Clinical Pearls & Morning Reports

Posted by Carla Rothaus, MD

Published August 2, 2023


Can RAS-associated autoimmune leukoproliferative disorder be confused with myeloid cancers?

A diagnosis of RAS-associated autoimmune leukoproliferative disorder can provide a unifying framework that accounts for a spectrum of autoimmune disorders and a clonal myeloid disorder in a patient. Read the NEJM Clinical Problem-Solving Article here.

Clinical Pearls

Q: Is Sjögren’s syndrome associated with an increased risk of lymphoid cancer?

A: Sjögren’s syndrome is a chronic autoimmune disease associated with lymphocytic infiltration of the lacrimal, salivary, and other exocrine glands. Patients often present with sicca symptoms, but extraglandular manifestations occur in approximately 20% of patients (although higher frequencies have been reported in some case series), including leukopenia (in 14 to 42% of patients). Sjögren’s syndrome is also associated with an increased risk of lymphoid cancer.

Q: What autoantibodies are typically present in patients with neuromyelitis optica spectrum disorder?

A: Neuromyelitis optica spectrum disorder is an autoimmune inflammatory demyelinating disease of the central nervous system. Patients with this disease may present with vision changes (optic neuritis), sensory changes or limb weakness (transverse myelitis), nausea and vomiting (involvement of the area postrema), or less commonly, symptoms associated with lesions in the hypothalamus, brain stem, or cerebrum. In addition to MRI, the diagnostic workup includes serum testing for AQP4 IgG, which is typically present.

Morning Report Questions

Q: Is RAS-associated autoimmune leukoproliferative disorder common?

A: Data on the prevalence of this disorder are limited, but RAS-associated autoimmune leukoproliferative disorder appears to be rare. Reported associated conditions include pericarditis, Sjögren’s syndrome, and neuromyelitis optica spectrum disorder, as well as glomerulonephritis, splenomegaly, and cutaneous involvement. Associated laboratory manifestations include somatic mutations in NRAS or KRAS, peripheral monocytosis, polyclonal hypergammaglobulinemia, and numerous autoantibodies (e.g., ANA, antibodies detected on a direct antiglobulin test, and rheumatoid factor). The clinical course is typically indolent, but treatment is often administered to suppress autoimmune manifestations.

Q: Can RAS-associated autoimmune leukoproliferative disorder be confused with myeloid cancers?

A: The diagnosis of RAS-associated autoimmune leukoproliferative disorder is challenging because there is clinical, pathologic, and molecular overlap with myeloid cancers, such as juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia (CMML). In patients with RAS-associated autoimmune leukoproliferative disorder, the somatic NRAS or KRAS mutation is thought to occur in a hematopoietic stem cell that contributes to mature myeloid and lymphoid lineages. By contrast, somatic RAS mutations in patients with CMML are typically late events that are restricted to the myeloid lineage and are associated with an increased risk of transformation to acute myeloid leukemia. Juvenile myelomonocytic leukemia (in children) and CMML (in adults) have been reported in isolated cases of RAS-associated autoimmune leukoproliferative disorder, which suggests that these clonal disorders probably exist along a biologic continuum. Therefore, hematologic surveillance is recommended in order to monitor for progression to an overt myeloid cancer.

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