ALK-Positive Histiocytosis: A Case Report and Literature Review
Omar Issa JABER1 , Doa’ AL JARRAH1, Mohammad HIASAT2, Maysa AL HUSSAINI1
1Department of Pathology and Laboratory Medicine, King Hussein Cancer Center, AMMAN, JORDAN
2Neuron Clinics, AMMAN, JORDAN
Keywords: Histiocytosis, Anaplastic lymphoma kinase (ALK), Adult, Spinal cord
ALK positive histiocytosis is a relatively new histiocytic proliferation disease with a characteristic gene translocation involving fusion of the
ALK gene with different partners, mostly KIF5B. We report a case of ALK-positive histiocytosis with literature review. A 27-year-old male
patient presented mainly with progressive lower limb weakness. Imaging studies showed an intradural extramedullary enhancing lesion at
the L3 level. A 1.5 cm mass was excised from the sensory nerve root in the filum terminale at the level of L3. Histologic examination showed
infiltration of the nerve by numerous histiocytes with moderate to abundant eosinophilic to clear-foamy and variably-vacuolated cytoplasm with
irregular-to-smooth contoured nuclei. The histiocytes were positive for CD68 and ALK1 and negative for S100 and CD1a. KIF5B-ALK fusion
was detected by real time-polymerase chain reaction. The patient is asymptomatic nine months after surgical excision. This is the first reported
localized case occurring in the nerve root of an adult patient, thus expanding the clinical manifestations of this disease. An integrated histological,
immunohistochemical and molecular approach is recommended for diagnosis. We recommend performing ALK1 immunohistochemical stain
on all histiocytosis cases to increase awareness and detection of this newly described entity.
ALK-positive histiocytosis is a relatively new histiocytic
proliferation disease with a characteristic gene translocation
involving fusion of the ALK gene with different partners,
mostly KIF5B. The first reported cases were infants who
presented with systemic manifestations including pallor,
anemia, thrombocytopenia, and hepatosplenomegaly
(1). A few years later, the same group expanded their
cohort by reporting seven additional cases that involved
older patients (age: 2-40 years old) with systemic as well
as localized disease (2). In this article, we report a case of
ALK-positive histiocytosis localized to the sensory nerve
root of a 27-year-old man who presented with neurologic
symptoms manifesting mainly as progressive lower limb
weakness. Confirmatory molecular testing detected the
presence of ALK-KIF5B gene fusion.
A 27-year-old male patient, not previously known to have
any medical chronic disease, presented complaining of a
4-month history of progressive left lower limb weakness,
low back pain, and left calf neuropathic pain. Physical
examination showed left plantar flexion weakness (4/5),
left extensor halluces longus (EHL) paralysis (0/5), and left knee flexion weakness (4/5). Lumbar spine MRI showed an
intradural extramedullary enhancing lesion at the L3 level.
Lumbar spine MRI with contrast revealed a small enhancing
nodule involving the filum terminale at the level of L3, with
an isodense signal in T1WI, an intermediate signal in T2WI,
and bright signal post-contrast images. Radiologically, the
main differential diagnosis was ependymoma. The patient
underwent surgery (a two-level laminectomy of L2 and
L3, and gross total resection of the intradural mass arising
from the sensory nerve root after releasing it from two
motor nerve roots contained within the arachnoid band).
Intraoperative neuromonitoring showed improvement
in the motor function of the left L5 and S1 nerve roots.
The post-operative course was uneventful with no new
neurological deficits. The previous neurological deficits
significantly improved and he was discharged 2 days
following surgery (Figure 1A
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|Figure 1: A) Intra-operative view of the
lesion at the filum terminale.
B) Gross appearance of the
lesion after excision.
Further workup that included a CT of the neck, chest,
abdomen, and pelvis in addition to bone scan did not
show any abnormalities. Nine months post-operatively the
patient was completely asymptomatic and regained full
power in the lower limbs. Contrasted lumbar spine MRI
showed no recurrence.
We received the case as a consultation following an outside
pathology diagnosis of Langerhans cell histiocytosis
(eosinophilic granuloma). Histologic examination showed
nerve tissue infiltrated by histiocytes with moderate
to abundant eosinophilic to clear-foamy and variablyvacuolated
cytoplasm. The nuclei ranged from oval in shape
to grooved with irregular outlines (Figure 2A). They had
fine chromatin with small nucleoli. Chronic lymphocytic
cell infiltrates were seen in the background. Rare Toutontype
multinucleated giant cells were found (Figure 2B) and
rare mitotic figures were seen (1/10 HPFs). No necrosis
was present. The histiocytes were positive for CD68 (Figure 3A) and negative for S100 protein, CD1a, and BRAF
V600E immunostains. ALK-1 immunohistochemical stain
showed diffuse positivity in the histiocytes (Figure 3B).
Therefore, ALK-positive histiocytosis was suspected and
confirmatory molecular testing for the presence of ALK
gene translocation, which was performed at an outside
facility, showed the presence of KIF5B-ALK gene fusion by
RT-PCR, confirming the diagnosis.
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|Figure 2: A) The histiocytes have eosinophilic to clear cytoplasm with round to irregular nuclei and occasional prominent nucleoli (H&E;
x400). B) A Touton-type multinucleated giant cell (arrow) (H&E; 400).
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|Figure 3: A) CD68 expression in ALK-positive histiocytosis (IHC; x400). B) ALK1 expression in ALK-positive histiocytosis (IHC; x400).
ALK-positive histiocytosis is a relatively recent entity among
the histiocytic disorders. The first series was published in 2008 and the reported three cases were neonates and
infants who presented with pallor, hepatosplenomegaly,
anemia, and thrombocytopenia. The organs involved
included the liver, spleen, bone marrow, and skin and
showed infiltration by histiocytes with ALK expression
by immunohistochemistry (1). Ten years later, the same
group added seven more cases which included patients
with a wider age range and broader clinical manifestations
(2). A few additional cases have been reported that
included localized and systemic involvement (3-5). In
general, systemic disease is more common in infants and
neonates (2, 3). The classic presentation includes anemia,
hepatosplenomegaly, and thrombocytopenia (2). Tissue
biopsy shows a variable degree of histiocytic infiltration in
the involved organs. The bone marrow usually shows subtle
involvement although overt infiltration can be seen (2, 3).
Systemic involvement of other organs has been reported,
including the kidneys, lungs, bone and intestine (2, 3) where
symptoms reflect the organ involved. Despite the apparently
complicated multi-organ clinical manifestations, gradual
spontaneous recovery usually occurs, sometimes with a
possible role for chemotherapy (2). Death from the disease
can rarely happen (2). On the other hand, localized disease
usually affects older children and adults with an age range
of 2-50 years. The reported sites include the skin (2), breast
(2), soft tissue of the foot (2), central nervous system (2,
4) and appendix (5). Generally, localized disease shows no
evidence of local recurrence after surgical resection, when
it is feasible (2, 4).
The histiocytic infiltrate in the reported cases shared almost
consistent histopathological and cytological features. For
most cases, the histiocytes show abundant eosinophilic, glassy cytoplasm that may show fine vacuoles. Occasionally,
histiocytes can show grayish foamy-to-fluffy cytoplasm
(3) and can be multinucleated (2). Typically, the nuclei
are clefted or lobulated and show irregular folding in the
nuclear membrane with fine chromatin and small nucleoli
(2). Although the nuclear features are usually typical, rare
cases can have oval to round nuclei without foldings or
grooves (2). Occasionally, cells may show emperipolesis,
phagocytosis of red blood cells or polymorphonuclear
leukocytes (2). Touton-type multinucleated giant cells
can be seen. Some variation in the pattern of histiocytic
infiltration has been reported in the form of spindling of
the histiocytes with associated fibrosis and a storiform
pattern (2, 3). When the liver is involved, the cells are
present predominantly in the liver sinusoids with variable
portal tract involvement (1-3). The bone marrow can show
focal, patchy or diffuse involvement (1-3).
By immunohistochemistry, the histiocytes are positive for
histiocytic markers (Factor XIII, CD68, fascin and CD163)
with variable expression of S100. They are consistently
negative for CD1a and BRAF V600E (1-5). The ALK-1
immunostain is uniquely positive in a cytoplasmic and/
or membranous pattern (1-5). The ALK1 expression by
immunohistochemistry corresponds to translocation
involving the ALK gene, most commonly with KIF5B which
was initially described by Chan et al (1). This translocation
can be detected with either fluorescent in situ hybridization
using a split apart probe for ALK or by RT-PCR and next
generation sequencing which identifies the fusion partner.
Despite being the most common fusion partner, other
genes have been reported beside KIF5B, including TPM3
(1,3) and COL1A2 (2). Interestingly, the reported case with ALK-COL1A2 gene fusion showed the less common
nuclear features of oval nuclei with distinct nucleoli and no
irregularities or folds in the nuclear membrane (2).
In general, the constellation of clinical presentation and
pattern of involvement, morphology, immunohistochemistry
and molecular testing help in excluding the other
main differential diagnoses (6, 7). The differential diagnosis
includes other histiocytic disorders including Erdheim-
Chester disease, Rosai-Dorfman disease, Langerhans
cell histiocytosis, and localized or disseminated juvenile
xanthogranuloma. A summarized detailed description of
the clinical, pathological and molecular findings of these
diseases is provided in Table I.
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|Table I: Clinical, pathological and molecular features of ALK positive histiocytosis and other histiocytic entities.
A benign localized subglottic histiocytic lesion harboring
the KIF5B-ALK fusion that clinically mimicked subglottic
infantile hemangioma was recently reported by Wolter et
al. (8). They described an infiltrate of histiocytic cells with
a mildly vacuolated and a slightly eosinophilic cytoplasm
with small round nuclei and no nucleoli. There was no
emperipolesis nor phagocytosis and the histiocytes were
mixed with spindle cells. No Touton-type multinucleated
giant cells were seen. The histiocytes but not the spindle
cells were positive for ALK1 immunostain in an interesting
pattern not described before: a perinuclear or cytoplasmic
dot-like pattern. Those features, despite being partially present
in some of the reported cases (2, 3), prompted them to
call the condition juvenile xanthogranuloma variant, ALK
positive with KIF5B-ALK gene fusion. Whether this condition
truly represents a variant of juvenile xanthogranuloma
or a continuation of the spectrum of ALK-positive histiocytosis
is debatable, although we favor the latter.
To the best of our knowledge, our case is the first to involve
the sensory nerve root in the filum terminale of an adult
patient, thus expanding the clinical manifestation of
this disease. It also shows a spectrum of nuclear features
that ranged from the classically folded nuclei to the less
common rounded and smooth contoured. Central nervous
system involvement has been described as a localized
disease involving the cavernous sinus (2), the cerebellar
vermis and cerebral cortex (4), and as part of a systemic
involvement (9). All localized cases were in children (15,
7 and 10 year old, respectively) whereas the systemic case
reported a 40-year-old male who presented with hepatic
parenchymal involvement, peritoneal and omental lesions,
osseous lesions, and scattered subcutaneous nodules along
with a homogenous lesion in the cervical cord at the level C3 to C4 (9). The reported symptoms for the localized
cases included headache, vomiting and refractory seizures
(4). Our patient presented mainly with progressive lower
limb weakness. The reported outcome for localized disease
is good with no local recurrence after surgical resection.
However, some cases such as the cavernous sinus case may
not be amenable to surgical resection (2). Interestingly,
this patient showed excellent response to ALK-inhibitor
therapy (crizotinib) with no disease after 6 months (2).
Response to ALK-1 inhibitors has also been reported in
KIF5B-ALK1 histiocytosis identified in two adults with
liver and skin involvement (10) and with the case who had
CNS involvement with systemic disease (9).
In conclusion, we presented the case of a 27-year-old
male who had ALK-positive histiocytosis involving the
sensory nerve root in the filum terminale. This is the first
reported localized case occurring in the nerve root of an
adult patient, thus expanding the clinical manifestation
of this newly described entity. It also shows a spectrum
of nuclear features in the same case ranging from the
folded to the smooth-rounded nuclei. ALK-positive
histiocytosis is characterized by expression of ALK1 by
immunohistochemical stain and shows fusion of the ALK
gene with different partners, most commonly KIF5B.
An integrated histological, immunohistochemical and
molecular approach is recommended during the workup of
histiocytic proliferative disorders. Of particular importance
is ALK1, which we propose to be performed on all cases,
not only to detect this probably under-recognized entity
but also because of the therapeutic benefit that may be
obtained from the use of ALK inhibitor therapy especially
in unresectable or systemic diseases.
The authors would like to thank Dr. Chang Kenneth from
the Department of Pathology and Laboratory Medicine
at KK Women’s and Children’s Hospital in Singapore for
performing the RT-PCR to detect the KIF5B-ALK fusion.
CONFLICT of INTEREST
The authors declare no conflict of interest.
Concept: OIJ, Design: OIJ, Data collection or processing:
DAJ, MH, MAH, Analysis or Interpretation: OIJ, MAH,
Literature search: OIJ, DAJ, Writing: OIJ, DAJ, MH,
Approval: OIJ, DAJ, MH, MAH.
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