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TESTICULAR GERM CELL TUMORS TUMORS: UNCOMMON BUT

OFTEN CHALLENGING

Alaskan Rocky Mountains

TESTICULAR TUMORS

CLASSIFICATION

• GERM CELL TUMORS

• GONADAL STROMAL TUMORS

• MIXED GERM CELL – GONADAL

STROMAL TUMORS

• MESENCHYMAL TUMORS

• LYMPHORETICULAR NEOPLASMS

• METASTATIC TUMORS

TESTICULAR GERM CELL TUMORS

INTRODUCTION

• Estimated 9,310 new cases and 400 related deaths

in USA in 2017 (Siegel et al. CA Cancer J Clin 68:7, 2018)

• Incidence (5 per 100,000) has been steadily

increasing over last few decades

• Major risk factors are cryptorchidism and low

birth weight

• Higher incidence in infertile men

• More common in Caucasians vs African Americans

• A disease of young adults (late teens to early 40’s)

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TESTICULAR GERM CELL TUMORS

CLASSIFICATION (WHO 2016)

Germ Cell Tumors Related to GCNIS

• Germ cell neoplasia in situ– Specific forms of intratubular germ cell neoplasia

• Seminoma– With syncytiotrophoblastic giant cells

• Embryonal carcinoma

• Yolk sac tumor

• Trophoblastic tumors– Choriocarcinoma

– Non-choriocarcinomatous trophoblastic tumors• Placental site trophoblastic tumor

• Epithelioid trophoblastic tumor

• Cystic trophoblastic tumor

• Teratoma, postpubertal-type

• Teratoma, with somatic-type malignancy

• Germ cell tumors of unknown type (regressed GCT)

TESTICULAR GERM CELL TUMORS

CLASSIFICATION (WHO 2016)

Germ Cell Tumors Unrelated to GCNIS• Spermatocytic tumor

• Teratoma, prepubertal type– Dermoid cyst

– Epidermoid cyst

– Well differentiated neuroendocrine tumor (monodermal teratoma)

• Mixed teratoma and yolk sac tumor, prepubertal type

• Yolk sac tumor, prepubertal type

GERM CELL NEOPLASIA IN SITU

• Most frequent adjacent to GCTs (up to 100%)

• Also seen in association with:

• cryptorchid testis (2% - 8%)

• biopsies of infertile men (1% - 2%)

• contralateral testis in GCT patients (5% - 8%)

• adjacent to regressed GCTs

• Infrequent in pediatric age group

• Progresses to invasive GCT in ~ 50% at 5 years

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GERM CELL NEOPLASIA IN SITU

• Large cells (approx. 3x size of normal germ

cells) with abundant clear cytoplasm (glycogen)

• Large nuclei with single macro nucleolus

• Hug the tubule basement membrane

• Tubules are usually but not always atrophic

• IHC: PLAP +, OCT4 +, CD117 +, CD30-

• If fill the tubules: seminoma or embryonal ca in

situ

• Watch for microinvasive disease

GERM CELL NEOPLASIA IN SITU

GERM CELL NEOPLASIA IN SITU

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GERM CELL NEOPLASIA IN SITU

Rete testis involvement

GERM CELL NEOPLASIA IN SITU

OCT4

CD117 PLAP

GERM CELL NEOPLASIA IN SITU

OCT4

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IT Seminoma IT Embryonal Ca

MICROINVASIVE SEMINOMA

INFERTILITY BIOPSY: 29 yo with a history of varicocele

OCT 3/4

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SEMINOMA• Young to middle aged adults

• Circumscribed, lobulated, homogeneous, pale tan

• Can see necrosis and hemorrhage

• Pale to clear cytoplasm, arranged in nests separated

by fibrous septae with lymphocytic infiltrate

• Granulomatous inflammation

• Syncytiotrophoblastic giant cells

• Problems with fibrosis or necrosis, amphophilic

cytoplasm, pseudotubular or pseudoglandular

architecture

• IHC: PLAP +, OCT4 +, CD117 +, CK +/-, CD30 -

SEMINOMA

SEMINOMA

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SEMINOMA

SEMINOMA – LYMPHOCYTE POOR

SEMINOMA WITH AMPHOPHILIA

CD117

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SEMINOMA WITH CORDS

SEMINOMA WITH CORDS

SEMINOMA WITH CORDS

OCT 3/4

CD 117 D2-40

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SEMINOMA WITH TUBULES

SEMINOMA WITH PSEUDOGLANDS

OCT4

CD117

SEMINOMA WITH PSEUDOPAPILLAE

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SEMINOMA WITH GRANULOMATA

SEMINOMA with SyncytiotrophoblastsSEMINOMA with Syncytiotrophoblasts

SEMINOMA with SyncytiotrophoblastsSEMINOMA with Syncytiotrophoblasts

ßHCG

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SALL4 CD20

Large B-Cell Lymphoma with

MYC rearrangement

EMBRYONAL CARCINOMA

• Young adults (~ 10 years younger than seminoma)

• No typical gross – often with hemorrhage and necrosis

• Solid, papillary and glandular growth

• Pleomorphic cells with amphophilic to basophilic cytoplasm, poorly defined cell borders

• Problems with clear cytoplasm

• IHC: PLAP +, OCT4 +, CD117 -, CK +, CD30 +

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EMBRYONAL CARCINOMA

EMBRYONAL CARCINOMA

EMBRYONAL CARCINOMA

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EMBRYONAL CARCINOMA

POLYEMBRYOMA

EMBRYOID BODIES

EMBRYONAL CA & SEMINOMA

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EMBRYONAL CA & SEMINOMA

CD 30

EMBRYONAL CA & SEMINOMA

CD117

YOLK SAC TUMOR

• Most common GCT in pediatric age group

• Rarely pure in adults

• Associated with alphafetoprotein production

• In children typically circumscribed and

yellow; no typical features in adults

• Wide range of histologic patterns – one of the

more frequent causes of disagreement

• IHC: AFP + (+/-), PLAP +, Glypican-3 +,

OCT4 -, CD117 -, CK +, CD30 -

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YOLK SAC TUMOR

Yolk Sac Tumor- Histologic Patterns

• Endodermal sinus (most distinctive)

• Reticular or microcystic (most common)

• Macrocystic

• Solid

• Glandular / alveolar

• Papillary

• Myxomatous (magma reticulare)

• Spindle cell

• Polyvesicular vitelline

• Hepatoid

• Enteric (primitive intestinal)

• Parietal

YOLK SAC TUMOR

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YOLK SAC TUMOR

Schiller Duval bodies

YOLK SAC TUMOR

HYALINE GLOBULES

YOLK SAC TUMOR

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YOLK SAC TUMOR

YOLK SAC TUMOR

YOLK SAC TUMOR

AFP

Glypican-3

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YOLK SAC TUMOR

CK (AE1/AE3)

YOLK SAC TUMOR – LATE RECURRENCE

YOLK SAC TUMOR –LATE RECURRENCE

AFPGLYPICAN-3

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CHORIOCARCINOMA

• Pure form very rare

• Associated with production of βHCG

• Metastases can be associated with

hemorrhage

• Grossly are hemorrhagic

• Made up of syncytiotrophoblasts and

cytotrophoblasts

• IHC: HCG +, PLAP +, OCT4 -, CD117 -,

CK +, GATA3 +, CD30 -

CHORIOCARCINOMA

CHORIOCARCINOMA

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CHORIOCARCINOMA

S

SS

C

CHORIOCARCINOMA

S

SS

C

βHCG

CHORIOCARCINOMA EPITHELIOID TYPE

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CHORIOCARCINOMA EPITHELIOID TYPE

ßHCG GATA3

p63 OCT4

CYSTIC TROPHOBLASTIC TUMOR

• Most commonly seen in post-chemotherapy

RPLND specimens with teratoma

• Can be found in primary germ cell tumors

• Serum ßHCG not or minimally elevated

• Considered to be “benign” in RPLND (not an

indication for additional chemotherapy)

CYSTIC TROPHOBLASTIC TUMOR

GATA3

ßHCG

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TERATOMA, POSTPUBERTAL-TYPE

• Can be pure or mixed

• Postpubertal are malignant; prepubertal are benign

• Cystic areas almost always are teratoma

• Combination of ectodermal, endodermal and mesodermally derived tissues

• No longer separated into mature and immature elements (overgrowth of PNET)

• Development of somatic malignancies

• Not responsive to chemotherapy/radiation therapy

• IHC: SALL4 +, OCT4 -, AFP +/- (depending on elements)

TERATOMA, POSTPUBERTAL-TYPE

TERATOMA, POSTPUBERTAL-TYPE

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TERATOMA, POSTPUBERTAL-TYPE

TERATOMA, WITH SOMATIC MALIGNANCY

• Defined as “a teratoma that develops a distinct secondary component that resembles a somatic-type malignant neoplasm, as seen in other organs and tissues”

• Most often present in RP lymph nodes but also in primary site

• Reported in 3% - 6% of germ cell tumors

• Sarcomas most common

• Requires at least one 4x field

• Distinguish from sarcomatoid YST

• Worse prognosis when present in post chemotherapy RP lymph nodes (or elsewhere)

SOMATIC MALIGNANCY - RHABDOMYOSARCOMASOMATIC MALIGNANCY - RHABDOMYOSARCOMA

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SOMATIC MALIGNANCY - RHABDOMYOSARCOMASOMATIC MALIGNANCY - RHABDOMYOSARCOMA

Myo D1

Myogenin

SOMATIC MALIGNANCY - PNET

Synaptophysin

GERM CELL TUMOR OF UNKNOWN TYPE

(REGRESSED “BURNED OUT” GCT)

• Patients presenting with metastatic GCT

without testicular mass

• US shows scar or microcalcifications

• Morphologic features include:

– Fibrosis with ghost tubules at periphery

– Lymphoplasmacytic infiltrate

– Angiomatous foci +/- hemosiderin

– Coarse calcifications (+/- intratubular)

• GCNIS +/- microinvasive GCT

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REGRESSED “BURNED OUT” GCT

REGRESSED “BURNED OUT” GCT

REGRESSED “BURNED OUT” GCT

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Burned out GCT with GCNIS

Burned out GCT with GCNIS

OCT4

SPERMATOCYTIC TUMOR

• Older age group

• Benign unless an associated sarcoma

• Circumscribed with mucoid surface

• Sheets of cells with fibrous septae and lymphocytic infiltrate of seminoma

• Discohesive with mucinous background

• Admixture of 3 sizes of cells: small, lymphocyte like; intermediate seminoma-like; and large cells

• IHC: PLAP -, OCT4 -, SALL4+, CD117 +/-, CK +/, CD30 -,

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SPERMATOCYTIC TUMOR

SPERMATOCYTIC TUMOR

SPERMATOCYTIC TUMOR

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SPERMATOCYTIC TUMOR

SPERMATOCYTIC TUMOR

SALL4

OCT4 PLAP

TERATOMA, PREPUBERTAL-TYPE

• Tumor unrelated to GCNIS

• Can occur in post-pubertal males

• Stringent criteria required for diagnosis

– No immature elements

– No GCNIS

– No scar

– No evidence of dysgenetic gonad

• Impaired spermatogenesis, tubular atrophy,

microlithiasis, Sertoli cell nodule

• Clinically these are benign

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TERATOMA, PREPUBERTAL-TYPE

TERATOMA, PRE-PUBERTAL TYPE

GCNIS Sertoli cell nodule

Impaired spermatogenesis Microlithiasis

EPIDERMOID CYST

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WELL DIFFERENTIATED NEUROENDOCRINE

TUMOR (MONODERMAL TERATOMA)

GERM CELL TUMORS:

IMMUNOHISTOCHEMISTRY

Ulbright TA, et al. Am J Surg Pathol 38:e50-e59, 2014

TESTICULAR TUMORSPATHOLOGY FEATURES IMPACTING

TREATMENT

• Type of tumor

– Germ cell tumors

• Seminoma

• Non-seminomatous

– Other tumor types

• Tumor stage (TNMS)

– Primary tumor

– Nodal status

– Metastases

– Serum markers

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TESTIS – DEFINITION OF TNM (2018)

Primary Tumor (T)

pTX Primary tumor cannot be assessed

pT0 No evidence of primary tumor (eg. histologic scar)

pTis Germ cell neoplasia in situ

pT1

pT1a

pT1b

Tumor limited to testis without lymphovascular invasion

Seminoma smaller than 3 cm in size

Seminoma 3 cm or larger in size

pT2 Tumor limited to the testis but with vascular/lymphatic

invasion or tumor invading hilar soft tissue or epididymis

or penetrating visceral mesothelial surface of tunica

albuginea with or without lymphovascular invasion

pT3 Tumor invades the spermatic cord with or without

lymphovascular invasion

pT4 Tumor invades the scrotum with or without

lymphovascular invasion

TESTIS – pT1 (2018)

TESTIS – pT1-Seminoma (2018)

pT1a pT1b

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TESTIS – pT2 (2018)

LYMPHVASCULAR INVASION HHILAR/EPIDIDYMAL INVASION

TESTIS – pT2 (2018)

“penetrating visceral mesothelial surface of tunica albuginea”

TA

TV

TESTIS – T AND THE SPERMATIC CORD

pT2 – intravascular tumor pM1 – discontinuous spread

pT3 – direct invasion to level of vas

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Orchiectomy – external surface

Orchiectomy – the first section

X

Orchiectomy – the first section

Spermatic cord margin

Xadditional cord sections

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Spermatic cord margin

Carry over “buttering” Positive margin

“Southern Alps” South Island, NZ