In this issue of Blood, Kemps et al1 provide an expanded view of the pathological, genomic, and clinical features of anaplastic lymphoma kinase (ALK)-positive histiocytosis, and demonstrate the clinical efficacy of ALK inhibition, with durable responses in 11 of 11 patients, including 10 with central or peripheral nervous system disease.

ALK-positive histiocytosis was first recognized by Chan et al,2 who identified 3 cases of a novel form of histiocytosis presenting in early infancy and associated with systemic involvement of bone marrow, spleen, and liver. The discovery of this condition was perhaps accidental, based on the frequent involvement of ALK in one of the more common forms of T-cell lymphoma in childhood: ALK-positive anaplastic large cell lymphoma. The early reports focused on cases presenting in the pediatric age group, but expanded examination of histiocytic lesions in children and adults showed a broader spectrum of this condition, with cases in adults more often presenting with localized disease, including involvement of skin and soft tissue, breast, and gastrointestinal tract.3,4 It also emerged that this condition was most often associated with a KIF5B-ALK fusion,5 a finding confirmed in the current report.

The current report in Blood is the largest series reported to date and includes 39 confirmed cases. The authors have shown that ALK-positive histiocytosis is clinically heterogeneous. They divide their cases into 3 clinical cohorts. Group 1A includes cases in infants with systemic disease, similar to the original report.2 Group 1B comprises children and adults with multisystem disease and frequent involvement of the central nervous system. Group 2 includes patients presenting with a single site of involvement, with some variation in age (0-41 years), but mainly presenting in infants and children (20 of 23; 87%). In comparison with prior cases reported in the literature, the current series identified fewer cases in adults, perhaps reflecting the personal interests and expertise of the authors, many of whom are experts in pediatric pathology and hematology.

The classification of histiocytic and dendritic cell neoplasms has evolved in fits and starts. Although the classification of B-cell and T-cell lymphomas developed from a concerted effort to relate the tumors to developmental and functional subsets of the normal immune system,6 many of the histiocytoses were initially thought to be reactive or inflammatory conditions. This list includes Erdheim-Chester disease (ECD), Rosai-Dorfman-Destombes disease, and Langerhans cell histiocytosis (LCH), all initially identified as clinical syndromes.

The modern and unifying landscape of the histiocytic and dendritic cell neoplasms has emerged through study of their molecular pathogenesis. Both the “histiocytoses,” which are typically formed by benign-appearing histiocytes and dendritic cells, and the histiocytic/dendritic cell (H/DC) sarcomas are characterized by frequent mutations in the MAPK pathway (see figure).7,8 A smaller subset of cases show evidence of activation of the phosphatidylinositol 3-kinase signaling pathway.9 These insights have led to advances in therapy, with the introduction of targeted therapy of H/DC tumors, through inhibition of components of the pathway including RAS, RAF, MEK, and mTOR.9,10 Nevertheless, many of the observed mutations are not specific to any individual entity. For example, BRAF V600E mutations can be encountered in all members of the disease family, inclusive of isolated LCH, systemic ECD, and H/DC sarcomas. The precise pathogenetic lesions that specifically define the clinical manifestations remain to be elucidated. Addition of ALK-positive histiocytosis to the umbrella concept of histiocytosis brings a new dimension to the spectrum of driver mutations in histiocytoses, implicating a receptor tyrosine kinase gene. ALK fusion leads to activation of many different signaling pathways, among which the MAPK pathway is highly relevant, reflecting convergence on a common pathway of tumorigenesis.

The histiocytoses show variation in clinical and pathologic features, but the molecular alterations that drive the neoplastic process typically converge on common signaling pathways. The same pathway is targeted in primary and secondary H/DC sarcomas, which typically show more marked cytologic atypia. The presence of specific inhibitors that can target components of the pathway has led to advances in clinical management and improved prognosis in neoplasms of the histiocytic and dendritic cell lineages. The figure has been adapted from Figure 1 in the article by Kemps et al that begins on page 256.

The histiocytoses show variation in clinical and pathologic features, but the molecular alterations that drive the neoplastic process typically converge on common signaling pathways. The same pathway is targeted in primary and secondary H/DC sarcomas, which typically show more marked cytologic atypia. The presence of specific inhibitors that can target components of the pathway has led to advances in clinical management and improved prognosis in neoplasms of the histiocytic and dendritic cell lineages. The figure has been adapted from Figure 1 in the article by Kemps et al that begins on page 256.

Close modal

The current report focuses on the successful use of ALK inhibitors for the treatment of ALK-positive histiocytosis, which led to sustained remissions in all treated patients. The authors also identified 10 histiocytic lesions that showed ALK immunoreactivity, but in which RNA sequencing (RNAseq) failed to identify an ALK fusion. The results of fluorescence in situ hybridization (FISH) are not reported. The authors fear that use of the term “ALK-positive histiocytosis” for these cases may lead to inappropriate or ineffective therapy with an ALK inhibitor. None of the 10 cases received an ALK inhibitor clinically, so a failure to respond is speculative in this setting. We also note that in lesions with low tumor cell content, RNAseq may lead to false-negative results; we have encountered cases that were negative by RNAseq but positive by FISH for ALK rearrangement. Furthermore, 2 of the 6 group 1A cases with classical clinical manifestations do not have demonstrable ALK fusion. It would seem discrepant to include these 2 cases in this histiocytosis category, but not the 10 cases with ALK immunostaining but no demonstrable ALK fusion by RNAseq.

The current report continues to illuminate the diverse spectrum of histiocytic neoplasms. An unanswered question is how ALK-positive histiocytosis relates to the broad category of juvenile xanthogranuloma, particularly because one-third of cases exhibit histologic features similar to juvenile xanthogranuloma. Is it a specific disease entity or a genetic variant within a larger group with overlapping clinical features and biology? This question, however, will likely be difficult to resolve, given the lack of specific criteria to define juvenile xanthogranuloma.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

1.
Kemps
P
G,
Picarsic
J
,
Durham
BH
, et al
.
ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition
.
Blood.
2022
;
139
(
2
):
256
-
280
.
2.
Chan
JK
,
Lamant
L
,
Algar
E
, et al
.
ALK+ histiocytosis: a novel type of systemic histiocytic proliferative disorder of early infancy
.
Blood.
2008
;
112
(
7
):
2965
-
2968
.
3.
Gupta
GK
,
Xi
L
,
Pack
SD
, et al
.
ALK-positive histiocytosis with KIF5B-ALK fusion in an adult female
.
Haematologica.
2019
;
104
(
11
):
e534
-
e536
.
4.
Kashima
J
,
Yoshida
M
,
Jimbo
K
, et al
.
ALK-positive histiocytosis of the breast: a clinicopathologic study highlighting spindle cell histology
.
Am J Surg Pathol.
2021
;
45
(
3
):
347
-
355
.
5.
Chang
KTE
,
Tay
AZE
,
Kuick
CH
, et al
.
ALK-positive histiocytosis: an expanded clinicopathologic spectrum and frequent presence of KIF5B-ALK fusion
.
Mod Pathol.
2019
;
32
(
5
):
598
-
608
.
6.
Jaffe
ES
,
Harris
NL
,
Stein
H
,
Isaacson
PG.
Classification of lymphoid neoplasms: the microscope as a tool for disease discovery
.
Blood.
2008
;
112
(
12
):
4384
-
4399
.
7.
Diamond
EL
,
Durham
BH
,
Ulaner
GA
, et al
.
Efficacy of MEK inhibition in patients with histiocytic neoplasms
.
Nature.
2019
;
567
(
7749
):
521
-
524
.
8.
Egan
C
,
Nicolae
A
,
Lack
J
, et al
.
Genomic profiling of primary histiocytic sarcoma reveals two molecular subgroups
.
Haematologica.
2020
;
105
(
4
):
951
-
960
.
9.
Shanmugam
V
,
Griffin
GK
,
Jacobsen
ED
,
Fletcher
CDM
,
Sholl
LM
,
Hornick
JL.
Identification of diverse activating mutations of the RAS-MAPK pathway in histiocytic sarcoma
.
Mod Pathol.
2019
;
32
(
6
):
830
-
843
.
10.
Emile
JF
,
Cohen-Aubart
F
,
Collin
M
, et al
.
Histiocytosis
.
Lancet.
2021
;
398
(
10295
):
157
-
170
.