Occult neurohypophyseal germinoma discovered during the course of long-term diabetes insipidus: illustrative case

Hironori Yamada Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Takatsuki, Japan

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Ryokichi Yagi Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Takatsuki, Japan

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Akihiro Kambara Department of Neurosurgery, Shimizu Hospital, Kyoto, Japan; and

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Yoshihide Katayama Department of Neurosurgery, First Towakai Hospital, Takatsuki, Japan

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Yuichiro Tsuji Department of Neurosurgery, Kano General Hospital, Osaka, Japan

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Ryo Hiramatsu Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Takatsuki, Japan

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Naokado Ikeda Department of Neurosurgery, Takeda General Hospital, Kyoto, Japan

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Masahiro Kameda Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Takatsuki, Japan

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Naosuke Nonoguchi Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Takatsuki, Japan

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Motomasa Furuse Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Takatsuki, Japan

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Shinji Kawabata Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Takatsuki, Japan

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Toshihiro Takami Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Takatsuki, Japan

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Masahiko Wanibuchi Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Takatsuki, Japan

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BACKGROUND

The authors report a case of occult neurohypophyseal germinoma detected in a patient with long-term diabetes insipidus. Central diabetes insipidus is the initial symptom in 95% of cases of neurohypophyseal germinoma. In occult neurohypophyseal germinomas, no abnormalities are seen on magnetic resonance imaging (MRI) at the onset of symptoms. It can take several months or even years for these changes to be detected on MRI.

OBSERVATIONS

A 20-year-old male was diagnosed with central diabetes insipidus at the age of 17 years, and gonadal and adrenal corticosteroid insufficiency was noted at the age of 19 years. Head MRI showed an enlarged and enhanced pituitary stalk. He was referred to our department for a suspected neoplastic lesion. Endoscopic transsphenoidal biopsy indicated a pure germinoma. He was treated with chemotherapy and radiotherapy and then was discharged.

LESSONS

In this case, new imaging findings appeared 19 months after the onset of diabetes insipidus, and the pathological diagnosis was made after almost 24 months. Because the patient had a history of growth hormone deficiency and had a positive test result for diabetes insipidus, occult neurohypophyseal germinoma was suspected, and periodic contrast-enhanced MRI monitoring was deemed essential.

ABBREVIATIONS

AFP = α-fetoprotein; CSF = cerebrospinal fluid; EP = etoposide; HCG-β = human chorionic gonadotropin-β; MRI = magnetic resonance imaging

BACKGROUND

The authors report a case of occult neurohypophyseal germinoma detected in a patient with long-term diabetes insipidus. Central diabetes insipidus is the initial symptom in 95% of cases of neurohypophyseal germinoma. In occult neurohypophyseal germinomas, no abnormalities are seen on magnetic resonance imaging (MRI) at the onset of symptoms. It can take several months or even years for these changes to be detected on MRI.

OBSERVATIONS

A 20-year-old male was diagnosed with central diabetes insipidus at the age of 17 years, and gonadal and adrenal corticosteroid insufficiency was noted at the age of 19 years. Head MRI showed an enlarged and enhanced pituitary stalk. He was referred to our department for a suspected neoplastic lesion. Endoscopic transsphenoidal biopsy indicated a pure germinoma. He was treated with chemotherapy and radiotherapy and then was discharged.

LESSONS

In this case, new imaging findings appeared 19 months after the onset of diabetes insipidus, and the pathological diagnosis was made after almost 24 months. Because the patient had a history of growth hormone deficiency and had a positive test result for diabetes insipidus, occult neurohypophyseal germinoma was suspected, and periodic contrast-enhanced MRI monitoring was deemed essential.

ABBREVIATIONS

AFP = α-fetoprotein; CSF = cerebrospinal fluid; EP = etoposide; HCG-β = human chorionic gonadotropin-β; MRI = magnetic resonance imaging

The purpose of this report is to stress the importance of head magnetic resonance imaging (MRI) in patients with diabetes insipidus with a background of growth hormone insufficiency. Central diabetes insipidus is the initial symptom in 95% of cases of neurohypophyseal germinoma. Anterior pituitary dysfunction and visual field disturbances have also been observed. In occult neurohypophyseal germinoma, imaging changes do not appear at the onset of symptoms; it takes several months or sometimes years for these changes to be detected on MRI. We report a case of occult neurohypophyseal germinoma in a male patient with a long-term history of diabetes insipidus and growth hormone deficiency.

Illustrative Case

History and Examination

A 20-year-old male had been started on replacement therapy for growth hormone deficiency in 2014 at the age of 12. The replacement therapy was terminated in 2017 because of improvement in his symptoms. In April 2021, he had a positive test result for central diabetes insipidus, as well as gonadal and adrenocortical hormone deficiencies, which prompted contrast-enhanced MRI of the pituitary region. The treating physician suspected a neoplastic lesion and referred him to our department. His past medical history included motor and speech tics since December 2019.

His physical examination revealed a height of 154.2 cm, weight of 40.9 kg, body mass index of 17.2 kg/m2, polyuria, polydipsia, bilateral hemianopsia, and decreased visual acuity (Fig. 1). There were no abnormalities in blood counts and blood biochemistry, and hormone-level analysis showed a decrease in testosterone and a mild reduction in adrenocorticotropic hormone. His α-fetoprotein (AFP) and human chorionic gonadotropin (HCG)-β levels were not elevated (Table 1). Cerebrospinal fluid (CSF) examination showed that his HCG-β levels were within the reference range.

FIG. 1.
FIG. 1.

Time course of gadolinium-enhanced T1-weighted MRI scans: June 2014 (A and D), November 2019 (B and E), and September 2021 (C and F). In 2014, there were no abnormal findings at the time of failure of growth hormone secretion. MRI in September 2021 showed an enlarged pituitary pattern and a contrast effect on the pineal gland (arrows).

TABLE 1.

Blood test results

Value
Hematological Measurement
 WBC5.1 × 103/μl
 Neut2,009/μl
 Lymph2,519/μl
 RBC4.20 × 106/μl
 Hb13.1 g/dl
 Ht37.8%
 Plt20.3 × 104/μl
Biochemistry
 TP7.4 g/dl
 Alb4.9 g/dl
 T-Bil1.4 mg/dl
 AST33 U/L
 ALT55 U/L
 LDH223 U/L
 ALP89 U/L
 γGTP15 U/L
 CK52 U/L
 AMY76 U/L
 CRP0.07 mg/dl
 BS71 mg/dl
 BUN15 U/L
 Cr1.21 mg/μl
 Na141 mEq/L
 K3.4 mEq/L
Hormone
 Testosterone<0.03 ng/ml
 GH0.79 ng/ml
 LH<0.3 IU/L
 FSH<0.3 IU/L
 Free T40.95 ng/dl
 TSH0.552 μIU/ml
 Cortisol14.3 μg/dl
 ACTH<3.0 pg/ml
 IGF-130 ng/ml
 HCG<1.0 mIU/ml
 AFP1.8 ng/ml
 IgG418.6 mg/dl

γGTP = gamma glutamyltranspeptidase; ACTH = adrenocorticotropic hormone; Alb = albumin; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AMY = amylase; AST = aspartate aminotransferase; BS = bile salts; BUN = blood urea nitrogen; CK = creatine kinase; Cr = creatine; CRP = C-reactive protein; Free T4 = free thyroxine; FSH = follicle-stimulating hormone; GH = growth hormone; Hb = hemoglobin; Ht = hematocrit; IGF-1 = insulin-like growth factor 1; K = potassium; LDH = lactate dehydrogenase; LH = luteinizing hormone; Lymph = lymphocyte; Na = sodium; Neut = neutrophil; Plt = platelet; RBC = red blood cell; T-Bil = total bilirubin; TP = total protein; TSH = thyroid-stimulating hormone; WBC = white blood cell.

There were no abnormalities in blood counts and blood biochemistry, and hormone-level analysis showed a decrease in testosterone and a mild reduction in ACTH. AFP and HCG-β levels were not elevated.

Thus, nonenhanced MRI done in June 2014 as well as the enhanced T1-weighted MRI from November 2019 did not show any abnormalities. The contrasted T1-weighted MRI done in September 2021 showed an enlarged and enhanced pituitary stalk. The T1-weighted image showed a high signal loss in the posterior pituitary gland, and the T2-weighted image showed a high signal area in the right basal ganglia. On the basis of these images and backgrounds, we suspected the presence of neoplastic lesions such as germinomas and malignant lymphomas and inflammatory diseases such as lymphocytic hypophysitis, Langerhans cell histiocytosis, immunoglobulin G4–related diseases, sarcoidosis, and tuberculosis. A biopsy was performed to make a definitive diagnosis.

Operative Findings

The biopsy of the lesion on the enhanced pituitary stalk was performed by endoscopic transsphenoidal surgery. A right nostril approach was performed to access the sphenoid sinus, and bone removal was performed at the base of the sella turcica. The arachnoid membrane and normal pituitary gland were observed via dural incision. After the arachnoid was incised, an enlarged pituitary stalk and normal optic chiasm were observed. After dissecting around the stalk, a neoplastic lesion was detected on the upper left side of the stalk, bordering the normal stalk. The lesion was biopsied by sharp dissection, and the surgery was completed with preservation of the normal stalk (Fig. 2).

FIG. 2.
FIG. 2.

An arachnoid incision revealed an enlarged pituitary stalk and optic chiasm (A). A neoplastic lesion bordering the normal stalk was found on the upper left portion of the stalk, so the lesion was biopsied and the normal stalk was preserved (B).

Postoperative Progress

Postoperatively, there was no obvious evidence of nerve loss or spinal fluid leakage, but the patient had poorly controlled diabetes insipidus. Hematoxylin and eosin staining revealed an accumulation of lymphocytes having small nuclei loaded with dense chromatin around blood vessels and epithelial-like cells with large nuclei proliferating in a paving stone–like pattern, depicting a two-cell pattern. The findings of immunostaining were positive for placental alkaline phosphatase, c-kit, and D2-40 and negative for CD30, AFP, and HCG (Fig. 3). The Ki-67 labeling index was 50%–80%. With the diagnosis of pure germinoma with a good prognosis, the patient underwent four courses of chemotherapy with cisplatin and etoposide (EP) and started radiation therapy (fractionated radiation, 24 Gy) at the same time. Contrast-enhanced MRI at the end of the three courses of EP therapy showed that the lesion had disappeared, and the patient was discharged home with a complete response.

FIG. 3.
FIG. 3.

Hematoxylin and eosin staining and immunostaining diagnosis. The two-cell pattern is observed in the perivascular area, with an accumulation of small nucleated lymphocytes with dense chromatin and large nucleated epithelial-like cells proliferating in a paving stone–like pattern (A). Immunostaining was positive for placental alkaline phosphatase, c-kit, and D2-40. CD30, AFP, and HCG were negative (B), and the diagnosis was pure germinoma. Original magnification ×40.

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

Observations

Germinomas are classified as pure germinoma, mature teratoma, immature teratoma, yolk sac tumor, choriocarcinoma, embryonal carcinoma, and their mixed types. Pure germinoma is the most common type, accounting for about 70% of cases, 3% of all brain tumors, and 15% of pediatric brain tumors.1 In neurohypophyseal germinoma, central diabetes insipidus is the first symptom in 95% of cases, anterior pituitary insufficiency in 68%, and visual field disturbance in 37%, and central diabetes insipidus is often the first symptom in occult neurohypophyseal germinomas.

The lesions may not be visible on MRI for several months to several years, resulting in possible discrepancies in the diagnosis. The imaging changes are the appearance of an enlarged pituitary pattern in enhanced T1-weighted MRI scans and the loss of brightness of the posterior pituitary on T1-weighted images, which are often detected after the appearance of anterior pituitary hypofunction in addition to central diabetes insipidus.2 However, because anterior lobe dysfunction is irreversible, early detection is important.3 It has also been reported that delayed detection increases the risk of tumor dissemination and recurrence and shortens the overall survival period.4

An algorithm has been proposed for detecting foci of central diabetes insipidus of unknown etiology, according to which, if the symptoms of diabetes insipidus are present, MRI must be performed; if a neoplastic lesion is detected, biopsy must be performed. It has also been stated that contrast-enhanced MRI is much more useful for diagnosis than simple MRI. If there are no abnormal findings, CSF and blood marker tests should be performed, and imaging evaluations should be performed every 6 months for 5 years. In the scenario of an enlarged pituitary stalk, periodic imaging examinations are recommended if the CSF and blood markers are negative.5 In the present case, biopsy was performed because the imaging showed an enlarged pituitary stalk and the progression of clinical symptoms such as hypofunction of the anterior pituitary gland.

In addition, the presence of neurohypophyseal germinoma can be suspected as a cause of anterior lobe hypofunction when growth hormone deficiency is associated with central diabetes insipidus.5–8 In a study of 12 cases of neurohypophyseal germinoma by Kato et al.,6 the mean age was 10.2 years, and the mean time from onset to diagnosis was 2.5 years. More than 80% of the cases showed anterior pituitary hypofunction at the time of diagnosis, and growth hormone deficiency was confirmed in all cases with anterior hypofunction.6 Mootha et al.5 diagnosed neurohypophyseal germinoma in six of nine patients with central diabetes insipidus, with a mean age of 10.5 years and an average time from presentation to confirmation via imaging changes of 8.2 months. All six patients with central diabetes insipidus had growth hormone deficiency.5

In our case, the pituitary pattern was noted to be enlarged 19 months after the onset of diabetes insipidus, and the pathological diagnosis was made at 24 months. This case differs from previous reports because the growth hormone–producing function had improved at the time of the onset of central diabetes insipidus and hypopituitarism, although growth hormone insufficiency had been observed in the past. However, a history of growth hormone deficiency and the diagnosis of central diabetes insipidus suggest that occult neurohypophyseal germinoma should have been suspected at an early stage and that periodic enhanced T1-weighted MRI evaluation was necessary.

Lessons

In patients with unexplained diabetes insipidus, periodic contrast-enhanced MRI of the head is necessary to consider the possibility of occult neurohypophyseal germinoma, even if the growth hormone deficiency has improved.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Yagi, Yamada, Kambara, Katayama, Tsuji, Wanibuchi. Acquisition of data: Yagi, Yamada, Kambara, Katayama, Ikeda. Analysis and interpretation of data: Yagi, Yamada, Katayama, Kameda, Furuse. Drafting the article: Yagi, Yamada, Katayama, Hiramatsu. Critically revising the article: Yagi, Yamada, Katayama, Tsuji. Reviewed submitted version of manuscript: Yagi, Yamada, Katayama, Tsuji, Ikeda, Kameda, Kawabata. Approved the final version of the manuscript on behalf of all authors: Yagi. Statistical analysis: Yagi, Yamada, Katayama. Administrative/technical/material support: Yagi, Yamada, Katayama, Takami. Study supervision: Yagi, Yamada, Katayama, Nonoguchi, Furuse, Kawabata, Wanibuchi.

References

  • 1

    Committee of Brain Tumor Registry of Japan. Brain Tumor Registry of Japan (2001–2004). Neurol Med Chir (Tokyo). 2014;54(Suppl):1102.

  • 2

    Chang HY, Chiu CF, Jung SM, Wong AMC, Wu CT, Lo FS. Neurological and endocrinological manifestations of 49 children with intracranial pure germinoma at initial diagnosis in Taiwan. Pediatr Neonatol. 2021;62(1):106112.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Kobayashi T, Tsugawa T, Hashizume C, et al. Gamma knife radiosurgery of brain metastasis from malignant pleural mesothelioma – report of three cases with autopsy study in a case. Nagoya J Med Sci. 2014;76(1–2):187193.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Phi JH, Kim SK, Lee YA, et al. Latency of intracranial germ cell tumors and diagnosis delay. Childs Nerv Syst. 2013;29(10):18711881.

  • 5

    Mootha SL, Barkovich AJ, Grumbach MM, et al. Idiopathic hypothalamic diabetes insipidus, pituitary stalk thickening, and the occult intracranial germinoma in children and adolescents. J Clin Endocrinol Metab. 1997;82(5):13621367.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Kato T, Sawamura Y, Tada M, et al. Occult neurohypophyseal germinomas in patients presenting with central diabetes insipidus. Neurosurg Focus. 1998;5(1):e6.

  • 7

    Leger J, Velasquez A, Garel C, Hassan M, Czernichow P. Thickened pituitary stalk on magnetic resonance imaging in children with central diabetes insipidus. J Clin Endocrinol Metab. 1999;84(6):19541960.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Maghnie M, Cosi G, Genovese E, et al. Central diabetes insipidus in children and young adults. N Engl J Med. 2000;343(14):9981007.

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  • FIG. 1.

    Time course of gadolinium-enhanced T1-weighted MRI scans: June 2014 (A and D), November 2019 (B and E), and September 2021 (C and F). In 2014, there were no abnormal findings at the time of failure of growth hormone secretion. MRI in September 2021 showed an enlarged pituitary pattern and a contrast effect on the pineal gland (arrows).

  • FIG. 2.

    An arachnoid incision revealed an enlarged pituitary stalk and optic chiasm (A). A neoplastic lesion bordering the normal stalk was found on the upper left portion of the stalk, so the lesion was biopsied and the normal stalk was preserved (B).

  • FIG. 3.

    Hematoxylin and eosin staining and immunostaining diagnosis. The two-cell pattern is observed in the perivascular area, with an accumulation of small nucleated lymphocytes with dense chromatin and large nucleated epithelial-like cells proliferating in a paving stone–like pattern (A). Immunostaining was positive for placental alkaline phosphatase, c-kit, and D2-40. CD30, AFP, and HCG were negative (B), and the diagnosis was pure germinoma. Original magnification ×40.

  • 1

    Committee of Brain Tumor Registry of Japan. Brain Tumor Registry of Japan (2001–2004). Neurol Med Chir (Tokyo). 2014;54(Suppl):1102.

  • 2

    Chang HY, Chiu CF, Jung SM, Wong AMC, Wu CT, Lo FS. Neurological and endocrinological manifestations of 49 children with intracranial pure germinoma at initial diagnosis in Taiwan. Pediatr Neonatol. 2021;62(1):106112.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Kobayashi T, Tsugawa T, Hashizume C, et al. Gamma knife radiosurgery of brain metastasis from malignant pleural mesothelioma – report of three cases with autopsy study in a case. Nagoya J Med Sci. 2014;76(1–2):187193.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Phi JH, Kim SK, Lee YA, et al. Latency of intracranial germ cell tumors and diagnosis delay. Childs Nerv Syst. 2013;29(10):18711881.

  • 5

    Mootha SL, Barkovich AJ, Grumbach MM, et al. Idiopathic hypothalamic diabetes insipidus, pituitary stalk thickening, and the occult intracranial germinoma in children and adolescents. J Clin Endocrinol Metab. 1997;82(5):13621367.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Kato T, Sawamura Y, Tada M, et al. Occult neurohypophyseal germinomas in patients presenting with central diabetes insipidus. Neurosurg Focus. 1998;5(1):e6.

  • 7

    Leger J, Velasquez A, Garel C, Hassan M, Czernichow P. Thickened pituitary stalk on magnetic resonance imaging in children with central diabetes insipidus. J Clin Endocrinol Metab. 1999;84(6):19541960.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Maghnie M, Cosi G, Genovese E, et al. Central diabetes insipidus in children and young adults. N Engl J Med. 2000;343(14):9981007.

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