Expanding Spectrum of Malignancies in ALPS: A Cancer Predisposing Syndrome?.

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of apoptosis characterized by lymphadenopathy, splenomegaly and peripheral accumulation of TCR αβ+ CD4-/CD8- double-negative T lymphocytes (DNT cells), often leading to multilineage cytopenias. ALPS-FAS with germline FAS mutations is the most common form of ALPS and has been associated with an increased risk for lymphoma (Straus, Blood 2001). We have now identified additional malignancies in our cohort, further underscoring the importance of cancer surveillance in ALPS patients.

This is an update of the ALPS-associated cancers within the NIH cohort consisting of 240 individuals with ALPS-FAS from 116 families and 106 patients with ALPS-U (undetermined genetic defect).

We previously reported 11 patients in our ALPS cohort with Hodgkin lymphoma (HL) and 9 patients with B cell Non-Hodgkin lymphoma (NHL)(Rao and Oliveira, Blood 2011). Here we report 6 additional types of malignancies associated with ALPS in 5 patients. Four of these patients have an intracellular FAS mutation. The frequency of malignancies within our ALPS cohort is 7.2% (25/346 patients) with a male:female gender distribution of 20:5. The age at the time of cancer diagnosis ranged from 5 to 60 years (median 22years).

As outlined in the Table below, ALPS-FAS patient #45.2 developed squamous cell carcinoma of the tongue that eventually led to his death from complications. His son also had ALPS-FAS with lymphoma. ALPS-FAS patient # 197.1 developed testicular cancer with malignant mixed germ cell tumor with seminoma and embryonal carcinoma elements. Marked leukocytosis during the first cycle of BEP chemotherapy led to a diagnosis of chronic myelogenous leukemia (CML) based on detecting a BCR-ABL translocation by PCR in peripheral blood and bone marrow.

A patient with ALPS-FAS who previously had lymphoma developed histiocytic sarcoma and died following failed alloBMT. ALPS-FAS patient #121.13 developed acinic tumor of the parotid gland. A patient with ALPS-U (i.e. undetermined genetic defect) developed Ph+ acute lymphoblastic leukemia treated with an allogenic matched unrelated donor stem cell transplant and he is currently doing well.

View large

View Large

Although lymphoma continues to be the most common type of malignancy seen in ALPS patients, we have observed additional types of cancers in this population suggesting a broader cancer predisposition than previously thought. While none of these additional cancers, except for squamous cell carcinoma, have been previously associated with somatic FAS mutation in the Catalogue of Somatic Mutations in Cancer (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/), germline mutations affecting the intracellular component of the Fas protein confer a greater risk for developing malignancy as 22 malignancies were noted among 200 ALPS-FAS patients with such intracellular mutations. While this limited sample size does not allow us to definitively associate these cancers with ALPS, our findings highlight the need for active cancer surveillance in ALPS patients. Moreover, ALPS should be suspected in patients with sporadic lymphomas and other cancers that have a pertinent clinical and family history of cytopenias, hypersplenism and lymphoproliferation.

No relevant conflicts of interest to declare.