PROSTATE
• P.I.N. (Prostatic Intraepithelial Neoplasia),
is like “dysplasia leading to
• INFILTRATION of “stroma”
• LYMPH NODES
• DISTANT, especially BONE
74. T1 CLINICALLY INAPPARENT LESION (BY PALPATION/IMAGING STUDIES)
T1a Involvement of ≤5% of resected tissue
T1b Involvement of >5% of resected tissue
T1c Carcinoma present on needle biopsy (following elevated PSA)
T2 PALPABLE OR VISIBLE CANCER CONFINED TO PROSTATE
T2a Involvement of ≤5% of one lobe
T2b Involvement of >5% of one lobe, but unilateral
T2c Involvement of both lobes
T3 LOCAL EXTRAPROSTATIC EXTENSION
T3a Extracapsular extension
T3b Seminal vesical invasion
T4 INVASION OF CONTIGUOUS ORGANS AND/OR SUPPORTING STRUCTURES
INCLUDING BLADDER NECK, RECTUM, EXTERNAL SPHINCTER, LEVATOR
MUSCLES, OR PELVIC FLOOR
N0 NO REGIONAL NODAL METASTASES
N1 METASTASIS IN REGIONAL LYMPH NODES
NO DISTANT METASTASES
DISTANT METASTASES PRESENT
Metastases to distant lymph nodes
Other distant sites
• Prostate is #1 most common malignancy in
men but NOT #1 killer. WHY?
• 80% over 80
• Every elderly male presenting with
widespread bone metastases is carcinoma
of the prostate until proven otherwise
• PSA (Prostate Specific Antigen) has been
controversial as a screening test but is
GREAT for follow up of a known prostate