Germ Cell Tumors

Seminoma of thymus showing compact nests of large tumor cells surrounded by lymphocyte-rich fibrous septa.

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Definition

Group of tumor of the thymus with a germ cell origin, that affect mainly males.

Clinical Features

≈20% of mediastinal tumors and cysts
Association with Klinefelter's syndrome:
- estimated incidence of Klinefelter's syndrome 30–40 times that in general population1–3
Gender:
- embryonal carcinoma, endodermal sinus tumor, teratocarcinoma, and choriocarcinoma:
  - predilection for males 4,5
- mature cystic teratoma:
  - affects both sexes equally 6

Mature Cystic Teratoma

Most common mediastinal germ cell neoplasm
Usually clinically apparent in early adult life

Teratocarcinoma

≈5% of all mediastinal germ cell tumors
Grows rapidly
Infiltrates widely

Nonseminomatous Germ Cell Tumors

Occasionally develop somatic-type malignant tumor such as:
- neuroendocrine tumors 13
- angiosarcoma
- rhabdomyosarcoma14–16
More prone to this than gonadal neoplasms, particularly sarcomas exhibiting skeletal muscle differentiation 17
Rarely develop hematologic neoplasia:18
- may be acute leukemia or systemic mast cell disease19,20
- particularly common if yolk sac component 1,21
- detection in these hematopoietic elements of i(12p) indicates that these cells originate from germ cell tumor rather than therapy-induced 22

Pathogenesis

Controversial:
- primary origin from extragonadal germ cells favored23,24
- mediastinal location specifically related to thymus even if normal germ cells have yet to be conclusively demonstrated in thymus 25–27
- no histogenetic relationship with true thymoma

Gross Pathology

Seminoma

Almost always within thymus (Fig. 1
Fig. 1: Seminoma of thymus. The tumor is solid and homogeneous, with no necrosis. Residual thymic tissue is seen at the periphery.
)

Mature Cystic Teratoma

May be large
Distinct, sharply delineated wall that often becomes calcified28
Cut surface predominantly cystic (Fig. 2
Fig. 2: Mature cystic teratoma with prominent cystic component. This tumor contained abundant pancreatic tissue, some of which was heavily inflamed.
)
Commonly adheres to surrounding structures
Prominent xanthogranulomatous inflammatory reaction if sebaceous material within escapes
May perforate into tracheobronchial tree and patient coughs up sebaceous oily material and hair

Embryonal Carcinoma

Invasive
Highly necrotic

Teratocarcinoma

Areas of hemorrhage and necrosis (Fig. 3
Fig. 3: Nonseminomatous germ cell tumor of the mediastinum of teratocarcinoma type that has undergone massive necrosis.
)

Histopathology

Seminoma

Identical to testicular seminoma27,29 (Figs 4 and 5
Fig. 4: Seminoma of thymus showing compact nests of large tumor cells surrounded by lymphocyte-rich fibrous septa.
Fig. 5: This semi-thin section shows particularly well the multiple prominent nucleoli with ragged edges that are typical of seminoma.
)
Ultrastructurally identical to testicular seminoma27,29

Mature Cystic Teratoma

Resembles more common mature cystic teratoma of ovary
Cysts:
- lined by stratified squamous epithelium
- contain:
  - sebaceous glands
  - hair follicles
Other common components:
- pancreatic tissue:30
  - may be islet cell elements and result in hypoglycemia
  - suggested that dense adhesions often found in this tumor may result from pancreatic enzyme secretion31

Immature Teratoma

Similar to mature teratoma
Also contains immature epithelial, mesenchymal, or neural elements
No component of embryonal carcinoma

Embryonal Carcinoma

Poorly differentiated

Yolk Sac Tumor

May occur admixed with other germ cell elements or (more rarely) as pure neoplasm32 (Fig. 6
Fig. 6: Yolk sac tumor of mediastinum, with well-developed Schiller–Duval bodies.
)
Yolk sac elements said to be more common in mediastinal than testicular neoplasms33
May:
- have prominent spindle cell features34
- contain hepatoid component35
- be secondary multilocular cystic changes in adjacent non-neoplastic thymus36

Teratocarcinoma

Combination of embryonal carcinoma and teratoma (mature and/or immature):
- areas of embryonal carcinoma alternate with mature foci, with abundance of foci of intermediate differentiation

Special Stains and Immunohistochemistry

Seminoma of Mediastinum

Immunohistochemically identical to testicular seminoma27,29
Immunoreactive for:
- placental alkaline phosphatase
- CD117
- often CD57(Leu7
Negative for CD45
Usually negative or only focally positive for keratin:37
- avoid misinterpreting entrapped thymic epithelial cells as neoplastic elements (Fig. 7
  Fig. 7: Infiltration and entrapment of thymic epithelium by seminoma cells, as seen with the keratin immunostain.
  )
Mutations of c-kit:
- common
- similar to those in testicular counterparts38

Embryonal Carcinoma

Reactivity for:
- keratin
- PLAP
- CD30
- CD57 (Leu7)

Diagnosis

Any mediastinal germ cell tumor may be a metastasis from testicular or ovarian primary lesion:
- rare if a single upper mediastinal tumor with no evidence of retroperitoneal involvement28,42,43
Admixtures of various types of germ cell tumors common:44,45
- important to describe components accurately 46

Embryonal Carcinoma

Important to consider possibility of germ cell tumor if a poorly differentiated malignant neoplasm of the mediastinum:
- especially if in a young male
- to avoid missing opportunity of remission or cure with current chemotherapeutic regimens47–51

Choriocarcinoma

Occult testicular primary lesion:
- more likely with choriocarcinoma than any other germ cell tumor due to:
  - tendency for choriocarcinoma to be very small and even regressed when metastases develop 7

Other Investigations

Serum elevation of hCG and/or AFP:
- ≈90% of malignant nonseminomatous germ cell tumors
- usually negative in pure seminoma39
Comparative genomic hybridization analysis or interphase chromosome painting of formalin-fixed paraffin-embedded material:40,41
- to reveal i(12p)
- diagnostically useful, particularly for differential diagnosis between embryonal carcinoma and undifferentiated carcinoma of pulmonary or thymic origin

Differential Diagnosis

Select up to 2 differential diagnoses to compare with Germ Cell Tumors

Seminoma

Differential diagnosis:
- thymoma
- large cell lymphoma
- Diagnosis of seminoma:
  - favored by:
    - fibrous septa infiltrated by lymphocytes and plasma cells
    - epithelioid granulomas
    - numerous germinal centers
    - large amounts of cytoplasmic glycogen
    - irregular, skein-like nucleolus
  - true nature may be obscured by:
    - very prominent granulomatous reaction
    - reactive follicular hyperplasia
    - epithelium-lined cystic formations of thymic origin (multilocular thymic cyst)
    - fibrosis52 (Fig. 8
      Fig. 8: Seminoma of thymus. The associated granulomatous response can obscure the true nature of the lesion.
      )

Immature Teratoma

Distinguish from:
- teratocarcinoma
- malignant transformation of mature cystic teratoma:
  - very rare

Genetics

i(12p):
- a gain of 12p, usually as isochromosome53,54
- >80% of cases regardless of microscopic type or whether primary or metastatic

Seminoma

Differs from testicular seminoma in:
- p53 immunostain:55
  - perhaps because greater percentage of mediastinal than gonadal seminomas show degree of atypicality and mitotic activity that places them in category of anaplastic seminoma

Management

Seminoma

Radiation therapy:
- primary treatment

Choriocarcinoma

Systemic chemotherapy

Prognosis

Seminoma

Very good51,54,56,57
10-year actuarial survival rate 69%56

Mature Cystic Teratoma

Excellent51

Immature Teratoma

Number of cases in mediastinum too small to determine behavior58

Yolk Sac Tumor

Very poor if pure endodermal sinus tumor:59
- better if encapsulated60

Choriocarcinoma

Extremely poor8

Nonseminomatous Germ Cell Tumors Of Mediastinum

Do not respond as well to chemotherapy as microscopically similar testicular counterparts:
- relapses more frequent
- patient survival worse33,61,62
Associated somatic-type malignancies do not respond to germ cell-type chemotherapeutic protocols as conventional germ cell tumors do 63

References

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Last updated: 7 Mar 2006