A 42‐Year‐Old Male with Diabetes Insipidus

Clinical Summary

A 42‐year‐old male with Hashimoto's thyroiditis presented in 2010 with an increased thirst and nocturia. MRI scans (Figure 1A,B) showed enlargement of the infundibulum. Following numerous laboratory tests, he was diagnosed with autoimmune hypophysitis. Following treatment he presented again in early 2013 and was found to have gonadotrophic insufficiency treated with testosterone. Scans were still consistent with hypophysitis. Six months later he was found to have corticotrophic insufficiency and an MRI scan in early 2014 showed increased size of the lesion with involvement of sella and suprasellar regions as well as new periventricular lesions (Figure 1C,D). A biopsy revealed only inflammation. Despite aggressive treatment, a year later MRI scans showed that the lesion had grown (Figure 1E,F) and another biopsy was performed in early 2015.

Figure 1.

 

Pathology

The first biopsy revealed fibrous tissue moderately infiltrated by lymphocytes (Figure 1G). Most lymphocytes were CD3‐positive (Figure 1I) with only rare CD20‐positive ones. PLAP immunostains were negative (Figure 1K). A nonspecific chronic inflammatory infiltrate was diagnosed. The second biopsy showed fibrotic inflammatory areas with dense lymphocytic infiltrates were seen (Figure 1J). As in the specimen obtained in the first operation, CD3‐positive T cells prevailed. In contrast, this biopsy had scattered islands of large epithelioid cells with big nuclei and prominent nucleoli were detected (Figure 1H). Remarkably, these islands contained only few lymphocytes. The large cells were positive for both PLAP (Figure 1L) and Oct 3/4. What is your diagnosis?

Diagnosis

Germinoma was diagnosed.

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. Germ cell tumors peak in the time of puberty and are most frequent in young males. A common 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 (HCGβ) and human placental alkaline phosphatase (hPLAP) can have additional benefit for further differentiation (8). The most common treatment of germinomas is radiotherapy 2. The prognosis of germinoma is good, reporting a 90% 5‐year survival rate.

Our case is of clinical and pathological interest considering also the differential diagnosis of primary hypophysitis. Hypophysitis is a rare autoimmune disease inflammation of the pituitary gland 1. Definitive diagnosis requires a biopsy. The differential diagnosis of hypophysitis is broad. 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. Measurement of antipituitary autoantibodies does not yet have sufficient sensitivity or specificity 1.

The gold standard is pituitary biopsy. 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. Typically there is a diffuse infiltration of inflammatory cells, 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 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. Therefore other therapies including azathioprine, MTX, rituximab and radiation have been applied in steroid refractory diseases 4. The initial clinical development therefore in this case was not unusual.

In the literature, hypophysitis masking a germinoma was first described in 1999. Later, other reports followed summing up to ten cases 3. 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 10 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. In the first biopsy of our patient, however, immunostains 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 histological evaluation with mixed infiltration by CD3‐positive T cells and CD20‐positive B cells and the other showing germinoma cells with the 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 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. Additional references for this case can be found at: http://path.upmc.edu/divisions/neuropath/bpath/cases/case357.html