15th October 2010, Volume 123 Number 1324
Daniel Garofalo, Rick Cutfield
A 21-year-old Māori male presented to hospital with a flu-like illness, fever and bilateral otitis externa. On examination he was overweight and hypogonadal (Tanner stage 2) with gynaecomastia. On further questioning he had experienced polyuria and polydipsia since high school.
Over the last few years he had presented to his family doctor with persistent, recurrent scalp lesions resembling an infected eczema. Assessment of pituitary function showed a testosterone level of 0.8 nmol/L (10-28), LH and FSH less than 1 IU/L (1–9), T4 9.6 pmol/L (9–19), T3 2.3 pmol/L (2.5–6), TSH 1.0 mU/L (0.4–4), 9 am cortisol 296 nmol/L (200–700), IGF-1 less than 25 ng/mL (110–350), and prolactin 80 mU/L (10–650). Urine osmolality after overnight water deprivation was 36 mmol/kg (50–1200).
A magnetic resonance (MR) scan showed a hypothalamic mass (Figure 1) for which differential diagnoses included a neoplastic process (primary or secondary) or an infiltrative disorder (such as sarcoidosis or histiocytosis). A chest X-ray was reported as normal, but a computed tomography (CT) scan of the chest revealed multiple cystic lesions compatible with Langerhans-cell histiocytosis (LCH).
Diagnosis was eventually confirmed by biopsy of the scalp lesions. He was treated for his endocrine deficiencies with DDAVP and thyroxine. For his LCH he received vinblastine, prednisone, 6-mercaptopurine and methotrexate, according to international guidelines.1
Figure 1. Irregular suprasellar mass measuring 1.7 cm in transverse diameter, with diffuse enhancement with gadolinium.
Initially he had a good clinical response and a partial radiological response, but subsequently relapsed, requiring prolonged maintenance therapy with azathioprine. He is currently clinically stable.
A second patient, an 18-year-old Pacific Island male, presented with a flu-like illness, myalgias, polyuria and polydipsia. A routine battery of blood tests showed mildly deranged liver function tests (mixed pattern). An overnight water deprivation test was strongly suggestive of diabetes insipidus (DI), with a urine osmolality of 106 mmol/kg and a serum Na of 148 mmol/L (135–145).
Pituitary function tests showed testosterone 12.9 nmol/L (10–28), FSH 1.9 IU/L (1–9), LH 3.1 IU/L (1–9), T4 11.4 pmol/L (9–19), TSH 1.9 mU/L (0.4–4), 9am cortisol 400 nmol/L (200–700), and prolactin 262 mU/L (10–650).
An MR scan showed loss of normal T1 high signal in the posterior pituitary (Figure 2) consistent with idiopathic DI; however a minimally bulky pituitary stalk with normal signal characteristics and measuring 3.5 mm was also noted. Replacement therapy with nasal DDAVP was started. He was followed in clinic and 11 months later he presented with left-sided headaches and nasal congestion.
Repeat endocrine function was normal except for a significant reduction in the testosterone levels down to 1.1 nmol/L. A repeat MR was carried out, which showed no changes in the pituitary stalk but revealed a lobulated enhancing lesion within the sphenoid sinus and possible early extension into the left cavernous sinus region.
A biopsy of this lesion confirmed the diagnosis of LCH. Treatment with vinblastine and prednisone has resulted in good clinical response and partial reduction in the pituitary stalk (to 2.0 mm) and in the sphenoid mass (currently 2 years since diagnosis).
Figure 2. Loss of normal T1 high signal in the posterior pituitary (arrow) consistent with idiopathic diabetes insipidus
Central diabetes insipidus (DI) can be idiopathic (30-50%), familial, or due to physical causes (trauma, fracture, surgery), tumours (germinoma, lymphoma) or, occasionally, infiltrative disorders such as LCH, sarcoidosis, lymphocytic hypophysitis and Wegener’s granulomatosis.2
LCH is characterised by a clonal proliferation of histiocytes with a recognised but unexplained predilection for the hypothalamus-pituitary axis (HPA). In autopsies, infiltration of the HPA has been reported in up to 50% of cases of LCH.3 DI is the most common endocrine abnormality, reported in 15–50% of cases of LCH, followed by growth hormone deficiency.3,4 TSH and ACTH deficiency usually only develop in the setting of panhypopituitarism.3
Pituitary involvement has been attributed to infiltration by histiocytes, scarring, or antibodies against vasopressin.5 In 6–40% of cases, DI can predate the diagnosis of LCH by months or years.2,5,6 DI is more common in patients with multisystem disease, bone disease (particularly the skull), and lung, liver and ENT involvement.5,7
Radiological findings include6 lack of the posterior pituitary bright spot on T1 images (undistinguishable from idiopathic DI) with or without infundibular thickening as in our second case (bearing in mind a normal stalk on MR does not exclude an infiltrative disorder2), a partial or completely empty sella or a hypothalamic mass, as in our first case.
Patients presenting with central DI should have a careful clinical history taken that includes questions about otitis externa, skin lesions, and bone pains. The laboratory work-up will include tests for pituitary function, an MR scan of the pituitary and relevant tumour markers (i.e. alpha fetoprotein and beta-HCG).
The search for extracranial lesions should focus on a dermatological survey, ENT exam, bone survey and a chest x-ray. The latter may reveal lesions suggestive of LCH or of other conditions also associated with central DI (Wegener’s granulomatosis, tuberculosis, sarcoidosis).
Extracranial lesions should be biopsied where possible. If no extracranial abnormalities are found, a CSF sample should be obtained for tumour markers and cytology. If the findings are non-contributory and the infundibulum measures more than 7 mm, a pituitary stalk biopsy should be strongly considered. If the infundibulum is less than 7 mm, regular clinical and radiological follow-up may be appropriate.2
Treatment should be conducted by a specialised oncology unit, using internationally agreed protocols.1
LCH has an unpredictable course, ranging from spontaneous remission to a rapid course with a fatal outcome. In most cases it will behave as a chronic disease with remissions and relapses. Mortality is about 20%.8 Adverse prognostic factors include older age, multi-organ dysfunction, the number of sites with active disease and response to therapy.
With more frequent and earlier use of chemotherapy in LCH, the incidence of DI appears to be getting lower, indicating a possible preventive effect of cytostatics.5Patients with DI will almost certainly develop multisystem disease, and once DI is established it is irreversible.3
The majority of patients with DI will eventually develop an anterior pituitary hormone defect.9 A rare but devastating complication of LCH, neurodegenerative CNS disease, appears to be more prevalent among patients with DI.5
In summary, LCH needs to be considered in the differential diagnosis of central DI secondary to infiltrative disorders, especially in younger patients. In these cases, imaging of the chest can yield important diagnostic information. DI in this setting is irreversible and a poor prognostic marker for LCH.
As central DI secondary to LCH can present as ‘idiopathic’ DI, both clinically and radiologically, close follow-up of central DI labelled as ‘idiopathic’ is warranted.
- Prosch H, Grois N, Prayer D, et al. Central Diabetes Insipidus as Presenting Symptom of Langerhans Cell Histiocytosis. Pediatric Blood and Cancer 2004;43:594-99.
- Kaltsas GA, Powles TB, Evanson J, et al. Hypothalamo-Pituitary Abnormalities in Adult Patients with Langerhans Cell Histiocytosis: Clinical, Endocrinological and Radiological Features and Response to Treatment. J Clin Endocrinol Metab 2000;85:1370-76.
- Nanduri VR, Bareille P, Pritchard J, Stanhope R. Growth and endocrine disorders in multisystem Langerhans’ cell histiocytosis. Clinical Endocrinology 2000;53:509-15.
- Grois N, Potschger U, Prosch H, et al. Risk factors for Diabetes Insipidus in Langerhans Cell Histiocytosis. Pediatric Blood and Cancer 2006;46:228-33.
- Grois, NG, Favara BE, Mostbeck GH, Prayer D. Central Nervous System Disease in Langerhans Cell Histiocytosis. Hematol Oncol Clin North Am 1998;12:287-305.
- Dunger DB, Broadbent V, Yeoman E, et al. The frequency and natural history of diabetes insipidus in children with Langerhans-cell histiocytosis. N Engl J Med 1989;321:1157-62.
- Mittheisz E, Seidl R, Prayer D, et al. Central Nervous System-Related Permanent Consequences in Patients With Langerhans Cell Histiocytosis. Pediatric Blood and Cancer 2007;48:50-56.
- Maghnie M, Cosi G, Genovese E, et al. Central Diabetes Insipidus in Children and Young Adults. N Engl J Med 2000;343:998-1007.