Bronchioloalveolar carcinoma: a new cancer in Peutz-Jeghers syndrome
Introduction
In 1921, Peutz described a Dutch family with multiple hamartomatous intestinal polyps and characteristic melanin spots of the skin and mucosa [1]. In 1949 Jeghers and colleagues described three further families seen at the Johns Hopkins Clinic with identical lesions [2]. Since, the eponym Peutz-Jeghers syndrome (PJS) is used for this hereditary disorder with autosomal dominant inheritance [3], [4]. The genetic basis of PJS was identified in 1997 as a germ line mutation in a gene localized on chromosome 19p13.3, which encodes a serin–threonine kinase number 11 (STK11) [5], [6], [7]. STK11 is the human homologue of the mouse gene LKB1, with approximately 90% protein identity [7], [8].
The major clinical problem of PJS patients is the disposition of intestinal polyps to mechanical complications [9]. In addition there is an increased prevalence of cancer (Johns Hopkins Registry: 28% [10]; St. Mark's Registry: 22% [11]), as well as of uncommon mostly non-malignant gonadal tumours [12]. Until 2000, a total of 143 cases of various PJS-associated cancers were reported, including six cases of lung cancer [12]. Curiously, most PJS-associated cancers arose in organs without PJS-related hamartomas [10], [11], [12], [13].
In 2002, inactivation of the PJS gene STK11/LKB1 was demonstrated as a common event in sporadic adenocarcinomas of the lung [14]. This raises interest into molecular studies of PJS-associated lung cancer, but these are not available to date. Herein, we report a new case with studies of the STK11/LKB1 gene locus.
Section snippets
Case report
A male patient was diagnosed during childhood with a classical phenotype of Peutz-Jeghers syndrome, i.e. melanotic macules of the lips (Fig. 1a) and multiple hamartomatous polyps in the small and large intestine (Fig. 1b) and stomach. His parents and sister did not have a PJS phenotype. He was under surveillance for possible complications of polyposis.
At the age of 22 years, the patient presented with recurrent pneumonia. Antibiotic treatment resulted in remission of pulmonary symptoms, but
Surgical pathology
In the right lower lobe, obtained at first operation, a tumour mass with a maximal diameter of 8.5 cm was present extending towards the visceral pleura, but without serosal perforation. Histologically, the tumour consisted of tall columnar cells with varying amounts of cytoplasmic mucin, and mild nuclear atypia. Tumour cells were growing along the alveolar walls, but without stromal, vascular, or pleural invasion (Fig. 2b). Alveolar spaces were frequently filled with mucinous secretions.
Molecular pathology
DNA of lung cancer, and DNA from normal lung and lymph node was extracted from formalin-fixed paraffin-embedded tissues that were obtained at surgery. Samples from BAC were dissected yielding approximately 80% tumour cells. After deparaffinization DNA was purified using the DNeasy Tissue Kit (Qiagen, Hilden, Germany).
Normal tissue DNA was analysed by automatic sequencing of the STK11 gene (ABI 310 Sequencer; Applied Biosystems). In exon 2, a frameshift caused by an insertion of an adenine in
Discussion
Bronchioloalveolar carcinoma (BAC) is a peculiar subtype of lung cancer [15]. We report, to the best of our knowledge, the first case of PJS-associated BAC, which is the seventh case of PJS-associated lung cancer [10], [11], [13]. In our patient BAC occurred as early as at the age of 22 years, while PJS-associated extra-gastrointestinal cancer is uncommon in patients before the age of 30 years [9], [12]. Patients with sporadic BAC have a mean age of 68 years at diagnosis [16], [17].
BAC has been
Acknowledgement
We thank Andrea Whalley, MD, Heidelberg, for help with the gross photographies.
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