Large Natural Killer Cell Lymphoma Arising From an Indolent Natural Killer Cell Large Granular Lymphocyte Proliferation

Archives of Pathology & Laboratory Medicine, Nov 2006 by Roullet, Michele R, Cornfield, Dennis B

COMMENT

In a recent review of LGL proliferations, it is estimated that approximately 5% are chronic, indolent NK expansions. 1 Patients with indolent NK-LGL proliferation have an entirely different clinical profile than those with aggressive NK cell leukemia, outlined in the most recent World Health Organization classification of hematolymphoid malignancies.3 The former have a chronic expansion of NK cells in the peripheral blood, generally few constitutional symptoms, absence of organomegaly at diagnosis, and usually a chronic, nonprogressive or slowly progressive clinical course. The latter typically have fever and other constitutional symptoms, hepatosplenomegaly, and an aggressive disease requiring systemic chemotherapy. Based on a molecular study of X-linked cytogenetic markers, 4 it would appear that most chronic NK-LGL expansions may be polyclonal rather than monoclonal, but the issue of clonality in this disorder has not yet been resolved.

Because of the relative rarity of chronic NK-LGL proliferations, only several small series have been published. The largest series available is from the Mayo Clinic.5 After a median follow-up of more than 5 years, none of the 14 patients had developed a lymphoma. One patient died of unrelated causes. The Japanese series of 33 patients with LGL lymphoid proliferations included 12 cases with a CD3-CD16 (NK) phenotype, 2 of which would now be classified as aggressive NK cell leukemia.6 The remaining 10 patients with NK-LGL proliferations all had stable or improving clinical courses; none developed a lymphoma.

The emergence of a clear-cut lymphoma in a patient with an indolent NK-LGL proliferation only recently has been well documented for the first time.2 Similar to our case, that patient developed a soft tissue mass with morphologic features of an aggressive, diffuse large NK-cell lymphoma after a period of relative clinical quiescence (9 months in that case, 4.5 years in our case). In both cases, the diagnosis of an aggressive NK-cell lymphoma was based on appropriate cytomorphologic features; an immunohistochemical profile consistent with, albeit not entirely specific for, true NK cells; negativity for tumoral EBV and for clonal rearrangement of the IGH and TCR genes; and a background setting of chronic NK-LGL lymphocytosis. Neither patient succumbed directly to the lymphoma. The first patient appears to have died of Guillain-Barre syndrome; our patient died of multiorgan failure after sepsis and a cerebral hemorrhage.

Although the observations described in these 2 reports at first appear unique, there is a suggestion in the medical literature of LGL proliferations that lymphoma may occasionally occur. In a series of 34 patients with LGL proliferations reported in 1987, 1 patient (number 31 of 34) developed splenomegaly, "an increasingly progressive clinical course" after a long quiescent period, and died 168 months after diagnosis.7 It is not clear whether this patient had a proliferation of NK-like T cells or of true NK cells. In a follow-up multicenter report in 1990 of a larger number of patients (N = 151) incorporating the previously mentioned series, 3 of 26 deaths were noted as having occurred secondary to an associated neoplasm, including "one with a diffuse undifferentiated lymphoma."8 No further details of that patient's underlying LGL proliferation or lymphoma were provided. The exact incidence of lymphoma emerging from a chronic NK-LGL proliferation is unknown but probably low. It is quite possible that cases that occur go unreported. Based on our literature review and on the present and recent case reports,2 we believe it would be prudent to consider the possibility of an aggressive lymphoma when a mass lesion occurs in a patient with a chronic NK-LGL proliferation.