4. Discussion
HCL is a rare indolent B-CLPD and represents 2% of all leukemias (2).
Typical clinical features of HCL concern patients with a median age at
diagnosis of 54 years with cytopenia (60-80%) and splenomegaly
(80-90%) (3). However, HCL can have rare articulation, skin, hepatic,
auto-immune or bone involvements (4-8). HCL was first described in 1958
by Bouroncle et al , and the first reported bone involvement
(osteolytic type) occurred almost 20 years later, in 1977 by Rhyneret al (9,10). Recently, a literature review of the MEDLINE
database looking for articles relating only to bone lesions in HCL was
performed by Robak et al (1). Bone involvement was observed in
about 3% (0-13%) of patients and very rarely observed at presentation.
Thirty-six cases were reported: one-third had symptomatic bone lesions
at the time of diagnosis, but the majority of bone involvement was
demonstrated later, up to several years (from two months to 22 years).
After review of the literature including known cases of HCL with
skeletal involvement, clinical features could be more specified. Indeed,
the data of Robak et al confirm the preponderant involvement of
the femur (head, neck or both) estimated at 75% of the bone lesions in
HCL (1). The second main localization of bone involvement is distributed
in the axial skeleton (6). There are only a few similar case reports in
the literature (6). Bone damage was mainly represented by osteolytic
lesions but rare cases of severe osteoporosis and aseptic necrosis have
also been described (1). Osteolytic lesions are nonspecific on imaging
and the first etiologies considered are solid tumor metastases or
myeloma, but the clinician must be vigilant about other diagnoses.
However, isolated bone presentation has been observed in HCL, with bone
lesions strongly associated with high tumor burden and bone marrow
infiltration (11). The main peculiarity of our two cases consisted in a
very symptomatic clinical presentation with exclusive bone pain of
increasing intensity that contrasted with a poorly informative
biological workup (absence of cytopenia) in relation to a mild marrow
infiltration. However, persistent bone pain of increasing intensity can
be considered as typical of skeletal involvement in HCL, estimated at
89% of patients (1).
Although our case is an uncommon clinical disease presentation, the
phenotype of hairy cell leukemia was typical with an immunological HCL
score of 4/4 (12). Moreover, the BRAFV600E mutation
was positive, excluding an HCL variant disorder (13). To note, a case
mimicking multiple myeloma has also been reported in a patient
presenting a painful upper left thigh with several hypermetabolisms at18F-FDG PET/CT and hypergammaglobulinemia with
positive immunofixation for monoclonal immunoglobulin A. Neither hairy
cells nor BRAFV600E mutation was identified in blood,
bone marrow aspirate and bone marrow trephine biopsy from the iliac
crest. The diagnosis of HCL was on the core biopsy of the left femoral
neck showing hairy cells with the positive BRAFV600Emutation (14). All these unusual clinical presentations exposed here
should induce hematologists not to neglect HCL in diagnostic hypothesis
in case of bone lesions and, above all, to carry out biopsy.
Concerning 18F-FDG PET/CT, its place in care of HCL
patients remains unclear and needs to be determined. Its use in HCL is
quite recent and is still being developed. First of all, radiography is
insufficient, many cases including ours had normal x-ray. Most of the
time, a CT scan or MRI is performed as a second step and then sometimes
a 18F-FDG PET/CT. Only a few cases of patients with
HCL who underwent 18F-FDG PET/CT have been published
and all of them showed hypermetabolic localization whether classical or
not (5, 6, 15-17). Some studies indicate that 18F-FDG
PET/CT is an interesting tool for the evaluation of the extension of
HCL. Indeed, all 18F-FDG PET/CT of HCL patients with
bone involvement show hypermetabolisms not only in areas of pain but
also in areas without clinical translation, suggesting other existing or
early asymptomatic bone lesions. MRI, while often used, is a less
specific and less sensitive technology than 18F-FDG
PET/CT to detect multiple and/or early localizations. In light of these
observations, it can be assumed that bone lesions at the time of
diagnosis of HCL are underestimated since imaging is only performed in
case of pain and not systematically at the time of discovery of the
hemopathy. The delay between the appearance of a bone lesion related to
HCL and the development of symptoms is therefore completely unknown.
Other studies indicate that 18F-FDG PET/CT is of
interest in the evaluation of response to treatment (18). In HCL
patients, 18F-FDG PET/CT showed normalization of FDG
uptake at all previously pathological sites following cladribine
treatment (17). However, it is unclear whether 18F-FDG
PET/CT is sufficiently sensitive to determine residual disease, which is
currently evaluated in bone marrow and blood (19). Based on these
observations and our cases, we think that 18F-FDG
PET/CT seems to be quite reliable to assess the disease. An
observational trial could be led first for epidemiological purposes in
order to better characterize disease presentation, especially at
diagnosis by the systematic 18F-FDG PET/CT to better
specify the frequency of bone involvement in HCL. All reported cases of
HCL with bone involvement have been treated because of pain and not
because of cytopenia or splenomegaly. However, Do asymptomatic
non-threatening bone lesions found by routine 18F-FDG
PET/CT at diagnosis represent treatment criteria on their own? Due to
low reported incidence, there exists no established recommendation for
this group of patients with HCL with bone involvement. It is clear that
this particular presentation needs to be better clarified as to its
actual frequency, pathophysiology, prognosis, and response to treatment.
Routine 18F-FDG PET/CT would seem to be a first step
to answering these questions. Moreover, this examination can guide a
possible biopsy if necessary (notably to eliminate a differential
diagnosis).
A quarter of patients with HCL are asymptomatic at diagnosis and require
regular monitoring for a variable period of months to years before
meeting at least one of the validated treatment criteria. These criteria
are: absolute neutrophil count <1x109/L,
hemoglobin <11g/dL, platelet count
<100x109/L, symptomatic splenomegaly,
infections or bleeding related to cytopenias (2). Purine nucleoside
analogues (PA) (pentostatin and cladribine) remain the standard
first-line treatment for HCL, achieving overall response (OR) rates of
90-100% and complete response (CR) in 70 to 90%. No significant
difference between the two agents has ever been observed even if no
randomized trials have compared both drugs (2,20). Remissions are
durable (median 15 years), and survival is close to that for an
age-matched general population (21,22).
Rituximab alone has not been formally tested in first-line therapy, but
given the relatively low response rates seen in relapsed HCL, it is not
recommended except in special circumstances: its use could be reserved
for patients ineligible for purine analogues or who have an active
infection. In contrast, it has been shown to improve remissions with a
combination of rituximab and a PA (23,24). A recent publication
comparing concurrent rituximab with delayed rituximab (≥6 months if
minimal residual disease (MRD) is detected in blood) showed a marked
improvement in MRD negative complete remission rates by concurrent
rituximab. The CR rate was 100% with concurrent immunochemotherapy
versus 88% with delayed administration, and the rates of undetectable
MRD were 97% versus 24%, respectively. Immediate hematologic toxicity
was greater (including transient grade 3-4 thrombocytopenia) but
recovery was faster at 4 weeks compared with delayed rituximab (25).
Chemoimmunotherapy combining cladribine (CDA) daily for five days and
rituximab weekly for eight weeks (CDAR regimen) could be an alternative
in high-risk HCL: splenomegaly > 3cm, leukocytosis
> 1x109/L, hairy cells in the blood at
5x109/L, beta-2 microglobulin > 2N,
resistance to PNA, HCL CD38 positive or IGHV unmutated (2). However,
neither treatment criteria nor risk stratification take into account
unusual clinical presentations, including bone involvement, which is one
of the most reported atypical presentations. Our first reported case
(the female patient with the threatening right frontal tumefaction) was
treated in 2012. At that time, rituximab just began to be used in HCL
and data on its efficacy and safety were not yet available. According to
the recommendations of the time, she received a CDA in monotherapy and
rituximab was delayed because of the detection of MRD in bone marrow six
months after PA administration. With therapeutic sequence, she achieved
an excellent and durable response. She is still currently in remission.
For the second case, we considered our young man’s femur fracture as a
high-risk criteria and opted for the CDAR association in light of recent
studies in order to maximize the therapeutic response and eradicate the
disease as long as possible in fear of a severe bone relapse even if, to
date, we have no precise data on the response to the treatment and the
prognosis of HCL with bone localizations compared to those with
classical presentation. Radiotherapy was not applied for even if it is
known that moderate doses are effective in supportive care,
nevertheless, side effects are far from negligible and it is not a
curative treatment of the disease.