Transcript Pathology of Male Genital System

Pathology of Male Genital
System
Doç. Dr. Işın DOĞAN EKİCİ
• Disorders of the male genital system
include:
• a variety of malformations,
• inflammatory conditions, and
• neoplasms involving the penis and
scrotum, prostate, and testes.
DEVELOPMENTAL
DISORDERS
HYPOSPADIAS
• Abnormal opening of the urethra onto the ventral
surface of the penis or scrotum.
• This results from failure of fusion of the urethral
folds, i.e., it is a form of feminization. Occurs 1 in
250 male alive births.
• There is often associated cryptorchidism,
ureterovesical reflux, inguinal hernia, and/or other
developmental problems.
• Right now there is a pop claim that hypospadias
has doubled in frequency in the past twenty
years, and the cause is chemical pollutants acting
as "endocrine disruptors".
• The urethral meatus may open on the ventral surface
of the penis, at the base of the penis or the perineum.
• This infant with ambiguous genitalia was a genetic
male. The arrow points to the urethral orifice that opens
unto the perineum.
PHIMOSIS
• Present when the preapuce can not be retracted over the
corona.
• Phimosis may be congenital, the orifice of the prepuce being
too small.
– More often, phimosis is due to poor hygiene, resulting in
chronic inflammation and scarring, which sets up a vicious
cycle requiring circumcision.
• Such an ongoing infection of the glans and prepuce is called
balanoposthitis.
• Paraphimosis results when a tight foreskin is forcibly
retracted, and edema of the glans prevents its replacement.
This can quickly lead to acute urinary retention and even
gangrene of the glans.
EPISPADIAS
• Abnormal opening of the urethra on the dorsal
surface of the penis.
• Epispadias is a form of extrophy of the urinary
bladder.
• There is usually an associated separation of the
pubic bones and inadequacy of the urinary
sphincters.
• Incontinence and bladder infections are usual.
• Epispadias is fortunately less common than
hypospadias and more difficult to correct surgically.
PRIAPISM
• A persistent, non-pleasurable erection.
• "Priapus" was the classical-era Greek god of
erections.
• Most cases of priapism are probably due to
obstruction of the deep dorsal vein of the penis.
• Causes:
• idiopathic
• sickle cell disease
• leukemia
• metastatic cancer
• papaverine treatment of impotence (rare)
• trauma.
INFLAMMATION of Male
Urogenital Tract
-Balanoposthitis
-Urethritis
-Cystitis
-Prostatitis
-Epididymitis
-Orchitis
• Fournier’s gangrene
• Necrotizing fasciitis
of genitalia and
perineum
• Usually due to Staph
or Strep in children;
gram negative rods
or anaerobic bacteria
in adults
• Affects Buck’s fascia
and foreskin, sparing
glans
• Risk factors:
trauma, burns,
anorectal disease,
diabetes, leukemia,
alcoholic cirrhosis
URETHRITIS
Gonorrhea and “non-gonococcal
urethritis” (“urethral syndrome”)
• Due to chlamydia, mycoplasma,
trichomonas, perhaps others,
• Important sexually-transmitted diseases.
• Gonorrhea tends to come on fast after the
contact, while chlamydia comes on
insidiously.
• Gonorrhea tends to have a more purulent
discharge.
Reiter's syndrome
The triad of
• (1) arthritis involving many joints,
• (2) conjunctivitis, and
• (3) urethritis.
• It is a male’s disease and lasts for several months.
• The urethritis is usually (if not always) chlamydia, and one new
study finds chlamydial RNA in the synovium; if the initial
episode of urethritis is treated appropriately,
• As with other "reactive arthropathies", there's an impressive
proliferation of T-cells specific for chlamydia within the affected
joints.
• Patients with Reiter's syndrome are likely to have circinate
balanitis, keratoderma blennorrhagica of soles, ulcers of the
mouth, iritis, or even ankylosing spondylitis.
Peyronie’s Disease
• Proliferation of dense fibrous tissue involving a portion of the
fascia.
• This leads to curvature of erection.
• Other names:
– "painful erection in the wrong direction",
– "squint of the cock".
• This is one of several abnormal hyperplasias of fibrous tissue
which are sometimes called "fibromatoses“.
– Another common one is palmar fibromatosis (Dupuytren's
contracture of the hand) which often occurs with Peyronie's
disease.
• Metaplastic ossification and calcification are common.
• Treatment for Peyronie's disease is not very satisfactory, and
many patients eventually require a penile prosthesis.
INFERTILITY
Female causes 50%
Male causes 50%
• Pretesticular
• Testicular
• Post testicular
Focal testicular atrophy
Testicular atrophy
– Spermatogenesis can be temporarily diminished
or even stopped by a host of factors ranging
from heavy drinking to anabolic steroid abuse to
alcoholism to bicycling.
– Obstruction of the sperm passages may be
more amenable than the above to surgical help.
CRYPTORCHIDISM (cryptorchism)
– Incomplete descent of the testis into the scrotal
sac.
– Unilateral or bilateral cryptorchidism occurs in
around 4% of prepubertal boys.
– Cryptorchid testes may be found anywhere
along the normal route of descent (abdomen,
inguinal canal, prepubic).
– The epididymis is likely to be malformed or at
least elongated.
– Ectopic testis is less common; it may stray into
the superficial inguinal region, penis, or femoral
sheath.
– Failure of the testes to descend into the scrotum causes
problems:
• The tubules will undergo atrophy and fibrosis, beginning in
infancy and advanced around puberty.
• There is an increased risk of torsion of the spermatic cord and
gangrene of the testis.
• The risk of germ cell cancer (usually seminoma) in undescended
testes is around 30x greater than normal.
– Most cryptorchidism is idiopathic.
– It may be accompanied by
• other developmental abnormalities,
• diethyl-stilbestrol exposure,
• poorly-understood anatomic and hormonal problems.
EPIDIDYMITIS and ORCHITIS
• Non-specific infections of the contents of the scrotum
are usually complications of urinary tract infection,
instrumentation or prostate surgery.
• Gonorrhea: the infection often spreads to the
epididymis, less often the testis.
• Mumps: orchitis is common in adolescents and
adults. It usually follows the onset of parotitis by a
week or so, and may cause atrophy of the germinal
epithelium and infertility. The Leydig cells are spared.
• Tuberculosis: granulomas involving the epididymis;
may spread to the testis.
• Syphilis: gummas involving the testis; may spread to
the epididymis.
TORSION OF SPERMATIC CORD
("torsion of the testis")
– Twisting of the spermatic cord is likely to result
in venous infarction and gangrene in a few
hours.
– This is quite common, especially in children
and adolescents.
– The involved testis is painful and elevated; the
cord is typically twisted.
– There may or may not be a history of trauma
(often minor, as in baseball or break dancing.
– The underlying problem may be abnormal
fixation of the testis or cryptorchidism.
Hydrocele
Hematocele
Spermatocele
HYDROCELE
• Fluid in the tunica vaginalis.
• Usually idiopathic
• A hydrocele may contain 100 cc or more of
serous fluid.
• If ascites is present and the patient has a
patent processus vaginalis, a hydrocele
will appear and disappear as the patient
changes position.
• One can distinguish a hydrocele from a
tumor mass by trans-illuminating it with a
bright flashlight in a dark room.
• Hematocele
• Blood in the tunica vaginalis.
• May follow trauma, or a sing of an underlying
testicular cancer.
• Chylocele
• Accumulation of lymphatic fluid in the tunica.
• Spermatocele
• A cystic lesion up to 1 cm or so in the area of the
rete testis, filled with fluid and dead sperms.
VARICOCELE
• Varicosities of the pampiniform plexus,
• Usually on the left side.
• This is common in young men, may cause fertility
problems by warming the testes.
• A new varicocele in an old man often indicates occlusion
of the vein by renal cell carcinoma.
PROSTATE
PROSTATITIS
• Acute and chronic prostatitis are uncomfortable problems, and
are common in
– sexually-transmitted urethritis
– lower urinary tract infections.
• E. coli is the most common etiologic agent of both acute and
chronic prostatitis.
• The diagnosis depends on physical and lab exams.
• In acute prostatitis the gland is exquisitely tender.
• Gonorrhea is an important cause of acute prostatitis
(secondary to urethritis; it can also cause epididymitis).
• In chronic prostatitis the gland is somewhat tender and the
prostatic fluid contains WBC's and bacteria.
• Granulomatous prostatitis may be due to
– Tbc (hematogenous spread from the lungs),
– "idiopathic" (no Tbc, no caseation, no clues as to
the etiology).
– The histiocytes may resemble cancer cells.
• In "non-bacterial prostatitis", the findings are as in
chronic prostatitis, but no organisms grow,
probably;
– Chlamydia
– Trichomonas
– Autoimmunity
– Heroic abstinence.
Prostatodynia
• is a stress-related pain syndrome in
which there are no WBC's in the
prostatic fluid.
• Other exacerbating factors include
– constipation,
– smoking,
– coffee,
– spices.
PROSTATIC HYPERPLASIA
• Benign prostatic hypertrophy or hyperplasia, BPH.
• Most men over about age 50; 10% of men living to
age 80 will need prostate surgery.
• The normal prostate weighs around 20 gm. Old
men's prostates enlarge to 60-200+ gm.
• The increased tissue is nodular overgrowth of
periurethral glands and stroma.
• Press upon the prostatic urethra.
• The hyperplasia most often involves the lateral and
median lobes.
• Median lobe hyperplasia by itself produces a
"median bar", obstruction without an enlarged
gland.
• The etiology of prostatic hyperplasia is obscure.
– Hormonal imbalance with ageing.
– Estrogen sensitive peri-urethral glands.
– Accumulation of dihydrotestosterone in the prostate
and its growth-promoting androgenic effect.
• Heroin abuse is also rumored to be a risk factor.
• The most interesting work right now focuses in a
nerve-growth factor-like protein produced by the
stromal cells which causes hyperplasia of both glands
and stroma
• Microscopy
– Nodular prostatic hyperplasia consists of
nodules of glands and intervening stroma
(mostly glands)
– The glands variably sized, with larger glands
have more prominent papillary infoldings.
• Nodular hyperplasia is NOT a precursor
to carcinoma.
Prostatism (This is a clinical term)
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frequency (i.e., only small amounts are voided at a time),
nocturia (urinating at night, same reason),
difficulty starting and stopping urination,
incontinence (dribbling),
dysuria (painful urination),
hernias (from straining),
acute urinary retention (emergency)
hematuria (due to stretching of veins),
bladder hypertrophy and trabeculation (accentuation of
the normal muscles),
• bladder diverticula, bladder stones,
• hydronephrosis,
• renal failure
The TUMORS of the
MALE REPRODUCTIVE
SYSTEM
Penis Tumors
WARTS
Condyloma acuminatum
• A papillary, keratinizing lesion caused by the sexuallytransmitted "human papilloma virus" (usually strain 6).
• In males, it commonly occurs in the urethral meatus, which is a
mess.
Condyloma latum
• Groups of flat-topped lesions which may ooze serous fluid
• caused by secondary syphilis.
• Typically occur in skin folds.
Pearly penile papules
• Little bumps, sometimes hairy, which pop up in young adults,
especially on the corona.
• Each is a single big dermal papilla. No need to treat.
PREMALIGNANT LESIONS OF THE PENIS
• Erythroplasia of Queyrat
– A raised, velvety plaque on the uncircumcised glans or
prepuce.
– Histologic study shows dysplasia of the squamous
epithelium.
– A minority of cases (5-10%) develop into squamous cell
carcinoma if not removed.
• Bowen's disease
– Carcinoma in situ of the skin, most often on the penis or
scrotum in men.
– Some cases (maybe 10%) develop into invasive squamous
cell carcinoma.
– In many cases, the appearance of Bowen's disease on the
skin heralds the growth of another malignancy internally.
– Bowen's disease tends to spare the sweat glands and
involve the hairs.
• Bowenoid papulosis
– Multifocal intraepithelial neoplasia, caused by HPV-16.
– The atypia is mild.
– Bowenoid papulosis tends to spare the hairs and
involve the sweat glands.
– Bowen's disease tends to spare the sweat glands and
involve the hairs.
• Giant condyloma of Buscké-Lowenstein
– verrucous carcinoma
– HPV-related, cauliflower-like lesion.
CARCINOMA of PENIS
• Almost all are variations on squamous cell
carcinoma
• This is a disease of older men (~60 years)
• It originates on glans and prepuce.
– Only 1% of cancers among American men
begin on the penis; the figure is as high as
18% in the Orient.
• Risk factors :
– phimosis,
– smegma,
– balanoposthitis,
– infection with HPV (notably HPV-16).
• Males circumcised as infants almost never get cancer of
the penis. The incidence is much lower in those
circumcised at a later age than among the
uncircumcised.
• Carcinoma of the penis spreads to the inguinal lymph
nodes.
• Five year survival is around 50% overall.
• Scrotal squamous cell carcinoma is the
subject of the famous chimney sweep
story.
• Many older men get a few angiokeratomas
(hemangiomas with each dermal papilla
stretched wide by a single ectatic blood
vessel), especially on their scrotums.
Testicular tumors
• Over 95% of tumors of the
testis are malignant germ
cell tumors.
• Testicular neoplasms are
the most important cause
of firm, painless
enlargement of the testis.
• Such neoplasms occur in
roughly 5 per 100,000
males, with a peak
incidence between the
ages of 20 and 34 years.
• Current thinking about the
histogenesis of cancers of
the testis emphasizes their
common origin from germ
cells:
• All present as painless, non-tender masses in the
testis.
• The primary may be occult, especially pure
choriocarcinomas.
• Many cause gynecomastia (after puberty) or
precocious puberty (children)
• Risk factors
– cryptorchidism
– some intersex malformations
– familial.
Germ-Cell tumors
•
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•
•
Seminoma
Embryonal carcinoma
Choriocarcinoma
Yolk sac tumor (endodermal sinus tumor)
Teratoma &Teratocarcinoma
Seminoma
• Cancer that closely resembles young spermatocytes.
• Grossly these tumors are homogeneously soft and
yellowish.
• Tumor cells have "fried egg" appearance (glycogen-rich
cytoplasm); arranged in masses separated by fibrous
septa with a lymphocytic infiltrate, may have
syncytiotrophoblast and/or granuloma formation.
– Variant: spermatocytic seminoma of older men has
somewhat different histology, no in situ phase, even
better prognosis (it almost never metastasizes).
• Chorionic gonadotropin (hCG) is a tumor marker for the
50% or so of seminomas that contain syncytiotrophoblast
(i.e., the man has a positive pregnancy test).
• Seminomas typically metastasize to the retroperitoneal
lymph nodes and then to the lungs.
• Seminomas are remarkable for their good response to
radiation or chemotherapy as appropriate, and even
widespread disease can usually be treated with five-year
survivals of 95% or better.
• Tumors with histology and response to therapy like
testicular seminomas (or other germ cell tumors) also arise
in other midline structures including the retroperitoneum,
thymus, and pineal ("germinomas"), as well as in the ovary
("dysgerminoma").
Lobules of neoplasitic cells have an intervening stroma with
characteristic lymphoid infiltrates. The seminoma cells are large
with vesicular nuclei, and pale watery cytoplasm.
Embryonal carcinoma
• A very primitive cancer that arises in the testis.
• Grossly these are grayish-white masses with hemorrhage and
necrosis.
• Tumors with an embryonal cell carcinoma component
metastasize to the retroperitoneum and everywhere else.
• The cured metastases may turn into scar tissue, or just plain
necrotic debris.
• Microscopically, the tumor cells grow in sheets, knobs, etc.
– Distinguish from a seminoma by absent glycogen and
positive staining for cytokeratin (seminomas are usually
weak or negative).
• Many embryonal cell carcinomas also contain differentiated
structures of a teratoma.
– Teratoma + embryonal cell carcinoma = teratocarcinoma.
• embryonal carcinoma mixed with teratoma in which
islands of bluish white cartilage from the teratoma
component are more prominent.
Choriocarcinoma
• The bloodiest tumor in pathology; solid areas may be hard to
find.
• The malignant cells resemble placenta, and the pathologist must
identify cytotrophoblast and syncytiotrophoblast.
• There are no villi.
• HCG levels are always very elevated (serum, urine.)
• Choriocarcinoma most often is a component in a
teratocarcinoma, but may be pure or mixed with any other germ
cell tumor components.
• Until recently, choriocarcinoma arising in the testis was always
lethal.
– Today the prognosis is not much worse than for embryonal
cell carcinoma, even if the tumor is "pure choriocarcinoma".
Yolk sac tumor (endodermal sinus tumor,
orchioblastoma, infantile embryonal cell
carcinoma):
• Rare
• The most common testicular tumor of children.
• It is composed of papillary structures (Schiller-Duval
bodies) with extracellular globs of alfa-fetoprotein and
alfa-1-protease inhibitor.
• Those PAS positive extracellular hyaline globoid
material is found typically in yolc sac tumor.
• This carcinoma is also unusual because it
metastasizes hematogenously.
• Schiller-Duval body consisting of tumor cells arranged
around a blood vessel.
• This structural arrangement is similar to that seen in
the developmental stages of the yolk sac.
Hyaline globules of
varying sizes are
present in
endodermal sinus
tumors. These
globules may be
mistaken for red
blood cells but they
vary in size and
have a differing
tinctorial quality
than red blood
cells. These
globules are
accumulations of
alpha-1-antitrypsin.
Teratoma & Teratocarcinoma
• Cystic teratoma of testis is rare (but common in
ovary) and seldom contains hair.
• Teratomas are the only testicular tumors that are often
cystic.
• Solid teratomas are of two types:
• Mature solid teratoma is benign, usually occurs in children.
• Immature solid teratoma is malignant, usually contains
embryonal cell carcinoma (teratocarcinoma) or sometimes
squamous cell carcinoma.
• Even if an adult's teratoma appears altogether
benign, there is likely to be nearby intratubular
carcinoma in situ.
Teratoma with different areas
WARNING: Any tumor of germ cell origin
may be mixed with any other tumor of
germ cell origin.
– Further, any tumor of germ cell origin may
metastasize as another histologic type of germ
cell tumor.
– We now know both in-situ and microinvasive
testicular cancer.
– Germ-cell tumors (seminomas, embryonal cell
tumors, teratocarcinomas, choriocarcinomas,
teratomas) can and do arise in the
retroperitoneum, and mediastinum.
Stromal tumors (sex-cord tumors)
– Leydig cell tumor
– Sertoli cell tumor (androblastoma).
• Leydig cell tumors >Sertoli cell tumors
• Less than 5% of all testicular tumors
• Benign (90%), malignant (10%)
– The gross and microscopic appearances are typical for
endocrine tumors.
– Criteria for malignancy are necrosis, mitotic figures, local
invasion, and nuclear pleomorphism.
• May elaborate androgens/androgens & estrogens
• Hormonally active (50%) Macrogenitosomia,
Precocious puberty, Gynecomastia
SUMMARY OF TESTICULAR GERM CELL TUMORS
Tumor
Peak
Age
(yr)
Seminoma
Morphology
Tumor Markers
40-50
Sheets of uniform polygonal cells with cleared cytoplasm;
lymphocytes in the stroma
10% have
elevated hCG
Embryonal
carcinoma
20-30
Poorly differentiated, pleomorphic cells in cords, sheets, or
papillary formation; most contain some yolk sac and
choriocarcinoma cells
90% have
elevated hCG or
AFP or both
Yolk sac
tumor
3
Poorly differentiated endothelium-like, cuboidal, or columnar
cells
90% have
elevated AFP
Chorio
carcinoma
(pure)
20-30
Cytotrophoblast and syncytiotrophoblast without villus
formation
100% have
elevated hCG
Teratoma
All
ages
Tissues from all three germ-cell layers with varying degrees of
differentiation
50% have
elevated hCG or
AFP or both
Mixed
tumor
15-30
Variable, depending on mixture; commonly teratoma and
embryonal carcinoma
90% have
elevated hCG
and AFP
OTHER TUMORS of TESTIS
• Lymphoma arises in the testes of older
men with some frequency.
• Adenomatoid tumor is a benign, hard
spherical nubbin, usually in the head of the
epididymis, derived from mesothelium.
PROSTATE CANCER
• Prostate cancer is the most common cancer in men (age:5080)
– Second cancer after lung carcinoma as a cause for tumorrelated deaths among males.
• Latent prostate cancer: found only at autopsy (incidental
prostate cancer)
• Occult prostate cancer might pop up in bone marrow or lymph
node prior to becoming symptomatic.
• The tremendous increase in the incidence of prostate cancer
during the 1990's (about 30%) reflects the improved
screening.
• The total number of people dying of the disease is actually
decreasing slightly.
General Features of Prostate Cancer
• Over age 50
– Prostate cancer is rare in Oriental folks in Asia,
– more common in Asian-Americans,
– common in U.S. whites,
– most common in U.S. Blacks.
• The majority, but not all, prostate cancers arise in the posterior lobe.
• Microcarcinoma : Some more recent studies suggest that, after a
man turns thirty, his percentage chance of having a little histological
cancer is about the same as his age (30%).
• This is the reason : Occult prostate cancers are common
"incidental" findings in prostate chips obtained at turp.
• Etiology of prostate cancer:
– Essentially unknown.
– Androgens
• early castration prevents the development of
adenocarcinoma (lack of sexual activity)
– Exposure to cadmium (i.e., battery factories)
– Animal fat / meat
– Prostate-cancer-family gene (HPC2 / ELAC2).
• Clinic:
– Cancer of the prostate presents as a painless lump in
the gland.
– These tumors are easier to feel than to see;
• they are firmer than hyperplastic nodules,
• poorly circumscribed, and yellowish.
– Diagnosis is by biopsy or fine-needle aspiration (first).
– Prostatectomy.
– PSA (prostate-specific antigen)
• urologists are likely to do sextant biopsies on
prostates of men with elevated PSA's and no
palpable lump.
Prostatic Intra-epithelial Neoplasia PIN
• The in-situ lesion (prostatic intra-epithelial
neoplasia “PIN”) is now well-characterized as well.
– There's always nuclear enlargement and
crowding, there are usually nucleoli
– Low-grade "PIN" is common in young men, and
it probably takes decades to transform
– Usually these lesions will involve part of a single
gland
– Nowadays, the feeling is that PIN requires
biopsy.
Grading of PIN
– Low grade
loss of secretion, piling up of cells ("tufting"), blue
cytoplasm,
– High grade
with high Nuclear/Cytoplasmic ratio
prominent nucleoli and a papillary or cribriform pattern
TURP-Bits (Diagnosis + Treatment )
• Histology of prostatic adenocarcinoma:
– prominent nucleoli in nuclei with marginated
chromatin
– invasion (especially perineural invasion; at least loss
of the normal gland-stroma interaction)
– obvious distortion of the architecture
– loss of the outer layer ("basal layer") of the glands
• (on fine needle biopsy, pathologists pay special
attention to the presence or absence of the basal
layer)
• As in breast, several benign lesions exist that are
easily mistaken for cancer.
Prostate adenocarcinoma
Prostate hyperplasia
Histologic Grading of Prostatic
adenocarcinoma:
• Gleason Scoring is used in routine practice.
• There are 5 Gleason patterns regarding to:
Gland formation and degree of differentiation
Grade 1: most well differentiated carcinoma;
neoplastic glands are uniform, round, and are
packed into well-circumscribed nodules.
Grade 5: Most poorly differentiated carcinoma. No
glandular differentiation.
Tumor cells infiltrate the stroma in form of cords,
sheets and nests
How does the scoring system
work?
• The most well differentiated tumors have a
Gleason score of 2(1+1)
• If a carcinoma shows only Gleason pattern 2;
the score would be: 4(2+2)
• If it shows a mixed pattern such as some areas
3, some 4; the score would be 7(3+4)
• Gleason score of 10 (5+5) represents the least
differentiated carcinoma.
Gleason Grade 1
Gleason Grade 2
Gleason Grade 3
Gleason Grade 4
Gleason Grade 5
Gleason Grade 5
Perineural invasion
• TNM Staging (affects prognosis):
– T1: CLINICALLY INAPPARENT LESION (BY PALPATION/IMAGING
–
–
–
–
STUDIES)
T2: PALPABLE OR VISIBLE CANCER CONFINED TO PROSTATE
T3: LOCAL EXTRAPROSTATIC EXTENSION
T4: INVASION OF CONTIGUOUS ORGANS AND/OR SUPPORTING
STRUCTURES INCLUDING BLADDER NECK, RECTUM,
EXTERNAL SPHINCTER, LEVATOR MUSCLES, OR PELVIC FLOOR
Uncommon prostate cancers include squamous and
endometrioid, plus adenoidcystic, colloid, carcinosarcoma,
signet-ring, oat-cell, carcinoid, and lymphoepithelioma.
• Prostate cancer is often indolent even when it has
metastasized, but some prostate cancers are very aggressive.
– Mucin-producing prostate cancer is an aggressive lesion.
• Metastases:
– regional lymph nodes
– axial skeleton (causing miserable
bone pain often with osteoblastic
lesions)
– leptomeninges (not the brain tissue).