Cushing´s syndrome: high aggressiveness of low-grade tumors
Faycal El Guendouz1,2,&, Sara Derrou1,2, Hassan Ouleghzal1,2, Somaya Safi1,2
1Department of endocrinology, Moulay Ismail Military Hospital of Meknes, Morocco, 2Sidi Mohamed Ben Abdellah University Fez, Morocco, 3Department of thoracic surgery, Moulay Ismail Military Hospital of Meknes, Morocco
Faycal El Guendouz, Department of endocrinology, Moulay Ismail Military Hospital of Meknes, Morocco
Cushing´s syndrome is caused by prolonged exposition supraphysiological to endogenous or exogenous cortisol. Ectopic production of adrenocorticotropic hormone by lung carcinoid tumors is relatively rare. Most documented cases have been reported individually. This rare neoplasm low grade that may secrete adrenocorticotropin (ACTH) leading to rapid development of hypercortisolism which is the main mode of discovery, can be a real aggressive form. This report shows a high aggressiveness of this endocrine neoplasia, wich was marked on the general, morphological, bone and psychiatric level. The trivialization of clinical signs had caused the delay in diagnosis with irreparable bone consequences.
Cushing´s syndrome (CS) is caused by prolonged exposition supraphysiological to endogenous or exogenous cortisol. Ectopic production of adrenocorticotropic hormone by carcinoid tumors is relatively rare and most documented cases have been reported individually . This rare neoplasm low grade that may secrete adrenocorticotropin (ACTH) leading to rapid development of hypercortisolism which is the main mode of discovery, can be a real aggressive form. This report shows a high aggressiveness of this endocrine neoplasia, wich was marked on the general, morphological, bone and psychiatric level. A complete response was objectified after surgery.
Patient and observation
A 31-year-old woman who consulted several times for dorsal spinal pain
one year before her admission to our department for suspected CS. She
accused progressive asthenia, hair loss, amenorrhea, weight gain (12
anxiety, insomnia and depressive symptoms. The notion of taking exogenous
steroids was unremarkable. In her physical examination there was non
hypertention, we revealed melanodermia and Cushingoid features: increased
fat around the
face, neck, nape (buffalo cervix) and supraclavicular region, facial
acne, (Figure 1 A)
and a purple striae more pronounced over her flanks and thighs (Figure
2 A, Figure 3 A).
Following psychiatric evaluation, the patient was diagnosed with severe
depression, suicidal ideation, and panic attacks. Nonspecific biology
hyperglycemia (FPG: 1.80, A1C: 7,9%), hypercholesterolemia (TC: 2.98
g/L, HDL- C: 0.69 g/L, LDL - C:1.92 g/L, and triglycerides 1.91 g/L),
hypokalemia ( 3.0 mmol/L), polymorphonuclear leukocytosis ( WBC: 11,110/mm3 and
PMNs: 8720/mm3), an increase in bone turnover with increase
serum alkaline phosphatase (ALP: 252 IU/L). The specific investigations
were in favor of CS, the nycthemeral cortisol cycle was broken with
a detectable cortisol at 23h00 (26 µg/dL), the 24h urinary free cortisol
(FLU) on two consecutive days were increased (1436 µg/day and 1342 µg/day
(RR < 176 µg/day)).
Seen melanoderma an ACTH-dependent CS are suspected and confirmed by
increased plasmatic ACTH (247 ng/L (RR: 10-50 ng/L)). The laboratory
test results are
summarized in Table
1. Given the high prevalence of cushing's disease, even in the absence
of suppression of serum cortisol and FLU in overnight, high-dose dexamethasone
suppression tests, pituitary MRI was performed and there was no identifiable
tumor. It was an indication to carry out a bilateral inferior petrosal
sinus sampling, but it was unavailable. Chest, abdomen, and pelvis
CT scan reviewed
to localize the source of ectopic cushings, revealed one nodular defined
lesion (12mm) in the left lung and confirmed by MRI (Figure
4), normal adrenal glands (no signs of hyperplasia, enlargement,
or nodules) and no other suspicious lesions. On the metaboic level,
in addition to secondary diabetes and secondary mixed hyperlipidemia,
the Bone assessment
was in favor of osteporosis, Magnetic resonance imaging (MRI) shows
osteoporotic vertebral compression fractures which explains dorsal
spinal pain (Figure
The patient received a ketoconazole titration with a better reponse after two
weeks on 600 mg per day in two takes (152 µg/day) without improvement
in the nycthemeral cortisol cycle (high midnight cortisol).The patient
underwent thoracic surgery with nodular resection by uniportal video-assisted
thoracoscopic. The histology revealed a bronchial typical carcinoid
tumor with positive immunostainings for for corticotropin, chromogranin A
After surgical removal, we noted a complete response and the patient
has adrenal insufficiency over two years (Table
1, Figure 1 B, Figure
2 B, Figure 3 B).
The incidence and the prevalence of ectopic ACTH syndrome (EAS) are imprecise because of the rarity of the disease and the underreporting of cases [2,3]. Based on the existing literature, the prevalence of EAS is between 9 and 18% of cases of ACTH-dependent CS . This is a disease mainly occurring in adults and pediatric cases are exceptional .
Despite efficient diagnostic tests (biological, radiological and functional), EAS frequently present a major problem of positive and etiological diagnosis . Indeed, when CS is suspected, the diagnosis involves three steps: confirmation of hypercortisolism, differentiation between ACTH-independent and ACTH-dependent CS, and finally differentiation between pituitary and EAS sources of ACTH. Regarding the first step, in the case of severe hypercorticism you just have to think about it, which is not obvious given non-specificity of the symptoms, especially at the start of the disease, this explains delayed diagnosis . In our case, the delay between the onset of the first symptoms (dorsal spinal pain) and the diagnosis was 12 months, it was the appearance of other symptoms of hypercatabolism such as skin signs that made one think of CS and prompted a specialist consultation. To confirm the diagnosis of CS, international guidelines suggest two of four investigations: two UFC, two measures of night salivary cortisol, overnight dexamethasone suppression test (ODST) or low-dose dexamethasone suppression test [3,4]. In our context we practice 2UFC and an ODST like most centers. If two tests are positive, the diagnosis of CS is certain. The confirmation in our case was easy because of severe hypercortisolism. In the second step, clinically the presence of melanoderma was a sign in favor of a dependent ACTH CS, the ACTH dosage confirms it if it exceeds 20ng/L. In the third step, ACTH hypersecretion is more frequently of pituitary origin (Cushing's disease) or of an extrahypophysial origin in EAS or an exceptional ectopic secretion of CRH.
The differentiation between a dependent and non-dependent ACTH CS is very easy (step 2), but the differential diagnosis between a Cushing's disease and EAS presents a real challenge. It is the same for identifying the cause of EAS [2,4]. Given the severity of symptoms, normal pituitary imaging and persistence of cortisol hypersecretion after high-dose dexamethasone suppression tests, EAS was very likely. The best approach to localise the source of EAS is high-resolution imaging and it did identify a pulmonary lesion in our case.
Based on the World Health Organization classification, they are two types of bronchopulmonary carcinoid tumors, typical carcinoids, which are low-grade tumors with a low mitotic rate (four times more frequent) and atypical carcinoids, which are intermediate-grade tumors with a higher mitotic rate and/or necrosis . Typical carcinoids tumors can be aggressive when associated with CS as in this case [6,7].
The ideal treatment is radical excision of the tumor; it allows remission in more than 83% of cases when the lesion is unique. Medical treatment has a central role pending identification of the etiology of EAS and in preparation for surgery ; our case illustrates the rapid efficacy and good tolerance of ketoconazole in preparation for surgery. Survival of patients with EAS depends on the source of the primary tumour and patients with bronchial carcinoids have the best prognosis.
We must remember that a tumor of benign morphology can cause malignant manifestations linked to the hormonal storm. This is the case for bronchopulmonary typical carcinoid tumor with hypercorticism which causes damage on the general, psychological and metabolic levels. Multidisciplinary approach is required for both diagnostic work-up and therapeutic management.
The authors declare no competing of interests.
All the authors contributed equally to drafting of the manuscript. All the authors read and approved the final version of the manuscript.
Table and figures
Table 1: pertinent laboratory findings
Figure 1: face picture before (A) and one year after surgery (B)
Figure 2: flanks pictures before (A) and one year after surgery (B), showing purple striae
Figure 3: thighs pictures before (A) and one year after surgery (B), showing purple striae
Figure 4: coronal chest MRI T2-weighted revealed one nodular defined lesion in the left lung (arrow)
Figure 5: axial chest MRI T2-weighted before (A) and one year after surgery (B) reveled buffalo neck (arrow 1 and 4) and vertebral compression fractures of D7 and D9 (arrow 2 and 3)
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