Abstract
Ectopic ACTH syndrome (EAS) is a potentially fatal endocrine disease that results from a variety of neuroendocrine tumors (NETs), such as small cell lung cancer (SCLC) and bronchial typical carcinoid. Typical carcinoid is usually slow growing, not associated with plasma progastrin releasing peptide (ProGRP) elevation. Here, we report a 47-year-old female smoker with progressive typical carcinoid and plasma ProGRP elevation. Several types of Cushingoid features were found on physical examination. In addition, laboratory examination showed elevated plasma ACTH and serum cortisol levels. These findings indicated ACTH-dependent Cushing’s syndrome. Moreover, the serum cortisol level was not suppressed by overnight high-dose dexamethasone treatment, suggesting the presence of an extra-pituitary tumor. Contrast-enhanced brain MRI revealed no pituitary adenoma, which also supported the idea that EAS occurred in the present case. Strikingly, chest computed tomographic (CT) scan showed a single 18-mm peripheral nodule in the right middle lobe of the lung. Tumor marker analysis revealed an elevation in plasma ProGRP. These data suggested a possibility that SCLC secreted ACTH and caused EAS in this patient. Of note, the plasma ACTH level was increased (1.7 fold) in l-desamino-8-D-arginine vasopressin (DDAVP) test, also suggesting the specific clinical feature in this case. After additional imaging examinations, we performed surgical resection with the suspicion of limited SCLC. As a result, pathological examination revealed a vasopressin receptor Ib (V1b) receptor-negative bronchial typical carcinoid with ACTH production and mediastinal lymphatic metastasis. In summary, we present a case of EAS caused by progressive bronchial typical carcinoid with plasma ProGRP elevation. We propose a novel subtype of lung typical carcinoid.
CUSHING’S SYNDROME is a severe endocrine disorder whose pathogenesis is based on a prolonged exposure to hypercortisolemia. Therefore, in Cushing’s syndrome, excessive glucocorticoid causes a variety of potentially fatal clinical features such as diabetes, hypertension, osteoporosis, hypokalemia and increased susceptibility to infection. On the basis of ACTH dependency, Cushing’s syndrome is classified into two main subtypes. ACTH-independent Cushing’s syndrome, except for iatrogenic causes, is usually caused by autonomic cortisol secretion from adrenal adenomas or adenocarcinomas. By contrast, ACTH-dependent Cushing’s syndrome is normally caused by pituitary adenomas, or rarely caused by extra-pituitary tumors. The former is known as Cushing’s disease, while the latter is known as ectopic ACTH syndrome (EAS). To distinguish these two diseases, CRH stimulation test and DDAVP stimulation test are commonly performed because pituitary adenomas, but not EAS-causative tumors, usually have receptors for CRH or DDAVP [1]. EAS is closely associated with neuroendocrine tumors (NETs) with ACTH secretion. In particular, lung NETs such as bronchial carcinoids and small cell lung cancer (SCLC) are the most common cause of EAS [2]. Both bronchial carcinoid and SCLC are different from one another in some clinical features. SCLC is one of the most rapid and progressive tumors that are frequently followed by an elevation of tumor markers including ProGRP [3-6]. On the other hand, tumor spread is relatively slow in bronchial carcinoids, which are not usually followed by an elevation of plasma ProGRP. In addition, bronchial carcinoid is histologically classified into atypical and typical carcinoid. Among them, typical carcinoid shows slower progression and less metastasis, resulting in a better prognosis in lung NET.
Here, we report a rare case of EAS caused by DDAVP-sensitive lung typical carcinoid with mediastinal lymphatic metastasis and plasma ProGRP elevation. These features seen in the present case were “atypical” of typical carcinoid. We propose the possibility of a novel subtype of lung NET.
Case Report
A 47-year-old woman with a smoking history exhibited bilateral pedal edema. Because her symptoms had continued for one month, she visited a local doctor and her symptoms transiently improved with diuretics. However, during the next two months, moon face, proximal muscle atrophy, and recurrence of edema rapidly occurred. Thus, she was referred to our hospital for further examinations. Strikingly, on physical examination, she presented with other Cushingoid features including facial acne, central obesity, buffalo hump, and skin thinning. This result strongly suggested that refractory pedal edema resulted from Cushing’s syndrome. In addition, laboratory examination revealed neutrophilia, lymphopenia, eosinopenia, hypokalemia, serum cortisol elevation, and plasma TSH reduction, also suggesting that Cushing’s syndrome occurred in this patient (Table 1). Moreover, elevation of plasma ACTH indicated ACTH-dependent cortisol production (Table 1). To evaluate the site of ACTH production, we performed several endocrinological tests. As a result, these tests revealed loss of circadian rhythms in both plasma ACTH and serum cortisol (Table 2) and a marked increase in urinary free cortisol excretion (Table 1). Additionally, serum cortisol was not suppressed by overnight low-dose (1 mg) dexamethasone treatment (Table 2). These results also supported the idea that serum cortisol in the present case was produced in an ACTH-dependent manner. Of note, overnight high-dose (8 mg) dexamethasone suppression test also revealed no response in plasma ACTH, indicating ectopic ACTH production (Table 2). Furthermore, both ACTH and cortisol showed no change in response to CRH stimulation (Table 2). These data strongly suggested that EAS occurred in the present case. Interestingly, plasma ACTH revealed a significant response (1.7 fold) to desmopressin (DDAVP) stimulation (Table 2), suggesting the involvement of vasopressin receptor in the pathogenesis of this disease.
Table 1
Results of laboratory tests
|
Admission |
Discharge |
Reference |
| WBC |
10,100/μL |
9,700/μL |
4,000–9,000/μL |
| Neu |
89% |
86.4% |
% |
| Lym |
6% |
9.5% |
% |
| Eos |
0% |
0.6% |
% |
| RBC |
3.92 × 104/μL |
3.57 × 104/μL |
3.8–5.4 × 104/μL |
| Hb |
12.5g/dL |
11.8g/dL |
11.5–15g/dL |
| Plt |
19.9 × 104/μL |
18.8 × 104/μL |
15–35 × 104/μL |
| Na |
142mEq/L |
143mEq/L |
136–147mEq/L |
| K |
2.7mEq/L |
3.6mEq/L |
3.5–5mEq/L |
| Cl |
102mEq/L |
107mEq/L |
98–110mEq/L |
| T-Bil |
0.7mg/dL |
0.4mg/dL |
0.2–1.2mg/dL |
| AST |
15U/L |
14U/L |
12–35U/L |
| ALT |
22U/L |
25U/L |
5–30U/L |
| γ-GTP |
25U/L |
U/L |
7–35U/L |
| LDH |
215U/L |
209U/L |
110–240U/L |
| ALP |
116U/L |
179U/L |
109–344U/L |
| BUN |
11.0mg/dL |
10.6mg/dL |
8–20mg/dL |
| Cr |
0.46mg/dL |
0.45mg/dL |
0.4–0.8mg/dL |
| TP |
5.0g/dL |
5.6g/dL |
6.1–8.1g/dL |
| Alb |
3.1g/dL |
3.1g/dL |
3.2–5g/dL |
| CRP |
0.1≧mg/dL |
0.9mg/dL |
0.3≧mg/dL |
| TSH |
0.06μU/mL |
μU/mL |
0.54–4.26μU/mL |
| FT4 |
2.08ng/mL |
ng/mL |
0.76–1.65ng/mL |
| FT3 |
0.98pg/mL |
pg/mL |
2.48–4.14pg/mL |
| ACTH |
242pg/mL |
2.0≧pg/mL |
7.2–63.3pg/mL |
| Cortisol |
52.1μg/dL |
33.5μg/dL |
6.2–19.4μg/dL |
| Urine cortisol |
2,450μg/day |
204μg/day |
11.2–80.3μg/day |
WBC, white blood cells; Neu, neutrophils; Lym, lymphocytes; Eos, eosinophil, RBC, red blood cells; Hb, hemoglobin; Plt, platelets; Na, sodium; K, potassium; Cl, chloride; T-Bil, total-bilirubin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γ-GTP, γ-glutamyl transpeptidase; LDH, lactate dehydrogenase; ALP, Alkaline phosphatase; BUN, blood urea nitrogen; Cr, creatinine; TP, total protein; Alb, albumin; CRP C-reactive protein; TSH, thyroid stimulating hormone; FT4, free thyroxine; FT3, free triiodothyronine; ACTH, adrenocorticotropic hormone
Table 2
Results of endocrinological tests
| Circadian rhythm of ACTH and cortisol |
|
8:00 |
16:00 |
22:00 |
| ACTH (pg/mL) |
242 |
206 |
286 |
| Cortisol (μg/dL) |
52.1 |
32.3 |
38.9 |
| Low- and high-dose overnight dexamethasone suppression test |
|
1 mg |
8 mg |
| ACTH (pg/mL) |
242 |
206 |
| Cortisol (μg/dL) |
52.1 |
32.3 |
| CRH stimulation test |
|
0 min |
30 min |
60 min |
90 min |
120 min |
| ACTH (pg/mL) |
335 |
340 |
346 |
343 |
318 |
| Cortisol (μg/dL) |
51.8 |
47.6 |
51.8 |
53.1 |
48.3 |
| DDAVP stimulation test |
|
0 min |
30 min |
60 min |
90 min |
120 min |
| ACTH (pg/mL) |
188 |
305 |
308 |
325 |
305 |
| Cortisol (μg/dL) |
65.7 |
62.6 |
67.6 |
64.7 |
68.2 |
Consistent with the clinical suspicion of EAS, contrast-enhanced brain MRI scan failed to detect pituitary adenoma. Because EAS frequently results from lung NETs, we immediately performed chest CT scan. Strikingly, this test showed a single 18-mm peripheral nodule in the medial segment of the right middle lobe of the lung (Fig. 1A). In addition, chest X-ray test retrospectively revealed this nodule at the same site (Fig. 1B). Due to the rapid progression of Cushingoid features, we suspected that this nodule was a malignant tumor. Therefore, we performed an additional analysis with tumor markers. This test revealed a significant elevation of plasma ProGRP, while there was no change among other tumor markers, including NSE, SCC, Cyfra, and SLX (Table 3). This result suggested a possibility that SCLC caused EAS in the present case. In addition, other imaging procedures, including contrast-enhanced abdominal and head CT scans or bone scintigraphy, showed this patient had no evidence of tumor metastasis or invasion. Finally, the present tumor was diagnosed as a clinical T1aN0M0; stage IA lung cancer. Therefore, we decided to perform surgical treatment.
Table 3
Results of tumor marker studies
|
Admission |
Post-operative |
Reference |
| Pro-GRP |
345pg/mL |
52.0pg/mL |
0–80.9pg/mL |
| NSE |
9.7ng/mL |
ng/mL |
0–16.3ng/mL |
| SCC |
0.5≧ng/mL |
ng/mL |
0–1.5ng/mL |
| Cyfra |
1.7ng/mL |
ng/mL |
0–3.5ng/mL |
| SLX |
31U/mL |
U/mL |
0–38U/mL |
ProGRP, pro-gastrin-releasing peptide; NSE, neuron-specific enolase; SCC, squamous cell carcinoma antigen; Cyfra, cytokeratin fraction; SLX, sialyl Lewis X
Because hypercortisolism increases a risk of some kinds of infectious diseases, we began to administer metyrapone (1,000 mg/day). After metyrapone treatment successfully suppressed hypercortisolism and its complications such as leukocytosis, lymphopenia and hypokalemia, we immediately performed thoracoscopic right middle lobectomy (Fig. 2). Contrary to our expectations, histological analysis showed that the resected round tumor (16 × 16 mm in size) had an alveolar, trabecular structure with <2 mitoses per 2 mm2 and the absence of necrosis. This observation suggested that the present tumor was pathologically diagnosed as a typical carcinoid but not SCLC (Fig. 3). Mild cytological atypia with uniform oval nuclei were defined at high magnification (Fig. 3). This fact also indicated typical carcinoid. In addition, Ki-67 staining revealed a low proliferation index (<1%) (data not shown). Importantly, immunohistological analyses showed diffuse positive staining for Synaptophysin and CD56, indicating this tumor had the pathological features of NETs (Fig. 4A, 4B). Furthermore, immunostaining also showed partial and faint positive staining for Chromogranin A, which is the other neuroendocrine marker (Fig. 4C). Most strikingly, strong diffuse staining for ACTH was observed, which indicated the production of a large amount of ACTH in carcinoid tumor cells (Fig. 4D). Moreover, to investigate the cause of DDAVP responsiveness, we performed immunohistological staining for V1b receptor, which is a DDAVP-binding receptor in Cushing’s disease [7, 8]. As a result, we found that V1b receptor was negative in the resected tumor, compared with pituitary adenoma in another patient as a positive control (Fig. 5). Taken together, histological analysis revealed that a DDAVP-sensitive but V1b receptor-negative typical carcinoid tumor with lymphatic metastasis caused EAS in the present case.
Following the operation, the levels of plasma ACTH (<2 pg/mL), serum cortisol (15.3 g/dL) and plasma ProGRP (52.0 pg/mL) dramatically returned to the normal range (Fig. 2 and Table 2), suggesting that the tumor was responsible for elevation in ACTH and ProGRP. During this time, replacement with hydrocortisone (150 mg/day) was initiated, tapered and discontinued. Consistent with the improvement in hormonal levels, the Cushingoid features rapidly disappeared. According to the pathological stage, we performed adjuvant chemotherapy for lung typical carcinoid. Based on the regimen for SCLC, the regimen consisted of cisplatin (80 mg/m2) on day 1 and etoposide (100 mg/m2) on day 1, 2 and 3, respectively, every four weeks for four courses. After completion of the adjuvant chemotherapy, the patient has been carefully followed up by measuring ACTH and ProGRP tumor markers. She has been free from recurrence for three years.
Discussion
A variety of extra-pituitary ACTH secreting tumors cause EAS, which accounts for 9–18% of ACTH-dependent Cushing’s syndrome [9]. Extra-pituitary tumors consist of bronchial carcinoid (22.7%), SCLC (21.7%), gastro-entero-pancreatic NET (13.3%), occult tumors (13.1%), thymic carcinoid (6.8%), NET of unknown primary (6.5%), medullary thyroid carcinoma (5.5%), pheochromocytoma (3.4%), and other tumors (7%) [10]. In contrast, previous reports showed that EAS occurs in 2.4% and 4.2% of patients with bronchial carcinoid and SCLC, respectively [11, 12]. In the present case, EAS was caused by pulmonary typical carcinoid, which is a low-grade, well-differentiated lung NET.
In the 2015 WHO classification, based on pathological appearance, lung NET is classified into typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma (LCNEC), and SCLC [13]. Assessment of mitotic number enables us to distinguish these tumors from each other. While typical carcinoid is defined as a neuroendocrine marker-positive tumor with <2 mitoses per 2 mm2, atypical carcinoid has 2–10 mitoses, and LCNEC or SCLC has >10 mitoses. In addition, the classification of lung tumors in the past decade is based on a broad range of histological appearances that could predict the prognosis of patients. The prognosis of lung NETs is also wide-ranging and dependent on histological type [14]. In Japan, the five-year survival rates of four histological types of lung NETs have been reported as follows: 96.2% for typical carcinoid, 77.8% for atypical carcinoid, 40.3% for large cell neuroendocrine carcinoma, and 35.7% for SCLC [15]. Thus, most would accept that the prognosis of typical carcinoid is relatively good; however, previous report showed that incomplete resection, paraneoplastic syndromes, nodal involvement, and old age are other prognostic factors [15]. In the present case, mediastinal lymph node metastasis and EAS indicates a poor prognosis. In addition, a retrospective prognostic analysis showed that ACTH secretion with Cushing’s syndrome is highly associated with local invasiveness and lymphatic metastasis [16]. This study suggests that ACTH production from typical carcinoid promotes tumor progression and results in a poor prognosis. Recent basic studies have shown that glucocorticoids enhance cancer cell proliferation in vitro and in vivo [17, 18]. These facts support the idea that ACTH could enhance tumor cell growth by increasing glucocorticoid secretion from the adrenal glands. There is a possibility that symptomatic ACTH secretion leads to a poor prognosis in the present case. Paradoxically, it should be noted that we can use plasma ACTH level as a biomarker of tumor.
Pro-gastrin-releasing peptide (ProGRP) is a precursor of GRP, which is isolated from porcine non-antral gastric and intestinal tissue [19]. ProGRP is the most reliable tumor marker for SCLC [4-6] because its sensitivity and specificity is extremely high compared with neuron-specific enolase (NSE). While the analysis of pulmonary NET from 10 Japanese institutes reported that the rate of positive ProGRP (>46 ng/mL) is 7.1% in typical carcinoid [15], clinical features of typical carcinoid with ProGRP elevation are incompletely understood. Accumulating evidence has shown that ProGRP is a prognostic factor of SCLC [3, 6, 20, 21]. These facts are supported by the basic research that overexpression of ProGRP promotes cell proliferation and progression in SCLC [22]. Furthermore, recent study revealed that elevation of ProGRP in patients with well-differentiated NET predicts a shorter survival [23]. In the present case, the elevation of plasma ProGRP could serve as a poor prognostic factor as well as paraneoplastic syndrome.
Desmopressin (DDAVP) is a synthetic derivative of Arginine Vasopressin, which stimulates V1b receptor [24]. Because most of ACTH-producing pituitary adenomas have V1b receptor, DDAVP stimulation test is a useful method for distinguishing Cushing’s disease from EAS [1, 7, 8]. In the present case, however, the pulmonary typical carcinoid with ACTH secretion was sensitive to DDAVP stimulation (Table 3). This result prompted us to examine whether the typical carcinoid in the present case had V1b receptor. Surprisingly, compared with a positive control, the resected tumor showed negative staining for V1b receptor (Fig. 5). These data suggest a possibility that DDAVP sensitivity in typical carcinoid but not in pituitary adenoma results from expression of other DDAVP-responsive receptors, such as V1a receptor, V2 receptor, or Oxytocin receptor [24, 25].
While previous reports showed that tumors in EAS occasionally respond to DDAVP [26-29], there are few studies about a prognostic impact of DDAVP sensitivity in EAS. However, previous reports showed that DDAVP sensitivity is a risk factor for the recurrence in Cushing’s disease [30, 31]. This fact suggests that DDAVP sensitivity could lead to a poor prognosis also in EAS. Cell line-based research showed that vasopressin has a cell-proliferation effect in rat pituitary cells [32], supporting the idea that a positive response to DDAVP could lead to tumor proliferation and poor prognosis in EAS. Thus, in the present case, the result of DDAVP stimulation test could predict an undesirable prognosis as well as the secretion of ACTH and ProGRP from typical carcinoid. Taken together, the present case has a very high risk for the recurrence of exceedingly progressive tumor due to triple tumor-promoting factors. In fact, before resecting the tumor, her general condition was severe and immediately life threatening. We successfully diagnosed the primary lung tumor and rapidly performed surgical treatment. As a result, she is currently free from recurrence at 3 years after the operation.
Surprisingly, another group in Japan reported a very similar case of a 41-year old female patient with a typical carcinoid that produced ACTH and ProGRP [33]. Lymph nodal involvement in mediastinum was also seen in this case. From this study and our experience, we propose a novel subtype of lung typical carcinoid. This subtype is characterized by progressive status and plasma ProGRP elevation, which are highly comparable with SCLC. We also suggest that immediate resection with mediastinal lymph node dissection is effective against such a SCLC-like typical carcinoid. In summary, we describe a rare case of EAS secondary to a DDAVP-sensitive but V1b receptor-negative lung typical carcinoid with lymphatic metastasis and ProGRP elevation.
Disclosure
The authors declare no conflict of interest associated with this research.
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