*Corresponding Address: Nahla AM Hamed, Professor of Clinical Hematology, Faculty of Medicine, Alexandria University, Egypt
How to cite this article: Nahla AM Hamed. Malignancy-Associated Hemophagocytic Lymphohistiocytosis: An Aggressive Entity Which Requires EarlyDiagnosis Canc Therapy & Oncol Int J. 2019; 13(2): 555856. DOI:10.19080/CTOIJ.2019.13.555856
HLH comprises two main groups: malignancy-associated HLH (or M-HLH) and non-malignancy associated HLH. Treatment of HLH depends on the severity of the presentation as well as the underlying cause. M-HLH is an important subgroup of HLH because its prognosis is dismal. In addition, patients with M-HLH are already immunocompromised and addition of further cytotoxic therapy as a part of treatment for HLH is not an appealing option. Furthermore, it is difficult to abort therapy of the underlying malignancy and switch to therapy of HLH.
The terms Hemophagocytic lymphohistiocytosis (HLH) and Lymphohistiocytic activation syndrome (LHAS) are equivalent . HLH is not a malignant disorder. It is a highly stimulated defective severe inflammatory syndrome and tissue destruction resulting from an excessive immune activation and an absence of down-regulation of abnormally activated lymphocytes and macrophages .
The incidence of HLH is estimated to be approximately 1.2 cases per million individuals per year, but this is almost certainly an underestimate . Recently, neoplasms have been recognized as triggers of HLH in children, with a prevalence of 8% to 11% .
Primary (genetic) HLH is a hereditary immune disorder  that may result from mutations in genes of cytolytic secretory pathway causing target cells apoptosis by perforin and granzymes. Primary HLH is divided into conditions in which HLH is the only disease manifestation (familial HLH, FHLH1-5), and those associated with other genetic causes in which HLH is one of several clinical manifestations .
Secondary HLH includes older children and adults who lack a family history or a known genetic cause for HLH . Secondary HLH is the most common form seen in adults . Extensive list of triggers is associated with secondary HLH .
i. Infection : The most common infection associated with acquired HLH is Epstein-Barr virus . Other implicated viruses are CMV, human immunodeficiency virus , respiratory syncytial virus, rotavirus, and adenovirus infections . Bacterial, protozoal or mycotic infection can also induce HLH .
ii. Malignancy : It can be divided into malignancy triggered forms, where malignancy itself leads to HLH, and the chemotherapy-associated HLH, where the antineoplastic treatment or its side effects trigger HLH . These two etiologies might overlap during treatment of malignancies making their clear discrimination difficult . HLH develops in the presence of malignancy, is known as malignancy-associated hemophagocytic syndrome (M-HLH) . High grade lymphomas, mainly T cell and Natural killer non-Hodgkin lymphomas are the most common malignant causes of secondary HLH . Other malignant causes are acute leukemias, myelodysplastic syndromes, Langerhans cell
histiocytosis, and histiocytic sarcoma . Other commonly
identified underlying malignancies included diffuse large B
cell lymphoma, Hodgkin lymphoma, CLL, CML, follicular lymphoma,
splenic marginal B-cell lymphoma, PTLD, CMML. Solid
tumors such as melanoma, breast cancer, testicular cancer,
prostate cancer, squamous cell carcinoma of the neck, and
pituitary mass were less frequently associated with HLH .
iii. Rheumatic diseases : the macrophage activation
syndrome (MAS) is a term commonly used to describe HLH
secondary to rheumatological diseases . MAS is most
often found as a complication of systemic juvenile idiopathic
arthritis, systemic lupus erythematosus, mixed connective
tissue disease , polymyositis, vasculitis , polyarteritis
nodosa, sarcoidosis, systemic sclerosis, Sjögren’s syndrome
and antiphospholipid syndrome .
iv. Drug hypersensitivity .
v. Spontaneous or iatrogenic immune suppression
related HLH . HLH has been observed in the setting of
immune suppression after kidney and liver transplant and
after allogeneic hematopoietic stem cell transplants .
vi. HLH can occur after prolonged periods of total
parenteral nutrition that include soluble lipids. A condition
known as fat overload syndrome .
vii. A case of HLH was reported in a neonate in association
with mitochondrial respiratory chain disorder .
Three main pathways of the inflammatory response are
central to HLH initiation and propagation:  hyperactivation
of CD8+ T lymphocytes and macrophages,  proliferation
and infiltration of these cells into organs and tissues, and 
uncontrolled hypercytokinemia  (cytokine storm) produced
by activated lymphocyte and macrophages . Cytotoxic T
cells and NK cells are unable to eliminate the overactivated
macrophages leading to their further activation, and increased
levels of interferon gamma, tumor necrosis factor alpha, soluble
receptor of Interleukin (IL) 2 or CD25, IL-6 and IL-10. In addition,
macrophages phagocytize host cells . A thorough search for an
underlying infection should be done  in any case of M-HLH
or chemotherapy-associated HLH . The hyperinflammatory
state and disease manifestation in these cases seems to be the
consequence of an inadequate reaction of the dysregulated
immune system against common infectious agents .
Patients are usually acutely and severely ill with multi-organ
failure and without specific etiology despite prolonged hospital
stay and evaluation. Common features include clinical deterioration,
associated with persistent fever, high ferritin, hypertriglyceridemia,
rash, lymphadenopathies, hepatosplenomegaly,neurologic symptoms, abnormal liver function tests, pancytopenia,
coagulopathies, and sometimes acute kidney injury . Differentiation
between primary and secondary HLH is difficult due
to indistinguishable clinical presentations, associated with excessive
inflammatory cytokines and activation of macrophages
The signs and symptoms, including prolonged fever and
hepatosplenomegaly can be nonspecific . Sepsis and shock
can cause similar clinical features . Decreased NK‑cell
activity and elevated sCD25 levels may help in differentiating
HLH from sepsis. Typical clinical symptoms of HLH may
resemble symptoms of malignant diseases or severe bacterial
infections often occurring during antineoplastic treatment
and subsequent immunodeficiency . Fever, cytopenias, and
hepatic dysfunction may all be explained by either malignant
disease or the chemotherapy. That is why HLH diagnosis may be
delayed in oncology patients . HLH may precede, noted at the
same time or even occurred after the diagnosis of malignancy.
HLH is not diagnosed in patients at the time of remission . The
index of suspicion must be kept high, especially in the context
of certain clinical disorders, such as immunosuppressed states,
hematologic, infectious and rheumatologic diagnoses .
Complete blood count, chemistry, liver and kidney function
tests, coagulation studies (PT-INR, PTT, fibrinogen and d-dimer),
serum triglycerides, ferritin, viral serologies and blood cultures.
Bone marrow examination should be done to assess presence of
hemophagocytes and to rule out lymphoproliferative disorders
and leukemia . About 1–10 hemophagocytes per 500 cells
seen in bone marrow are considered positive . All patients
should also have cerebral spinal fluid studies, brain MRI and
CT scan of the neck, chest, abdomen and pelvis to exclude any
Central Nervous System pathology or other malignant etiology.
Specialized immunologic testing should be done to patients
highly suspected of having HLH: levels of soluble IL-2 receptor
alpha; NK function or cell surface expression of CD107 alpha;
soluble levels of the hemoglobin-haptoglobin scavenger receptor
(sCD163), and perforin . Studies to identify the underlying
disorder should also be performed .
Currently, HLH 2004 diagnostic criteria are followed
worldwide in spite of the presence of a newer proposal put forth
by HLH society in 2009 . The 2004 diagnostic criteria for
HLH requires 5 out of the following 8 clinical and pathological
variables to be present: fever> 38.5 °C, splenomegaly, cytopenia
in at least 2 lineages (hemoglobin <9 g/dl; platelets <100,000/
μl; absolute neutrophil count <1000/μl), hypertriglyceridemia
(fasting triglycerides >265 mg/dL) / hypofibrinogenemia
(fibrinogen <150 mg/dL), hemophagocytosis on pathology
examination (in bone marrow, spleen, lymph node, or liver),
low/ absent NK cell activity, ferritin greater than 500 g/L  and elevated soluble CD25 (soluble IL-2 receptor alpha) two
standard deviations above age-adjusted laboratory-specific
norms (> 2400 Ul/ml) . The two criteria (sIL2rα and natural
killer-cell activity) have to be met among these 5 criteria .
The presence of either hemophagocytosis, or
lymphohistiocytosis or hyperferritinemia alone may not
be specific or sufficient to confirm or refute a diagnosis of
HLH in adults . Presence of hemophagocytosis in bone
marrow alone is highly supportive but is neither diagnostic
nor pathognomonic for HLH diagnosis . Hyperferritinemia,
mainly more than 10,000 g/dL is of highly sensitive and specific
value in diagnosing HLH . The HLH-2004 criteria developed
for children may be inadequate for accurately diagnosing HLH
in adults . Clinicians should never wait to meet these criteria
to make the diagnosis and start the adequate treatment .
Strict use of the HLH-2004 criteria for diagnosis has pitfalls.
Importantly, these criteria do not distinguish primary from
secondary disease. Rather, they categorize a common phenotype
characterized by toxic immune activation secondary to a range
of disease processes, many of which have different treatments
. Identification of HLH in adults may require inclusion of
additional diagnostic variables, especially variables that are
easily obtained on routine laboratory or physical examination
(9). Diagnostic criteria are usually used for clinical trials and are
unlikely to be detected in every case of HLH .
It is a fatal syndrome with high mortality rate  so treatment
should never be delayed while awaiting some genetic tests or
other specific immunologic testing . Two considerations
to be considered are suppression of hyperinflammation and
targeting of the underlying disease if possible . HLH specific
treatment is based mainly on the HLH-94 protocol or clinical
trials enrollment rather than treatment based on the HLH-2004
protocol . High risk patients are those having HLH mutations,
CNS disease and hematologic malignancies .
All primary HLH patients require allogeneic stem cell
transplantation for cure as the problem is genetic . The
interferon-gamma inhibitor NI-0501 was recently approved
breakthrough designation for the treatment of primary HLH .
In secondary HLH: Treatment of the underlying trigger(s)
generally resolves immune dyregulation . However, there
are several obstacles to effective therapy in adult HLH. One of
the major reasons is the presentation this entity at an advanced
stage when it is not feasible to initiate effective therapy due to
delay in its recognition . M-HLH is an important subgroup
of secondary HLH  because of its association with increased
mortality . In addition, patients with M-HLH are already
immunocompromised and addition of further cytotoxic therapy
is not an appealing option. Furthermore, it is difficult to abort
therapy of the underlying malignancy and switch to therapy of HLH .
In M‑HLH, once symptoms are controlled, the disease‑specific
therapy for underlying malignancy should obviate the trigger
and prevent recurrence . Hemopoietic stem cell transplant
is generally recommended in patients with recurrent/refractory
disease, persistent NK‑cell dysfunction, or CNS involvement
. The interferon-gamma inhibitor may prove to be a major
milestone in the therapy of secondary and M-HLH. This agent
does not cause myelosuppression and may be potentially given
concomitant with anti-tumor therapy .
Secondary HLH in adults frequently manifests as an aggressive
disease . The earlier the diagnosis is made, and the quicker the
treatment is given, the better will be the prognosis. Administration
of the adequate treatment can dramatically increase the survival
. Approximately 56–70% of patients have a median overall
survival of 36–230 days. The 3-year survival of M-HLH patients
is 18–55% . Out of all secondary triggers, M‑HLH seems to
have the worst outcome . Mortality rates range from 8% in
MAS complicating systemic juvenile idiopathic arthritis to >80%
in M-HLH . Approximately, 50% of secondary HLH patients
die of irreversible multiorgan damage . Prognostic factors
associated with mortality include thrombocytopenia, high onset
age, possible lymphoma (prognosis is better for B-cell than
T-cell lymphoma-triggered HLH), increased ferritin levels, low
fibrinogen level and EBV-DNA > 1,000 copies . Infections,
especially EBV infection and invasive fungal infection, may be
the major factors in chemotherapy associated HLH patients .
Other predictive factors are CD3+ cells number, glycosylated
ferritin concentration and 18F-2-fluoro-2-deoxy-D-glucose
(FDG) bone marrow uptake on PET/CT .
Initiation of a comprehensive work-up for HLH to all patients
who would have been diagnosed with hepatic or renal failure of
unknown etiology, sudden onset multi-organ failure, culturenegative
sepsis and encephalopathy of unknown etiology .