Paraneoplastic (non-metastatic) adrenal insufficiency ...

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Unusual presentation of more common disease/injury: Paraneoplastic (non-metastatic) adrenal insufficiency preceded the onset of primary lung cancer by …

BMJ Case Rep. 2009; 2009: bcr08.2008.0690.

PMCID: PMC3029429

Published online May 25, 2009. doi: 10.1136/bcr.08.2008.0690 Unusual presentation of more common disease/injury

Paraneoplastic (non-metastatic) adrenal insufficiency preceded the onset of primary lung cancer by 12 weeks Ghanshyam Palamaner Subash Shantha,1 Anita A Kumar,1 Vijay Jeyachandran,1 Deepan Rajamanickam,1 Emmanuel Bhaskar,1 Vinod K Paniker,2 and Georgi Abraham1 1 Sri Ramachandra University, General Medicine, Plot no. 70, Door no. 12, Kattabomman Street, Alw arthirunagar, Chennai, Tamilnadu, 600087, India 2 Sri Ramachandra University, Pathology, Plot no. 70, Door no.12, Kattabomman Street, Alw arthirunagar, Chennai, Tamilnadu, 600087, India Ghanshyam Palamaner Subash Shantha, Email: [email protected] Copyright 2009 BMJ Publishing Group Ltd

Abstract Clinically evident adrenal insufficiency associated with lung cancer is a rare entity. Among reported cases, adrenal insufficiency has occurred with or succeeded the primary lung cancer. Adrenal insufficiency has also been secondary to metastasis to the adrenal gland. The present report concerns a 61-year-old man, a chronic smoker, who presented to us with symptomatic adrenal insufficiency. He had no evidence of lung cancer during this visit. The primary lung cancer was only identified 12 weeks later. Additionally, his adrenals showed no evidence of metastasis. Hence his adrenal insufficiency had been a paraneoplastic manifestation of the lung cancer, and it had also preceded the primary by 12 weeks.

BACKGROUND Clinically evident adrenal insufficiency associated with lung cancer is a rare entity. In all the published series, adrenal insufficiency has been secondary to adrenal metastasis from a primary lung cancer.1 ,2 Adrenal insufficiency has always presented along with or succeeded the diagnosis of primary lung malignancy.1 ,2 Even in reports where adrenal insufficiency was the first presentation, the lung primary cancer was already present in the patient and this was diagnosed immediately on imaging.1 –3 Clinically evident adrenal insufficiency in a patient with malignancy also usually indicates terminal stages of the disease, as nearly 90% of the functional adrenal cortical tissue must be destroyed before abnormal gland function can be detected.4 Here, we present a case where symptomatic adrenal insufficiency preceded the primary lung malignancy by a period of 12 weeks. The adrenal glands also showed no evidence of metastasis.

CASE PRESENTATION A 61-year-old man presented to the outpatient department of a tertiary care centre in South India in November 2007 with complaints of postural giddiness for the last 2 weeks. He had no comorbid diseases such as hypertension, diabetes mellitus or ischaemic heart disease. There was no past history of tuberculosis. He was married and had two sons. He had smoked 25 to 30 cigarettes a day for the last 30 years. On examination he was hypotensive with a blood pressure of 90/60 mm Hg, with an orthostatic fall to 74/50 mm Hg. There were no areas of hyperpigmentation on general physical examination. A systems exam was unremarkable. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3029429/?report=printable

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INVESTIGATIONS Chest x ray was essentially normal with no evidence of mass lesion. Abdominal ultrasound, performed twice, was reported to be normal. Admission laboratory tests showed hyperkalaemia, hyponatraemia and a low–normal random glucose value (table 1). On work-up for adrenal insufficiency (table 2), his random plasma cortisol was 3.1 μg/dl and a plasma adrenocorticotropic hormone (ACTH) level of 129 pg/ml (normal range 9 to 52 pg/ml). An ACTH stimulation test demonstrated a plasma cortisol level of 2.9 μg/dl at baseline and 3.9 μg/dl 1 h after 0.25 mg cosyntropin stimulation. He was euthyroid and his serum calcium, phosphorus and alkaline phosphatase were within normal limits. A CT scan of the abdomen showed normal adrenals and a thoracic CT scan showed no evidence of mass lesion or pleural effusion.

DIFFERENTIAL DIAGNOSIS Autoimmune adrenal disease. Tuberculosis of the adrenal gland. HIV infection of the adrenal gland.

TREATMENT The patient was treated with oral hydrocortisone 20 mg in the morning and 10 mg at night with fludrocortisone 100 μg daily for his adrenal insufficiency.

OUTCOME AND FOLLOW-UP Within 3 days the patient was symptomatically better and was ambulant. His blood pressure improved to 110/70 mm Hg without an orthostatic drop and hence the patient was discharged with the above medications and was kept on regular weekly follow-up. At 12 weeks later he presented to the emergency department in a sick state with complaints of fever, cough and sputum of 5 days duration. His chest x ray showed a left-sided pleural effusion and the pleural fluid analysis was positive for malignant cells. An abdominal ultrasound revealed multiple liver metastases. A repeat thoracic CT scan (fig 1) showed a central type bronchogenic carcinoma arising in the left perihilar region with extensive mediastinal invasion. He died on the second day after admission. A postmortem lung biopsy showed sheets of small cells that were round to oval to spindle shaped having granular chromatin in some of the cells, and the presence of many mitotic figures suggestive of small cell bronchogenic carcinoma (fig 2). Liver biopsy revealed a focus of parenchymal infiltration by small pleomorphic and hyperchromatic cells suggestive of malignant infiltration from a small cell carcinoma (fig 3). The adrenal glands were normal in gross appearance and histology of the adrenal gland was normal with no evidence of metastasis or inflammation (fig 4).

DISCUSSION This patient had a risk factor, namely heavy smoking. But during his first admission he had no evidence of malignancy. There were no respiratory symptoms. Chest x ray and CT scan of the thorax did not show a mass lesion. Ultrasound of the abdomen (performed twice) was normal. His sputum was negative for malignant cells. He had symptomatic and laboratory evidence suggestive of primary adrenal insufficiency (table 2). CT scan of the abdomen at this time showed normal sized adrenals with no evidence of metastasis. Hence he was treated with hydrocortisone 20 mg in the morning and 10 mg in the night along with fludrocortisone 100 μg daily, as recommended for adrenal insufficiency.5 He showed significant improvement with steroid replacement. Serology for HIV1 and 2 were non-reactive. The other possible causes for adrenal insufficiency were tuberculosis of the adrenal gland or an autoimmune adrenal disease. With a normal erythrocyte sedimentation rate, normal chest x ray, normal adrenal imaging and the three samples of sputum http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3029429/?report=printable

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analysis being negative for acid fast bacillus, the possibility of tuberculosis seemed unlikely. With regard to the question of whether his adrenal insufficiency could be secondary to an autoimmune process, antibodies against 21 hydroxylase commonly seen in autoimmune adrenalitis6 were not demonstrated in his serum (table 2). Autoimmune disorders and polyglandular syndromes are common in women and generally present at a young age (30–40 years).6,7 Additionally, autoimmunity affects multiple endocrine glands.6,7 The patient, being a 61-year-old man with no evidence of diabetes mellitus, thyroid or parathyroid dysfunction (table 2), made the possibility of autoimmunity and polyglandular syndrome seem unlikely. The cause for his adrenal insufficiency still remained unclear. He was readmitted within 12 weeks with a mass lesion in his left lung with malignant pleural effusion and liver metastasis, and soon succumbed to the disease. In all published data on the association between clinically evident adrenal insufficiency and lung cancer, the adrenal insufficiency has occurred simultaneously with the primary condition.1 –3 Even in reports where adrenal insufficiency was the presenting feature, the lung primary tumour was already present in the patient and this was diagnosed immediately upon imaging.8 There is a case report where adrenal insufficiency was the first sign of metastatic recurrence of lung cancer.9 But to the best of our knowledge there has been no previous report where symptomatic adrenal insufficiency has preceded the onset of the lung primary. Our case report is therefore probably the first of its kind. Anther unique feature of our case report is that clinically evident adrenal insufficiency has always been secondary to adrenal metastasis from a lung primary.1 –3,8,9 In our patient, however, clinically significant adrenal insufficiency occurred in the absence of adrenal metastasis, as proved by imaging and histology of the adrenal glands. Hence the patient had paraneoplastic (non-metastatic) adrenal insufficiency secondary to a lung cancer. The second feature is that all published data has generally associated adrenal insufficiency with non-small cell lung cancer,8,1 0 however our patient had adrenal insufficiency in association with small cell lung cancer. Finally the occurrence of clinically significant adrenal insufficiency in association with lung cancer signifies terminal stages of the disease. The reason being, with progressive destruction of the adrenal cortical cells, cortisol secretion is lowered, consequently (as a negative feedback mechanism) ACTH secretion from the pituitary is enhanced. Therefore, cortisol secretion is generally preserved unless over 90% of the functional cortical tissue is destroyed.4 But in our patient the adrenals were normal even after the patient died; histologically there was no evidence of destruction (fig 4). However, he had had symptomatic adrenal insufficiency as the earliest presentation in this disease process. The mechanism by which the small cell lung primary tumour caused adrenal insufficiency 12 weeks prior to its onset remains unclear. Since this presentation resembles a paraneoplastic syndrome, there could have been an unidentified tumour product that could have been the culprit. The possibility of this culprit substance being an antibody against adrenal antigens seems less likely as the adrenal gland histology showed no evidence of autoimmunity or chronic inflammation. It is therefore possible that this unidentified tumour product could have been an inhibitor of steroid hormone synthesis. LEARNING POINTS

Adrenal insufficiency can be a paraneoplastic syndrome associated with lung cancer. In unexplained adrenal insufficiency in a chronic smoker, bronchogenic carcinoma should be one of the differentials. Clinically evident adrenal insufficiency can rarely precede the primary lung cancer.

Footnotes Competing interests: None. Patient consent: Patient/guardian consent was obtained for publication. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3029429/?report=printable

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REFERENCES 1. Nishizawa Y , Kasahara T, Akira S, et al. A case of pulmonary adenocarcinoma manifesting Addison disease due to metastasis to bilateral adrenal glands [in Japanese]. Haigan 2000; 40: 623. 2. Kimura K, Sotoyama K, Ryo H, et al. A case of pulmonary adenocarcinoma developing Addison disease due to metastasis to bilateral adrenal glands [in Japanese]. Haigan 2000; 42: 135. 3. Beniko M, Midorikawa S, Masao Y , et al. A case of lung cancer with concurrent adrenal insufficiency due to metastasis to bilateral adrenal glands [in Japanese]. Naibunpitsu-Tonyobyoka 2005; 20: 94. 4. Barker NW. The pathologic anatomy in twenty-eight cases of Addison’s disease. Arch Pathol 1929; 8: 432–50. 5. Gordon HW, Robert GD. Disorders of the adrenal cortex. : Kasper DL, Braunwald E, Fauci AS, et al., editors. , eds. Harrison’s principles of internal medicine, Vol 2, 16th edn New Y ork, USA: Mc Graw Hill Inc, 1991: 2143. 6. Betterle C, Dal Pra C, Mantero F, et al. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev 2002; 23: 327–64. [PubMed: 12050123] 7. Barbara AM, Parag P. Autoimmune polyglandular syndrome, type II. Am Fam Phys 2007; 75: 667. 8. Sirachainan E, Kalemkerian GP. Unusual presentations of lung cancer: case 2. Adrenal insufficiency as the initial manifestation of non-small-cell lung cancer. J Clin Oncol 2002; 20: 4598–600. [PubMed: 12454119] 9. Payne DK, Levine SN, Franco DP, et al. Adrenal insufficiency due to metastatic lung carcinoma and shown by abdominal CT scan. South Med J 1984; 77: 1592–3. [PubMed: 6505770] 10. Leslie R, James HM, John JE, et al. Adrenal insufficiency secondary to carcinoma metastatic to the adrenal gland. Cancer 1983; 52: 1312–16. [PubMed: 6309357]

Figures and Tables Table 1

Admission laboratory values Test

Result

Blood urea nitrogen

1 1 mg/dl

Serum creatinine

0.9 mg/dl

Serum potassium: First day

4.3 meq/litre

Second day

5.7 m eq/litre

Serum sodium

129 m m ol/litre

Serum chloride

1 03 meq/litre

Serum bicarbonate

25 meq/litre

Total protein

6.2 g/dl

Serum albumin

3.9 g/dl

Random plasma glucose 7 2 mg/dl

Values in bold type are suggestive of adrenal insufficiency in this setting. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3029429/?report=printable

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Table 2

Work-up for adrenal insufficiency Test

Result

Plasma cortisol (random)

3.1 μg/dl

Serum aldosterone

2.2 ng/dl

Plasma adrenocorticotropic hormone (ACTH) 1 29 pg/ml ACTH stimulation test: Baseline cortisol

2.9 μg/dl

1 h cortisol

3.9 μg/dl

Serum calcium

9.2 mg/dl

Serum phosphorus

3.9 mg/dl

Alkaline phosphatase

1 21 U/litre

Ery throcy te sedimentation rate (ESR)

1 1 mm/h

Thy roid-stimulating hormone (TSH)

3.1 2 µIU/ml

Free T4 test

1 .1 ng/dl

Anti-21 hy drox y lase antibodies

negativ e

Sputum analy sis

Negativ e for acid fast bacillus and malignant cells

Serology for HIV 1 and 2

Non-reactiv e

Mantoux test

Negativ e

Figure 1

CT scan of the thorax (contrast study ) showing a large irregular mass lesion in the left perihilar region with mediastinal inv asion, collapse consolidation of left lung with bilateral pleural effusion.

Figure 2

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Lung biopsy showing sheets of small cells that were round to ov al to spindle shaped hav ing granular chromatin suggestiv e of small cell bronchogenic carcinoma. H&E stain, 200× magnification.

Figure 3

To the left of the image: infiltration by small pleomorphic and hy perchromatic cells suggestiv e of malignant infiltration from a small cell carcinoma. To the right is normal liv er tissue. H&E stain, 1 00× magnification.

Figure 4


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Adrenal gland biopsy showing normal looking cortex and medullary lay ers with no ev idence of metastasis or inflammation. H&E stain, 1 00× magnification. Articles from BMJ Case Reports are provided here courtesy of BMJ Group


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