Page 1138 - Williams Hematology ( PDFDrive )

1112 Part VIII: Monocytes and Macrophages Chapter 71: Inflammatory and Malignant Histiocytosis 1113

weight loss. A few patients have polyarthralgia, rheumatoid arthritis, with oral dexamethasone, oral methotrexate, oral 6-mercaptopurine,
glomerulonephritis, asthma, and diabetes mellitus. Painless maculopap- intravenous cladribine, or intravenous vinorelbine plus methotrex-
ular eruptions, sometimes reddish or bluish, or yellow xanthomatous ate. 208–211 Intravenous clofarabine may be the best therapy for patients
rashes occur in 16 percent of patients. Subcutaneous nodules can be with bone and CNS involvement. 84
found anywhere in the body. Another 16 percent of patients have nasal
cavity and paranasal sinus involvement with obstruction of the airways, COURSE AND PROGNOSIS
epistaxis, septal displacement, and mass lesions infiltrating the sinuses.
Ten percent have eyelid or orbital masses with proptosis. Unlike patients Most patients will have a slow but steady decrease in the size of their
with LCH, patients with RDD uncommonly (10 percent) have osteolytic lymph nodes over months to years. For those patients requiring treat-
bone lesions. These have irregular borders, but may have sclerotic mar- ment because of impingement on vital organs responses are variable.
gins. Bilateral parotid or submandibular gland swelling may also be pres- Because no clinical trials have been done, treatment has been based on
ent. Less than 10 percent of patients have CNS, intracranial, epidural, or anecdotal reports.
dural masses, as solitary or multiple lesions leading to headaches, nerve
palsies, or syncope. Other organ system involvement in 1 to 3 percent of HEMOPHAGOCYTIC
cases includes the kidney, genitourinary tract, lungs, larynx, liver, tonsil, LYMPHOHISTIOCYTOSIS
breast, gastrointestinal tract, and heart. Up to 43 percent of patients have
lymphadenopathy coupled with extranodal involvement of the skin, soft DEFINITION AND HISTORY
tissue, upper respiratory tract, bone, eye, or retroorbital tissue. 203
Farquhar and Claireux first described this disease in siblings in 1952.
212
LABORATORY FEATURES Although many case reports using several eponyms ensued, Henter
and Elinder provided a logical organization of the diverse clinical pre-
Patients may have a hemolytic anemia or anemia of chronic disease, sentations. HLH is an aggressive and potentially fatal syndrome that
213
elevated erythrocyte sedimentation rate, and polyclonal hyperimmuno- results from inappropriate prolonged activation of lymphocytes and
globulinemia. Elevation of liver enzymes and other laboratory abnor- macrophages. The name describes the characteristic (but not diag-
malities depend on the organs involved. Hepatic features include nostic) pathologic finding of macrophages engulfing all types of blood
204
capsular and pericapsular fibrosis. The lymph node sinuses are enlarged cells in marrow, lymph nodes, spleen, or liver biopsies (see Fig. 71–3).
by a proliferation of histiocytes with large round or oval vesicular nuclei HLH is also known as autosomal recessive familial HLH, familial ery-
and a prominent nucleolus. Mitoses are rare. The cytoplasm is pale and throphagocytic lymphohistiocytosis, viral-associated hemophagocytic
eosinophilic, although some may have a foamy cytoplasm. The key diag- syndrome, and infection-associated hemophagocytosis. “Primary” or
nostic finding is intact lymphocytes in macrophages (active ingestion, or “familial” HLH has been used to describe young children with HLH
emperipolesis, the penetration of a smaller cell into larger one). Because with known gene mutations or a family history of HLH. Older children
the lymphocytes are inside vacuoles, they are not degraded. Accompa- with HLH, or children without identifiable mutations, are sometimes
nying the histiocytes are numerous plasma cells. The pathologic mac- described as having “secondary” or “acquired” HLH with the assump-
rophages in this disease infiltrate the sinuses of lymph nodes and are tion that the condition is caused by infection or other stimulus and not
phagocytosing lymphocytes and plasma cells as well as erythrocytes. a result of genetic predisposition. The same mutations may be present in
Although the histiocytes are S100-positive, they are CD1a-negative, both situations, and there is no rapid and definitive gene-testing strat-
unlike the LCs, which are positive for both markers. The macrophages egy to distinguish the two groups. In general, presentation and outcome
express CD68, CD14, CD15, lysozyme, transferrin receptor, IL-2 recep- are the same for primary and acquired HLH. Hypomorphic muta-
214
tor, and CD163. 196 tions in HLH-associated genes and compound heterozygous mutations
have been described in patients who develop HLH at an older age or
DIFFERENTIAL DIAGNOSIS in the context of autoimmune disease. 215,216 Thus, this distinction is not
clinically useful in the acute setting as they both must be diagnosed
Any other cause of lymphadenopathy, such as infections, lymphomas, promptly and treated aggressively.
leukemias, Gaucher disease, melanoma, and other malignancies,
should be ruled out by a biopsy. The massive cervical lymph nodes are EPIDEMIOLOGY
strikingly similar to those of patients with the autoimmune lymphop- The incidence of HLH in Sweden was estimated at 1.2 children per 1
roliferative syndrome. Inflammatory pseudotumor and RDD have million children per year, or 1 in 50,000 livebirths with equal sex distri-
205
been found in the same patient suggesting a histologic continuum. 206 bution. At the Texas Children’s Hospital, HLH was diagnosed in 1 of
213
Clinicians should be aware that the sinuses of many reactive lymph 3000 inpatient admissions in a 2-year study. The incidence in adults
217
nodes contain macrophages (histiocytes) and pathologists will report is unknown and the outcomes may be worse than for children. Many
218
that presence as “sinus histiocytes or sinus histiocytosis.” This is not evi- adult patients with HLH also have lymphoma. 219
dence for RDD because in those cases the sinus histiocytes do not have
lymphocytes within their cytoplasm. ETIOLOGY AND PATHOGENESIS
THERAPY Defects in the function of natural killer (NK) cells and cytotoxic T cells
have been found in HLH patients. This results in the inappropriate acti-
Many cases are self-limited and do not require therapy. Surgery may vation of T cells and macrophages, which produce proinflammatory
be useful for symptomatic treatment of local large lymph nodes. Mul- cytokines, including IFN-γ, tumor necrosis factor-α, IL-6, IL-10, IL-12,
tiorgan involvement or dysfunction, and association with immune and soluble IL-2 receptor-α (sCD25). 220,221 In an animal model, perforin
dysfunction are poor prognostic indicators and indicate the necessity deficiency leads to inability to “prune” antigen-presenting DCs, result-
of treatment. Several therapies have been used, including glucocor- ing in increased activation of cytotoxic CD8+ T cells. The hypercytok-
222
207
ticoids and chemotherapy, with success in some cases. Several case inemia and pathologic activation of T cells and macrophages result in
reports have described improvement or cure of patients with the disease multiorgan dysfunction that can rapidly lead to death.

Kaushansky_chapter 71_p1101-1120.indd 1113 9/17/15 3:51 PM