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Endocrine Care |
Departments of Endocrinology, Thoracic Surgery (J.P.L.R.), and Pathology (F.G.), Centre Hospitalier Universitaire Côte de Nacre, 14000 Caen, France; and Laboratoire d’Explorations Fonctionnelles Endocriniennes, Hôpital Trousseau (M.C.R.-D., F.G.), 75012 Paris, France
Address all correspondence and requests for reprints to: Prof. Jacques Mahoudeau, Service d’Endocrinologie, Niveau 18, CHU Côte de Nacre, 14000 Caen, France. E-mail: mahoudeau-j{at}chu-caen.fr
Abstract
The increases in the level of plasma lipotropin (LPH) and in the LPH/ACTH ratio are considered diagnostic tools in ectopic ACTH syndrome. However, plasma ACTH is also elevated in this syndrome. We report a case of a small carcinoid tumor with an increase in both ACTH and LPH in plasma before surgery. Eight months after the tumoral resection, plasma LPH alone was increased again, whereas plasma ACTH and plasma and urinary cortisol remained normal in this apparently cured patient. This repeated abnormality was the only available feature that allowed successful removal of the occult tumoral residue.
THE ECTOPIC SECRETION of ACTH may be difficult to distinguish from Cushing’s disease in ACTH-dependent Cushing’s syndrome. The cortisol and ACTH responses to dynamic tests may be confusing (1), and finally, ACTH measurement in both inferior petrosal sinuses may be necessary to demonstrate its ectopic secretion (2). The plasma level of lipotropin (LPH) is generally increased in ectopic Cushing’s syndrome, and the elevated LPH/ACTH ratio is considered a diagnostic argument in occult extrapituitary tumors (3).
We report below a case of ectopic secretion of ACTH and LPH by a lung carcinoid tumor with parallel increases in both hormones in plasma. During the follow-up, however, the increased level of plasma LPH alone, not ACTH, allowed diagnosis of the presence of malignant cells not detected by the imaging techniques, leading to successful reoperation.
Case Report
A 36-yr-old woman was admitted to hospital with symptoms and
signs of Cushing’s syndrome: 6-kg weight gain, round face,
hypertension, amyotrophy, severe psychiatric disturbances, and
hypokalemia (2.9 mmol/L). The magnetic resonance imaging of the
pituitary was normal. The main biological data, shown in Table 1
, allowed the diagnosis of ectopic ACTH
secretion from a tumor of unknown origin.
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Treatment with ketoconazole (1000 mg/day for 4 months) resulted in a biological decrease in cortisol secretion (0800 h plasma cortisol, 1,630 to 386 nmol/L; urinary free cortisol, 21,800 to 150 nmol/day) without clinical improvement, and, as expected, both plasma ACTH and LPH remained elevated (36 pmol/L and 1,444 ng/L, respectively). Biological features of hepatotoxicity occurred, and the dose of ketoconazole was reduced to 600 mg/day. Plasma cortisol increased 1 month later to 801 nmol/L at 0800 h and 745 at 2000 h.
Searching again for a tumor by a repeat CT scan, we detected a 10-mm
nodule within the middle lobe of the right lung (Fig. 1), which could not be seen on the
previous scan 4 months earlier and was believed to be a metastasis of
unknown origin. A large biopsy (45 g tissue) was performed by a small
thoracotomy, and this allowed the diagnosis of carcinoid tumor with
intense immunostaining for chromogranin and ACTH (Fig. 2). Surprisingly, this limited resection,
performed for diagnostic purpose, resulted in a dramatic clinical
improvement in Cushing’s syndrome, with complete normalization of
hormonal abnormalities within 1 month (Table 2), while the patient was still receiving
ketoconazole (600 mg/day). This drug was withdrawn, and the patient was
given hydrocortisone (20 mg/day for 1 month).
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Plasma ACTH and LPH were normal 9 days after this operation and
remained normal in successive samples. The patient remains healthy, and
the values of cortisol, ACTH, and LPH are normal 18 months after this
operation (Table 2
).
Hormone assays
Cortisol (in plasma and urine) was measured by a commercial RIA kit purchased from INCSTAR Corp. (Stillwater, MN). Urinary 17-hydroxycorticosteroid excretion was measured by a standard colorimetric method. ACTH was measured using an immunoradiometric assay (ELSA-ACTH assay, CIS-Bio International). This assay is based on the use of two solid phase monoclonal antibodies while a third one is labeled with 125I. Standard is human ACTH-(1–39). Intra- and interassay variations are less than 5%. The detection threshold is 5 pg/mL (0.4 pmol/L).
LPH was measured by RIA as previously described (3). This
assay uses an antibody directed toward the common
NH2-terminal end of 
- and ßLPH. Synthetic
[Tyr1–38]LPH (Neosystem) is used as
standard and tracer. Intra- and interassay variations are,
respectively, 10% and 12%. The sensitivity threshold is 20 pg/mL.
CLIP was measured after separation from ACTH by high performance liquid
chromatography; eluted fractions were submitted to an ACTH RIA using an
antibody directed toward the common C-terminal fragment of ACTH and
CLIP.
Discussion
A strong increase in plasma LPH levels is usually found in patients with ectopic ACTH syndrome, and the measurement of plasma LPH has been found to be more sensitive than that of ACTH for the diagnosis of ACTH-dependent Cushing’s syndrome in a large series of patients (3).
In our case, plasma levels of both ACTH and LPH were very high before therapy, and therefore, the diagnosis of ectopic Cushing’s syndrome was very likely despite our failure to demonstrate the nature and site of the ACTH/LPH-secreting tumor. Both ACTH and LPH plasma levels dropped into the normal range after the excision of a small carcinoid tumor. During the follow-up, however, only plasma LPH, not plasma ACTH, rose above the normal limits 6 months later. In this apparently cured patient, with repeatedly normal cortisol and ACTH values, we confirmed the increase in plasma LPH alone in three successive blood samples before deciding on reoperation. Interestingly, this increase in plasma LPH has been the only feature supporting the decision for aggressive therapy in a clinically healthy person. In our case, the LPH assay has been more sensitive to detect the recurrence (or persistence) of malignant cells than the imaging techniques, including position emission tomography scan. Finally, the excision of additional tumoral tissue, namely two invaded lymph nodes, resulted in the normalization of plasma LPH, with an 18-month follow-up.
The explanation of this LPH/ACTH discrepancy in our patient is
unclear. Both ACTH and LPH are produced via the proteolytic conversion
of POMC (4). High plasma levels of POMC have been found in
both Cushing’s disease with pituitary macroadenomas and ectopic
Cushing’s syndrome and are considered a marker of tumor aggressivity
rather than a diagnostic tool for ectopic ACTH syndrome
(5). In the normal human pituitary, in corticotroph
adenomas responsible for Cushing’s disease, and in Nelson’s syndrome,
the processing of the POMC generates parallel amounts of ACTH and LPH
(6, 7). Conversely, the processing of POMC may be abnormal
in nonpituitary tumors producing this precursor; the POMC may be poorly
processed and may be intact (7, 8, 9) or further processed
via cleavage of ACTH into two small end products, CLIP and 
MSH, and
cleavage of ßLPH into small end products such as ßMSH
(10).
The processing of ACTH into its smaller end products has been correlated to the presence of the prohormone convertase PC2 in extrapituitary tumors producing ectopic Cushing’s syndrome (10), and this might explain a lowered immunologically detectable amount of ACTH in tumors with sustained processing of POMC into other end products such as LPH. The fact that we did not find an overproduction of CLIP in our patient does not support the hypothesis of further processing of ACTH in this carcinoid tumor. It has been suggested that the longer half-life of LPH compared with that of ACTH (11, 12) might explain in part the higher plasma level of LPH when it is secreted in large amounts (3). Whatever the mechanism involved in our patient, the increase that we observed only in plasma LPH has been of crucial practical interest, allowing an efficient therapeutic decision. To our knowledge, this is the first reported case where the postoperative residual tumor could be detected only by increased LPH plasma level, with a long-lasting normal ACTH value and failure of imaging procedures. However, in the large series reported by Kuhn et al. (3), single assays of plasma LPH and ACTH before therapy detected 3 patients with normal ACTH within 41 patients with histologically confirmed ectopic ACTH syndrome and elevated LPH plasma levels. These researchers concluded that plasma LPH was a better index than ACTH in the management of Cushing’s syndrome, including Cushing’s disease. Our case, with a sustained discrepancy between normal ACTH and elevated LPH suggests the same conclusion and emphasizes the clinical usefulness of plasma LPH measurement in the follow-up of ectopic Cushing’s syndrome.
Acknowledgments
We are indebted to Dr. Catherine Derboule for referring this patient, and to Dr. J. M. Kuhn for helpful discussion.
Received December 13, 2000.
Revised March 2, 2001.
Accepted March 14, 2001.
References
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