Ectopic Source Of ACTH Research Articles

Do Inferior Petrosal Sinus Drainage Variations Affect the Sampling Lateralization Results?

Objective: To evaluate the relationship between adenoma lateralization and the variations in petrosal sinus drainage. Materials and Methods: A total of 24 patients diagnosed as ACTH dependent Cushing Syndrome (CS) in the Department of Endocrinology and Metabolism Disorders between May 2006 and May 2012 were evaluated. The patient files for data, including laboratory results and imaging records, were analyzed retrospectively. MRI was performed using a 1.5-T scanner. The femoral vein was cannulated using the Seldinger technique and bilateral venous sheaths were inserted for bileteral inferior petrosal sinus sampling (BIPSS). Results: Microadenomas were detected with MRI in 12 patients. Right lateralization has been determined in 12 patients (54.5%), left lateralization in 5 patients (22.7%) and central gradient in 2 patients (22.8%). No peripheral/central gradient was obtained by BIPSS in 3 patients compatible with an ectopic source of ACTH. Pituitary surgery was performed in 19 patients. Conclusion: BIPSS may avoid unnecessary pituitary surgery. Asymmetric drainage may affect the results of lateralization. This study suggest that drainage variations may have subgroups.

A challenging case of an ectopic cushing syndrome.

Bronchopulmonary carcinoids are rare pulmonary neoplasms although they account for most cases of ectopic ACTH syndromes. When feasible, the mainstay treatment is surgical resection of the tumor. We report the case of a 52-year-old woman with signs and symptoms suggestive of hypercortisolism for 12 months, admitted to our department because of community acquired pneumonia. Blood hormone analysis showed increased levels of ACTH and urinary free cortisol and nonsuppressibility to high- and low-dose dexamethasone tests. Pituitary MRI showed no lesion and no central-to-peripheral ACTH gradient was present in bilateral inferior petrosal sinus sampling. CRH stimulation test suggested an ectopic ACTH source. Thoracic CT scan revealed a nodular region measuring 12 mm located in the inferior lingular lobule of the left superior lung with negative uptake by 18-FDG-PET scan and negative SRS. The patient was successfully treated with an atypical lung resection and histology revealed an atypical bronchial carcinoid tumor with positive ACTH immunoreactivity. This was an interesting case because the patient was admitted due to pneumonia that may have been associated with her untreated and chronic hypercortisolism and a challenging case of ectopic ACTH syndrome due to conflicting results on the diagnostic exams.

Is prolactin measurement of value during inferior petrosal sinus sampling in patients with adrenocorticotropic hormone-dependent Cushing's Syndrome?

Inferior petrosal sinus sampling (IPSS) is considered the gold standard test to distinguish between Cushing's disease (CD) and ectopic ACTH syndrome (EAS). Anomalous venous drainage, abnormal venous anatomy, and lack of expertise can lead to false-negative IPSS results and thereby misclassification of patients with ACTH-dependent Cushing's syndrome. Prolactin measurement during IPSS can improve diagnostic accuracy and decrease false negative results. A baseline prolactin inferior petrosal sinus to peripheral (IPS/P) ratio (ipsilateral to the dominant post-CRH ACTH IPS/P ratio) of 1.8 or more suggests successful catheterization during IPSS. Prolactin-normalized ACTH IPS/P ratios can then be used to differentiate between a pituitary and ectopic source of ACTH. Values ≤ 0.7 are suggestive of EAS and those ≥ 1.3 are indicative of CD, but the implication of values between 0.7 and 1.3 remains unclear and needs further investigation. Larger prospective studies are also needed for further evaluation of the role of contralateral prolactin IPS/P ratios, post- CRH prolactin values, and prolactin-adjusted ACTH inter-sinus ratios for tumor localization in CD.

The search for ectopic ACTH production in a 9-year-old boy

Ectopic ACTH syndrome (EAS) is rare in children and is challenging to differentiate from Cushing's disease. A 9-year-old boy presented with a history of worsening fatigue, muscle weakness, weight gain and acne, and he appeared cushingoid with central obesity and hyperpigmentation of his palmar creases. Investigations demonstrated an elevated ACTH and an elevated morning cortisol that did not suppress with low or high dose dexamethasone suppression tests. Brain imaging inconsistently showed a small pituitary lesion. Chest and abdomen computed tomography (CT) showed adrenal hyperplasia and a liver hemangioma. [18F]fluorodeoxyglucose positron emission tomography CT was normal. Ultrasound and abdominal magnetic resonance imaging (MRI) also showed a liver hemangioma. Bilateral inferior petrosal sinus sampling, however, was consistent with ectopic ACTH production. An octreotide scan revealed a small focus of increased activity in the liver, which was the likely source of ectopic ACTH production. The patient was managed with metyrapone followed by a wedge liver resection. Pathology showed a well-differentiated neuroendocrine tumor (NET) that stained positive for ACTH. Post-operatively, the signs and symptoms of EAS are resolving and his hypothalamic-pituitary-adrenal axis is recovering. This case describes the first pediatric patient with EAS caused by a liver NET. It illustrates the challenges in localizing the source of ectopic ACTH and treating this rare condition.

Cushing Syndrome due to Ectopic Adrenocorticotropin Secretion by Oncocytic Thyroid Nodule

A 60-yr-old woman presented with osteoporosis and atraumatic fractures of the spine and ribs in our neurological hospital in Linz, Upper Austria. She had a clinical history of bipolar affective disorder and cognitive decline, but the actual medical problem was lumbar pain. Treatment for osteoporosis already included bisphosphonates, vitamin D, and calcium. Endocrine evaluation for secondary osteoporosis revealed low TSH (0.17 U/ml) under prophylactic levothyroxine treatment (75 g/d) for multinodular goiter and ACTH-dependent hypercortisolism. Clinical evaluation presented obesity (weight, 75 kg, for 150 cm height), arterial hypertension, and diabetes mellitus. ACTH was elevated at 106 pg/ml, whereas morning serum cortisol (22 g/dl) was still in the normal range. Cortisol measured in 24-h urine was highly elevated at 502 g/d (normal range, 40–158 g/d). Dexamethasone suppression test with 1, 4, and 8 mg failed to suppress either plasma ACTH or cortisol in serum and/or 24-h urine (ACTH, 45 pg/ml; and cortisol, 20 g/dl and 400 g/d in all tests). Brain magnetic resonance imaging showed mild cortical atrophy and did not present any alterations of the pituitary. Because petrosal sinus catheterization cannot be practiced in the federal state of Upper Austria, it was postponed. Whole body fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) was done in May 2009 for tumor screening to detect a possible ectopic source of ACTH. A single nodule of the right thyroid lobe proved to be FDG avid (Fig. 1). Additionally, CT detected a lesion of the right kidney with a diameter of 2 cm that did not accumulate FDG. Because a former thyroid evaluation in March 2009— practiced in a regional institute in the “Salzkammergut” in Upper Austria—had evaluated this FDG-avid lesion as a cold nodule by Technetium-scintiscan and fine-needle-aspiration had shown oncocytic transformation of thyrocytes, we recommended thyroid surgery as the next step. Calcitonin screening had been negative in the patient. Near-total resection of the thyroid took place in June 2009, histology revealed regressive goiter, and a malignant lesion was not detected. The suspicious nodule was

An Unusual Case of Ectopic ACTH Syndrome

Ectopic ACTH-syndrome is a rare cause of Cushing's disease. Despite extensive diagnostic procedures the source of ACTH secretion often remains occult. This case describes a 45-year old woman with an ectopic Cushing's syndrome. Extensive imaging procedures including CT scan of chest and abdomen, octreotide scan and MRI of the chest and pituitary did not reveal the source of ACTH secretion. In consideration of an occult source of ACTH secretion we started a therapeutic trial with cabergoline (0.5 mg/d), a dopamine receptor agonist, which has been shown to be effective in ectopic Cushing's syndrome. 2 months after cabergoline treatment had been initiated, ACTH and cortisol levels normalized in association with significant improvement of the clinical symptoms. During follow-up a [(68)Ga-DOTA-dPhe(1), Tyr(3)]-octreotate ([(68)Ga-DOTA]-TATE) PET-CT was performed revealing a somatostatin receptor positive lesion in the right sphenoidal sinus suggesting the source of ACTH secretion. The patient was cured by transnasal resection of the polypoid lesion, which was immunohistochemically characterized as an ACTH-positive neuroendocrine tumor. This case report demonstrates the management of ectopic ACTH-syndrome by molecularly -targeted therapy with dopamine receptor -agonists as well as improved detection of the ectopic ACTH source by novel imaging modalities, such as [(68)Ga-DOTA]-TATE PET specifically targeting somatostatin receptor subtype-2 with high affinity.

Imaging in Cushing's syndrome

Once the diagnosis of Cushing's syndrome (CS) has been established, the main step is to differentiate between ACTH dependent and independent disease. In adults, 80% of CS is due to ACTH-dependent causes and 20% due to adrenal causes. ACTH-secreting neoplasms cause ACTH-dependent CS. These are usually anterior pituitary microadenomas, which result in the classic Cushing's disease. Non-pituitary ectopic sources of ACTH, such as a small-cell lung carcinoma or carcinoid tumours, are the source of the remainder of ACTH-dependent disease. In the majority of patients presenting with clinical and biochemical evidence of CS, modern non-invasive imaging can accurately and efficiently provide the cause and the nature of the underlying pathology. Imaging is essential for determining the source of ACTH in ectopic ACTH production, locating the pituitary tumours and distinguishing adrenal adenomas, carcinomas and hyperplasias. In our chapter we review the adrenal appearances in ACTH-dependent and ACTH-independent CS. We also include a discussion on the use of MRI and CT for the detection and management of pituitary ACTH secreting adenomas. CT of the chest, abdomen and pelvis with intravenous injection of contrast medium is the most sensitive imaging modality for the identification of the ectopic ACTH source and detecting adrenal pathology. MRI is used for characterising adrenal adenomas, problem solving in difficult cases and for detecting ACTH-secreting pituitary adenomas.

The usefulness of combined biochemical tests in the diagnosis of Cushing’s disease with negative pituitary magnetic resonance imaging

The etiological diagnosis of ACTH-dependent Cushing's syndrome is often a problem. In fact, no endocrine or radiological examination can conclusively distinguish the ectopic from the pituitary source of disease. The aim of our study was to evaluate the role of stimulation and suppression endocrine tests in the diagnostic and therapeutic approach of patients with Cushing's disease (CD) and negative pituitary magnetic resonance imaging (MRI), considering their post-surgical outcome in comparison with patients with CD and positive MRI. We retrospectively analyzed 31 patients (25 women and 6 men, median age 40 +/- 15 years) with a confirmed diagnosis of CD who underwent transsphenoidal pituitary surgery by the same neurosurgeon between 2001 and 2005. Preoperative endocrine assessment included corticotropin-releasing hormone (CRH), desmopressin (dDAVP), and overnight 8 mg dexamethasone suppression tests (8-DST) in all patients. Fifteen patients had a normal pituitary MRI and sixteen had a clearly evident pituitary microadenoma. Bilateral inferior petrosal sinus sampling (BIPSS) was performed in patients with discordant biochemical results or with signs and symptoms highly suggestive of an ectopic source of ACTH. Post-surgical median follow-up was 38.4 +/- 22.0 months. Among patients with negative MRI, 60% had concordant positive endocrine tests and underwent neurosurgery without other examinations. BIPSS was performed in three other patients prompted by discordant endocrine tests (negative dDAVP) and in two patients with clinical suspicion of ectopic disease. Among patients with positive MRI, 87% underwent neurosurgery without BIPSS that was performed in two patients because of negative concomitant response to dDAVP and CRH tests. A pituitary adenoma, confirmed by pathological examination, was found in 40 and 81% of patients with negative and positive MRI respectively (P<0.05), corticotroph hyperplasia resulted more frequent in the group with negative MRI. Remission rate was not different between patients with negative and positive MRI (73 and 75% respectively; P=0.61) and between patients with negative MRI who did not undergo BIPSS and patients with positive MRI (P=0.56). The recurrence rate was also similar between groups (P=0.64), but higher, although not statistically different (P=0.07) in patients with corticotroph hyperplasia at histology. An accurate evaluation of presurgical endocrine tests results enabled us to reduce the number of BIPSS in patients with a negative MRI without any fallout on their post-surgical outcome. In the hands of an expert pituitary surgeon, the outcome after surgeryand the subsequent recurrence rate are much the same in patients with negative or positive MRI.

Indium-111 Pentetreotide Imaging of Carcinoid Tumor of the Thymus

Carcinoid tumors are relatively rare and can occur in the thorax, abdomen, or pelvis. Indium-111 pentetreotide scanning is useful for the identification of these tumors. In this report, we present imaging findings and discussion pertaining to a 43-year-old man who presented with Cushing's syndrome resulting from a thymic carcinoid tumor. The imaging is of interest because there is not only marked uptake of In-111 pentetreotide in the thymic carcinoid tumor, but also within the adrenal glands attributable to elevated tumor-derived ACTH. Planar and single-photon emission computed tomography (SPECT) images of the chest and abdomen were obtained 15 minutes after the injection of 6.6 mCi of In-111 pentetreotide. Further planar and SPECT images were obtained approximately 4 and 24 hours after injection of the radiopharmaceutical. Correlation of In-111 pentetreotide SPECT was made with laboratory results and CT evaluation of the chest and abdomen. Initial clinical workup for Cushing's syndrome included a contrast-enhanced brain magnetic resonance image that showed a small pituitary lesion thought to represent a microadenoma. Normal inferior petrosal venous sinus sampling for ACTH suggested there was an ectopic ACTH source. Subsequent CT of the chest identified a 3 x 3-cm enhancing mediastinal mass. Avid uptake within the mass on In-111 pentetreotide images suggested that the underlying cause of Cushing's syndrome was ACTH production from a thymic carcinoid. Increased uptake of In-111 pentetreotide was also noted within hyperplastic adrenal glands. Surgical resection and histologic evaluation established the diagnosis of a moderately differentiated thymic carcinoid tumor. This case illustrates the complementary ability of In-111 pentetreotide planar and SPECT imaging and CT to diagnose an ACTH-producing thymic carcinoid tumor leading to adrenal hyperplasia and Cushing's syndrome.

Use of radioguided surgery with [111In]-pentetreotide in the management of an ACTH-secreting bronchial carcinoid causing ectopic Cushing’s syndrome

Intraoperative [111In]-pentetreotide scintigraphy with a hand-held gamma detector probe has recently been proposed to increase the intraoperative detection rate of small neuroendocrine tumors and their metastases. We report a case of a 28-yr-old woman with ectopic Cushing's syndrome due to an ACTH-secreting bronchial carcinoid, in whom the use of radioguided surgery improved disease management. At presentation, radiolabeled pentetreotide scintigraphy was the only procedure able to detect the ectopic source of ACTH. After radiologic confirmation, the patient underwent removal of a bronchial carcinoid, with disease persistence. After surgery, pentetreotide scintigraphy showed pathologic uptake in the mediastinum not previously detected at surgery and only subsequently confirmed by radiologic studies. Despite a second thoracic exploration, hormonal, scintigraphic, and radiological evidence of residual disease persisted. Radioguided surgery was then performed using a hand-held gamma probe 48 h after iv administration of a tracer dose of radiolabeled [111In-DTPA-D-Phe1]-pentetreotide, which permitted detection and removal of multiple residual mediastinal lymph node metastases. Clinical and radiologic cure, with no evidence of tracer uptake at pentetreotide scintigraphy, was subsequently observed. The use of an intraoperative gamma counter appears a promising procedure in the management of metastatic ACTH-secreting bronchial carcinoids.

Management of occult adrenocorticotropin-secreting bronchial carcinoids: limits of endocrine testing and imaging techniques.

The differential diagnosis and the identification of the source of ACTH in occult ectopic Cushing's syndrome due to a bronchial carcinoid still represents a challenge for the endocrinologist. We report our experience in six patients with occult bronchial carcinoid in whom extensive hormonal, imaging, and scintigraphic evaluation was performed. All patients presented with hypercortisolism associated with high plasma ACTH values. The CRH test and high dose dexamethasone suppression test suggested an ectopic source of ACTH in three of six patients. During bilateral inferior petrosal sinus sampling, none of the patients showed a central to peripheral ACTH gradient. At the time of diagnosis, none of the patients had radiological evidence of the ectopic source of ACTH, whereas pentetreotide scintigraphy identified the lesion in two of four patients. Finally, a chest computed tomography scan revealed the presence of a bronchial lesion in all patients, and pentetreotide scintigraphy identified four of six lesions. In all patients a bronchial carcinoid was found and removed. In one patient with scintigraphic evidence of residual disease after two operations, radioguided surgery, using a hand-held gamma probe after iv administration of radiolabeled pentetreotide, was performed; this allowed detection and removal of residual multiple mediastinal lymph node metastases. In conclusion, our data show that there is not a single endocrine test or imaging procedure accurate enough to diagnose and localize occult ectopic ACTH-secreting bronchial carcinoids. Radioguided surgery appears to be promising in the presence of multiple tumor foci and previous incomplete removal of the tumor.

Association of hypertension and hypokalemia with Cushing's syndrome caused by ectopic ACTH secretion: a series of 58 cases.

Cushing's syndrome is associated with hypertension in approximately 80% of cases. Hypertension contributes to the marked increased mortality risk of past or current Cushing's syndrome, largely because of increased cardiovascular risk. Observation of the pathophysiological effect of chronically elevated ACTH and cortisol values in patients with ectopic ACTH secretion complements the available data from acute studies of the effects of ACTH and glucocorticoid infusions in normal volunteers. In a retrospective case review, we identified 58 patients with Cushing's syndrome caused by ectopic ACTH secretion, who were treated at the National Institutes of Health between 1983-1997. The diagnosis of an ectopic ACTH cause was confirmed by inferior petrosal sinus sampling and/or pathologic examination of tumor. The commonest causes were bronchial carcinoid (40%) and thymic carcinoid (10%), but 18 of 58 (31%) patients had an unknown source of ectopic ACTH. Hypertension (systolic blood pressure >140 mmHg and/or diastolic blood pressure >90 mmHg in adults) was noted in 45 of 58 (78%) ectopic Cushing's patients, a prevalence similar to that noted in other endogenous Cushing's syndrome etiologies. Hypertension was severe, deemed to require 3 or more drugs by the treating physicians, in 26 of 58 (45%) patients. Hypokalemia was much more prevalent than in patients with other causes of Cushing's syndrome, affecting 33 of 58 (57%) patients. The range of plasma ACTH (17-1557 pg/mL, normal <60) and 24-hour urine cortisol (UC) excretion (192-1600 mcg/24 hr, normal <90) allowed analysis of the influence of these hormones on blood pressure and plasma potassium. There was a significant relationship between 24-hour UC excretion and the presence of hypokalemia (P = 0.003). Eight of nine patients with a UC >6000 mcg/24 hr had hypokalemia. There was no relation between ACTH level and hypokalemia. In addition, we did not find blood pressure severity to be related to UC excretion or ACTH levels. Urine and plasma cortisol and cortisol metabolite measurements suggest that cortisol may act as a mineralocorticoid when in excess, perhaps by saturating the 11beta-hydroxysteroid-dehydrogenase (11beta-HSD2 enzyme) that inactivates cortisol at the renal tubule. The current data suggest that high cortisol levels may be the principal cause of hypokalemic alkalosis in Cushing's syndrome, rather than inhibition of the 11betaHSD2 enzyme by ACTH or the effects of adrenal steroid biosynthetic intermediaries with mineralococorticoid activity.

The long-term outcome after adrenalectomy and prophylactic pituitary radiotherapy in adrenocorticotropin-dependent Cushing's syndrome.

We have reviewed our experience of adrenalectomy performed as part of the management of 56 patients with ACTH-dependent Cushing's syndrome between 1946 and 1993. Forty-three patients were operated on at our institution. Surgery-related mortality did not occur, but complications developed in 14 (33%); these were minor in 12. Eleven patients (29%) of the 38 for whom long-term follow-up data were available and who did not have a proven ectopic source of ACTH subsequently developed Nelson's syndrome, diagnosed on the basis of clinical pigmentation and markedly elevated ACTH levels that were not normally suppressible with glucocorticoids. The effects of prophylactic pituitary radiotherapy were assessed in 38 patients who underwent adrenalectomy at our institution and 18 who underwent surgery elsewhere. Patients who had received prophylactic radiotherapy were less likely to develop Nelson's syndrome (5 of 20, 25%) compared to those who did not (18 of 36, 50%; P > 0.07), and there was a low incidence of radiotherapy-induced hypopituitarism. We conclude that total adrenalectomy has proved to be a safe and effective operation and still may be indicated in selected patients with ACTH-dependent Cushing's syndrome; because prophylactic pituitary radiotherapy reduces the incidence of subsequent Nelson's syndrome by 50%, it should always be considered in the management of these patients.

Ectopic ACTH Secretion: A Misnomer

Ectopic ACTH production is a common cause of Cushing's syndrome. In most patients, the neoplasm is obvious and is readily identified as the source of ACTH. However, in some patients, the neoplasm is not obvious and differentiating the tumor from a pituitary source is difficult. Current data demonstrate that virtually all normal tissues produce small amounts of a biologically inactive precursor ACTH molecule, probably proopiomelanocortin (POMC). All cancers produce this same substance in increased quantities. Selected cancers, correlated with histologic type, convert POMC to biologically active ACTH to produce the so-called ectopic ACTH syndrome. In this context, ectopic ACTH production is not ectopic.

An Evaluation of the Distinction of Ectopic and Pituitary ACTH Dependent Cushing's Syndrome by Clinical Features, Biochemical Tests and Radiological Findings

The efficiency of various laboratory and radiological investigations in the differentiation of ectopic from pituitary dependent Cushing's syndrome was studied, based on findings in 23 patients with verified Cushing's disease and seven patients with the ectopic ACTH syndrome. Clinical features strongly favouring the ectopic type were male sex and history for less than 18 months. Basal biochemical features strongly indicating the ectopic syndrome included plasma K+ less than 3.0 mmol/l and HCO3 greater than 30 mmol/l; serum cortisol at 9 a.m. or midnight of greater than 800 nmol/l; urine free cortisol greater than 1300 nmol/24 hours; plasma ACTH greater than 100 ng/l. In the high-dose dexamethasone suppression test, suppression by less than 50 per cent of 9 a.m. serum cortisol, urine free cortisol or 17-oxogenic steroids was usually indicative of an ectopic source of ACTH. A mean suppressed value of greater than 450 nmol/l for the 9 a.m. and midnight cortisol combined occurred in all of those with the ectopic syndrome, but in none of the 23 patients with Cushing's disease. For urine free cortisol, a mean suppressed value of less than 1000 nmol/24 hours was found in all patients with Cushing's disease, but in none of those in the ectopic group. In the metyrapone test, there was an increase of less than or equal to 3-fold in 11-deoxycortisol at 24 hours in patients with ectopic ACTH; the increase was greater than 3-fold in all but one of the patients with Cushing's disease. Failure to respond to either dexamethasone or metyrapone was found in only one of the patients with Cushing's disease (Patient 16); in the ectopic group, all patients except Patient D failed to respond to either test. It is concluded that patients presenting with clinically obvious Cushing's syndrome along with measurable plasma ACTH can be reliably divided by conventional tests into those that are driven from the pituitary and those driven by ectopic ACTH.

Thymic Hyperplasia With Occult Ectopic ACTH Syndrome

To the Editor. —We read with particular interest case No. 10 (occult ectopic adrenocorticotropic hormone [ACTH] secretion with thymic hyperplasia) in a recent article in theArchivesby Findling and Tyrrell 1 because it presented similarities with a patient we have treated. Our patient (36 years of age) presented in November 1983 with the classic features of Cushing's disease. Evaluation showed the patient's adrenal cortisol production to be relatively nonsuppressible with high-dose (8 mg/d) dexamethasone therapy. A computed tomographic (CT) scan of the pituitary gland was normal, and the suspected ectopic source of ACTH could not be found. (Computed tomographic scans of the patient's chest and abdomen were normal except for bilateral adrenal hyperplasia). Sampling of petrosal sinus, jugular veins, and superior and inferior vena cava, in January 1984 suggested a nonpituitary source of ACTH. Further workup for an ectopic source of ACTH, including celiac angiography, was, again, negative.

Cushing's syndrome with small cell carcinoma of the uterine cervix

A 28 year old white woman was found to have a cervical tumor in the 25th week of pregnancy. Pathologic examination revealed a nonkeratinizing small cell carcinoma. After delivery by cesarean section, pelvic lymph node exploration was carried out, and all 15 nodes were free of tumor. Her condition was staged as II-A, and she was treated with local radiation. Metastatic disease became manifest almost a year later and was histologically similar to her primary disease. A Cushingoid appearance was noticed and plasma cortisol levels were elevated. Twenty-four hour urinary 17-hydroxycorticosteroid (17-OHCS) and 17-ketosteroid (17-KS) levels were elevated and failed to suppress with dexamethasone. Plasma adrenocorticotropin (ACTH) level was elevated. Electron microscopic examination of the tumor tissue revealed neurosecretory granules. Immunoperoxidase stains for ACTH were positive. The patient's course was one of progressive decline and eventual death. A literature review revealed two other cases in which carcinoma of the uterine cervix was considered to be the source of ectopic ACTH. Some small cell carcinomas of the cervix may arise from cells of the APUD series. Small cell carcinoma of the uterine cervix may behave differently from the more commonly encountered keratinizing and large cell nonkeratinizing carcinomas of the cervix and may not respond as well to standard therapy. Ectopic hormone production, production of abnormal peptides or of vasoactive amines may be more common in small cell carcinoma of the cervix than is currently recognized, and these products may be clinically useful as tumor markers.

ECTOPIC ACTH SYNDROME AND MEDULLARY THYROID CARCINOMA

ABSTRACT A 40 year old patient with medullary thyroid carcinoma subsequently developed Cushing's syndrome with presumably ectopic ACTH formation. The immunoreactive calcitonin in the plasma was greatly and ACTH slightly increased. Despite the excessively high calcitonin concentration the patient finally developed a serious osteoporosis which presumably resulted from Cushing's syndrome. In this case at least, a raised endogenous plasma calcitonin level did not prevent an osteoporosis caused by hypercortisolism. The autopsy revealed a bilateral hyperplasia of the adrenal cortex and a normal pituitary gland suggesting that Cushing's syndrome was probably caused by an ectopic ACTH source. Twenty-two additional cases of medullary thyroid carcinoma with Cusing's syndrome reported in the literature have been reviewed. Eighteen out of 23 patients were alkalotic which is typical of an ectopic ACTH production. In these patients the characteristic clinical signs of hypercortisolism were nearly as frequently observed (70 %) as in patients with non-ectopic Cushing's syndrome (91 %). An ectopic Cushing's syndrome occurs only in 2–4 % of advanced cases of medullary thyroid carcinoma and is a serious complication. Among the 23 patients 18 died with an average survival time of only 4.5 months after the diagnosis of Cushing's syndrome was established.

Plasma immunoreactive corticotrophin and lipotrophin in Cushing's syndrome and Addison's disease.

Plasma immunoreactive corticotrophin (ACTH) and lipotrophin (LPH) were measured in patients with raised circulating concentrations from a pituitary or an ectopic source. They were measured again in seven patients after they had received hydrocortisone. Plasma ACTH concentrations were higher than LPH concentrations in patients with a pituitary source of their hormones, whereas this relation was reversed when the source was ectopic. After hydrocortisone administration the half life of immunoreactive ACTH was 40 minutes and that of LPH 95 minutes, resulting in a reversal of the normal relation of ACTH to LPH. The use of two antisera with different specificities for measuring LPH has further shown that pituitary LPH differs from ectopic LPH. Relatively less gamma-LPH than beta-LPH was produced from ectopic sources, the relation being reversed in patients with a pituitary source for their raised concentrations. Measuring plasma LPH as well as ACTH might therefore help in deciding whether a patient with Cushing's syndrome has a pituitary or ectopic source of ACTH, which sometimes presents a difficult clinical problem.