Atypical pulmonary carcinoid tumour in a 28-year-old nonsmoker with Prader–Willi syndrome

To the Editors:

In recent years, the life expectancy of patients with Prader–Willi syndrome (PWS) has increased, unveiling several cases of early-onset cancer and raising the question whether the condition predisposes to tumourigenesis. We encountered a unique occurrence of pulmonary atypical carcinoid in a young never-smoker with PWS.

A 28-yr-old, morbidly obese male with PWS was admitted as a candidate for gastric bypass. He was a lifetime nonsmoker, and his height, weight and body mass index were 1.78 m, 175 kg, and 55.2 kg·m⁻², respectively. Polyphagia, obesity and a failure to achieve psychosocial milestones became apparent at the age of 5 yrs, when PWS was diagnosed based on clinical findings and a de novo deletion of the proximal region of chromosome 15 (del(15)(q11–q13)). Type II diabetes mellitus was diagnosed at the age of 17 yrs, and dietary control along with administration of sulfonylurea was initiated. The remainder of the anamnesis included low levels of testosterone, which were treated with monthly intramuscular depot injections of testosterone enanthate (250 mg).

On admission, the patient reported mild shortness of breath, nonproductive cough and malaise of indeterminate origin. A physical exam revealed markedly increased subcutaneous fat, picking scars, hypoplastic external genitalia and a polyphonic wheeze over the right hemithorax. Pulse was regular and of normal rate, diastolic blood pressure was elevated (98 mmHg) and haemoglobin oxygen saturation was 96% in room air. Electrocardiography was normal. Laboratory data, including blood cell counts, routine serum biochemistry and coagulation times, were within normal limits, except for fasting plasma glucose (178 mg·dL⁻¹) and lipids (total cholesterol 233 mg·dL⁻¹; high-density lipoprotein cholesterol 32 mg·dL⁻¹; triglycerides 322 mg·dL⁻¹).

A pre-operative chest radiograph, performed routinely but also prompted by the patient’s wheeze, showed a round, regular-shaped opacity of soft-tissue quality measuring 7×5 cm superimposed on the right pulmonary hilum (fig. 1a). Computed tomography confirmed a 7.5×6.5×5 cm well-demarcated mass of soft-tissue density partially attached to the posteromedial structures of the right hemithorax in very close proximity to the posterior mediastinum (fig. 1b). Fibreoptic bronchoscopy revealed a pale tumour with well-defined margins measuring ∼1 cm in diameter and obliterating the bronchus intermedius by 90% (fig. 1c). The endobronchial portion of the tumour rested on a relatively limited base and was bronchoscopically removed.

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Figure 1–

a) Posteroanterior chest radiograph. Arrow indicates the tumour. b) Contrast-enhanced chest computed tomography at the pulmonary artery level. Arrow indicates the tumour. c) Bronchoscopic appearance of right bronchus intermedius tumour. Arrow indicates the endobronchial portion of the tumour. Inset: arrow indicates the location of the tumour in the tracheobronchial tree. d) Histology of pulmonary carcinoid tumour showing focal areas of necrosis. Arrows indicate necrotic areas (magnification 100×) Inset depicts tumour architecture and relative abundance of mitoses (400×). e) Two to 10 mitoses per high-power field were detected by Ki67 immunostaining. Arrows indicate mitoses (100×). f) High cytokeratin 8 expression indicated an epithelial origin. Brown colour indicates immunoreactivity (100×). High g) CD56, h) chromogranin and i) synaptophysin expression indicated neuroendocrine differentiation. Brown colour indicates immunoreactivity (100×). Scale bars = 100 μm.

Histopathological examination of endobronchial biopsies (fig. 1d–i) showed an atypical carcinoid with focal areas of necrosis (fig. 1d), two to 10 mitoses per 2 mm² detected by Ki67 immunostaining (fig. 1e), high cytokeratin 8 expression indicating epithelial origin (fig. 1f), and high CD56, chromogranin and synaptophysin expression indicating neuroendocrine differentiation (fig. 1g–i) [1]. There was no evidence of neoplasms of the pituitary, pancreas and parathyroid, as determined by brain magnetic resonance imaging and octreotide scanning. The tumour was pre-operatively staged as T3N0M0 (stage IIB) according to the 2009 TNM7 system, as the primary tumour measured >7 cm, but no locoregional or distant metastases were found [2]. Surgical resection was decided upon, and middle and lower bilobectomy was successfully performed, including removal of mediastinal lymph nodes. Post-operative histopathology showed a radical resection of all tumour with clear operative margins and no infiltration of lymph nodes by carcinoid tissue. The intra- and post-operative course was uneventful and the tumour had not recurred after 2 yrs of follow-up.

PWS, a multisystemic neurogenetic disorder first reported in 1956, affects ∼1 in 25,000 individuals. Commonly associated clinical features include infantile central nonprogressive hypotonia, hyperphagia, obesity, short stature, dysmorphism, small hands and feet, distinctive facial features, mental retardation, hypogonadism, hypogenitalism and cryptorchidism [3]. PWS is correlated to significant morbidity and mortality, with an associated death rate of 3% per year. However, with improved care, the life expectancy of patients with PWS has increased considerably in recent years, unmasking possible protumourigenic susceptibility [4]. Several reported cases of malignancy in persons with PWS, including Wilms’ tumour, leukaemia, lymphoma, seminoma, ovary teratoma, hepatoblastoma and multiple endocrine neoplasia type I, have raised the question of whether PWS predisposes to cancer, similar to the increased cancer risk associated with other congenital disorders with chromosomal defects [5]. To our knowledge, this is the first report of an atypical pulmonary carcinoid in a patient with PWS.

PWS is due to a combination of genomic imprinting (i.e. allele-specific silencing of gene expression via promoter methylation) combined with genetic lesions or alterations in Mendelian patterns of chromosomal inheritance and is regarded as a prototype of inherited epigenetic disorders [3]. In this regard, a critical region at bands q11–13 on maternal chromosome 15 is silenced by methylation; only the paternal allele is expressed. Hence, if this expressed paternal allele is lost via deletion, translocation, imprinting defect or inheritance of both chromosomes 15 from the mother, this region is not expressed at all. Approximately 70% of patients with PWS present a deletion of the paternal chromosome 15 at band q11–13 (del(15)(q11–q13)), whereas the syndrome develops in 25–30% as a result of maternal uniparental disomy for chromosome 15; in <1% of cases, the molecular abnormality is an imprinting defect [3].

Atypical carcinoids, tumours of intermediate malignancy in the spectrum of pulmonary neuroendocrine tumours, are rare: they represent 20% of pulmonary carcinoids, which, in turn, account for only 1% of all lung tumours in the USA, with an age-adjusted incidence rate of 0.5 per 100,000 population [6]. In contrast to typical carcinoid, atypical pulmonary carcinoid tumours present at an older mean age (65 versus 55 yrs) and are possibly epidemiologically associated with smoking [1]. Pulmonary carcinoids may arise solitarily or may contribute to the spectrum of multiple endocrine neoplasia type 1 syndrome. Atypical pulmonary carcinoid is diagnosed histologically, based on the presence of necrosis (which is never observed with typical carcinoid) and an intermediate mitotic index of two to 10 mitoses per 2 mm² (10 high-power fields of view on most microscopes); typical carcinoids, i.e. the low-grade counterparts of atypical carcinoids, have less than two mitoses per 2 mm⁻², whereas high-grade small cell and large cell neuroendocrine lung cancers feature >10. Genetic abnormalities documented in atypical carcinoids include 3p deletions in 73% of cases, loss of heterozygosity of the retinoblastoma gene in 22% and of 11q13 in 50%, and TRP53 abnormalities in 45% [1, 7].

Based on the present and previous reports of early-onset malignancies in patients with PWS, it is intriguing to hypothesise that one or more important tumour suppressor genes are located within the critical del(15)(q11–q13) region imprinted and/or deleted in PWS. Indeed, Necdin (NDN) is such a candidate tumour suppressor located within this chromosomal region. NDN protein functions similarly to the retinoblastoma (RB)1 tumour suppressor protein and interacts with tumour-related protein (TRP)53 to facilitate TRP53 degradation [8]. Interestingly, although NDN was identified as a gene imprinted in human and mouse, reduced expression of which might be responsible for PWS, mouse models of Ndn loss did not link Ndn with PWS [9]. Instead, evidence suggests that Ndn, as well as other genes located on del(15)(q11–q13), such as MKRN3, MAGEL2 and SNURF-SNRPN, may function as tumour suppressors in various tissues [8]. Indeed, cross-examining the genetic lesions found in pulmonary carcinoid tumours and PWS, one can hypothesise a possible pathway of carcinoid development in patients with PWS. In this regard, if a stabilising mutation occurs in the TRP53 tumour suppressor gene on an inherited background of PWS-associated NDN gene loss, excess nonlabile (i.e. mutant) TRP53 protein may accumulate intracellularly, leading to prevention of apoptosis of tumour-initiated neuroendocrine cells and carcinoid formation. In support of this hypothesis, approximately one-fifth of pulmonary carcinoids that develop in patients without inherited genetic disorders lack both or one of the two functional RB1 alleles, as well as normal TRP53 [1]. Since NDN functions complimentary to the RB1 tumour suppressor, it is plausible to hypothesise that, in patients with PWS who, by definition, lack functional NDN, TRP53 mutations may be more sustainable by initiated cells, leading to lung carcinoid tumour formation. In this regard, combined Rb1 and Trp53 inactivation in the respiratory epithelium has been shown to trigger high-grade neuroendocrine lung neoplasia in mice [10]. In humans with PWS, combined NDN and TRP53 inactivation could similarly present critical events. leading to pulmonary carcinoid tumours or their more aggressive counterparts, small and large cell neuroendocrine lung cancers.

In conclusion, we present a unique case of atypical bronchial carcinoid in a young patient with PWS. Together with published observations of early-onset neoplasia in patients with PWS, the case reported herein suggests a possible link between genetic lesions present in PWS and enhanced/early onset carcinogenesis in several organ systems. In the lungs, inherited loss of NDN, a gene contained within the critical locus on chromosome 15 that is deleted and/or imprinted in PWS, together with mutations in TRP53 and/or RB1, genes known to be frequently mutated in pulmonary neuroendocrine tumours, could provide a mechanistic link between PWS and enhanced neoplasia. As the survival of PWS patients gradually increases, this relationship is worthy of investigation.

• ©ERS 2011