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1108 Part VIII: Monocytes and Macrophages Chapter 71: Inflammatory and Malignant Histiocytosis 1109

percent of treated patients unresponsive and 20 percent with grades 3 to clonal B/T-cell receptor gene rearrangements. Now because more cases
4 hematologic toxicity as opposed to intravenous vinblastine plus oral of “transdifferentiation” between lymphoid malignancies and HS are
prednisone after which there was an 84 percent of patients without a sat- being recognized, these gene rearrangements are being included among
isfactory response and 75 percent grades 3 to 4 neurotoxicity. Patients HS. Among the prior or subsequent malignancies associated with HS
receiving cladribine had an inadequate response 59 percent of the time are B- or T-lymphoblastic lymphoma/leukemia, mature B-cell lym-
and had a 37 percent incidence of hematologic toxicity. The relatively phomas, follicular lymphoma, 100,131 chronic lymphocytic leukemia with
promising efficacy and safety of cytarabine in adults with LCH should BRAF V600E mutation in both malignancies, 100,132 mantle cell lymphoma,
be confirmed in a prospective study. extranodal marginal zone lymphoma of mucosa-associated lymphoid
As in pediatric cases, extensive or mutilating surgery to remove tissue, splenic marginal zone lymphoma, and diffuse large B-cell lym-
skin lesions, teeth or jaw bones is not indicated. Systemic chemother- phoma. A series of four cases of HS with acute leukemia of ambiguous
apy will cause bone lesions to regress and the involved teeth and jaw or myeloid lineage have also been reported. 100
bones can reform. Oral thalidomide and oral methotrexate have also Acute myelogenous leukemias with a dominant monocytic phe-
been effective in adults with skin disease. 69,70 Anecdotal reports have notype represent the other group of malignant disorders involving
described the successful use of the intravenous bisphosphonate pamid- monocytic cells. Descriptions of the clinical presentation, biology, and
ronate in controlling severe bone pain in patients with multiple osteo- treatment of the monocytic leukemias and large cell lymphomas are
lytic lesions. 120,121 presented elsewhere in this book (Chaps. 88 and 98, respectively).
A consensus document authored by experts treating adults with Histologically, the tumors consist of large, overtly malignant-ap-
LCH with guidelines for evaluation and management has been pub- pearing cells in a diffuse, noncohesive array often in the lymph node
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lished. A clinical trial for adults with LCH was conducted for an sinuses or paracortical areas. They are round to oval and sometimes
agent that inhibited AKT signaling activity, with responses in some spindle shaped. Hemophagocytosis may be seen. The nuclei may be
123
patients. There are no current clinical trials for adult LCH patients, oval, indented, convoluted, or irregular, and may display mild to severe
although some studies enrolling patients for treatment with MAPK atypia. 130
pathway inhibitors may include LCH among the diagnoses being The markers most specific for histiocytic cells include monocyte/
studied. macrophage colony-stimulating factor (M-CSF) receptor, lysozyme,
Adult Langerhans Cell Histiocytosis Patients with Lung Dis- Ki-M8, S100+, Ki-M4, cathepsins D and E, CD21−, and CD35−. If a
ease and Who Smoke Cigarettes Most adult patients with LCH have dendritic-histiocytic cell proliferation meets a combination of criteria
gradual disease progression with continued smoking. The disease may as “malignant,” such as having a clonal cytogenetic abnormality, aneu-
regress or progress with the cessation of smoking. Lung transplanta- ploid DNA profile, malignant histocytomorphology, other evidence of
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tion may be necessary for adults with extensive pulmonary destruction monoclonality, and an aggressive clinical course, it is classified as a HS.
from LCH. A multicenter study documented a 54 percent survival at An international panel of experts carefully reviewed 61 cases of
125
10 years after lung transplantation, with 20 percent of patients having tumors of histiocytes and accessory DCs. Seventeen cases (27 per-
133
recurrent LCH, which did not impact on survival, but longer followup cent) were classified as HS and were CD68+, lysozyme+, CD1a−,
of these patients is needed. S100−/+, CD21−, and CD35−. LC tumors (24 cases, 38 percent) were
CD68+, lysozyme−/+, CD1a+, S100+, and CD21/35−. Interdigitat-
ing DC sarcomas (four cases, 7 percent) were CD68+/−, lysozyme−,
MALIGNANT HISTIOCYTIC DISEASES CD1a−, S100−/+, and CD21/35−. Follicular DC tumors (13 cases, 21
percent) were CD68+/−, lysozyme−, CD1a−, S100−/+, and CD21/35+.
DEFINITION AND HISTORY Four cases were unclassifiable. The 2008 WHO classification added
The original description of this group of malignant histiocytosis is immunostaining with anti-CD163, a hemoglobin scavenger recep-
attributed to Scott and Robb-Smith who, in 1939, reported cases of a tor, as a criterion, which identifies monocytes and histiocytes and is
rapidly fatal disease with jaundice, lymphadenopathy, anemia, leuco- more specific than anti-CD68. HS found with or subsequent to B-cell
penia, and hepatosplenomegaly that they called histiocytic medullary lymphomas may have that tumor’s immunophenotype and particular
reticulosis. They believed the malignant cell was a histiocyte based features such as BCL6 nuclear staining and BCL2 protein expression.
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upon the accepted morphologic criteria of that time. Advanced immu- BRAF V600E mutations were reported in five of eight patients with HS and
nohistochemical techniques resulted in identifying cells as either lym- 5 of 27 with follicular DC sarcoma by Sanger sequencing and quantita-
phocytes or histiocytes. The disease was labeled giant cell reticulosis and tive PCR. 100,134
the cells reticulum cells based upon their large size, but revealed little as
to the place of these cells in the immune system. Later, Rappaport intro- EPIDEMIOLOGY
duced the term malignant histiocytosis, as he believed the morpho- Although malignant dendritic/histiocytic cell tumors affect all age
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logic characteristics identified the histiocyte as the malignant cell. There groups, the median age is 33 years. Males are affected more often
133
has been considerable debate about the identity of malignancies of LC than females and most patients had HSs and LC tumors. One review
histiocytes as the majority of patients with “histiocytic lymphoma or of more than 2000 lymphoma cases found eight patients (0.4 percent)
malignant histiocytosis” reported in the literature had one of the vari- with HSs. Another review found 1 percent of all hematolymphoid
135
ants of large cell lymphoma. 128,129 By excluding patients with anaplastic neoplasms to be HS with a median age at diagnosis of 46 years. 130
large cell lymphomas and other T- or B-lineage large cell lymphomas,
the resulting number with malignancies of histiocytes becomes very
small. Favara and colleagues suggested that such diseases should be CLINICAL FEATURES
considered sarcomas of histiocytic or macrophage-related lineage. An Systemic symptoms of fever, headache, malaise, weight loss, dyspnea,
updated review of the histologic features of these neoplasms based upon and sweating occur in patients with diffuse disease. 133,135,136 Lymphade-
the 2008 World Health Organization (WHO) Classification has been nopathy is the most common presenting feature, but involvement of the
published. One of the major changes is that the 2001 WHO definition spleen, gastrointestinal tract, skin, and soft tissue are common. Marrow
130
of histiocytic sarcoma (HS) stated that the neoplasms could not have involvement occurs in approximately 25 percent of the patients.

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