TRIAD OF FEVER, MASSIVE HEPATOSPLENOMEGALY AND

PANCYTOPENIA : DIAGNOSTIC DILEMMA FOR THE

INTERNIST

or

Presentation with SIRS: An Uncommon Cause

INTRODUCTION

Natural killer (NK) cell malignancies are rare lethal tumors. Their rarity and
myriad presentation often leads to a delayed diagnosis.

CASE PRESENTATION

A 25 year old previously healthy Hispanic male presented with a two-month

history of fever, night sweats and weight loss. Physical examination was
significant for tachycardia, hypotension, and massive hepatosplenomegaly.
He met the criteria for SIRS (systemic inflammatory response syndrome) and
was admitted to the unit

Admitting laboratory studies revealed pancytopenia, ( WBC 1600/uL, HgB 8.9

g/dl and Platelets 52 k/ul) elevated fibrin split products, ferritin (3817 ng/ml),
LDH (1448 U/L ) and liver enzymes. The differential diagnoses included viral
infections including HIV, hemophagocytic syndrome , infiltrative diseases
and hematologic malignancies .
Hemoglobin 8.9 g /dl
White Blood Cell count 1600 / uL
Platelets 52k /uL
Ferritin 3817ng/ml
LDH 1448 U/L
Fibrin Split Products
D-Dimer
Fibrinogen
Triglycerides
CT abdomen-pelvis showed hepatomegaly (22cm), splenomegaly (20cm) and
bilateral inguinal nodes. CT nasal cavities and sinuses was negative.
Serology for HIV, Hepatitis A,B and C, cytomegalovirus, influenza,
parainfluenza and adenovirus were negative. Epstein-Barr virus was
positive by polymerase chain reaction. Blood and CSF cultures for bacteria
and fungi were negative as were Quantiferon and RPR.

Addition of high dose steroids to empiric antibiotics and hydration produced

dramatic clinical improvement

Hematology was consulted with bone marrow, lymph node and liver
biopsies performed.
The bone marrow biopsy and aspirate was hypercellular (95-100%) with rare
atypical lymphocytes identified in the aspirate smear( see figure). Occasional
hemophagocytic histiocytes were noted An inguinal node demonstrated
effacement by a medium-sized monotonous infiltrate of malignant
lymphocytes.The liver biopsy contained an infiltrate of identical cells

Flow cytometry on the bone marrow demonstrated 11% NK cells(see figure).

These cells were CD2, CD56, cytoplasmic CD3epsilon positive and CD25, CD30,
CD3 surface and T- cell receptor (α , β , γ and δ ) negative. Flow cytometry
on the inguinal node showed similar findings. This pattern determined that
this was an aggressive NK cell lymphoma/leukemia (NKcLL). Chromosome
Analysis on the bone marrow demonstrated deletions of chromosome 6 and
isochromosome 17. The patient was started on SMILE regimen of
chemotherapy ( steroids, methotrexate, ifosfamide, L- asparaginase,
etoposide).

DISCUSSION

NK cell lymphomas represent less than 6 % of all lymphomas and are more
common in Native Americans, Latinos and Asians. They are classified as
nasal type (NT), non-nasal type (NNT) and aggressive (NKcLL). NKcLL has
equal sex incidence , peaks in the third decade and presents with
symptoms including fevers, hepatosplenomegaly, pancytopenia and DIC.
Usually there is minimal involvement of the bone marrow and peripheral
blood with extensive organ infiltration.

Conventional chemotherapy rarely results in remission ,with many patients

dying within days to weeks of diagnosis. Experimental therapy with stem cell
transplants have produced mixed results.

The Differential diagnosis for patients with a triad of fever,

hepatosplenomegaly and pancytopenia is extensive.

DISEASES ASSOCIATED WITH LYMPHADENOPATHY

1. Infectious diseases
a. Viral : infectious mononucleosis syndromes (EBV, CMV), infectious
hepatitis, herpes simplex, herpesvirus-6, varicella-zoster virus,
rubella, measles, adenovirus, HIV, epidemic keratoconjunctivitis,
vaccinia, herpesvirus-8
b. Bacterial: streptococci, staphylococci, cat-scratch disease,
brucellosis, tularemia, plague, chancroid, melioidosis, glanders,
tuberculosis, atypical mycobacterial infection, primary and secondary
syphilis, diphtheria, leprosy
c. Fungal: histoplasmosis, coccidioidomycosis, paracoccidioidomycosis
d. Chlamydial: lymphogranuloma venereum, trachoma
e. Parasitic: toxoplasmosis, leishmaniasis, trypanosomiasis, filariasis
f. Rickettsial: scrub typhus, rickettsialpox, Q fever
2. Immunologic diseases
a. Rheumatoid arthritis
b. Juvenile rheumatoid arthritis
c. Mixed connective tissue disease
d. Systemic lupus erythematosus
e. Dermatomyositis
f. Sjogren's syndrome
g. Serum sickness
h. Drug hypersensitivity: diphenylhydantoin, hydralazine, allopurinol,
primidone, gold, carbamazepine, etc.
i. Angioimmunoblastic lymphadenopathy
j. Primary biliary cirrhosis
k. Graft-vs.-host disease
l. Silicone-associated
m. Autoimmune lymphoproliferative syndrome
3. Malignant diseases
a. Hematologic: Hodgkin's disease, non-Hodgkin's lymphomas, acute
or chronic lymphocytic leukemia, hairy cell leukemia, malignant
histiocytosis, amyloidosis
b. Metastatic: from numerous primary sites
4. Lipid storage diseases: Gaucher's, Niemann-Pick, Fabry, Tangier
5. Endocrine diseases: hyperthyroidism
6. Other disorders
a. Castleman's disease (giant lymph node hyperplasia)
b. Sarcoidosis
c. Dermatopathic lymphadenitis
d. Lymphomatoid granulomatosis
e. Histiocytic necrotizing lymphadenitis (Kikuchi's disease)
f. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman
disease)
g. Mucocutaneous lymph node syndrome (Kawasaki's disease)
h. Histiocytosis X
i. Familial mediterranean fever
j. Severe hypertriglyceridemia
k. Vascular transformation of sinuses
l. Inflammatory pseudotumor of lymph node
m. Congestive heart failure

DISEASES ASSOCIATED WITH SPLENOMEGALY

Enlargement Due to Increased Demand for Splenic
Function
Reticuloendothelial system hyperplasia (for removal of
defective erythrocytes)
Spherocytosis
Early sickle cell anemia
Ovalocytosis
Thalassemia major
Hemoglobinopathies
Paroxysmal nocturnal hemoglobinuria
Pernicious anemia
Immune hyperplasia
Response to infection (viral, bacterial, fungal, parasitic)
Infectious mononucleosis
AIDS
Viral hepatitis
Cytomegalovirus
Subacute bacterial endocarditis
Bacterial septicemia
 Congenital syphilis
Splenic abscess
Tuberculosis
Histoplasmosis
Malaria
Leishmaniasis
Trypanosomiasis
Ehrlichiosis
Disordered immunoregulation
Rheumatoid arthritis (Felty's syndrome)
Systemic lupus erythematosus
Collagen vascular diseases
Serum sickness
Immune hemolytic anemias
Immune thrombocytopenias
Immune neutropenias
Drug reactions
Angioimmunoblastic lymphadenopathy
Sarcoidosis
Thyrotoxicosis (benign lymphoid hypertrophy)
Interleukin 2 therapy
Extramedullary hematopoiesis
Myelofibrosis
Marrow damage by toxins, radiation, strontium
Marrow infiltration by tumors, leukemias, Gaucher's disease
Enlargement Due to Abnormal Splenic or Portal Blood
Flow
Cirrhosis
Hepatic vein obstruction
Portal vein obstruction, intrahepatic or extrahepatic
Cavernous transformation of the portal vein
Splenic vein obstruction
Splenic artery aneurysm
Hepatic schistosomiasis
Congestive heart failure
Hepatic echinococcosis
Portal hypertension (any cause including the above): "Banti's
disease"
Infiltration of the Spleen
Intracellular or extracellular depositions
Amyloidosis
Gaucher's disease
 Niemann-Pick disease
Tangier disease
Hurler's syndrome and other mucopoly-saccharidoses
Hyperlipidemias
Benign and malignant cellular infiltrations
Leukemias (acute, chronic, lymphoid, myeloid, monocytic)
Lymphomas
Hodgkin's disease
Myeloproliferative syndromes (e.g., polycythemia vera,
essential thrombocytosis)
Angiosarcomas
Metastatic tumors (melanoma is most common)
Eosinophilic granuloma
Histiocytosis X
Hamartomas
Hemangiomas, fibromas, lymphangiomas
Splenic cysts
Unknown Etiology
Idiopathic splenomegaly
Berylliosis
Iron-deficiency anemia

SPLENOMEGALY WITH SPLENOMEGALY WITH

APPROPRIATE HYPERSPLENISM
Hereditary hemolytic anemias
Hereditary spherocytosis
Hereditary elliptocytosis
Thalassemia
Sickle cell anemia (infants)
Autoimmune cytopenias
Idiopathic thrombocytopenia
Essential neutropenia
Acquired hemolytic anemia
Infections and inflammations
Infectious mononucleosis
Subacute bacterial endocarditis
Miliary tuberculosis
Rheumatoid arthritis (Felty
INAPPROPRIATE
HYPERSPLENISM
Congestion (Banti syndrome)
Cirrhosis of the liver
Portal vein thrombosis
Splenic vein obstruction
Budd-Chiari syndrome
Congestive heart failure
Infiltrative disease
Leukemias, chronic and acute
Lymphomas
Polycythemia vera
Agnogenic myeloid metaplasia
Gaucher disease
Niemann-Pick disease
Glycogen storage disease
 syndrome) Amyloidosis
Lupus erythematosus
Sarcoidosis
Brucellosis
Leishmaniasis
Schistosomiasis
Malaria

TABLE 60-3. DISEASES ASSOCIATED WITH MASSIVE

SPLENOMEGALYa
Chronic myelogenous Gaucher's disease
leukemia
Lymphomas Chronic lymphocytic leukemia
Hairy cell leukemia Sarcoidosis
Myelofibrosis with myeloid Autoimmune hemolytic anemia
metaplasia
Polycythemia vera Diffuse splenic hemangiomatosis
a
The spleen extends greater than 8 cm below left costal margin
and/or weighs more than 1000 g.

TABLE 60-3. DISEASES ASSOCIATED WITH MASSIVE SPLENOMEGALYa

Chronic myelogenous leukemia Gaucher's disease
Lymphomas Chronic lymphocytic leukemia
Hairy cell leukemia Sarcoidosis
Myelofibrosis with myeloid Autoimmune hemolytic anemia
metaplasia
Polycythemia vera Diffuse splenic hemangiomatosis
a
The spleen extends greater than 8 cm below left costal margin and/or weighs more than
1000 g.

DISORDERS ASSOCIATED WITH

HEPATOMEGALY
Inflammation
Viral hepatitis
Idiopathic neonatal hepatitis
Bile acid enzyme defects
Canalicular bile acid transport defects
Hepatic abscess
Toxin and drug reaction
Cholangitis
Kupffer cell hyperplasia
Sepsis
 Granulomatous hepatitis
Vitamin A toxicity
Congestion
Congestive heart failure
Pericardial tamponade
Budd-Chiari syndrome
Infiltration
Erythroblastosis fetalis
Metastatic tumor
Langerhans cell histiocytosis
Leukemia
Lymphoma
Storage
Glycogen storage diseases
Mucopolysaccharidoses
Gaucher disease
Niemann-Pick disease
a1-Antitrypsin deficiency
Amyloidosis
Hepatic porphyria
Steatosis (fatty liver)
Malnutrition (kwashiorkor)
Hyperalimentation
Cystic fibrosis
Fatty acid oxidation defects
Diabetes mellitus
Galactosemia
Wolman disease
Reye syndrome
Steatohepatitis
Mitochondrial enzyme defects
Tumors
Congenital hepatic fibrosis/polycystic liver
disease
Hereditary hemorrhagic telangiectasia
Hepatoblastoma
Hepatocellular carcinoma

CAUSES OF MASSIVE SPLENOMEGALY

Chronic myeloid leukemia
Gaucher disease
Hairy cell leukemia
Idiopathic and secondary myelofibrosis
Leishmaniasis (kala azar)
Lymphoma
Malaria
Thalassemia major

When a diagnosis is elusive and the response to empiric treatment is poor,

then “thinking out of the box” is warranted. Diagnosing rare conditions such
as NKcLL lymphoma requires a high index of suspicion. Early biopsies of
affected organs must be obtained and appropriate ancillary studies must be
performed prior to initiating definitive therapy.

REFERENCES

1 Kwong YL. Natural killer – cell malignancies: diagnosis and treatment,

Leukemia 2005 ; 19: 2186-94

2 Kwong YL, Anderson BO, Advani R et al. Management of T cell and natural –
killer cell neoplasms in Asia: consensus statement from the Asian
Oncology Summit 2009,

Lancet Oncology 2009; 10: 1093-1101

3 Yamaguchi M, Suzuki R, Kwong YL et al. Phase I study of dexamethasone,

methotrexate, ifosfamide, L-asparaginase and etoposide (SMILE)
chemotherapy for advanced–stage, relapsed or refractory extranodal natural
killer (NK/T-cell lymphoma and leukemia.

Cancer Science 2008; 99: 1010-20