Colecchia Who Non Germ Cell Tumors Update

Department of Pathology
IRCCS National Cancer Institute Milan
Non-germ cell tumors of the testis.

WHO update
MAURIZIO COLECCHIA
MILAN
WHO 2004
Some general characteristics…

• Rare tumors – 3-6% of testicular tumors in large series (AFIP, British Panel &Registry)
• Causes and risk factors unknown , no racial or ethnical differences
• Age of patients : 0-90 ; most cases between 5th and 6th decade ; 30 % in childhood
• Pathogenesis unknown – molecular data show sporadic gene-mutations, whose

impact on the tumor genesis is not clear:
 CTNNB1 mutation and ß –catenin accumulation in Sertoli cell tumors

 Germline mutation of DICER1 gene – mostly in the ovarian tumors
 Gain of chromosome X and sporadically loss of chromosome 2
“…In the sex cord-stromal tumous, the sclerosing

Sertoli Cell tumour is no longer separately
classified. These tumours are now considered the
morphologic variants of
the Sertoli cell tumour, not otherwise specified
[NOS]..:”
..the disappearance of
sclerosing variant
Sclerosing SCT Department of Pathology
From M Colecchia ed. “Pathology of IRCCS National Cancer Institute Milan
”
Testicular and Penile Neoplasms Springer , Basel 2016
4-2C. Sertoli cell tumour

Genetic profile
The most frequent chromosomal aberrations in one study
included gain of chromosome X (~40%) and much less
commonly losses of the entirety or part of chromosomes 2 and
19 {17333264}. Studies of Sertoli cell tumors of no specialized
type demonstrated CTNNB1 gene (which encodes β-catenin)
mutations in 70% {24061522} and also in a high proportion of
tumors with sclerosing morphology {25025367}.
24061522: Perrone F, Bertolotti A, Montemurro G, Paolini B, Pierotti MA, Colecchia M,

PubDate:Jan 2014, Frequent mutation and nuclear localization of β-catenin in sertoli cell tumors
of the testis.. The American journal of surgical pathology. Volume: 38, Issue:1, p 66-71
25025367: Colecchia M, PubDate:Aug 2014, Observations on the paper "sclerosing Sertoli cell
tumor of the testis: a clinicopathologic study of 20 cases" by Kao et al.. The American journal of
surgical pathology. Volume: 38, Issue:8, p 1160
Mutational analysis Department of Pathology
In this study performed on 14 SCT 10/14 CASES (71,4%) showed beta

catenin gene mutation
ß-catenin (Perrone F et al. Am J Surg Pathol 2014;38:66–71)
Normal SCT CTNNB1 mutation

Mukul Divatia, Steven Smith, Maurizio Colecchia, Manju Aron, Mitual Amin, Steven Shen, Donna
Hansel, Pheroze Tamboli, Gladell Paner, Mariza de Peralta-Venturina, Loren Herrera Hernandez, Allen Department of Pathology
Gown, Mahul Amin. USCAP 2015 Abstract 860 IRCCS National Cancer Institute Milan
(pp.216A)
Conclusions: SF-1 is the

most sensitive marker
amongst the common
types of TSCSTs.
Among traditional
markers, inhibin,
calretinin and Melan A
offer overall similar
sensitivity, although
calretinin lacks
specificity considering
the tumors in the
differential diagnosis at
this site.
A combination of SF-1,
inhibin and Melan A or
calretinin as a first line
IHC panel provides
maximum sensitivity
identifying > 80% of
TSCSTs.
Sertoli-cell-tumor Department of Pathology
≤ 1% of all testicular tumors
Age : any age (average 45 year)

30 % children
30 % 3. – 4. decade
Symptoms: 20% Gynecomastia

( malignant > benign)
decrease in libido ( estrogen-production )
12 % ( ? ) malignant ( 8 – 79 years )
Metastases: retroperitoneal lymph nodes, skin, lung, bones

Sertoli-cell-tumor - macroscopy Department of Pathology
a-inhibin
Lipid rich Sertoli cell tumor Department of Pathology
Sclerosing SCT
Tubular seminoma vs. SCT
Actas Urol Esp. 2010;34:481-3.

[Sertoli cell tumor of the testis with positive neuroendocrine markers].
[Article in Spanish]
Jiménez JD,Cebrian JL, Guarch R, Hualde A

. ESCOP
Krakow
2012
Chr A
ESCOP
Krakow
2012
Useful immunohistochemistry Department of Pathology
Divatia et. al. USCAP 2015 Abstract 860 (pp.216A)
Type LCT SCT USCST GCT LCCST TTAG

36P 72M 13P 5M 8 6 P 3M 4 2
SF-1 92 75 57 50 50 100
FOXL2 21 83 67 100 - -
ß-catenin 50 83 60 100 50 100
Inhibin 97 67 38 67 75 100
Melan A 94 67 75 50 50 100
Calretinin 97 56 75 44 75 100
WT-1 0 82 57 50 75 50
CD99 74 56 25 86 0 0
Synaptophyin 65 24 29 0 0 50
CK 22 78 17 43 67 -
S100 28 28 43 38 75 0
LCT = Leydig CT ; SCT = Sertoli CT; USCST = Unclassified CST; GCT = Granulosa CT
LCCST = Large cell calcifying SCT ; TTAG = Testicular tumor of adrenogenital syndrome
Age (years) benign average 17 (2-38)
malignant average 39(28-73)
Location benign 28%

bilateral and multifocal
malignant unilateral and unifocal
In young patients associated with:
Carney syndrome
Peutz-Jeghers syndrome
Gynecomastia
Tuberous sclerosis
Androgen insensitivity syndrome
Large cell calcifying SCT Department of Pathology
Courtesy
dr. MIKUZ
LCCST Department of Pathology
LCCST can be a part of Carney syndrome, whose other characteristics are

skin pigmentation, endocrine overactivity (Cushing syndrome,acromegaly), and
multiple myxomas localized in the breast, skin,and heart. Young patients with
LSCCT, as well as their relatives,consequently have to undergo cardiologic
examination due to association with cardiac myxoma, which can cause a sudden
death.!!!!
Malignant LCCSTs do not manifest associations with genetic disorders.
Courtesy
dr. MIKUZ

36P 72M 13P 5M 8 6 P 3M 4 2
SF-1 92 75 57 50 50 100
FOXL2 21 83 67 100 - -
ß-catenin 50 83 60 100 50 100
Inhibin 97 67 38 67 75 100
Melan A 94 67 75 50 50 100
Calretinin 97 56 75 44 75 100
WT-1 0 82 57 50 75 50
CD99 74 56 25 86 0 0
CK 22 78 17 43 67 -
S100 28 28 43 38 75 0
Intratubular large cell hyalinizing Sertoli cell neoplasia

Therapy
There is no specific therapy for malignant stromal tumor,

the benefit of RPLND is due to the small number of cases not clear.
Nicolai N et al.. UROLOGY 85: 402e406, 2015 .
Most of the patients with TSCST had a favorable prognosis. Testis-sparing surgery may be feasible
and effective in case of small tumors. Few patients had metastatic spread, but only those with
nodal metastases may benefi t from an early retroperitoneal lymph node dissection. Risk factors
associate with disease behavior, but indications to prophylactic intervention remain
controversial.
Malignancy criteria Department of Pathology
Mikuz G, Colecchia M : Tumors of sex cord/gonadal stroma

in G.Mikuz.ed. Clinical Pathology of Urologic Tumors, Informa,London 2008
Leydig cell tumor Department of Pathology
1 - 3 % of all testicular tumors
Age : 2 - 81 years 1st decade 20%

10-30 years 25%
30-50 years 30%
>50 years 25%
Symptoms: Prepubertal: isosexual pubertas praecox

Adults: 15 % gynecomastia
dicrease in libido and potency
Hormone: Androstenodione, estradiol, progosterone, inhibin

11 % malignant (aged men)
Location of metastases:
Morphology: Tu Ø> 5cm LN 68 %
Lung 45 %
Liver 45 %
Bones 27 %

36P 72M 13P 5M 8 6 P 3M 4 2
SF-1 92 75 57 50 50 100
FOXL2 21 83 67 100 - -
ß-catenin 50 83 60 100 50 100
Inhibin 97 67 38 67 75 100
Melan A 94 67 75 50 50 100
Calretinin 97 56 75 44 75 100
WT-1 0 82 57 50 75 50
CD99 74 56 25 86 0 0
CK 22 78 17 43 67 -
S100 28 28 43 38 75 0
Therapy
There is no specific therapy for malignant stromal tumor,

the benefit of RPLND is due to the small number of cases not clear.
Hendry et al. SpringerPlus (2015) 4:20 –study of 5 malignant LCT:
Despite surgery, overall outcomes for Stage II appear to be poor due to the disease
Phenotype..
Nicolai N et al.. UROLOGY 85: 402e406, 2015.
Most of the patients with TSCST had a favorable prognosis. Testis-sparing surgery may be feasible
and effective in case of small tumors. Few patients had metastatic spread, but only those with
nodal metastases may benefi t from an early retroperitoneal lymph node dissection. Risk factors
associate with disease behavior, but indications to prophylactic intervention remain
controversial.
Granulosa cell tumor of adult type Department of Pathology
 Granulosa cell tumor of adult type is a rare tumor with 50 cases reported to date.
 The youngest patient was 16, the oldest 78 years old.
 The morphology does not differ from those arising in the ovary.
 The tumor diameters range from 0.7 to 13 cm; the color is yellow.
 Symptoms : Slow enlargement of the testis and, in 20%, gynecomastia are important
symptoms.
Serum inhibin and anti-mullerian hormone (AMH) can be elevated.
GCT –adult type case reports until 2014* Department of Pathology
Schubert TE et al. Diagn Pathol. 2014;9:107. - * after our publication 5 more cases were reported
GCT –adult type case reports until 2014 Department of Pathology
2 DOD (3mo and 11 y) 2AWD (6m and 6y) 13 NED (3mo and 17 y)
Granulosa cell tumor of adult type Department of Pathology
Schubert TE et al., Adult type granulosa cell tumor of the testis with a heterologous sarcomatous
component:case report and review of the literature. Diagn Pathol. 2014 ;9:107
CK
CD99

36P 72M 13P 5M 8 6 P 3M 4 2
SF-1 92 75 57 50 50 100
FOXL2 21 83 67 100 - -
ß-catenin 50 83 60 100 50 100
Inhibin 97 67 38 67 75 100
Melan A 94 67 75 50 50 100
Calretinin 97 56 75 44 75 100
WT-1 0 82 57 50 75 50
CD99 74 56 25 86 0 0
CK 22 78 17 43 67 -
S100 28 28 43 38 75 0
Granulosa cell tumor of juvenile type Department of Pathology
 The juvenile type is the most common testicular tumor in the first 6
months of life and accounts for 6% of all prepubertal testicular
 Because of the age of the patients and, to a lesser degree, because of similarities,
the tumor is confused with the yolk sac tumor; this can be a tragic mistake, since
the juvenile granulosa tumor is absolutely benign and does not require any therapy
other than simple surgical enucleation.
 In 30% of cases, the tumor is located in an intraabdominal cryptorchid testis and

20% of children have ambiguous genital organs.In such cases numerical aberrations
of the XY chromosomes (mosaic 45X/46XY) or structural anomalies of Y chromosome
were described.
Caveat :The high mitotic count can

erroneously suggest malignancy!
Thecoma – fibroma type tumors Department of Pathology
So far 25 cases were reported in men in their 4th to 5th decade.
Inhibin
Mixed forms and incompletely differentiated gonadal stroma tumors IRCCS National Cancer Institute Milan
 Mixed tumors usually contain well-differentiated Leydig cells and

less-differentiated Sertoli cells but combinations with granulosa cells also
occur.
 Single cells can react with inhibin, but usually they are positive only for
smooth muscle actin and S-100 protein.
 The classical cytopathologic hallmark of malignancy can be missed even in

metastasizing cases, but large sizeis an important predictor.
 Patient age ranges from 6 months to 60 years.
 Few cases have presented with gynecomastia.
 In childhood the tumors are perfectly benign, whereas ¼ of tumors in

adults metastasized to the retroperitoneal lymph nodes and/or abdominal
organs.
a-inhibin IRCCS National Cancer Institute Milan

Incompletely differentiated gonadal Department of Pathology
stromal tumor
Incompletely differentiated gonadal stroma tumor: Department of Pathology
Sertoli cell differentiation

Myoid Gonadal Stromal TumorA Clinicopathologic Study of Three Cases of a
Distinctive Testicular Tumor Department of Pathology
Chia-Sui Kao, MD, Thomas M. Ulbright, MD

Am J Clin Pathol. 2014;142:675-682.
S100 SMA
FOXL2 h-caldesmon
Gonadoblastoma Department of Pathology
From M Colecchia ed. “Pathology of IRCCS National Cancer Institute Milan
”
Testicular and Penile Neoplasms Springer , Basel 2016
Mixed germ cell stromal tumor : Gonadoblastoma Department of Pathology
Gonadoblastoma arises only in intersex patients with a Y chromosome.

The candidate gene TSPY (testis-specific-protein-Y) is located in the
pericentromeric region of the short arm (Yp11.1-Yp11.2). TSPY protein is
normally expressed in spermatogonia but also IGCNU, seminoma, and
prostate cancer. The highest risk for gonadoblastoma is in patients with
gonadal dysgenesis (46XY,46X/46XY) with intra-abdominal dysgenetic
testes and/or streaks.
In high-risk patients, prophylactic gonadectomy is required. In case the
neoplastic germ cells (seminoma, embryonal carcinoma) have already
overgrown the gonadal stroma components, therapy follows the standard
protocols for germ cell tumors.
ESCOP
Krakow
2012
a-inhibin CAM 5.2 Department of Pathology
“…Gonadoblastoma is now
recognized as the only entity in
the mixed germ cell-sex cord
stromal category with the
unclassified form of germ cell-
sex cord stromal tumor
considered not sufficiently
established by the available
evidence.”
“..In contrast to the prior classification

there is no recognized benign
mesothelioma category… The well
differentiated papillary mesothelioma was
considered ..to be a variant of
mesothelioma that tends to behave
indolently…”

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Department of Pathology

IRCCS National Cancer Institute Milan

Non-germ cell tumors of the testis.

Some general characteristics…

• Causes and risk factors unknown , no racial or ethnical differences

• Pathogenesis unknown – molecular data show sporadic gene-mutations, whose

 CTNNB1 mutation and ß –catenin accumulation in Sertoli cell tumors

“…In the sex cord-stromal tumous, the sclerosing

4-2C. Sertoli cell tumour

24061522: Perrone F, Bertolotti A, Montemurro G, Paolini B, Pierotti MA, Colecchia M,

In this study performed on 14 SCT 10/14 CASES (71,4%) showed beta

Normal SCT CTNNB1 mutation

Conclusions: SF-1 is the

≤ 1% of all testicular tumors

Age : any age (average 45 year)

Symptoms: 20% Gynecomastia

Metastases: retroperitoneal lymph nodes, skin, lung, bones

Actas Urol Esp. 2010;34:481-3.

Jiménez JD,Cebrian JL, Guarch R, Hualde A

Divatia et. al. USCAP 2015 Abstract 860 (pp.216A)

Type LCT SCT USCST GCT LCCST TTAG

Age (years) benign average 17 (2-38)

malignant average 39(28-73)

Location benign 28%

malignant unilateral and unifocal

In young patients associated with:

LCCST can be a part of Carney syndrome, whose other characteristics are

Malignant LCCSTs do not manifest associations with genetic disorders.

Divatia et. al. USCAP 2015 Abstract 860 (pp.216A)

Type LCT SCT USCST GCT LCCST TTAG

Intratubular large cell hyalinizing Sertoli cell neoplasia

There is no specific therapy for malignant stromal tumor,

Mikuz G, Colecchia M : Tumors of sex cord/gonadal stroma

1 - 3 % of all testicular tumors

Age : 2 - 81 years 1st decade 20%

Symptoms: Prepubertal: isosexual pubertas praecox

Hormone: Androstenodione, estradiol, progosterone, inhibin

Divatia et. al. USCAP 2015 Abstract 860 (pp.216A)

Type LCT SCT USCST GCT LCCST TTAG

There is no specific therapy for malignant stromal tumor,

Hendry et al. SpringerPlus (2015) 4:20 –study of 5 malignant LCT:

Nicolai N et al.. UROLOGY 85: 402e406, 2015.

 The youngest patient was 16, the oldest 78 years old.

Divatia et. al. USCAP 2015 Abstract 860 (pp.216A)

Type LCT SCT USCST GCT LCCST TTAG

 In 30% of cases, the tumor is located in an intraabdominal cryptorchid testis and

Caveat :The high mitotic count can

So far 25 cases were reported in men in their 4th to 5th decade.

 Mixed tumors usually contain well-differentiated Leydig cells and

 The classical cytopathologic hallmark of malignancy can be missed even in

 Patient age ranges from 6 months to 60 years.

 Few cases have presented with gynecomastia.

 In childhood the tumors are perfectly benign, whereas ¼ of tumors in

a-inhibin IRCCS National Cancer Institute Milan

Sertoli cell differentiation

Chia-Sui Kao, MD, Thomas M. Ulbright, MD

Gonadoblastoma arises only in intersex patients with a Y chromosome.

“..In contrast to the prior classification

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