Infections in Oncology
Toxoplasmic Lymphadenopathy Clinically Presenting as Lymphoma
Eva S. Quiroz, MD; Dominic M. Castellano, BS; John N. Greene, MD;
Ramon L. Sandin, MD; and Lynn C. Moscinski, MD
H. Lee Moffitt Cancer Center & Research Institute, Tampa, Fla
Introduction
The clinical spectrum of Toxoplasma gondii infection ranges from no symptoms to
a syndrome of fever and lymphadenopathy to diffuse multisystem organ involvement.
Lymphadenopathy occurs in 10% to 20% of acute cases and may be accompanied by
constitutional symptoms. The differential diagnosis is broad, considering the diverse
presentation. Symptomatic toxoplasmosis occurs with increased frequency in patients with
hematologic malignancies and solid tumors that display defects in cell-mediated immunity.
We present a case of toxoplasmic lymphadenitis clinically presenting as non-Hodgkin’s
lymphoma and briefly review the literature.
Case Report
A 50-year-old man had lived in Peru since 1991 and worked as a security officer in the
Cuzco jungle at 2,500 meters above sea level. In April 1996, he developed chills, night
sweats, and fevers up to 105°F. He had eaten a local animal indigenous to the jungle a
week prior to his illness. He had no prior medical illnesses, no risk factors for human
immunodeficiency virus (HIV), and no known exposure to tuberculosis. He had been
vaccinated for hepatitis A and hepatitis B. The region where he worked was infested with
rats, and he has several cats at home. He is a Vietnam veteran diagnosed with
posttraumatic stress disorder. Evaluation for malaria, typhoid fever, and brucellosis was
negative. He was treated with oral ciprofloxacin for one week. Because of continued fever
with new onset of dyspnea, he was admitted to a hospital in Lima, Peru, in May 1996.
Fever, cyanosis, bilateral basilar rales, tachycardia, and hepatosplenomegaly were noted.
Chest radiography revealed cardiomegaly and interstitial infiltrates with bilateral small
pleural effusions. An abdominal ultrasound demonstrated hepatosplenomegaly with no focal
lesions. Echocardiogram revealed no valvular abnormalities or vegetations. Thoracentesis
was performed and the pleural fluid was consistent with a transudate, cultures were
negative, and cytology was negative for malignancy. He was tentatively diagnosed with
pneumonia and completed a nine-day course of intravenous antibiotics. Six weeks later, on
June 18, 1996, he presented with adenopathy in the left postauricular and left inguinal
region as well as in the cervical, supraclavicular, and epitrochlear areas. Blood and
urine cultures were negative. A bone marrow biopsy revealed normal bone marrow cellularity
with no evidence of malignancy. Further laboratory workup in Peru included a Creactive
protein at 18 mg/dL (normal), an alkaline phosphatase of 386 U/L (elevated), and an
alanine aminotransferase level of 110 U/L (elevated). Serology for Brucella sp,
hantavirus, Yersinia sp, HIV-I and -II, leptospirosis, and cytomegalovirus were all
negative. A urinalysis was also negative. Computed tomography scans of the chest, abdomen,
and pelvis revealed no enlargement of the liver or spleen and showed no para-aortic
adenopathy. On July 23, 1996, a left inguinal lymph node biopsy was interpreted as
nonspecific inflammation. On August 5, 1996, a second opinion was sought and the lymph
node biopsy was interpreted as non-Hodgkin’s lymphoma. Combination chemotherapy and
radiation therapy were recommended but not administered. A third opinion at a cancer
institute in Peru interpreted the biopsy as reactive lymphadenitis. Multiple serology
testing confirmed the diagnosis of acute toxoplasmosis (Table). Sulfadoxine/pyrimethamine
(Fansidar), sulphamethoxazole/trimethoprim (Bactrim), and clindamycin were given for four
days followed by Fansidar for five weeks.
The patient presented to our center in September 1996 for evaluation and a fourth
opinion. He had no symptoms other than fatigue and history of weight loss (20 pounds) over
the last year. Physical examination was unremarkable with no fever, lymphadenopathy, or
hepatosplenomegaly. Ophthalmologic examination revealed no retinal lesions or visual
impairment. Slides from the lymph node biopsy were reviewed at our institution and were
consistent with florid follicular and interfollicular hyperplasia, with normal
immunoblasts in the interfollicular regions. The germinal centers were enlarged and
prominent. There was no evidence of malignancy, and no cysts with bradyzoites or detached
tachyzoites were seen in the parenchyma of the biopsy. Further serology included negative
cytomegalovirus titers and titers for HIV-I antibody, recombinant pseudo-retrovirus, human
herpes simplex virus 6 IgM, and cat scratch fever (Bartonella henselae).
Epstein-Barr virus (EBV) early antigen was <1:10 (normal), EBV nuclear antigen was 1:40
(normal <1:2), EBV viral capsid IgG was 1:640 (normal <1:40), and EBV viral capsid
IgM was <1:10 (normal <1:10), consistent with past infection.
In March 1996, a diagnosis of acute toxoplasmosis with resolution of symptoms was made
on the basis of history, clinical presentation, toxoplasma serology, and the absence of
malignancy in histologic specimen. Although the May 2, 1996, titers show an elevated IgG
and normal IgM for T gondii, the remaining titers are consistent with acute
infection.
Discussion
T gondii is one of the most widely distributed intracellular parasites that
infect humans and animals. It is an intracellular protozoan, a member of the phylum
Apicomplexa that includes Eimeria sp, Plasmodium sp, Cryptosporidium
sp, and Sarcocystis sp. The three life forms of T gondii are oocysts,
tachyzoites, and bradyzoites (tissue cysts). The oocysts contain sporozoites and are the
product of the sexual cycle in the intestinal epithelium of its definitive hosts (cats and
other felines), which form oocysts that are shed in their feces. The tachyzoite is the
asexual invasive form, which replicates essentially within all nucleated cells.1
They reside within a vacuole that becomes incapable of fusing with any membrane-bound
organelle within the host endocytic system and is effectively hidden from the host where
it can replicate rapidly. The tissue form or bradyzoite stage can remain dormant within
the tissue for decades. Bradyzoides can emerge when the host immunity wanes or, as in our
case, can present as acute toxoplasmosis.
Although cats serve as the definitive host, birds and domesticated animals may serve as
reservoirs to transmit the infection. Humans acquire T gondii infection mainly by
ingesting food and water contaminated with oocysts passed in feces of infected cats or by
ingesting tissue cysts in undercooked infected meat, as our patient did.2 After
ingestion and dissemination of infection, the early phase is characterized by a rapid
tachyzoite multiplying stage in different tissues causing mononuclear inflammatory
reactions that lead to small necrotic foci.1 Parasite multiplication during
this stage occurs in the liver, lung, lymphoid tissue, and brain. In the immunocompetent
person, the tachyzoites are cleared from the host tissues, and necrotic foci are
generated. The parasites then appear as the bradyzoites contained within cysts that
predominantly form in the central nervous system, but they also may be present in the eye,
heart, and skeletal muscle. Inflammation or necrosis in these organs is often
insignificant, and the person can remain asymptomatic. The latent infection can become
active when the immune system is severely compromised, especially with cell-mediated
immunodeficiency (eg, AIDS, solid tumors, hematologic malignancies, and
lymphoproliferative disorders). This expansion can also occur when treatment includes
antineoplastic agents.3
Cysts can persist in tissues during the chronic or latent phase of the infection. Due
to their resistance to digestive juices, cysts can be transmitted in raw or undercooked
meat. Tissue cysts have been found in 25% of lamb and pork samples4 but have
rarely been isolated from beef. In one report, five of 11 Korean soldiers who ate raw
liver of a domestic pig developed diffuse lymphadenopathy.2 Cysts are
transmitted to humans through two major avenues: oral and congenital. However, laboratory
workers can become infected through handling feline fecal specimens, human or animal
tissue, or cultured organisms.5 All toxoplasma isolates should be considered
pathogenic to humans.6 The oocysts are resistant to chemicals or the
environment. Therefore, instruments and glassware contaminated with oocysts should be
boiled and autoclaved. Cases of laboratory-acquired infection have been reported.5
Infection can result from ingesting the organism or from skin puncture (needle stick),
mucous membrane contact, or a wound such as an animal bite.
A five-year prospective cohort study of toxoplasma cysts in cats, rodents, birds, and
soil and the incidence of seroconversion in children has been performed in Panama,7
in which a cumulative incidence of 12.6% was reported. A high correlation of dog contact
with seroconversion in children may be due to the possibility that the dogs, by eating and
rolling in cat feces, were instrumental in transmitting infection. Flies and, to a lesser
extent, cockroaches may also promote fecal oral transmission. The municipal water supply
was the source of recent outbreak of toxoplasmosis in Victoria, Canada.8
Cases of toxoplasmosis have occurred in cancer patients, most commonly those with
Hodgkin’s disease.3 Other risk groups include patients with
non-Hodgkin’s lymphoma, acute and chronic lymphocytic leukemia, acute myelogenous
leukemia, chronic myelogenous leukemia, hairy-cell leukemia, angioimmunoblastic
lymphadenopathy, and myeloma. Toxoplasmosis has occurred in patients with ovarian tumor
and lung carcinoma, thymoma and seminoma, melanoma, myelodysplastic syndrome, chromophobe
adenoma, and neuroblastoma. This incidence is most likely related to the treatment of
malignancy with resultant immunosuppression and defects in cell-mediated immunity.
Clinical Presentation
The clinical presentation of toxoplasmosis ranges from the absence of symptoms to a
syndrome of fever and lymphadenopathy to diffuse organ system involvement. In the
immunocompetent host, infection is frequently asymptomatic. Lymphadenopathy occurs in 10%
to 20% of cases and may be accompanied by fevers, chills, night sweats, myalgia, sore
throat, and enlarged liver and spleen.9 The clinical picture may be similar to
that of a glandular, fever-like illness. Chronic or recurrent toxoplasmosis in the
immunocompetent host is rare.10,11 In most cases, toxoplasmosis presents as
asymptomatic cervical lymphadenopathy, but all lymph node groups may be enlarged. The
nodes are usually discrete and nontender, are rarely more than 3 cm in diameter, may vary
in firmness, and are not suppurative.12 However, they can be tender or matted.
The lymph nodes most commonly involved are the cervical, suboccipital, supraclavicular,
axillary, and inguinal nodes.13 Some of the symptoms are malaise, night sweats,
myalgias, sore throat, maculopapular rash, hepatosplenomegaly, and an atypical
lymphocytosis (<10%).14 In addition, retroperitoneal or mesenteric
lymphadenopathy may produce abdominal pain.15
The potential for confusion with lymphoma is clear. Lymphadenopathy may wax and wane
and, in some unusual cases, may persist for one year or longer. Acute toxoplasmosis is
usually characterized by isolated asymptomatic lymphadenopathy without a rash.11
In patients with AIDS, clinical presentation may include central nervous system
involvement, acute hepatitis,16 or adult respiratory distress syndrome.17 Cerebral
or disseminated toxoplasmosis may follow bone marrow transplantation, with the highest
incidence occurring at two to three months following transplantation.18
Diagnosis
The clinical manifestations of toxoplasmosis may be nonspecific; therefore,
toxoplasmosis must be carefully considered in the differential diagnosis with a large
variety of clinical presentations. The acute infection is diagnosed by the identification
of T gondii in blood or body fluids such as cerebrospinal fluid, by demonstration
of characteristic lymph node histology, or by demonstration of toxoplasma tissue cysts in
the placenta, fetus, or neonate.19 The diagnosis of toxoplasma lymphadenitis is
established by histologic examination and confirmed by serologic studies. The toxoplasma
serologic profile may include IgG (dye test) and IgM antibody test, IgA, IgE, IgE
immunosorbent agglutination assay, and differential agglutination (AC/HS) test. In a
recent study, T gondii could be ruled out if the dye test and an IgM were negative
for antibody within three months of clinical onset of adenopathy.20 Although a
high titer of toxoplasma-specific IgM suggests acute infection, it may persist for 18
months or more.5,21 The other serologic studies aid in the diagnosis,
especially when patients present with negative, low-positive, or equivocal titers on IgM,
which is common when serum samples are obtained more than three months after the
lymphadenopathy occurs.20 Very sensitive and specific "in-house"
assays by the polymerase chain reaction (PCR) are being reported increasingly as powerful
diagnostic adjuncts. In one study, PCR of peripheral venous blood was useful in the
diagnosis of cerebral toxoplasmosis in AIDS patients.22 Other than a brain
biopsy, PCR of peripheral blood or cerebral spinal fluid could be the most sensitive
diagnostic tool for diagnosing cerebral infection. The PCR has also been very effectively
applied to prenatal diagnosis of congenital toxoplasmosis on amniotic fluid,23
as well as cell lysates.24
A lymph node biopsy is usually performed to distinguish malignancy from toxoplasmosis
when lymphadenopathy occurs. The histopathologic changes in toxoplasma lymphadenitis are
distinctive and often diagnostic. There is a striking degree of reactive follicular
hyperplasia with numerous mitoses and karyorrhectic debris in the germinal centers.
Clusters of histiocytes were observed in the interfollicular cortical and paracortical
zones, and the histiocytes characteristically encroached on and blurred the margins of the
reactive follicles.12,25
Hodgkin’s disease and toxoplasmosis can be difficult to differentiate since
epithelioid histiocytes and prominent reactive follicles can occur in both disorders. The
local reactional mechanism of lymph nodes to generalized infection has been described as
Kikuchi’s histiocytic necrotizing lymphadenitis (KHNL), a recognized cause of lymph
node enlargement. Toxoplasma infection can mimic KHNL.26 Other causes of
lymphadenitis include tuberculosis, Yersinia sp, EBV, human herpes simplex virus
type 6, parvovirus B19, HIV, and systemic lupus erythematosus.
Treatment
The most effective therapeutic regimen includes pyrimethamine and either sulfadiazine
or trisulfapyrimidines plus folinic acid. The duration of therapy is two to four weeks for
acute disease and can range to months when visceral organ involvement is encountered or
when severe symptoms persist.5 Alternative treatments include
trisulfapyrimidines and sulfamethazine or sulfamethazine and sulfadiazine. All are active
against tachyzoites and are synergistic in combination.
The tissue cyst form of toxoplasma is resistant to antimicrobial agents, except
azithromycin and atovaquone.27,28 Clindamycin’s mechanism of action on T
gondii is unknown. In combination with pyrimethamine, it has comparable efficacy and
toxicity when compared with pyrimethamine and sulfadiazine.29
Conclusions
Our patient probably acquired toxoplasmosis from consumption of wild animal meat
followed by a systemic illness and then diffuse lymphadenopathy. The clinical presentation
of toxoplasmosis can easily be confused with lymphoma both by clinicians and pathologists,
as this case illustrates. However, after a careful history, appropriate serology, and a
careful review of lymph node biopsy material, the distinction can be made between the two
and unnecessary toxic therapy can be avoided.
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