Discussion
Approximately 10% of Cushing syndrome is paraneoplastic and may result in many tumours, preferentially lung cancer (50–60% of time), with 1–2% of lung NET and about 5% of small-cell lung cancer associated with Cushing syndrome [8, 11, 13]. Others reported sites of malignancy include the thymus, thyroid, pancreas, and adrenals. Except for the pancreas, PCS secondary to GI NET (appendix, duodenum, ileum, colon, and anal canal) is extremely rare, and only isolated case reports have described this syndrome.
In paraneoplastic endocrine syndrome cases, symptoms are due to secretion of hormones by malignant cells or secondary to the impact of neoplastic cell antibodies on normal cells. PCS arises from tumour secretion of ACTH or CRH, resulting in production and release of cortisol from the adrenal glands. Unlike paraneoplastic endocrine syndromes that present most of the time after cancer diagnosis, PCS typically appears before cancer detection and similarly relapse may herald tumour recurrence [11, 14]. In our case, no symptoms related to hypercortisolaemia led the patient to consult before obstructive syndrome. The occurrence of hypercortisolaemia 12 months after diagnosis was not linked to imaging progression according to RECIST criteria. However, concurrent CgA increase should be noted.
Commonly measured tumour markers in NETs include serum CgA and 5-HIAA, the final secreted product of serotonin, levels in a 24-h urine sample. Elevated levels of circulating of CgA have been associated with almost all types of NETs, including those arising from GI tract but also pheochromocytomas [15]. The clinical sensitivity of CgA has been demonstrated to depend on the threshold cut-off, on NET primary location, and on the spread of the disease, especially the existence of liver metastases [16]. Indeed, a higher sensitivity was found in patients with midgut NETs and liver metastases, as in our patient. Moreover, with our cut-off level (94 ng/mL) approximately the same as used in 2 studies [16, 17], sensitivity was 62%–67% and specificity was 96%. Furthermore, Korse et al. [18]. postulated that serum CgA was superior to urinary 5-HIAA concerning the prognostic relevance in the follow-up of metastatic midgut NETs. These data are consistent with our patient outcomes for which 5-HIAA was not increased unlike CgA. However, although CgA is currently the best available tumour marker indicating tumour recurrence [19], there are many comorbidities and drugs that may increase CgA levels and lead to false-positive results. As a result, it is questionable whether the CgA increase in our patient was not rather secondary to cardiovascular or GI disorders, inflammatory diseases, diabetes, or even food intake before CgA measurement [16, 20, 21]. Similarly, many drugs, foods, natural stimulants, and comorbidities may alter the level of 24-h urinary 5-HIAA, positively or negatively.
Cushing syndrome is due to hypercortisolism. Two-thirds of endogenous elevated cortisol is caused by ACTH-secreting pituitary tumours, 15% by primary adrenal glands and 15% by ectopic PCS [22]. The first step is laboratory tests with cortisol and ACTH levels to differentiate ACTH-dependent or ACTH-independent Cushing syndrome. When ACTH-dependent Cushing syndrome is confirmed, differentiation between PCS and Cushing disease can be difficult. The high-dose dexamethasone suppression tests help distinguish Cushing disease from PCS, as in our presented case. Indeed, no decrease in blood cortisol during the high-dose test and high ACTH levels are consistent with PCS. Nevertheless, 21–26% of ectopic ACTH secretions have a positive suppression, about one-third of MRI scans for pituitary adenoma exclusion are false-negative, and occult ectopic ACTH-secreting tumours have been described in about 15% of adult patients [23–26]. In our patient, both MRI and high-dose dexamethasone suppression test are consistent with PCS. The gold standard diagnosis – inferior petrosal sinus sampling – that demonstrates gradient in ACTH concentration between the affected side sinus and the periphery in pituitary lesions, whereas the absence of this gradient in PCS was not performed because of its invasiveness and its neurological accident risks [27]. Note however although the ACTH level at diagnosis suggests ACTH-dependent Cushing syndrome, the occurrence of adrenal metastasis few months after the diagnosis and explaining the sudden deregulation could be possible and consistent with the CgA increase but refuted by adrenal gland histology.
Clinical features of PCS depend on the source of production and rate of ACTH synthesis. Characteristically, these patients have severe hypercortisolaemia, leading to low serum potassium levels, diabetes, generalized infections, hypertension, and psychosis. To confirm whether rapidly growing tumours produce sudden onset of symptoms, gradual physical signs are noticed in slower growing tumours [28], as for our patient for whom we suppose that liver metastases started to produce ACTH ectopically. An option for non-resectable neuroendocrine liver lesions, given that the majority of them are hypervascular, is hepatic directed procedures, which include ablative therapy, transarterial embolization, transarterial chemoembolization, and selective internal radiation therapy with yttrium-90 microspheres [29]. Hepatic artery chemoembolization for the treatment of liver metastases from NETs is useful for tumour size reduction and symptom palliation and can be associated with prolonged survival [30]. Nevertheless, chemoembolization on NET liver metastasis-producing ACTH is not well documented. Given the fact that hepatic metastasis chemoembolization was ineffective on hypercortisolism and despite Octreoscan results, there is still a small chance that he harbours somewhere else metastasis-producing ACTH. Indeed, PET-CT imaging with 68Gallium-DOTATATE has recently replaced Octreoscan as the new gold standard with a higher detection rate in GI NETs [31].
Hypercortisolism requires a prompt therapeutic management to reduce the risk of development of a potentially fatal emergency. Synchronous bilateral adrenalectomy is an effective and safe treatment for patient with unmanageable ACTH-dependent hypercortisolism [12]. Taking account of the risks to the patient and the lack of effective medical therapeutic possibilities, we have chosen to perform this surgery.
According to the recent consensus guidelines for digestive NETs of the jejunum and ileum, the 5-year survival rate is 36% in patients with distant metastases [32]. Several analyses suggest a significant survival benefit in patients who received surgery for the primary tumour even in the presence of metastasis [33]. Moreover, the impact of liver resection or liver-directed therapies on the survival of patients with liver metastasis is unclear with conflicting results [33]. PCS can cause a poor clinical outcome due to various complications with an increase in susceptibility to infection and GI ulceration. Indeed, for small-cell lung cancer and gynaecological malignancies, PCS is associated with accelerated decompensation and poorer response to chemotherapy (Mitchell et al. [14]). Whether these findings can be extrapolated to other malignancies is unknown. However, an early diagnosis and a prompt management can improve patient outcomes through earlier cancer diagnosis or relapse and thus earlier administration of treatment, as was the case with our patient.
Filed under: Cushing, Cushing's, Rare Diseases | Tagged: ectopic, gastrointestinal, neuroendocrine, Paraneoplastic Cushing Syndrome | Leave a comment »
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