Systemic mastocytosis in a patient with Cowden syndrome
Authors: Srinivas K. Tantravahi, Jonathan Schumacher, Randall W. Burt, Todd W. Kelley, Michael W. N. Deininger
Journal: American Journal of Hematology (2014)

To the Editor: A 22-year-old woman presented with chronic lower back pain, abdominal pain and intermittent constipation, and diarrhea. MRI of the lumbar spine showed abnormal signal intensity in the vertebral bodies, suggesting marrow expansion. Past history included laparoscopic hysterectomy for early stage endometrial cancer (age 15), local excision of a benign breast tumor (age 16), and endoscopic removal of multiple colonic polyps from age 17. Physical examination was notable for mild macrocephaly, oral papillomas, and facial trichilemmomas. Complete blood count and serum chemistries, including tryptase, were normal. Sequencing of peripheral blood revealed a heterozygous PTEN Arg335X (1003C>T) mutation (Fig. 1A), establishing a diagnosis of Cowden syndrome; the identical mutation was detected in the patient's mother. No mutations were detected in the MLH1, MSH2, and MSH6 genes. Bone marrow biopsy showed hypercellular marrow with aggregates of abnormal spindle shaped mast cells (>15 cells per high power field) co-expressing CD2 (Fig. 1B), but not CD25 (not shown). Karyotyping was normal. Review of previously removed colonic polyps showed increased mast cells in the lamina propria, some appearing spindle shaped (Fig. 1C). Allele-specific PCR on bone marrow and single cell DNA from mast cells obtained through laser microdissection of colon biopsies showed no evidence of a KIT exon 17 mutation including D816V. Skeletal survey and bone density were normal. A diagnosis of indolent systemic mastocytosis (SM) was made per the WHO 2008 classification and mediator-targeted therapy initiated, with clinical improvement. A: Sequencing electropherogram, showing a germline heterozygous pathogenic mutation in the PTEN (c.1003C>T, p.Arg335X) gene (black arrow). B: Bone marrow biopsy showing a large cluster of atypical spindle shaped mast cells (mast cell tryptase immunohistochemical stain; 400× magnification). C: Colon biopsy showing increased CD117-positive mast cells in the lamina propria (CD117 immunohistochemical stain; 1000× magnification). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Cowden syndrome is an autosomal dominant familial cancer syndrome caused by germline mutations in the phosphatase and tension homolog (PTEN) gene 1, a tumor suppressor gene on chromosome 10q23 that negatively regulates the phosphatidyl inositol 3′ kinase (PI3K)-AKT- mTOR signaling pathway 2. Loss of PTEN function in somatic cells is caused by inactivating mutations in the second allele, which promote oncogenesis, following the classical tumor suppressor paradigm 3. SM is a clonal hematopoietic disorder characterized by proliferation of morphologically and phenotypically abnormal mast cells. Most patients with SM harbor somatic gain of function mutations of KIT, most commonly KITD816V in the activation loop of the kinase. These mutations lead to constitutive kinase activation, increased cell proliferation and decreased apoptosis 4. The PI3K pathway plays a critical role in KIT mediated oncogenesis by increasing levels of phosphatidylinositol triphosphate (PIP3), a second messenger involved in activation of downstream signaling cascades 5. In physiological conditions, PI3K is counterbalanced by PTEN, which dephosphorylates PIP3. Knockdown of PTEN in human mast cells leads to increased levels of PIP3, enhanced cytokine production, proliferation, and survival and PTEN-/- mice develop a mastocytosis like disease 6. To our knowledge, SM has not been reported in patients with Cowden syndrome, suggesting that another yet unidentified mutation may be required to establish the disease. Nonetheless our patient further illustrates the critical regulatory effects of PTEN and PI3K pathway for mast cell proliferation and demonstrates that mutations in the PTEN gene may contribute to SM, possibly in the absence of activating KIT mutations. A bone marrow biopsy and specific staining of gastrointestinal biopsies should be considered in patients with Cowden disease who develop SM like symptoms. Srinivas K. Tantravahi1*, Jonathan Schumacher2, Randall W. Burt1, Todd W. Kelley3, and Michael W. N. Deininger1 1Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah; 2ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah; 3Department of Pathology, University of Utah and ARUP Laboratories, Salt Lake City, Utah