meant for medical college UG students

1. Pathology of testis
Dr. Guvera Vasireddy
Osmania Medical College

2. Cryptorchidism
• Frequency 3.4 % in term boys
• By 1 yo, incidence 0.8%
• 89% of untreated males with bilateral
cryptorchidism develop azoospermia
• Lifetime risk of neoplasia 2-3%
– 4 fold higher than average risk

3. Risk Factors
• IUGR, prematurity
– Incidence in premies 30%
• First-or second-born
• Perinatal asphyxia
• C-section
• Toxemia of pregnancy
• Congenital subluxation of hip
• Seasonal (especially winter)

4. Etiopathogenesis
• Testicular descent occurs in two morphologically and
hormonally distinct phases.
• During the first, the transabdominal, phase, the testis
comes to lie within the lower abdomen or brim of the
pelvis.
• This phase is believed to be controlled by a hormone
called müllerian-inhibiting substance.
• In the second, or the inguinoscrotal, phase, the testes
descend through the inguinal canal into the scrotal sac.

5. Etiopathogenesis
• This phase is androgen dependent and is
possibly mediated by androgen-induced release
of calcitonin gene–related peptide, from the
genitofemoral nerve.
• Although testes may be arrested anywhere
along their pathway of descent, defects in
transabdominal descent are uncommon,
accounting for approximately 5% to 10% of
cases.

6. Clinical presentation
• In most patients the undescended testis is palpable
in the inguinal canal.
• Even though testicular descent is controlled by
hormonal factors, cryptorchidism is only rarely
associated with a well-defined hormonal disorder .
• The condition is completely asymptomatic, and
• Found by the patient or the examining physician
only when the scrotal sac is discovered not to
contain the testis.

7. Hypothalamus
Pituitary
Sertoli
Androgen resistance
Dysgenesis/anorchia
Testosterone biosynthetic problems
Hypopituitarism
Low/absent GnRH
Kallmann’s
Prader Willi
Testosterone
dihydrotestosterone
Androgen receptor
Post-receptor effects
Leydig Germ cells
GnRH
MIF
FSH LH
5 α reductase 5 α reductase deficiency
MIF deficiency/persistent Mullerian ducts

8. Morphology
• Cryptorchidism is unilateral in most cases, but
it may be bilateral in 25% of patients.
• Histologic changes in the malpositioned testis
begin as early as 2 years of age.
• They are characterized by an arrest in the
development of germ cells.
• Marked hyalinization and thickening of the
basement membrane of the spermatic tubules.

9. Morphology - Late changes
• Tubules appear as dense cords of hyaline
connective tissue outlined by prominent
basement membranes.
• There is concomitant increase in interstitial
stroma. Because Leydig cells are spared,
they appear to be prominent.

10. Normal testis shows tubules with active spermatogenesis. B, Testicular
atrophy in cryptorchidism. The tubules show Sertoli cells but no spermatogenesis. There is
thickening of basement membranes and an apparent increase in interstitial Leydig cells.

11. Morphology – untreated
cryptorchidism
• With progressive tubular atrophy, the cryptorchid
testis is small in size and is firm in consistency as a
result of fibrotic changes.
• Histologic deterioration, associated with a paucity
of germ cells, has also been noted in the
contralateral (descended) testis in males with
unilateral cryptorchidism,
• Supporting an intrinsic defect in testicular
development

12. Consequences – surgical
• Sterility.
• Undescended testis is at more risk for
trauma.
• Concomitant inguinal hernia accompanies
the undescended testis in about 10% to 20%
of cases.

13. Risk for malignancy
• Undescended testis is at a greater risk of developing
testicular cancer than is the descended testis.
• During the first year of life the majority of inguinal
cryptorchid testes descend spontaneously into the
scrotum.
• Those that remain undescended require surgical
correction, preferably before histologic deterioration
sets in at around 2 years of age.

14. Does orchiopexy protect?
• Orchiopexy does not guarantee fertility;
• It is unclear to what extent the risk of cancer is reduced after
orchiopexy.
• According to some studies, orchiopexy of unilateral
cryptorchidism before 10 years of age protects against cancer
development.
• Malignant change may occur in the contralateral, normally
descended testis.
• Studies suggest that cryptorchidism is associated with a defect
in testicular development and cellular differentiation that is
unrelated to anatomic position.

15. Tumors of the testis
Dr. Guvera Vasireddy
Osmania Medical College

16. Important facts about testicular
tumors
• Uncommon, incidence: 5/100,000 men
• <1% of all malignancies in men
• Peak: 30-40 years, rare in prepubertal
children & elderly
• >90% are of germ cell origin
• >90% are malignant
• Serum tumor markers found in 50% of
patients. Eg: AFP, hCG

17. Risk factors for testicular cancers
• Sex chromosome abnormalities: Germ
cell tumors occur at a rate of 25% in
dysgenetic gonads,intersexes,
hermaphrodites & pseudohermaphrodites.
• Cryptorchidism: 10-fold increase in
incidence of testicular germ cell tumors.

18. Risk factors
• GCT are associated with testicular dysgenesis syndrome
(TDS) .
• This syndrome includes cryptorchidism, hypospadias, and
poor sperm quality.
• Some of these conditions might be due to in utero exposures
to pesticides and nonsteroidal estrogens.
• There is a strong family predisposition associated with the
development of testicular germ cell tumors.
• Possible that genetic polymorphisms at the Xq27 locus may
be responsible for this susceptibility.

19. Risk factors
• Cryptorchidism is the most important risk
factor.
• Klinefelter syndrome (a TDS condition) is
associated with an increased risk (50
times greater than normal) for the
development of mediastinal germ cell
tumors, but these patients do not develop
testicular tumors.

20. Histiogenesis of GCT
• Seminomatous tumors are composed of cells that ressemble
primordial germ cells or early gonocytes.
• The non-seminomatous tumors may be composed of
undifferentiated cells that resemble embryonic stem cells.
• Malignant cells can differentiate into various lineages
generating yolk sac tumors, choriocarcinomas and teratomas.
• Germ cell tumors may have a single tissue or mixtures of
seminomatous and non-seminomatous components.

26. Histogenesis of germ cell tumors
• Originate from intratubular germ cells that have
undergone malignant transformation
• ITTGCN is usually diagnosed incidentally during
biopsy for infertility workup.
• About 50% of individuals with ITGCN develop invasive
germ cell tumors within five years after diagnosis.
• Practically all patients with ITGCN eventually develop
invasive tumors.

27. ITGCN – pathogenesis
• ITGCN has not been implicated as a precursor lesion of pediatric
yolk sac tumors and teratomas, or of adult spermatocytic seminoma.
• ITGCN is believed to occur in utero and stay dormant until puberty,
when it may progress into seminomas or non-seminomatous
tumors.
• The lesion consists of atypical primordial germ cells with large nuclei
and clear cytoplasm, which are about twice the size of normal germ
cells.
• These cells retain the expression of the transcription factors OCT3/4
and NANOG, which are associated with pluripontentiality and are
expressed in normal embryonic stem cells.

28. Genetic changes in ITGCN
• ITGCN share genetic alterations found in
GCTs like isochromosome - i(12p).
• This change is invariably found in invasive
tumors regardless of histological type.
• Activating mutations of c-KIT, which may be
present in seminomas, are also present in
ITGCN.

29. Germ cell tumors
Seminomatous tumors
•Seminoma
•Spermatocytic
•seminoma
Non-seminomatous tumors
•Embryonal carcinoma,
•Yolk sac (endodermal sinus)
•tumor
•Choriocarcinoma
•Teratoma

30. Clinical classification of testicular
tumors
• Seminomas (40%)
• Nonseminomatous germ cell tumors
(NSGCT) (40%)
• 15% of tumors have both seminomatous &
nonseminomatous elements.
• Nonseminomatous elements are more
malignant, therefore such tumors are
clinically treated as NSGCT.

31. Seminoma
• Most common type of germinal tumor (50%)
• Most patients are 25-45 years of age
• Presents as a scrotal mass
• Most tumors diagnosed early
• No serologic tumor markers for seminoma
• Treatment: surgery, radiation therapy &
chemotherapy
• Cure rate>90%

32. Gross features of seminoma:
• Produces bulky masses, sometimes10x
normal testis
• Homogenous, grey-white, lobulated cut-
surface, usually devoid of hemorrhage &
necrosis
• Replaces entire testis in half of cases

34. Histologic features of seminoma:
• Composed of single cell type
• Tumor cells have clear cytoplasm, filled
with glycogen
• Tumor cells are arranged in lobules which
are surrounded by fibrous stroma
• The fibrous septa are infiltrated by
lymphocytes & plasma cells

36. • Metastases occur in paraaortic abdominal
lymph nodes

37. Spermatocytic seminoma
• Rare but distinct clinicopathologic variant
of seminoma that occurs only in the
descended testes of elderly men and
forming about 5% of seminomas
• The tumor is bilateral in about 6% of cases
compared to about 2% in classic
seminoma

38. Morphology of spermatocytic
seminoma:
• Gross:The tumor tends to be poorly demarcated,
usually soft with a gelatinous or mucoid appearance.
• Cystic areas, especially in the center, are common
but hemorrhage or necrosis is almost always
absent.
• Micro: Three populations of tumor cells, separated
according to size, are seen: 1) small cells that
superficially resemble lymphocytes, 2) intermediate
or medium-sized cells, the commonest cell type,
have round nuclei and finely granular chromatic
pattern, and 3) large or giant cells.

39. Biological behaviour of
spermatocytic seminoma:
• Spermatocytic seminoma is an extremely
indolent tumor with rather limited
malignant potential and rarely if ever
metastasizes.

40. Embryonal carcinoma
• This subtype of GCTs represents the most
primitive form of the NSGCTs.
• It accounts for about 15 to 35% of
testicular GCTs.

41. Gross
• Grossly, the tumors
are large, often
hemorrhagic and
necrotic producing a
variegated cut
surface.

42. Morphology
• Histologically, they are extremely
pleomorphic and show a variety of patterns
forming glands, tubules, and even primitive
embryo-like structures.
• Many mitotic figures are present.
• Embryonal carcinoma metastasizes early and
widely via both lymphatic and hematogenous
routes

43. • Embryonal carcinomas share some
markers with seminomas such as OCT 3/4
and PLAP
• but differ by being positive for cytokeratin
and CD30, and negative for c-KIT.

44. Embryonal carcinoma: Sheets of cells with large,
hyperchromatic nuclei, prominent nucleoli and poorly-defined
cell borders

45. Yolk Sac Tumor (Endodermal
Sinus Tumor)
• Testicular yolk sac tumors occur in two forms: either
as a pure form in young children or as a focal
differentiation within other NSGCTs, mainly
embryonal carcinoma, in adults.
• Pure YST of the adult testis is rare.
• It is noted for its resemblance to rat fetal yolk sac
and the presence of microscopically distinctive
structures known as Schiller-Duval bodies.

46. Pathologic features of yolk sac
tumor
• Gross: The cut
surface is gray-white
and may be cystic.

47. Microscopic features of yolk sac
tumor
• Microscopically, the
tumor shows a variety
of patterns,
• the commonest of
which is a loose
meshwork of small
spaces and cysts
(producing a sieve-
like appearance) lined
by either flattened
cells or vacuolated
cells

50. Serum markers in yolk sac tumor
(YST)
• YST is almost invariably associated with
production of large amounts of alpha-
fetoprotein (AFP) and also alpha-1
antitrypsin (a -1AT).
• AFP may be followed as a marker of
disease progression in the patient's
serum.

51. Teratoma
• A tumor typically composed of several tissues
representing two or more germinal layers
• Teratomas are further subdivided into mature,
immature and teratoma with malignant
transformation.
• In the postpubertal male all teratomas are regarded as
malignant, capable of metastatic behavior whether the
elements are mature or immature.
• Consequently, it is not critical to detect immaturity in a
testicular teratoma of a postpubertal male.

52. Mature teratoma showing cysts lined by mucous epithelium (left) and
keratinizing squamous epithelium (right).

53. Immature teratoma with primitive brain tissue (upper left corner) and well-
differentiated glands (lower half).

54. Choriocarcinoma
• This is a highly malignant neoplasm that is
usually widely disseminated and frequently
fatal.
• In this form of testicular GST the cells
differentiate in the direction of trophoblastic
(placental) tissue
• The tumor typically presents in adolescent or
young adults with widespread disease,

55. Choriocarcinoma: large, hemorrhagic, necrotic tumor.

56. Microscopically, the tumor is composed of two types of cells:
Syncytiotrophoblasts, large multinucleate cells with abundant vacuolated
cytoplasm containing hCG and Cytotrophoblasts, polygonal cells with
distinct cell borders and single nuclei, which grow in clusters and are
surrounded by the syncytiotrophoblasts

57. Sex cord-stromal tumors of the
testis

58. Leydig cell tumor key facts:
• Can develop at any age from infancy to
old age
• Most are benign, some are malignant
• Most tumors are hormonally active, but
some are inactive
• May secrete androgens or estrogens
-Androgen excess: Premature puberty &
macrogenitosomia
-Estrogen excess: Gynecomastia in adult males

59. Sertoli cell tumor
• These tumors are more rare than Leydig
cell tumors.
• They elaborate androgens or estrogens.
• Occasionally, they cause gynecomastia
but sexual precocity is infrequent.

60. Testicular tumors – Clinical course
• Any solid testicular mass should be considered neoplastic unless
proved otherwise.
• Biopsy of a testicular neoplasm is associated with a risk of tumor
spillage.
• Consequently, the standard management of a solid testicular mass is
radical orchiectomy based on the presumption of malignancy.
• Lymphatic spread is common to all forms of testicular tumors.
• In general retroperitoneal para-aortic nodes are the first to be involved.
• Subsequent spread may occur to mediastinal and supraclavicular
nodes.

61. SGCT vs NSGCT
• Tumors of the testis are segregated into two broad categories:
seminoma and nonseminomatous germ cell tumors
(NSGCTs).
• Seminomas tend to remain localized to the testis
• NSGCTs are biologically more aggressive and in general have
a poorer prognosis.
• Hematogenous spread is primarily to the lungs, but liver,
brain, and bones may also be involved.
• The histology of metastases may sometimes be different from
that of the testicular lesion.

62. Staging
• Stage I: tumor confined to the testis,
epididymis, or spermatic cord
• Stage II: distant spread confined to
retroperitoneal nodes below the diaphragm
• Stage III: metastases outside the
retroperitoneal nodes or above the
diaphragm

64. Treatment
• Seminoma, which is extremely radiosensitive and tends to remain
localized for long periods, has the best prognosis.
• More than 95% of patients with stage I and II disease can be cured.
• Among NSGCTs, the histologic subtype does not influence the
prognosis significantly, and hence these are treated as a group.
• Approximately 90% of patients with NSGCTs can achieve complete
remission with aggressive chemotherapy, and most can be cured.
• Pure choriocarcinoma has a poor prognosis.
• With all testicular tumors, distant metastases, if present, usually
occur within the first 2 years after treatment.

66. Important Qs
1. Investigation of male infertility
2. Classification of testicular tumors, both
clinical as well as pathologic
3. Seminoma in detail
4. All germ cell tumors, in brief
5. Functional tumors of the testis
6. Serum markers for testicular tumors