Case Records of the Massachusetts General Hospital

Founded by RichardC.Cabot
EricS.Rosenberg,M.D.,Editor
JoAnneO.Shepard,M.D.,Associate Editor
SallyH.Ebeling,Assistant Editor

NancyLeeHarris,M.D.,Editor
AliceM.Cort,M.D.,Associate Editor
EmilyK.McDonald,Assistant Editor

Case 40-2014: A 57-Year-Old Man

with Inguinal Pain, Lymphadenopathy,
and HIV Infection
RajeshT.Gandhi,M.D., TarikK.Alkasab,M.D., ValentinaNardi,M.D.,
and JohnA.Branda,M.D.

Pr e sen tat ion of C a se

Dr. Harshabad Singh (Medicine): A 57-year-old man with human immunodeficiency
virus (HIV) infection and a history of inguinal hernias was seen in the emergency
department of this hospital because of pain in the left inguinal region.
The patient had a 10-year history of inguinal hernias (larger on the left side
than on the right side), with intermittent bulging that could be reduced without
difficulty. Approximately 3 months before this presentation, pain associated with
the bulging increased. During the 3 weeks before this presentation, the hernia on
the left side enlarged, and the patient noted intermittent subjective fevers, with
associated night sweats. The week before this presentation, he noted hard lumps
next to the hernia that were tender on palpation. On the night before this presentation, the oral temperature was 38.1C. The next morning, he came to the emergency department of this hospital for evaluation.
The patient reported pain that he rated at 3 on a scale of 0 to 10 (with 10 indicating the most severe pain), with no chills, nausea, vomiting, or abdominal pain.
HIV infection had been diagnosed 8 years earlier, when he had a CD4 T-lymphocyte
count of 66 per cubic millimeter; antiretroviral therapy (ART) was begun shortly
thereafter. On the most recent testing, performed 2 months earlier, HIV RNA was
undetectable (assay range, 20 to 10,000,000 copies of nucleic acid per milliliter)
and the CD4 T-lymphocyte count was 250 per cubic millimeter (reference range,
348 to 1456). He had had Kaposis sarcoma of the left calf and palate 8 years previously that resolved after treatment with bleomycin; in addition, he had had molluscum contagiosum, anal dysplasia, pulmonary Mycobacterium avium complex infection (which was diagnosed 9 years earlier and for which he received 18 months
of treatment), pneumocystis pneumonia, thrush, preseptal cellulitis, and diarrhea
caused by cryptosporidium. He also had had transiently elevated results of liver-function tests 3 years earlier that were thought to be caused by fatty liver disease or
alcoholic liver disease. A test for toxoplasma IgG antibodies, which was performed
shortly after he received the diagnosis of HIV infection, was negative, as were
multiple rapid plasma reagin tests, which were performed between 8 and 5 years
n engl j med 371;26nejm.org December 25, 2014

From the Departments of Medicine

(R.T.G.), Radiology (T.K.A.), and Pathology
(V.N., J.A.B.), Massachusetts General Hos
pital, and the Departments of Medicine
(R.T.G.), Radiology (T.K.A.), and Pathology
(V.N., J.A.B.), Harvard Medical School
both in Boston.
N Engl J Med 2014;371:2511-20.
DOI: 10.1056/NEJMcpc1404518
Copyright 2014 Massachusetts Medical Society.

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Table 1. Laboratory Data.*

Reference
Range,
Adults

Variable

On
Presentation

Hospital
Day 2

Hematocrit (%)

41.053.0
(in men)

37.6

38.0

Hemoglobin (g/dl)

13.517.5
(in men)

12.6

12.8

450011,000

12,100

9600

Neutrophils

4070

83.9

78.7

Lymphocytes

2244

8.3

11.5
8.0

White-cell count (per mm3)

Differential count (%)

Monocytes

411

6.8

Eosinophils

08

0.6

1.3

Basophils

03

0.2

0.2

Glucose (mg/dl)

70110

144

* To convert the values for glucose to millimoles per liter, multiply by 0.05551.
Reference values are affected by many variables, including the patient popula
tion and the laboratory methods used. The ranges used at Massachusetts
General Hospital are for adults who are not pregnant and do not have medi
cal conditions that could affect the results. They may therefore not be appro
priate for all patients.

before this presentation; he had no known history

of other sexually transmitted infections (STIs).
Medications included emtricitabine, tenofovir, and
rilpivirine in combination. He was allergic to tri
methoprimsulfamethoxazole, which had caused
hemolytic anemia.
The patient was heterosexual and divorced
and lived with his female partner, who was also
HIV-positive and receiving ART. His most recent
sexual activity with his partner had reportedly
occurred 2 years earlier, with condom use, and he
reported no other recent sexual activity. He had
smoked cigarettes for 30 years (and continued to
do so), drank one or two alcoholic beverages daily,
and did not use illicit drugs. He worked in the
construction industry. He had a 22-year-old cat,
for which he changed the litter; he did not recall
any bites or scratches. He had traveled to Oklahoma approximately 6 months before this presentation. He was of white European ancestry. His
father had coronary artery disease, and his mother
had fibromyalgia; his siblings and adult children
were healthy.
On examination, the temperature was 36.8C,
the blood pressure 155/79 mm Hg, the pulse 82
beats per minute, the respiratory rate 18 breaths
per minute, and the oxygen saturation 100% while
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he was breathing ambient air. The abdomen was

soft, without tenderness or distention. The patient had inguinal hernias (larger on the left side
than on the right side) that were easily reducible,
with minimal tenderness in the inguinal canal on
scrotal invagination. There was bulky and slightly tender lymphadenopathy, including three large
lymph nodes (maximum diameter, 3 cm) in the
left inguinal region. The remainder of the examination was normal. The platelet count, red-cell
indexes, and results of tests of renal function and
coagulation were normal, as were blood levels of
electrolytes, calcium, and lipids; other test results
are shown in Table1. The patient was admitted
to this hospital.
Dr. Tarik K. Alkasab: Computed tomography (CT)
of the abdomen and pelvis, performed after the
administration of intravenous and oral contrast
material, revealed multiple enlarged lymph nodes
in the left common iliac, left external iliac, and
left inguinal regions (Fig.1), with associated
stranding in the soft tissues of the anterior pelvic walls. Areas of hypodensity consistent with
necrosis were seen in a left external iliac node,
measuring 2.4 cm in the short-axis diameter,
and in a partially visualized left inguinal node,
measuring 2.2 cm in the short-axis diameter;
small paraaortic and right inguinal nodes (<1 cm
in diameter) were also seen. There were small,
fat-containing bilateral inguinal hernias; the hernia on the left side was larger than the hernia on
the right side (3.8 cm and 1.8 cm in greatest dimension, respectively). There was enlargement
of the liver (span, 22 cm), with the inferior tip
reaching below the iliac crest, and borderline enlargement of the spleen, which measured 12.8 cm
in length. Nonobstructing renal calculi were visualized on the left side; there was no evidence
of bowel strangulation or obstruction.
Dr. Singh: The next morning, additional laboratory test results were obtained (Table1), and a
diagnostic test was performed.

Differ en t i a l Di agnosis
Dr. Rajesh T. Gandhi: I am aware of the diagnosis
in this case. This 57-year-old man with chronic
HIV infection presented with a fever, night sweats,
and increasing inguinal lymphadenopathy that
had lasted for several weeks. Although there are
many potential causes of lymphadenopathy in this
patient (Table2), we can begin to narrow the dif-

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Case Records of the Massachuset ts Gener al Hospital

Figure 1. Abdominal CT Scans.

Axial (Panels A and B) and coronal (Panel C) images
from CT scans that were obtained after the administra
tion of oral and intravenous contrast material show
lymphadenopathy in the left iliac and left inguinal re
gions. An enlarged lymph node in the left external iliac
region (Panel A, arrow) measures 2.4 cm in the short
axis dimension, and a partially visualized lymph node
in the left inguinal region (Panel B, arrow) measures
2.2 cm in the shortaxis dimension. Both of these
nodes contain an area of hypodensity consistent with
necrosis. Other enlarged lymph nodes were also seen
in the left inguinal region (Panel C, ellipse), as was en
largement of the liver (Panel C).

ferential diagnosis on the basis of the imaging

findings. Dr. Alkasab, would you tell us your differential diagnosis in light of the findings on the
CT scan?
Dr. Alkasab: The presence of these abnormal
lymph nodes in an HIV-infected patient suggests
two major disease categories: infection and neoplasm.1 Lymphadenopathy could be associated C
with any localized infectious process with lymphatic drainage to the left groin, including infections of the left leg and the perineum. The
necrosis in the affected nodes brings mycobacterial infection to the top of the list of possibilities.
However, other infectious processes, including
cat scratch disease, are also associated with enlarged, necrotic lymph nodes.2 The affected nodes
could also represent metastatic disease from a
malignant tumor in the left leg or perineum; the
appearance of the nodes does not suggest a specific cancer. However, the apparent necrosis lowers the likelihood of non-Hodgkins lymphoma,
because necrosis would be atypical in untreated
disease.3 Recurrence of Kaposis sarcoma is also
unlikely, because lymph nodes that are affected
by that process are typically hyperdense.1
Dr. Gandhi: This patient had lymphadenopathy
in the inguinal and iliac regions that may have
been caused by reactive changes, cancer, or infection, including an infection of the leg or lower cluding the effective use of ART and the characabdominal wall, an STI, or an infection that spread teristics of the lymph nodes. The large size of
hematogenously.4
this patients lymph nodes (>1.5 cm by 1.5 cm)
suggests cancer or granulomatous disease rather
Reactive Lymphadenopathy
than nonspecific lymphadenopathy.6 The lymph
Reactive lymphadenopathy frequently occurs in nodes were tender, which suggests an inflammapatients with untreated HIV infection and com- tory cause, although hemorrhage into a neoplasmonly occurs in the inguinal region. However, tic lymph node may also cause pain. Finally, as
there are several features of this patients presen- compared with younger persons, persons who are
tation that make a reactive process unlikely,5 in- older than 40 years of age are 20 times as likely
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Table 2. Differential Diagnosis of Lymphadenopathy in This Patient.

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to have malignant or granulomatous lymphadenopathy.

Cancer
Non-Hodgkins lymphoma

Cancer

Hodgkins lymphoma

Lymphoma is a possible cause of this patients

lymphadenopathy. The clinical features of lymphoma have been reported to mimic those of an
inguinal hernia.7 HIV-infected patients are at increased risk for non-Hodgkins and Hodgkins
lymphomas.8 Although lymphoma is a possible
diagnosis in this case, I think it is less likely than
other diagnoses for two reasons. First, the patient
had been receiving ART for years, and the incidence of lymphoma among HIV-infected persons
decreases after initiation of ART.9 Second, he had
features of a rapidly progressive and widespread
disease, including a short duration of symptoms
and hepatosplenomegaly; if he had advanced
lymphoma, I would expect bone marrow involvement, yet his blood counts were close to normal.
Another possibility is a cancer related to human herpesvirus 8, such as Kaposis sarcoma
(which this patient had had in the past) or multicentric Castlemans disease. This patient was receiving ART, which reduces the incidence of Kaposis sarcoma. Although Kaposis sarcoma has
been described in older HIV-infected men who
are receiving ART,10 such patients present with
relatively indolent cutaneous manifestations, not
visceral disease. Multicentric Castlemans disease
causes lymphadenopathy, but systemic symptoms,
including fevers with high temperatures, are also
common and were not prominent in this case.
Because of this patients history of anal dysplasia, he is at increased risk for anal cancer. Tumors of the anus can spread to inguinal lymph
nodes, but he did not report anal pain or bleeding
or an anal mass. The patients history of smoking
increases his risk for metastatic cancer, but he
did not have evidence of a primary neoplasm.

Kaposis sarcoma
Castlemans disease
Anal cancer
Metastatic carcinoma
Genital cancer
Melanoma
Neuroendocrine tumor (Merkel-cell carcinoma)
Infection
Bacterial
Bartonellosis
Syphilis
Lymphogranuloma venereum
Chancroid
Tularemia
Yersinia pestis infection
Staphylococcus aureus infection
Streptococcal infection
Brucellosis
Mycobacterial
Mycobacterium tuberculosis infection
Nontuberculous mycobacterial infection
Viral
Herpes simplex virus
EpsteinBarr virus
Cytomegalovirus
Human immunodeficiency virus
Fungal
Cryptococcosis
Histoplasmosis
Blastomycosis
Coccidioidomycosis
Sporotrichosis

Infection

Protozoal (toxoplasmosis)
Other causes
Immune reconstitution inflammatory syndrome
Sarcoidosis
Drug-related hypersensitivity
Autoimmune disease (systemic lupus erythematosus)
Kikuchis disease (histiocytic necrotizing lymphadenitis)
Kimuras disease
RosaiDorfman disease (sinus histiocytosis)

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A variety of infections must be considered in this

patient. Bacterial cellulitis may cause inguinal
lymphadenopathy, but this patient had no evidence
of a leg infection. Staphylococcus aureus and streptococcal infections can cause lymphadenitis, but
this patient had no erythema, fluctuance, or suppuration. Patients infected with Yersinia pestis,
the agent of bubonic plague that is transmitted
through exposure to infected fleas, rodents, or
rabbits, usually present with erythema and edema
of the overlying skin, tender lymphadenopathy,

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Case Records of the Massachuset ts Gener al Hospital

and systemic symptoms. Patients with ulcerogland

ular or glandular tularemia may present with
regional lymphadenopathy. However, this patient
had no known exposures to contaminated animals
or ticks, few systemic symptoms, and no ulcerative lesions.
Although disseminated fungal infections can
cause lymphadenopathy, this patient did not have
respiratory findings suggestive of histoplasmosis,
blastomycosis, or coccidioidomycosis, nor did he
have skin lesions suggestive of sporotrichosis.
Infection with such viruses as EpsteinBarr virus
or cytomegalovirus, HIV rebound (which can occur when ART is discontinued), or HIV superinfection seem unlikely because patients with such
viral infections usually present with generalized
lymphadenopathy. For the same reason, acute
toxoplasmosis, a protozoal infection that can be
manifested as diffuse lymphadenopathy, also
seems unlikely.
I think the most likely infections in this patient are mycobacterial lymphadenitis, cat scratch
disease, and an STI. M. tuberculosis is a common
cause of lymphadenitis worldwide, and the incidence of M. tuberculosis infection is increased among
HIV-infected patients. Patients with mycobacterial
lymphadenitis may present with necrosis of the
lymph nodes, as was seen in this patient. However, this patient had no known exposure to tuberculosis. Nontuberculous mycobacterial infections, such as M. avium complex infection, can
cause lymphadenitis, but when disseminated disease occurs in HIV-infected patients, the CD4
T-lymphocyte count is generally less than 50 per
cubic millimeter, which is much lower than the
count in this patient.
Another possible diagnosis is cat scratch disease, caused by Bartonella henselae. After a scratch
or bite occurs, a primary papule or pustule appears and typically lasts for a few weeks. Ipsilateral lymphadenopathy develops several weeks after the scratch or bite occurs and may persist for
months. The enlarged lymph nodes are usually
tender and may suppurate, and the overlying skin
may be erythematous. In HIV-infected patients,
B. henselae can cause bacillary angiomatosis or
peliosis hepatis and splenitis, complications that
are due to neovascular proliferative lesions. These
complications usually occur in patients with a CD4
T-lymphocyte count of less than 100 per cubic millimeter.
This patient could have had cat scratch disease,
but several features of his presentation were not

typical for this diagnosis. First, he had no known

cat scratches or bites. Second, he had an elderly
cat, and bartonella is more commonly transmitted by kittens,11 perhaps because they are more
likely to have bacteremia12 and have a greater
propensity to scratch than older cats. Third, the
patient did not have a cutaneous lesion, which is
often present in patients with cat scratch disease. Finally, lymphadenopathy in patients with
cat scratch disease is more commonly manifested
in the axillae, neck, and jaw than in the inguinal
region.11
Another potential cause of this patients inguinal lymphadenopathy is an STI.6 Chancroid,
caused by Haemophilus ducreyi, is manifested as
painful genital ulcers and unilateral tender inguinal lymphadenopathy that may suppurate (a condition known as buboes); the absence of these
features in this patient makes this diagnosis unlikely. Lymphogranuloma venereum, caused by
serovars L1, L2, and L3 of Chlamydia trachomatis,
may be manifested as a small, painless genital
papule or ulcer that is often overlooked, and unilateral lymphadenitis may develop, which can become fluctuant and rupture. When the infection
involves the femoral lymph nodes, the groove
sign may be present, which is the visible separation of enlarged femoral lymph nodes from
enlarged inguinal lymph nodes by Pouparts ligament. In the United States, however, lymphogranuloma venereum is most common among men
who have sex with men. Herpes simplex virus infection is usually manifested as painful genital
vesicles or ulcers and bilateral lymphadenopathy.
I think syphilis is the STI that is most likely
to be the cause of lymphadenopathy in this patient. During the past decade, syphilis rates have
more than doubled; the incidence is especially
high among men who have sex with men.13 In
patients with primary syphilis, a painless, indurated chancre usually appears at the site of inoculation, but this finding may not be noticed
by the patient or clinician. Patients may also
have nonsuppurative inguinal lymphadenopathy,
which sometimes persists for months. Secondary
syphilis usually develops 6 to 8 weeks after the
chancre heals, although the primary lesion may
still be present. Patients with secondary syphilis
often have constitutional symptoms, maculopapu
lar rash, mucous-membrane lesions, and generalized lymphadenopathy; inguinal lymphadenopathy is common.14 Secondary syphilis may resolve
without treatment and become latent; however,

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relapses can occur, especially during the first year

after infection.
Syphilitic lymphadenitis, although uncommon,
may be manifested as painful inguinal masses15
and may simulate an inflammatory pseudotumor,16,17 features that are similar to those seen
in this case. Luetic lymphadenopathy may occur
during any phase of infection, and direct involvement of lymph nodes by Treponema pallidum has
been described.18 Hepatosplenomegaly has been
associated with secondary syphilis. Up to 25% of
patients with secondary syphilis have abnormal
results of liver-function tests, often with dis
proportionately elevated levels of alkaline phos
phatase.19-23
Other Causes

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sexually active recently. Luetic lymphadenitis has

been reported to occur during all phases of infection, and relapses of secondary syphilis may
occur, especially during the first year after acquisition. In addition, it is possible that the patient had been sexually active more recently than
he reported.
To make the diagnosis, I would perform serologic testing for syphilis, bartonella, and chlamydia, as well as chest imaging studies to look
for evidence of fungal or mycobacterial infection
in the chest and tests for latent tuberculosis infection. I would perform a lymph-node biopsy to
evaluate the patient for infections and lymphoma and other cancers.
Dr. Eric S. Rosenberg (Pathology): Dr. Bebell, what
was your impression when you first evaluated
this patient?
Dr. Lisa M. Bebell (Infectious Diseases): Our
leading diagnosis was cat scratch disease. However, given the many possible causes of this patients lymphadenopathy, we recommended that
he undergo an excisional lymph-node biopsy. We
also recommended performing serologic tests and
blood cultures for bartonella and performing
mycobacterial blood cultures, given the patients
history of M. avium complex infection. However,
we thought a diagnosis of disseminated M. avium
complex infection was unlikely because of his
relatively robust CD4 T-lymphocyte cell count.
Other recommendations included serologic testing for toxoplasma, a polymerase-chain-reaction
(PCR) assay for EpsteinBarr virus, and measurement of the serum lactate dehydrogenase level to
evaluate the patient for lymphoma. We advised
against the use of empirical antimicrobial therapy, since he was clinically stable and appeared to
be relatively well.

In HIV-infected patients, an immune reconstitution inflammatory syndrome is a consideration

during the first few months after the initiation
of ART, but this patient had been receiving ART
for years, and thus this diagnosis is unlikely.
Medication-induced lymphadenopathy has been
associated with such drugs as allopurinol, indomethacin, and phenytoin. This patient had been
taking the antiretroviral drug rilpivirine, which
can cause a hypersensitivity reaction; however,
this reaction usually occurs soon after the medication is first administered and is often manifested as a rash, with abnormal results of liverfunction tests. Finally, several autoimmune and
idiopathic processes may cause lymphadenopathy.
Patients with sarcoidosis usually present with hilar lymphadenopathy. (We are not told the results
of chest radiography in this case.) Kikuchis disease (histiocytic necrotizing lymphadenitis) and
Kimuras disease typically occur in young Asian
women and men, respectively. Patients with Rosai
Dorfman disease (sinus histiocytosis) present with
massive lymphadenopathy, usually in the neck.
Cl inic a l Di agnosis
Systemic lupus erythematosus more commonly
occurs in women than in men, and lymphade- Bartonella infection (cat scratch disease).
nopathy is typically noted at the onset of disease
or during an exacerbation; this patient had no
Dr . R aje sh T. G a ndhis Di agnosis
other manifestations of this disease.
Syphilitic lymphadenitis.
Diagnostic Testing

My top three diagnoses in this patient are syphPathol o gic a l Discussion

ilis, cat scratch disease, and lymphoma. I believe
syphilitic lymphadenitis is the most likely diag- Dr. Valentina Nardi: An excisional lymph-node binosis. We are told that the patient had not been opsy was performed, and examination of the sec-

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Figure 2. Lymph-NodeBiopsy Specimen (Hematoxylin and Eosin and Silver Stains).

Hematoxylin and eosin staining of an inguinal lymphnodebiopsy specimen reveals focal capsular thickening, fol
licular hyperplasia, and irregularly shaped microabscesses (Panels A through D, within black dashed lines), lined by
epithelioid histiocytes (Panel D, contained by white dashed lines). Steiner silver staining (Panel E) and Warthin
Starry silver staining (Panel F) reveal black pigmented structures at the periphery of a microabscess.

tions of the enlarged inguinal lymph node revealed

an intact architecture, focal capsular thickening,
capsular and interfollicular plasmacytosis, prominent reactive follicular hyperplasia, rare small

n engl j med 371;26

granulomas, and several irregularly shaped microabscesses, lined by epithelioid histiocytes (Fig. 2A
through 2D). The abscesses contained fibrin, neutrophils, and cellular debris.

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Figure 3. Lymph-NodeBiopsy Specimen (Immunohistochemical Stain).

Immunohistochemical staining specific for Treponema
pallidum reveals numerous coiled microorganisms
(Panels A and B, stained in brown) outside and within
the abscesses (Panel A, within dashed lines).

These histologic features were not suggestive

of cancer or other noninfectious, non-neoplastic
processes such as Kikuchis disease or sarcoidosis.
Special stains for mycobacterial species were negative. Grams staining, performed with the use of
the BrownHopps technique, showed rare pink
structures. This finding, as well as the clinical
differential diagnosis, prompted us to perform
staining with Steiner and WarthinStarry silver
stains, which are used to detect gram-negative
bacteria (e.g., B. henselae) and spirochetes. Both
silver stains highlighted structures between the
reactive follicles and only occasionally within the
abscesses (Fig. 2E and 2F), findings that some
pathologists interpreted as representing coccobacillary organisms and others interpreted as being
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consistent with argyrophilic granules in cells

and tissue. Our anatomical diagnosis was necrotizing lymphadenitis due to infection. The differential diagnosis included infection with coccobacillary organisms, among other bacteria. We
consulted our colleagues in the microbiology laboratory to further explore the possibility of B. henselae infection.
Dr. John A. Branda: Bacterial cultures performed
on tissue from the lymph-nodebiopsy specimen
yielded only commensal skin flora, despite extended incubation for fastidious, slow-growing
bacteria, such as bartonella or francisella species.
Mycobacterial and fungal cultures of the lymphnode tissue were negative, as were routine and
mycobacterial blood cultures, despite extended incubation. A urinary nucleic acid amplification test
for C. trachomatis, a urinary test for histoplasma
antigen, and serologic tests for C. trachomatis, toxoplasma, brucella, and Coxiella burnetii were also
negative. Seropositive status for cytomegalovirus
infection had been documented 9 years previously. Tests for B. henselae and B. quintana IgM and
IgG antibodies were negative on initial presentation. However, 1 week later, tests for B. henselae and
B. quintana IgG antibodies were both borderline
positive, with a titer of 1:128 (reference value,
<1:128), whereas tests for IgM antibodies remained negative. These results, coupled with the
equivocal findings on tissue silver staining and
the clinical suspicion of cat scratch disease,
prompted us to send tissue from the lymph-node
biopsy specimen to a reference laboratory for
analysis with the use of a PCR assay for bartonella,24 which was negative. However, a PCR assay
with universal primers targeting the bacterial 16S
ribosomal RNA gene25 detected T. pallidum.
At a follow-up visit 13 days after the patients
initial presentation, a serum test for treponemalspecific antibodies was positive, and a rapid plasma reagin test was reactive, at a 1:64 dilution. On
the basis of these laboratory test results, the diagnosis of syphilis was established.
Dr. Nardi: In light of the molecular and serologic findings, we performed immunohistochemical staining for T. pallidum on the inguinal lymphnodebiopsy specimen; the stain highlighted
numerous spirochetes around and within the microabscesses, in the wall of small veins, and in
rare granulomas (Fig. 3). In hindsight, we could
determine that the structures that were seen with
the silver stains were not microorganisms but argyrophilic granules.

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In retrospect, there were histologic clues to

this diagnosis in this case, although none were
specific for luetic lymphadenitis. These include
capsular thickening (albeit focal), follicular hyperplasia, capsular and interfollicular plasmacytosis, microabscesses, and rare granulomas containing neutrophils. Our revised diagnosis was
necrotizing lymphadenitis due to T. pallidum, which
we established on the basis of molecular and
immunohistochemical findings and further histologic review.

M a nagemen t a nd Fol l ow-up

One week after the first injection, the inguinal pain had diminished, the aminotransferase
levels had normalized, and the alkaline phosphatase level had decreased from 738 to 638 U
per liter (reference range, 45 to 115). At the patients 3-month follow-up visit, he felt completely
well and back to normal. He still reported firm
lymph nodes in his left groin, but they were slowly resolving. A rapid plasma reagin test, which
had previously been reactive at a dilution of 1:64,
was reactive at a dilution of 1:4. At this visit, we
asked him again about any sexual activity, and
he reported that between 1 and 2 years previously he had had a sexual contact that he had
not mentioned in previous interviews. In fact, we
had checked the results of a treponemal assay
that had been performed about 2.5 years previously and it was negative. Unfortunately, the patient was very guarded in discussing his sexual
history, and we were unable to determine exactly
how or when he acquired syphilis. In any case,
he had a complete recovery.

Dr. Bebell: I saw this patient at a follow-up visit

1 week after he was discharged from his brief
hospital admission. When the serologic test for
bartonella was borderline positive, we started
treatment for cat scratch disease with azithromycin and rifampin. This antibiotic regimen required
us to change the patients antiretroviral regimen
because of an interaction between rifampin and
rilpivirine.
At a follow-up visit 1 week after the initiation
Fina l Di agnosis
of therapy for cat scratch disease, the patient was
feeling well, but we noted that he had a very ele- Necrotizing lymphadenitis due to Treponema pallivated alkaline phosphatase level and mildly elevat- dum (syphilis).
This case was presented at the Harvard Medical School posted aminotransferase levels. Approximately 10 days
graduate course Internal Medicine: Comprehensive Review and
after the start of therapy, when the immunohis- Update, directed by Ravi I. Thadhani, M.D., M.P.H., Sekar
tochemical staining showed spirochetes, we dis- Kathiresan, M.D., and Katrina Armstrong, M.D.
Gandhi reports receiving grant support from Gilead, Janscontinued the azithromycin and rifampin and sen,Dr.ViiV,
and Roche; and Dr. Branda, receiving grant support
started treatment with penicillin G injections. from DiaSorin, Alere, bioMrieux, and Immunetics and fees for
We treated the patient with three successive week- serving on an advisory board from AdvanDx. No other potential
conflict of interest relevant to this article was reported.
ly penicillin injections for late latent syphilis or
Disclosure forms provided by the authors are available with
syphilis of unknown duration.
the full text of this article at NEJM.org.
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