UPMC Dermatopathology "Case of the Month" Presentations
UPP - Department of Dermatology, Dermatopathology Unit
Kristina Paley, MD ; Drazen Jukic, MD, PhD; Joseph C. English III, MD
JULY 2007 CASE OF THE MONTH
DISCUSSION & DIAGNOSIS
Diagnosis
Cowden Syndrome
Discussion
Clinical findings of Cowden or multiple hamartoma syndrome were first described by Costello in 1940 in a female patient who died from breast cancer at an early age.1 In 1963, a term Cowden syndrome was coined by Lloyd and Dennis after their patient, Rachel Cowden, with family history of the disorder, presented with multiple cutaneous and mucosal lesions, fibrocystic disease of the breast and thyroid abnormalities. 1
Even though the genetic basis behind Cowden syndrome was strongly suspected, it was not until 1996 that the gene responsible for the multiple hamartoma syndrome was mapped to chromosome 10 2 and then identified as PTEN.3 PTEN which stands for phosphatase and tensin homolog deleted on chromosome 10, is a tumor suppressor gene which encodes a phosphatase that normally dephosphorylates serine and threonine residues thus opposing the activity of downstream AKT serine/threonine kinase.1 When functioning normally, PTEN regulates cell cycle, cell migration, angiogenesis and apoptosis through various interconnecting pathways.1 Mutations in PTEN have been found in a number of malignancies most of which are common to Cowden syndrome including breast carcinoma, meningioma, endometrial carcinoma, ovarian tumors, renal cell carcinoma and melanoma. 1
The most prominent and common features of the Cowden syndrome are the mucocutaneous hamartomas (most often trichilemmomas) that present as facial papules and lead to cobblestone appearance of the mucosa in as many as 80% of the patients.1,4 Acral, including palmoplantar keratoses, hemangiomas, lipomas, neuromas and xanthomas are other cutaneous lesions that can be seen in patients with this multiple hamartoma syndrome. 4
As the history of our patient demonstrates, all patients with Cowden syndrome must be regularly screened for breast, thyroid and endometrial carcinomas that are part of the International Cowden Consortium Diagnostic –Major Criteria.1 Other malignancies associated with Cowden Syndrome but with less frequency include SCCs, BCCs, Merkel cell carcinomas, melanomas, lymphomas, hepatocellular and renal cell carcinomas. 1
Differential diagnosis of Cowden syndrome should always include a family of Hamartomatous Tumor Syndromes (PHTS) that also have been found to have PTEN gene abnormalities with variable frequencies. In this category is Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba Syndrome, Proteus Syndrome and VATER syndrome. 1
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