Allergies Don’t Cause a Fever — At Least, Not Directly

New Method Differentiates Leukemias In WHO's 5th Edition

Large granular lymphocytic leukemias (LGLLs) are a heterogeneous group of rare chronic lymphoproliferative disorders characterized by the clonal proliferation of cytotoxic lymphocytes. Among them, T-cell LGLL (T-LGLL) and NK-cell LGLL (NK-LGLL) are the most prominent. Due to overlapping morphological, clinical, and immunophenotypic characteristics, distinguishing these disorders from related entities such as T-prolymphocytic leukemia (T-PLL), adult T-cell leukemia/lymphoma (ATLL), Sézary syndrome (SS), and aggressive NK-cell leukemia (ANKL) presents a significant diagnostic challenge. This review integrates recent molecular insights and updates from the WHO 5th edition classification to refine diagnostic precision and inform individualized patient management strategies.

T-cell Large Granular Lymphocytic Leukemia (T-LGLL)

T-LGLL presents with chronic neutropenia, anemia, and autoimmune phenomena—most notably rheumatoid arthritis. Morphologically, cells are small to medium-sized with azurophilic granules. Immunophenotyping reveals a CD8+ cytotoxic profile with frequent expression of CD57, CD16, and granzyme markers. A defining molecular feature is the presence of STAT3 mutations, with STAT5B mutations occasionally observed in CD4+ variants. Clonality is confirmed by T-cell receptor (TCR) gene rearrangement. The WHO's updated diagnostic criteria emphasize increased circulating cytotoxic T cells, aberrant immunophenotype, and TCR monoclonality, with bone marrow infiltration and STAT mutations as supportive findings. T-LGLL generally has a favorable prognosis when treated with immunosuppressive agents like methotrexate or cyclophosphamide.

Natural Killer-cell Large Granular Lymphocytic Leukemia (NK-LGLL)

NK-LGLL shares many clinical features with T-LGLL, including cytopenias and autoimmune associations, but lacks TCR rearrangement. Morphologically indistinct from T-LGLL, diagnosis hinges on flow cytometric identification of aberrant NK-cell receptor expression (e.G., restricted KIR isoforms, altered CD94/NKG2A). STAT3 and TET2 mutations are common, with unique subtypes defined by CCL22 mutations. Though indolent, treatment is only initiated in symptomatic cases.

T-Prolymphocytic Leukemia (T-PLL)

T-PLL is a highly aggressive peripheral T-cell leukemia. It typically presents with marked lymphocytosis, splenomegaly, and lymphadenopathy. T-PLL is molecularly defined by TCL1A or MTCP1 rearrangements, often accompanied by ATM mutations and JAK/STAT pathway activation. Immunophenotyping reveals CD4+/CD8+ coexpression and overexpression of TCL1A, which helps differentiate it from LGLLs. Despite recent therapeutic advances such as alemtuzumab and stem cell transplant, prognosis remains poor.

Adult T-cell Leukemia/Lymphoma (ATLL)

ATLL is etiologically linked to HTLV-1 infection and typically affects individuals from endemic regions. Clinical presentation varies across four subtypes: acute, lymphomatous, chronic, and smoldering. Hallmark features include hypercalcemia, lymphadenopathy, and flower-like nuclei in atypical cells. Immunophenotyping shows CD4+/CD25+ expression with HTLV-1 integration confirmed via molecular techniques. Diagnosis requires demonstration of HTLV-1 proviral integration. Prognosis is subtype-dependent but generally guarded.

Sézary Syndrome (SS)

SS is a leukemic form of cutaneous T-cell lymphoma, presenting with erythroderma, lymphadenopathy, and circulating cerebriform T cells. Immunophenotypic markers include CD4 positivity with loss of pan-T-cell antigens and high PD1 expression. Genetic studies reveal clonal TCR rearrangement and frequent mutations in genes like STAT5B, TP53, and PLCG1. SS differs from LGLLs in morphology, skin tropism, and aggressive clinical course, with median survival around 32 months.

Aggressive NK-cell Leukemia (ANKL)

Though morphologically similar to LGLLs, ANKL is rapidly progressive, often associated with Epstein-Barr virus (EBV), and displays severe cytopenias and systemic symptoms. It is negative for TCR rearrangement and has a poor prognosis, necessitating prompt differentiation from indolent NK-LGLL.

Conclusion

This review highlights the diagnostic complexity of LGLLs and their mimics, emphasizing the importance of integrating morphological, immunophenotypic, and molecular data in line with the WHO 5th edition. Molecular mutations such as those in STAT3, TET2, and TCL1A play pivotal roles in refining classifications and prognostic stratification. While diagnostic clarity has improved, further large-scale studies are needed to validate these frameworks and explore novel therapeutic approaches tailored to individual molecular profiles.

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Higgs, R. Thiopurines increase risk of lymphoproliferative disorders in patients with IBD. Nat Rev Gastroenterol Hepatol 7, 67 (2010). Https://doi.Org/10.1038/nrgastro.2009.227

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DNR Seeks Help With Wild Turkey Assessment

BRAINERD — The Minnesota Department of Natural Resources is conducting a wild turkey health assessment this spring, and through collaboration with the Minnesota chapter of the National Wild Turkey Foundation, all participating hunters will be entered in a raffle to win a Winchester SXP Waterfowl Max 7.

"In fall 2024, the MNDNR Wildlife Health Program received numerous reports of turkeys with lesions on their heads," Elizabeth Baker, DNR wildlife health specialist, said in a news release. "Several of these turkeys were tested for Avian Poxvirus (which is known to circulate in Minnesotan wild turkeys) and Lymphoproliferative Disease Virus (LPDV, which was not previously known to be circulating in Minnesota, but a disease of concern in southern US states). Surprisingly, all turkeys tested positive for both Avian Poxvirus and LPDV. While these diseases do not infect humans, they may impact survival and reproduction in both wild and domestic turkeys. These detections heightened the need for a better understanding of what pathogens may be circulating in our wild turkeys, which prompted the DNR to initiate a pilot project to assess turkey health."

The DNR is specifically looking for hunters to submit samples from their harvested birds in Turkey Permit Area 507. If the season is successful, the DNR hopes to expand to a statewide data collection in 2026. Turkey Permit Area 507 includes Wadena, Hackensack, Backus and Little Falls.

To participate in the health assessment, hunters can request a collection kit at bit.Ly/TurkeyAssessment . If a turkey is harvested in Turkey Permit Area 507 during the 2025 spring hunting season, participating hunters will be responsible for collecting the requested samples by following the kit instructions. The kit will then be returned to the DNR, and test results from the harvested turkey will be given back to the hunter and used in the project's summary.

Hunters should note all testing, shipping and sample collection supplies are provided at no cost to hunters. The kits will begin shipping on March 31 and will be shipped within three days of request. There are 600 kits available.

The raffle drawing will take place at the National Wild Turkey Foundation Strutting Blackbeards sponsor dinner at 5 p.M. Aug. 15, courtesy of the Minnesota chapter of the foundation. For more information on the raffle, contact Chapter President Ralph Warzecha at Turkeywhisperer57@gmail.Com or 320-766-1692.

"The NWTF is grateful that the MNDNR is doing a health assessment on our wild turkey populations before there are any immediate health concerns to address," said Clayton Lenk, National Wild Turkey Foundation district biologist for Minnesota, North Dakota, South Dakota and Wisconsin. "The information from this health assessment will give us important knowledge about what viruses and diseases might be on the landscape and will also give us great information on how to further protect the great number of commercial turkey producers in the state."

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