Correspondence *Department of Medical Genetics, McGill University Health Centre, 1650 Cedar Avenue, Room L10–120, Montreal, Quebec H3G 1A4, Canada

Email laura.palma@muhc.mcgill.ca

The case

A 73-year-old white man was referred to a cancer genetics clinic for evaluation of his extensive upper and lower gastrointestinal polyposis. Approximately 12 months before referral, a biopsy of two gastric polyps had revealed synchronous gastric carcinomas: one was a moderately differentiated adenocarcinoma (Figure 1A), and the other was a poorly differentiated adenocarcinoma that arose in a gastric adenoma (not shown). The gastric carcinomas were independent, primary lesions and were both classified as pathological stage 1 (pT1) lesions. The patient underwent a total gastrectomy, omentectomy and cholecystectomy. In addition to the gastric carcinomas, the gastrectomy specimen revealed the presence of one adenoma, multiple sessile polyps and multiple hyperplastic polyps, mainly in the proximal stomach.

Figure 1 Histological and endoscopic features of the case patient.

(A) Moderately differentiated adenocarcinoma invading into the submucosa (arrow), in proximity to the submucosal blood vessels (asterisk). Stained with hematoxylin and eosin, magnification 50. (B) Ganglioneuroma of the colon. Note the ganglion cells (asterisks) scattered within the lamina propria, intermixed with a neural spindle-cell component (arrow). Stained with hematoxylin and eosin, magnification 200. (C) Endoscopic image that shows the lumpy nature of the esophageal wall, owing to the presence of diffuse glycogenic acanthosis. (D) Glycogenic acanthosis of the esophagus with mucosal thickening, caused by excess glycogen levels (stained with hematoxylin and eosin magnification 100).

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A review of the patient's medical records confirmed an approximate 20-year history of gastric and colonic polyps, for which he had undergone serial screening colonoscopies and gastroscopies. At age 61, an inflamed fibroma had been excised from the dorsum of his right hand, and 4 years later, small, colonic polyps that were histologically identified as ganglioneuromas, were removed during colonoscopy (Figure 1B). Colonoscopy specimens obtained before the gastrectomy also revealed the presence of numerous inflammatory and hyperplastic polyps, and two tubular adenomas had been excised—one each from his cecum and rectum. Upper-gastrointestinal endoscopy performed before the gastrectomy revealed diffuse esophageal lesions (Figure 1C), and microscopic examination of some of these lesions showed glycogenic acanthosis (Figure 1D).

Review of the patient's family history revealed that his mother had died at 78 years of a gastric adenocarcinoma, although the available medical records provided no evidence of a prior history of gastrointestinal polyps. The patient reported that his daughter had a gastric polyp removed, but no other notable features in his family history suggested Cowden's syndrome; in particular, no cases of breast, thyroid or endometrial cancers had been reported.

Physical examination revealed that the patient was normotensive. His head circumference measured 59 cm; above the 97^th percentile for his age. He had multiple, hyperpigmented macules involving his lower lip, and multiple mucosal swellings on his inner lip that had a cobblestone appearance. Examination of the patient's skin revealed multiple skin tags, located mainly on his upper limbs and trunk. Examinations of his neck and thyroid did not reveal anything remarkable. A soft, painless, freely mobile swelling that was clinically consistent with a lipoma was noted to the right of his abdominal midline. No penile hyperpigmentation or freckling was observed, and a neurological examination did not find clinical signs suggestive of cerebellar dysfunction.

Genetic and molecular pathology investigations

A clinical diagnosis of Cowden's syndrome was made on the basis of macrocephaly, mucosal lesions, gastrointestinal hamartomas, abdominal-wall lipoma and fibroma of the hand. Molecular genetic analysis of phosphatase and tensin homolog (PTEN), the only gene known to be associated with Cowden's syndrome, was organized. Full sequencing of PTEN (exons 1–9) and intron–exon boundaries was undertaken and a heterozygous G>T nucleotide change was identified in exon 8 of PTEN. This mutation results in replacement of the normal glycine codon (GGA) at amino acid 293 with a stop codon (TGA), which is denoted Gly293X. Of interest, this mutation has not previously been reported in association with Cowden's syndrome. Immunohistochemical staining of both gastric cancers showed loss of PTEN protein, whereas surrounding non-neoplastic tissues retained PTEN immunoreactivity (Figure 2); this difference suggests that PTEN had a key role in the development of this patient's gastric cancer. Although Gly293X is a novel mutation, the clinical and molecular pathology findings provide supportive evidence that this nonsense mutation is the cause of Cowden's syndrome in this patient.

Figure 2 PTEN immunohistochemistry results that show positive (brown) staining within endothelial cells (internal control) and no staining of the adenocarcinoma (counterstained with hematoxylin and eosin, magnification 400).

 

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Discussion of diagnosis

Cowden's syndrome is a rare, but probably under-recognized multiple hamartoma disorder caused by mutations in the tumor-suppressor gene, PTEN.¹ This syndrome is one of a group of heterogeneous disorders known collectively as the PTEN hamartoma tumor syndrome (PHTS). The majority of patients with Cowden's syndrome have pathognomonic, mucocutaneous lesions, and macrocephaly is a notable feature. Affected individuals usually develop clinical features by their second decade of life;² however, the diagnosis of some patients can be delayed because of the considerable heterogeneity in clinical presentation. Importantly, Cowden's syndrome confers an increased risk of benign and malignant tumors of the breast, endometrium and thyroid.²

The hamartomatous polyps that are seen in 60–90% of patients with Cowden's syndrome can be found throughout the gastrointestinal tract and can occur in association with ganglioneuromas and lipomatous and inflammatory polyps.³ Although hamartomatous polyps are generally regarded as having low malignant potential, malignant transformation within adenomatous polyps has been observed in patients with Cowden's syndrome who have mixed adenomatous and hamartomatous polyps.⁴ Screening recommendations for Cowden's syndrome published by the National Comprehensive Cancer Network (NCCN), however, do not provide specific guidelines for endoscopic screening of the gastrointestinal tract,⁵ partly because the risk of gastrointestinal cancers in these patients is not well characterized. Furthermore, among sporadic gastric cancers, genetic and epigenetic alterations of PTEN seem to be rare,⁶ which suggests that PTEN does not have an important role in gastric carcinogenesis of the general population.

To our knowledge, only one other case of gastric cancer that was diagnosed in a patient with Cowden's syndrome has been reported in the literature. Hamby et al.⁷ described a case of gastric carcinoma in situ, which arose in a hyperplastic polyp of a 66-year-old woman who had previously unrecognized Cowden's syndrome. A case of gastrointestinal cancer that involved synchronous colonic carcinomas of the ileocecal valve and ascending colon was also reported in a 56-year-old patient with Cowden's syndrome. In this case, the adenocarcinomas seemed to arise within hyperplastic polypoid lesions, and heterozygosity for the PTEN wild-type allele was confirmed by loss-of-heterozygosity analysis.⁸

Differential diagnosis

Disseminated hamartomatous polyps of the upper and lower gastrointestinal tracts are a well-recognized feature of Cowden's syndrome.⁴ The diagnosis of Cowden's syndrome in this patient, however, was complicated by the presence of predominantly nonhamartomatous gastrointestinal polyps, with the exception of the colonic ganglioneuromas. These polyps, however, could have easily been overlooked on screening colonoscopy, because the other colonic polyps tended to be either hyperplastic or inflammatory. In addition, the patient had multiple adenomatous, gastrointestinal polyps in the stomach, cecum and rectum. Together, these findings highlight the diagnostic challenges of differentiating between hamartomatous and adenomatous hereditary polyposis syndromes, particularly in the absence of additional clinical, pathological and/or molecular findings. The presence of diffuse, esophageal glycogenic acanthosis in the patient we describe emphasizes the importance of additional histopathological features in making such a distinction. Glycogenic acanthosis in the presence of features of Cowden's syndrome is associated with a high probability of identifying a PTEN mutation.⁹ Some clinicians propose that the finding of glycogenic acanthosis should be considered pathognomonic of Cowden's syndrome in patients with benign gastrointestinal polyps.¹⁰

The clinical overlap between hamartomatous polyposis syndromes and PTEN-related disorders¹¹ is also demonstrated in the family described in this article. Although hyperpigmented macules of the lips have been seen in patients with Cowden's syndrome, this finding is more suggestive of Peutz–Jeghers syndrome, particularly in the presence of adenomatous polyps.¹² A mature age of disease onset, along with the presence of other clinical and histopathological features, enabled clinical exclusion of Peutz–Jeghers syndrome in our patient. Although seen in Cowden's syndrome, lipomas are more commonly associated with BRRS, a hamartomatous polyposis syndrome within the PHTS spectrum that is also caused by mutations in PTEN. A clear overlap can be identified between BRRS and Cowden's syndrome within this spectrum of disorders; however, the patient described in this article satisfied the diagnostic criteria for Cowden's syndrome as adapted by the International Cowden's Consortium.² He had pathognomonic mucosal lesions as well as macrocephaly as a major criterion, and gastrointestinal hamartomas, hand fibroma, abdominal-wall lipoma and multinodular goiter as minor criteria. A diagnosis of BRRS is, however, probably more correct in the patient's son and grandson, which again highlights that Cowden's syndrome and BRRS do not represent distinct disorders, but one and the same disorder along a broad spectrum.

Treatment and management

Conclusions

We highlight the importance of a thorough diagnostic work-up in the diagnosis and management of patients with gastrointestinal polyposis. The contribution of clinical examination clues to the overall diagnostic process cannot be overemphasized, and the features of the patient presented here clearly demonstrate this point. In light of the considerable clinical heterogeneity of PHTS, we also highlight the necessity of accurate histological typing of polyps, as well as a detailed medical and family history, in establishing a diagnosis of Cowden's syndrome or its related conditions. The rare occurrence of two synchronous gastric adenocarcinomas in this patient also emphasizes the need for further research to characterize the risk of gastrointestinal cancers in patients with Cowden's syndrome.

Acknowledgments

Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Subject areas under which this article appears: Cancer | Genetics