Contributed by Bremer Pais I, MD, Bernreuther C, MD, Minnemann T, MD, Saeger W, MD, Hagel C, MD, Iking-Konert C, MD, Aberle J, MD, Flitsch J, MD
DIAGNOSIS
Germinoma
DISCUSSION
Germinomas are malignant neoplasms belonging to the germ cell tumors of the brain. They are the most common CNS germ cell tumors and account for about 3 % of all primary brain tumors (14).
In general germ cell tumors peak in the time of puberty and are seen more frequently in young male patients, but rarely affect the middle age group (7). A typical clinical presentation is polyuria and polydipsia due to diabetes insipidus showing an involvement of the posterior pituitary. A deficiency of the growth hormone axis is also described frequently.
Most frequently germinomas are found in midline structures of the CNS, the suprasellar region and pineal region. The diagnosis is proven by lumbar puncture in the presence of malignant cells or by histology on surgical specimen (9, 17). In case of pathological lesions on MRI in the pituitary as well as pineal region, the diagnosis of germinoma can be made without biopsy. As the tissue specimen may not be representative, evaluation of the cerebrospinal fluid and serum for alpha-fetoprotein(AFP), beta-human chorionic gonadotropin (HCG?), and human placental alkaline phosphatase (hPLAP) can have additional benefit for further differentiation (8). The most common treatment of germinomas is achieved by radiotherapy (6, 11, 16, 17). The prognosis of germinoma is good, reporting a 90% survival rate 5 years after the diagnosis (15).
Our reported case is of clinical and pathological interest considering also the differential diagnosis of primary hypophysitis. Hypophysitis is a rare disease that is accepted to be autoimmune in its cause, showing an inflammation and cellular infiltration of the pituitary gland (1). Its prevalence among pituitary masses is described with 1%. Definitive diagnosis requires a histopathological evaluation. The differential diagnosis of hypophysitis is broad as there are various diseases that have a similar clinical presentation and radiological imaging characteristics. A typical MRI shows a homogenous enhancing sellar mass with diffuse thickening of the pituitary infundibulum and loss of the normal bright spot as it was seen in our patient on the initial MRI. When the clinical and radiological findings are typical for autoimmune hypophysitis it is generally agreed not to force biopsy but to have regular imaging control as well as lab follow ups (1,4). Measurement of antipituitary autoantibodies have no sufficient sensitivity or specificity so far (1).
The gold-standard to proof the diagnosis of autoimmune hypophysitis is pituitary biopsy as performed in our patient. Our patient presented with a typical initial posterior pituitary inflammation and diabetes insipidus. The insufficiency of the corticotropic and gonatotropic axes in the course of the disease suggested an involvement of the anterior pituitary. If a biopsy is performed the typical histological finding is a diffuse infiltration of inflammatory cells. These cells are mostly T and B lymphocytes that can be surrounded by necrosis and fibrosis. The first biopsy in our patient showed typical histological signs for hypophysitis.
The treatment management of hypophysitis is controversial. In some cases spontaneous healing has been reported. When treatment is initiated glucocorticoids have shown a return of pituitary function and shrinkage of the pituitary mass, but failure of steroids are also described (18). Therefore other therapies including azathioprine, MTX, rituximab and radiation have been applied in steroid refractory diseases (18, 21). The initial clinical development therefore in this case was not unusual.
In the literature hypophysitis masking a germinoma was first described in 1999 (3). Later other reports followed summing up to ten cases (2, 5, 10, 12, 13, 19, 20). In seven of these cases initial diagnosis was made by typical clinical history and treatment with GC steroids was started. Because of an atypical clinical development further evaluation including a biopsy showed the diagnosis of germinoma in the further run of the disease.
In three of the reported ten cases initial biopsy showed lymphocytic hypophysitis. Further evaluation was due to unusual clinical development as in our case showing the unexpected diagnosis of germinoma in the repeated biopsy.
When only a few neoplastic cells are surrounded by predominant sheets of lymphocytes the diagnosis of neoplastic germ cell tumors can be missed, because of predominant lymphocytic infiltration. In the first biopsy of our patient, however, immunohistochemical staining did not show any positivity for neoplastic cells whereas in the second biopsy two spatially separate histological patterns were observed, one resembling the result of the first histologic evaluation with mixed infiltration by CD3-positive T-cells and CD20-positive B-cells and the other showing germinoma cells with expression of PLAP and Oct 3/4 as well as a high proliferative activity demonstrated by labeling with Ki-67-antibodies with only few surrounding lymphocytes. This highlights the necessity to not only thoroughly search for germinoma in a given specimen but also to extensively sample if germinoma is suspected.
Regular clinical and radiological follow up should be performed particularly in young patients with the diagnosis of lymphocytic hypophysitis to rule out the possibility of malignant disease with adjacent inflammation mimicking a lymphocytic hypophysitis in the further course of the disease.
ACKNOWLEDGEMENTS
This tumor is included in the German Registry of Pituitary Tumors which is sponsored by Novartis Pharma GmbH (Nürnberg), Novo Nordisk Pharma GmbH (Mainz), Phizer Pharma GmbH (Berlin) and Ipsen Pharma GmbH (Ettlingen).
REFERENCES
Contributed by Bremer Pais I, MD, Bernreuther C, MD, Minnemann T, MD, Saeger W, MD, Hagel C, MD, Iking-Konert C, MD, Aberle J, MD, Flitsch J, MD
International Society of Neuropathology