Non-Neoplastic Morphologic Abnormalities of White Blood Cells and Macrophages

Pelger-Huet Anomaly

The Pelger-Huet anomaly is characterized by granulocytes that are either bilobed or completely unsegmented ( Fig. 3.1 ). The bilobed neutrophils are referred to as pince-nez (“nose pinch”) forms, referring to an old style of eyeglasses that sat on the bridge of the nose. Eosinophils typically have a unilobated nucleus. The chromatin is mature with heavy condensation, which is the same as seen in normal mature neutrophils. All cells in a peripheral blood smear will be affected. The cells are typically found only on manual review of peripheral blood smears, because automated hematology analyzers do not detect the neutrophils as abnormal in patients with Pelger-Huet anomaly. Inheritance of Pelger-Huet anomaly is usually autosomal dominant, although it is likely that new mutations are common. The prevalence is estimated at 0.01%. The unilobed forms of Pelger-Huet cells are occasionally called Stodtmeister forms. These cells can be the predominant cell type in the exceedingly rare homozygous form of Pelger-Huet anomaly. Homozygous patients may have varying degrees of psychomotor retardation, abnormal body stature, macrocephalus, ventricular septal defect, polydactyly, developmental delay, epilepsy, and skeletal abnormalities. In heterozygous Pelger-Huet anomaly, neutrophil function is normal, and there are no other clinical abnormalities. The Pelger-Huet anomaly is due to mutations in the laminin beta-receptor (LBR) gene that have been discovered in several kindreds. The gene maps to chromosome 1q41-q43.

Morphologic mimics of Pelger-Huet anomaly are more common than the true disorder ( Table 3.1 ). The changes of hypolobation can be seen primarily in three circumstances: as a reactive condition in association with infections (typically severe), in association with medications or drugs such as mycophenolate or valproate, or in cases of myelodysplastic syndromes or other myeloid stem cell disorders. When this hypolobation is seen in these circumstances, it is referred to as pseudo–Pelger-Huet or Pelgeroid change . Distinguishing the mimics and true Pelger-Huet anomaly is usually straightforward. In the case of myelodysplastic syndrome (MDS) or other myeloid neoplasms, the hypolobation is often accompanied by hypogranulation of neutrophils, as well as other dysplastic changes seen in erythroid elements, platelets, and megakaryocytes. In particular, isolated isochromosome 17q is a cytogenetic abnormality specifically associated with these changes. Patients with a myeloid neoplasm with isolated i17q have been characterized as having MDS/myeloproliferative features (including Pelgeroid changes), wild-type TP53, but frequent recurrent mutations in SRSF2, SETBP1, ASXL1 , and NRAS (30% to 60% reported incidence for each gene). In both reactive conditions and dysplastic-type changes, only a subset of neutrophils is usually affected, in contrast to the entire population in Pelger-Huet anomaly. Toxic changes of granulocytes may also be seen in cases associated with infection. Identification of drug-related cases requires knowledge of the clinical history and a high index of suspicion.

Myelokathexis

Myelokathexis is an exceedingly rare disorder of neutrophil development and function. Patients exhibit severe neutropenia, evident in infancy, which results in recurrent bacterial or fungal infections. The inheritance pattern is typically autosomal dominant, but recessive and sporadic cases have been described. Neutrophil precursors and especially mature neutrophils are retained in the bone marrow ( kathexis = retention), leading to hypercellularity and increased myeloid-to-erythroid (M:E) ratio. Morphologically, the neutrophil and neutrophilic marrow precursors have marked abnormalities of nuclear shape and lobation ( Fig. 3.2 ). Often, the chromatin appears fragmented and broken, with pyknotic chromatin lobes connected by a long strand of chromatin. Cytoplasmic vacuoles may be present. There are significant functional abnormalities of neutrophils and other marrow lineages, leading to abnormal innate immunity. Other abnormalities that have been associated with myelokathexis include skeletal abnormalities and growth retardation. Treatment with growth factors has been successful in some patients. Mutations in the chemokine receptor type-4 gene ( CXCR4 ; CD184 ) appear to be responsible for WHIM syndrome, which includes myelokathexis as a key component. CXCR4 signaling plays a critical role in bone marrow cellular homing.

WHIM syndrome is an autosomal-dominant immunodeficiency disease characterized by w arts, h ypogammaglobulinemia, i mmunodeficiency, and m yelokathexis. These patients have increased susceptibility to human papillomavirus infection and increased upper respiratory infections. CXCR4 also plays a role in lymphocyte trafficking and B-cell development and affinity maturation. A small molecule antagonist of CXCR4 (plerixafor) improves mobilization of neutrophils from bone marrow, and this and similar drugs may significantly improve quality of life in patients with WHIM syndrome.

Chédiak-Higashi Syndrome

Chédiak-Higashi syndrome (CHS) is an autosomal-recessive disorder that manifests in early childhood. It is characterized by immunodeficiency, recurrent infection, oculocutaneous albinism, bleeding tendency, and multiple neurologic abnormalities. The molecular defect has been defined as mutation in the CHS1 (LYST) gene located on chromosome 1q42.1-1q42.2. This gene product is involved in lysosomal trafficking. Abnormal endosomal-lysosomal fusion occurs in these patients and results in large, abnormal granules within granulocytes, monocytes, and lymphocytes ( Fig. 3.3 ). These abnormal granules result from fusion of normal secondary granules of neutrophils, eosinophils, basophils, or the cytotoxic granules of monocytes or lymphocytes. Peripheral blood smears show abnormal giant cytoplasmic granules in leukocytes.

The neutrophils do not function appropriately, leading to increased susceptibility to bacterial infections. Natural killer (NK) cell function is also impaired. Deficiencies of pigmentation are due to abnormal, giant melanosomes.

Patients who do not succumb to infection may eventually develop an unusual lymphoproliferative syndrome, the so-called accelerated phase of the disorder, characterized by generalized lymphohistiocytic infiltrates, fever, jaundice, hepatosplenomegaly, lymphadenopathy, pancytopenia, and bleeding. Allogeneic bone marrow transplantation has been successful in some cases and improves the hematologic and immunologic defects but does not affect the neurologic complications.

Morphologic changes similar to CHS occur rarely in acute myeloid leukemia (AML) or MDS, including acute promyelocytic leukemia. In these instances, there may be abnormal large granules; however, they are not found in the context of a pediatric patient with other genetic anomalies, but usually in adult patients with underlying myeloid disorders. Furthermore, the abnormal granules are usually limited to a subset of cells; they are most commonly seen in a population of myeloid blasts and are not seen in other cell lines such as granular lymphocytes.

Alder-Reilly Anomaly

The morphologic changes in myeloid cells termed Alder-Reilly anomaly are seen in patients with mucopolysaccharidoses (MPS). Seen predominantly in granulocytes, although also variably present in monocytes, there are large numbers of relatively coarse, azurophilic granules in the cytoplasm resembling toxic granulation ( Fig. 3.4 ). Patients with MPS have either X-linked or autosomal-recessive abnormalities in the metabolism of mucopolysaccharides. Historically, eponymous names (e.g., Hunter syndrome, Hurler syndrome, Morquio syndrome, Sanfilippo syndrome, Scheie syndrome) and the term gargoylism, referring to the coarse facies seen in these patients, have been used to refer to this group of diseases; currently they are classified according to the underlying enzymatic defects, and then named according to type (e.g., MPS type I, type II, etc.). All these disorders are associated with numerous other physical abnormalities with varying degrees of severity, which are beyond the scope of this chapter, and the interested reader is referred to the reference list. The Alder-Reilly anomaly should not be mistaken for typical toxic granulation. A mimic has also been described in association with myelodysplasia.