The n e w e ng l a n d j o u r na l of m e dic i n e

Case Records of the Massachusetts General Hospital

Founded by Richard C. Cabot

Eric S. Rosenberg, M.D., Editor
Virginia M. Pierce, M.D., David M. Dudzinski, M.D., Meridale V. Baggett, M.D.,
Dennis C. Sgroi, M.D., Jo‑Anne O. Shepard, M.D., Associate Editors
Allison R. Bond, M.D., Case Records Editorial Fellow
Emily K. McDonald, Sally H. Ebeling, Production Editors

Case 9-2018: A 55-Year-Old Man with HIV

Infection and a Mass on the Right Side
of the Face
Kevin L. Ard, M.D., Hillary R. Kelly, M.D., Rajesh T. Gandhi, M.D.,
and Abner Louissaint, Jr., M.D., Ph.D.​​

Pr e sen tat ion of C a se

Dr. Robert H. Goldstein (Medicine): A 55-year-old man with Crohn’s disease and a new From the Departments of Medicine
diagnosis of human immunodeficiency virus type 1 (HIV-1) infection was seen in (K.L.A., R.T.G.), Radiology (H.R.K.), and
Pathology (A.L.), Massachusetts General
the infectious diseases clinic of this hospital because of a mass on the right side Hospital, the Departments of Medicine
of the face. (K.L.A., R.T.G.), Radiology (H.R.K.), and
Fifteen days before the current evaluation, while the patient was undergoing Pathology (A.L.), Harvard Medical School,
and the Department of Radiology, Massa‑
extraction of carious teeth, a health care worker sustained a needlestick injury, chusetts Eye and Ear (H.R.K.) — all in
which prompted evaluation of the patient for infections caused by bloodborne Boston.
pathogens. Hepatitis C virus antibodies were not detected, but a rapid screening N Engl J Med 2018;378:1143-52.
test for HIV antibodies was positive, as was a fourth-generation combination assay DOI: 10.1056/NEJMcpc1800321
for HIV-1 and HIV type 2 (HIV-2) antibodies and HIV-1 p24 antigen. A supplemen- Copyright © 2018 Massachusetts Medical Society.

tal Western blot assay confirmed the diagnosis of HIV-1. The plasma HIV-1 RNA
viral load was 69,300 copies per milliliter, and the blood CD4+ T-cell count was
65 per cubic millimeter (reference range, 348 to 1456). The patient was referred to
the infectious diseases clinic of this hospital for treatment.
Eight days later, 1 week before the current evaluation, the patient was seen in
the infectious diseases clinic. He reported that he had lost approximately 18 kg
during the past 2 years, that he had chronic orodental pain and a chronic cough
at night, and that the skin on his forehead, cheeks, and chest was peeling. He had
Crohn’s disease, for which a total colectomy had been performed during child-
hood; he had been evaluated on multiple occasions during the past year for increased
ostomy output and dehydration. He had no known history of sexually transmitted
infections.
Fourteen years earlier, the patient had undergone fine-needle aspiration of an
enlarged lymph node on the right side of the neck. Cytologic examination of the
aspirate revealed findings consistent with reactive hyperplasia, with no evidence
of a monoclonal B-cell or unusual T-cell population. Nineteen months before the

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 The n e w e ng l a n d j o u r na l
current evaluation, an excisional biopsy of a
mass on the right side of the neck had been
performed. Histopathological examination of the
biopsy specimen revealed an enlarged lymph
node with florid follicular and paracortical hy-
perplasia.
The patient took diazepam and had no
known allergies to medications. He resided in
an urban area of New England. He was retired
and had previously worked for the government.
He did not smoke tobacco, drink alcohol, or use
illicit drugs. He reported that he had never had
sex but that he had been assaulted in the past.
His mother had had lung cancer, and his father
had had congestive heart failure.
On examination in the clinic, the patient ap-
peared anxious. The vital signs were normal,
and the weight was 75.7 kg; 2 years earlier, the
weight had been 93.2 kg. The maxilla was eden-
tulous, and the few remaining mandibular teeth
appeared carious. The abdomen was scaphoid,
with an ostomy in the right lower quadrant, and
the skin on the face and chest was erythematous
and peeling; the remainder of the examination
was normal. The anion gap and blood levels of
glucose, calcium, alanine aminotransferase, as-
partate aminotransferase, alkaline phosphatase,
total bilirubin, direct bilirubin, vitamin B12, folic
acid, testosterone, and glycated hemoglobin were
normal, as were the results of renal-function
tests; other laboratory test results are shown in
Table 1. Topical ketoconazole–based shampoo,
trimethoprim–sulfamethoxazole, and a fixed-
dose formulation of elvitegravir, cobicistat, em-
tricitabine, and tenofovir alafenamide were pre-
scribed.
One week later, the patient returned to the
infectious diseases clinic for follow-up (the cur-
rent evaluation) and reported that a lump had
developed on the right side of his face. He had
adhered to the prescribed regimen, and his ap-
petite had increased during the past week. On
examination, the vital signs were normal, and
the weight was 76.7 kg. At the angle of the right
mandible, there was a firm, fixed, tender mass
measuring 0.5 cm in diameter, with no overlying
erythema or warmth. The erythema of the skin
on the face and chest had decreased; the re-
mainder of the examination was unchanged. An
interferon-γ release assay for a cell-mediated im-
mune response to Mycobacterium tuberculosis was
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of m e dic i n e
negative. Chest radiography revealed minimal
linear and reticular opacities in the right middle
lobe, lingula, and left lower lobe; these findings
had not changed from previous examinations.
A follow-up appointment was arranged for the
following week.
One week after this evaluation, repeat exami-
nation in the infectious diseases clinic revealed
that the size of the mass on the right side of the
face had increased to 1 cm in diameter. One
week later, the size of the mass had increased to
1.5 cm in diameter, and numbness of the right
pinna had developed. Imaging studies were ob-
tained.
Dr. Hillary R. Kelly: Computed tomography (CT)
of the neck (Fig. 1A and 1B) revealed asymmetric
enlargement of the right parotid gland, with no
surrounding inflammatory change. There was
an ill-defined, central focus of hypoattenuation
in the right parotid gland, a finding that raised
concerns about a fluid collection or mass lesion.
Scattered cervical lymph nodes were seen through-
out the neck; these nodes were thought to be
larger and more numerous than expected for an
otherwise healthy 55-year-old patient but did not
meet the size criteria for enlargement due to
cancer. CT of the head revealed enlargement of
the prepontine and premedullary cisterns and
of the fourth ventricle, a finding that reflected
disproportionate volume loss in the brain stem
relative to the cerebral hemispheres. Magnetic
resonance imaging (MRI) was recommended for
further characterization of the facial mass.
MRI of the neck was performed after the
administration of intravenous contrast material
(Fig. 1C through 1F). A large, multilobulated
mass or confluent cluster of nodules occupied
most of the deep and superficial lobes of the
right parotid gland, extending through and wid-
ening the stylomandibular tunnel. There was a
small rind of normal parotid parenchyma sur-
rounding this mass. The mass had an isointense
signal on T1-weighted imaging, restricted diffu-
sion on diffusion-weighted imaging, and hetero-
geneous enhancement on contrast-enhanced im-
aging. There was a central focus of hypointense
signal on T2-weighted imaging that correspond-
ed to the focus of hypoattenuation that had been
seen on the CT scan of the neck. The maximum
dimensions of the mass were 4.2 cm transverse
by 3.3 cm anteroposterior by 5.6 cm craniocaudal;
 Case Records of the Massachuset ts Gener al Hospital

Table 1. Laboratory Data.

Reference Range, Infectious Diseases Clinic,

Variable Adults* 1 Wk before Presentation
Hematocrit (%) 41.0–53.0 30.4
Hemoglobin (g/dl) 13.5–17.5 10.3
White-cell count (per mm3) 4500–11,000 5200
Differential count (%)
Neutrophils 40–70 75.0
Lymphocytes 22–44 19.0
Monocytes 4–11 4.8
Eosinophils 0–8 1.0
Basophils 0–3 0.2
3)
Platelet count (per mm 150,000–400,000 232,000
Red-cell count (per mm3) 4,500,000–5,900,000 3,730,000
Mean corpuscular volume (fl) 80–100 81.5
Mean corpuscular hemoglobin (pg) 26–34 27.6
Mean corpuscular hemoglobin concentration (g/dl) 31–37 33.9
Red-cell distribution width (%) 11.5–14.5 15.3
Sodium (mmol/liter) 135–145 133
Potassium (mmol/liter) 3.4–5.0 4.0
Chloride (mmol/liter) 98–108 99
Carbon dioxide (mmol/liter) 23–32 20
Protein (g/dl)
Total 6.0–8.3 8.4
Albumin 3.3–5.0 3.6
Globulin 1.9–4.1 4.8
Interferon-γ release assay for cell-mediated immune Negative Unable to perform because insuffi‑
response to Mycobacterium tuberculosis cient peripheral-blood mononu‑
clear cells isolated from sample
Enzyme-linked immunosorbent assay for antitreponemal Negative Positive
­antibodies
Rapid plasma reagin test Nonreactive Nonreactive
Treponema pallidum–particle agglutination assay Nonreactive Reactive
Varicella–zoster virus IgG antibodies Negative Positive
Varicella–zoster virus IgM antibodies Negative Negative
Cytomegalovirus IgG antibodies Negative Positive
Hepatitis A virus IgG antibodies Negative Positive
Hepatitis A virus IgM antibodies Negative Negative
Hepatitis B surface antibodies, qualitative Negative Negative
Hepatitis B core antibodies, total Negative Negative
Hepatitis B surface antigen Negative Negative
Toxoplasma gondii IgG antibodies Negative Negative

* Reference values are affected by many variables, including the patient population and the laboratory methods used. The
ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions
that could affect the results. They may therefore not be appropriate for all patients.

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 The n e w e ng l a n d j o u r na l
A B
C D
E F
Figure 1. Imaging Studies.
Coronal and axial CT scans of the neck (Panels A and B, respectively), ob‑
tained after the administration of intravenous iodinated contrast material,
show asymmetric enlargement of the right parotid gland (Panel A, arrow‑
heads) as compared with the left parotid gland (Panel A, arrow), with no
surrounding inflammatory change. There is an ill-defined, central focus of
hypoattenuation (Panel B, arrows) in the right parotid gland, a finding that
raises concerns about an underlying fluid collection or mass lesion. An axial
T1-weighted MRI of the neck (Panel C), obtained after the administration of
intravenous gadolinium, shows a large mass (arrowheads) that replaces most
the deep and superficial lobes of the right parotid gland, extending through
and widening the stylomandibular tunnel. A T2-weighted image (Panel D)
shows a central focus of hypointense signal (arrows) that corresponds to
the focus of hypoattenuation seen in Panel B. The lesion bows the external
carotid artery anteriorly and abuts the posterior border of the mandibular
ramus; there is no evidence of cortical erosion or abnormal signal in the
marrow. A diffusion-weighted image and an apparent-diffusion-coefficient
map (Panels E and F, respectively) show restricted diffusion (arrows).
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of m e dic i n e
the parotid gland was more enlarged than it had
been on the CT scan. The lesion bowed the ex-
ternal carotid artery anteriorly and abutted the
posterior border of the mandibular ramus; there
was no evidence of cortical erosion or abnormal
signal in the marrow. The fat adjacent to the
stylomastoid foramen was preserved, and there
was no abnormal enhancement along the intra-
temporal segment of the right facial nerve or
along the auriculotemporal nerve that would
suggest perineural spread. In addition, there were
multiple enlarged cervical nodes bilaterally, find-
ings consistent with those seen on the CT scan
of the neck.
Dr. Goldstein: A diagnostic procedure was per-
formed.
Differ en t i a l Di agnosis
Dr. Kevin L. Ard: This 55-year-old man with newly
diagnosed HIV-1 infection presented with rapid
enlargement of the right parotid gland within
weeks after the initiation of antiretroviral ther-
apy (ART). I have participated in the care of
this patient and am aware of the diagnosis in
this case.
There are several possible causes of parotid-
gland enlargement, including infection, anatomi-
cal causes, mechanical obstruction, autoimmune
disorders, benign neoplasms, and cancer. Four
features of this patient’s presentation are helpful
in formulating a differential diagnosis. First, he
had advanced HIV infection with a CD4+ T-cell
count of 65 per cubic millimeter, which confers
a diagnosis of the acquired immunodeficiency
syndrome (AIDS) and places the patient at risk
for opportunistic infections and cancer. Second,
the abrupt onset and rapid progression of parotid-
gland enlargement favor infection, anatomical
causes, and cancer over autoimmune processes
and benign neoplasms. Third, the imaging stud-
ies showed a solid lesion with no stones and
therefore ruled out a cyst of the branchial cleft,
sialocele, and sialolithiasis. Finally, the timing
between the initiation of ART and the develop-
ment of the mass raises concerns about the im-
mune reconstitution inflammatory syndrome
(IRIS) and cancer.
Infection
Viral and bacterial infections can cause rapidly
enlarging parotid masses. The classic viral cause
is mumps. However, mumps is unlikely in this
 Case Records of the Massachuset ts Gener al Hospital
case because of the unilateral nature of the
symptoms, absence of associated fever and myal-
gias, and month-long duration of illness with no
improvement.1 Other viruses that can cause par-
otitis, such as adenovirus, cytomegalovirus, influ-
enza virus, and parainfluenza virus, are unlikely
for the same reasons.
Acute suppurative bacterial parotitis, which is
commonly caused by Staphylococcus aureus, strepto-
cocci, gram-negative bacilli, or anaerobic bacte-
ria,2 can result in rapid, unilateral parotid-gland
enlargement and abscess formation. This con-
dition must be considered in this patient, who
had undergone a dental procedure approximately
2 weeks before the current presentation. Redness,
pain, and fever are usually present, and pus can
often be expressed from Stensen’s duct; these
features were notably absent in this case. In ad-
dition, MRI revealed no surrounding inflamma-
tion and no abscess, making acute suppurative
bacterial parotitis unlikely.
Both M. tuberculosis and M. avium complex can
cause parotid masses in patients with advanced
HIV-1 infection.3 The negative interferon-γ release
assay and absence of epidemiologic risk factors
for M. tuberculosis infection decrease the likeli-
hood but do not rule out the possibility of this
diagnosis. Although tuberculosis can occur in a
patient with HIV infection and any CD4+ T-cell
count, M. avium complex most commonly causes
disease when the CD4+ T-cell count is less than
50 per cubic millimeter.4 M. avium complex infec-
tion has protean manifestations, which range
from fever to localized lymphadenitis. Involve-
ment of the parotid gland is not common, but
when it occurs, the infection is often unilateral
and is not associated with systemic symptoms5;
these features were seen in this case. However,
the typical findings of abscess and necrosis on
imaging were not present in this patient. Never-
theless, mycobacterial infection remains a key
consideration in the differential diagnosis of
this patient’s illness.
Immune Reconstitution Inflammatory
Syndrome
The timing between the initiation of ART and
the development of parotid-gland enlargement
raises the possibility of IRIS, a syndrome in which
an improvement in immune function unmasks a
subclinical infection in a patient with advanced
HIV infection. Treatment with integrase strand
transfer inhibitors, such as elvitegravir (which
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was taken by this patient), rapidly reduces vire-
mia and is associated with a higher incidence of
IRIS than the incidence with other ART regi-
mens.6 There are numerous possible causes of
IRIS, but in this patient, I am most concerned
about IRIS due to mycobacterial infection, which
can cause localized lymphadenitis and could be
compatible with this patient’s presentation. How-
ever, IRIS tends to occur weeks after the initia-
tion of ART7; in one prospective study, the me-
dian time from the initiation of ART to the
development of IRIS was 33 days.8 In this pa-
tient, symptoms developed less than 1 week after
the initiation of ART, which would be uncom-
monly rapid for IRIS.
Autoimmune Diseases
Sjögren’s syndrome can cause both unilateral
and bilateral parotid-gland enlargement. The
patient’s dental caries and chronic orodental pain
could have been caused by xerostomia due to the
diminished salivary function associated with this
condition. Enlargement of the salivary gland can
wax and wane in Sjögren’s syndrome, but the
sudden onset and rapid progression that were
seen in this patient would be unexpected. Sar-
coidosis and IgG4-related disease can also cause
parotid-gland enlargement. However, parotitis due
to sarcoidosis usually appears alongside other,
more typical manifestations of the disease,9,10
and parotitis due to IgG4-related disease is usu-
ally bilateral.11
Neoplasms
Both benign and malignant neoplasms can af-
fect the parotid gland. Benign lymphoepithelial
lesions of the parotid gland are an important
cause of parotid swelling in patients with HIV
infection. These lesions are typically indolent,
bilateral, and manifested by cysts with thick
septations on imaging studies.12 The classic im-
aging features of a benign lymphoepithelial le-
sion were absent in this case, and the develop-
ment of the mass was more rapid than would be
expected with this condition. The diffuse infil-
trative lymphocytosis syndrome is a rare disorder
that can cause massive parotid swelling in per-
sons with HIV infection.13 However, the parotid-
gland enlargement associated with the diffuse
infiltrative lymphocytosis syndrome tends to be
bilateral and to progress more slowly than the
enlargement seen in this case. Other benign neo-
plasms of the parotid gland, such as pleomorphic
1147
 The n e w e ng l a n d j o u r na l
adenoma and Warthin’s tumor, grow slowly over
a period of years and would not be compatible
with this patient’s clinical presentation.
Several features that are “red flags” for can-
cer are present in this patient,14 including numb-
ness of the pinna (which suggests neurologic
impingement), rapid growth, and the fixed na-
ture of the mass. Non-Hodgkin’s lymphoma is
the AIDS-associated cancer that is most likely to
affect the parotid gland. Persons with HIV infec-
tion have a markedly higher risk of lymphoma
than nonimmunosuppressed persons,15 and lym-
phomas in persons with HIV infection tend to
be clinically aggressive.16 Diffuse large-B-cell
lymphoma is the most common type of non-
Hodgkin’s lymphoma; the second most common
type is Burkitt’s lymphoma.17 Although either
type could account for the brisk parotid-gland
enlargement seen in this patient, the rapid
growth raises particular concerns about Burkitt’s
lymphoma. The incidence of lymphoma appears
to be highest during the first 6 months of ART,18
which would be compatible with this patient’s
presentation. A diagnosis of lymphoma would
not necessarily rule out other conditions in the
differential diagnosis. For example, Sjögren’s syn-
drome can lead to lymphoma involving the sali-
vary gland, and cases of lymphomatous trans-
formation of benign lymphoepithelial lesions
have also been described.12 Several cancers that
are not associated with HIV, including mucoepi-
dermoid carcinoma and adenoid cystic carcino-
ma, can arise in the parotid gland, but they do
not tend to enlarge as quickly as the mass seen
in this case.
In view of the underlying advanced HIV infec-
tion, the rapid parotid-gland enlargement, and
the absence of inflammatory changes on physi-
cal examination and imaging studies, I think
that this patient’s parotid-gland enlargement is
due to cancer, most likely an aggressive lym-
phoma. I would pursue a biopsy of the parotid
gland for pathological evaluation.
Regardless of the diagnosis, it is unfortunate
that this patient’s HIV infection was first recog-
nized at an advanced stage of disease, despite
previous contacts with the health care system.
Routine HIV screening of all adults is recom-
mended by both the Centers for Disease Control
and Prevention and the U.S. Preventive Services
Task Force because early diagnosis and treatment
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of m e dic i n e
reduce morbidity and mortality,19 as well as the
likelihood of transmission to others.20 If the final
diagnosis in this patient is an opportunistic
infection or an AIDS-associated cancer, earlier
diagnosis and treatment of HIV infection may
have prevented the illness.
Dr. Virginia M. Pierce (Pathology): Dr. Goldstein,
what was your impression when you evaluated
this patient?
Dr. Goldstein: When this patient, who had newly
diagnosed advanced HIV infection, presented
with a tender lump on the right jaw 1 week after
he started ART, we first suspected an abscess
related to his recent dental work. However, with
the rapid enlargement of the mass over the en­
suing weeks, we grew increasingly concerned
about cancer. Imaging studies were obtained,
and the patient was referred to an otolaryngolo-
gist. He underwent fine-needle aspiration and
biopsy of the mass.
Cl inic a l Di agnosis
High-grade lymphoma associated with human
immunodeficiency virus infection.
Dr . K e v in L . A r d’s Di agnosis
Lymphoma.
Pathol o gic a l Discussion
Dr. Abner Louissaint, Jr.: Fine-needle aspiration of
the mass was performed, and examination of the
aspirate revealed numerous large, abnormal lym-
phoid cells, a finding consistent with lymphoma.
Flow cytometric analysis of the aspirate revealed
a monoclonal population of CD19+, CD20+, and
CD10+ B cells, with restricted expression of
lambda immunoglobulin light chain.
A biopsy of the mass of the right parotid
gland was subsequently performed. The parotid
gland was densely infiltrated by monomorphic
sheets of neoplastic lymphoid cells with mod-
erate amounts of cytoplasm, round-to-irregular
nuclei, open chromatin, and variably promi-
nent nucleoli (Fig. 2A). Abundant single-cell
necrosis and phagocytic histiocytes were pres-
ent in the background, imparting a “starry sky”
appearance. Immunohistochemical stains showed
that the neoplastic cells were CD20+PAX5+BCL6+
 Case Records of the Massachuset ts Gener al Hospital

Figure 2. Biopsy Specimen of the Mass of the Parotid A B

Gland.
On hematoxylin and eosin staining, the mass is com‑
posed of monomorphic sheets of neoplastic lymphoid
cells with moderate amounts of cytoplasm, round-to-
irregular nuclei, open chromatin, and variably prominent
nucleoli (Panel A). On immunohistochemical staining,
the neoplastic cells are CD20+ B cells (Panel B). On
staining for Ki-67, the proliferation fraction is greater
than 95% (Panel C); the neoplastic cells have weak ex‑
pression of C-MYC (Panel D). On a standard interphase C D
fluorescence in situ hybridization assay with the use of
MYC break-apart probes, the neoplastic cells are nega‑
tive for MYC rearrangements (Panel E). The red signal
represents a probe that is immediately upstream of the
5′ (centromeric) end of MYC; the green signal represents
a probe that is immediately downstream of the 3′ (telo‑
meric) end of MYC. The colocalization of one red and
one green signal represents an intact MYC locus (i.e.,
no MYC rearrangement). Diagnostic microarray analy‑
sis for the detection of copy-number variants confirms
a pattern of copy-number gains of 11q23–24 (Panel F, E
in blue) followed by adjacent distal losses of 11q24–tel
(Panel F, in pink).

B cells that were negative for BCL2, MUM1, and

cyclin D1 (Fig. 2B); on in situ hybridization, the
F
cells were negative for Epstein–Barr virus–encoded
RNA. On staining for Ki-67, the proliferation
fraction was greater than 95% (Fig. 2C). Ap-
proximately 60% of the cells were weakly posi-
tive for C-MYC (Fig. 2D). There were numerous F
small, mature, admixed CD3+ T cells in the
background.
Taken together, the findings were diagnostic
of a high-grade lymphoma. Although the mor-
phologic and immunophenotypic features were
most consistent with Burkitt’s lymphoma, the
weak staining for C-MYC stood out as being
unusual for Burkitt’s lymphoma. In addition, a
standard interphase fluorescence in situ hybrid-
ization (FISH) assay with the use of break-apart
probes did not reveal the presence of MYC re­ assay designed to detect aberrations at chromo-
arrangements (Fig. 2E). Biopsy specimens were some 11q was positive for a gain of 11q23–24
sent to a colleague at the Institute of Human and a telemetric loss of 11q24–tel (including ETS
Genetics, University Hospital of Ulm (Ulm, Ger- proto-oncogene 1 [ETS1]). Diagnostic microarray
many), for the performance of additional molec­ analysis for the detection of copy-number vari-
ular genetic assays to rule out cryptic MYC re- ants confirmed the pattern of copy-number
arrangements and assess for the presence of gains followed by losses at chromosome 11q
aberrations at chromosome 11q. FISH assays (Fig. 2F). In addition, trisomy 7 and trisomy 12
designed to detect cryptic MYC translocations were identified, and chromosome 10 showed a
(e.g., IGH-MYC, IGK-MYC, and IGL-MYC) were complex pattern of aberrations, with an overall
negative for such rearrangements, but a FISH tetrasomy of the chromosome.

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 The n e w e ng l a n d j o u r na l
In summary, the morphologic and immuno-
phenotypic features similar to those of Burkitt’s
lymphoma, the absence of MYC rearrangements,
and the presence of proximal gains and telo-
meric losses at chromosome 11q are characteris-
tic of Burkitt-like lymphoma with 11q aberra-
tions, a rare condition that was recently added as
a provisional entity to the 2017 World Health Or-
ganization lymphoma classification of tumors.21-23
In the few cases reported thus far, the clinical
course appeared to be similar to that of Burkitt’s
lymphoma.23
Discussion of M a nagemen t
Dr. Rajesh T. Gandhi: Before the advent of effective
ART, the incidence of non-Hodgkin’s lymphoma
in persons with HIV infection was markedly
higher than the incidence in the general popula-
tion. Now that effective ART is available, there
has been a substantial change in the incidence of
HIV-associated lymphoma, although this change
has not been consistent across different types of
lymphoma. In a 2014 study, the standardized
incidence ratio for non-Hodgkin’s lymphoma in
persons with HIV as compared with the general
U.S. population was 11.5.24 However, although
rates of diffuse large-B-cell lymphoma and pri-
mary central nervous system lymphoma have
steeply declined over time, the standardized inci-
dence ratio for Burkitt’s lymphoma has not sub-
stantially decreased. This difference may be relat-
ed to the fact that diffuse large-B-cell lymphoma
and primary central nervous system lymphoma
generally occur in severely immunocompromised
persons with HIV infection, whereas Burkitt’s
lymphoma may occur in persons with HIV infec-
tion who have CD4+ T-cell counts of more than
200 per cubic millimeter.
In this patient, the rapid growth of lympho-
ma soon after the initiation of ART raises the
question of whether these two events are linked.
Rates of lymphoma among patients with HIV
infection are highest during the first 6 months
after the initiation of ART, especially among
those with low CD4+ T-cell counts.18 In addition,
there have been reports of lymphoma being
unmasked within weeks after the initiation of
ART,25-27 a phenomenon termed “lymphoma IRIS.”
Indeed, in a recent study involving 482 persons
with HIV infection who had received a diagnosis
1150 n engl j med 378;12 nejm.org  March 22, 2018
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of m e dic i n e
of lymphoma, 12% had lymphoma IRIS.28 The
brisk growth of this patient’s mass was most
likely related to the rapidly dividing cells that
are characteristic of Burkitt’s lymphoma, and
a component of IRIS may have hastened the
process.
This patient was treated with dose-adjusted
EPOCH-R (etoposide, prednisone, vincristine,
cyclophosphamide, doxorubicin, and rituximab).
The rationale for the development of this inter-
mediate-intensity regimen, in which several drugs
are continuously infused over a period of 96
hours, included the observation that tumor cells
had less resistance to killing in vitro with sus-
tained low-concentration drug exposure than with
short high-concentration exposure.29 EPOCH-R
for the treatment of HIV-associated Burkitt’s
lymphoma has yielded promising results and is
being investigated in an ongoing multicenter
trial.30,31 Because of improvements in chemo-
therapy and the availability of lifesaving ART,
5-year survival among patients with HIV-associ-
ated Burkitt’s lymphoma has increased from less
than 15% in the early 1990s to more than 50%
in the mid-2000s.32
An important consideration in treating this
patient is the potential for interactions between
antineoplastic agents and antiretroviral medica-
tions and overlapping toxic effects. In response
to these concerns, an ART regimen of tenofovir
alafenamide, emtricitabine, and dolutegravir was
chosen. This regimen does not have substantial
effects on the cytochrome P450 CYP3A4 system,
which metabolizes several classes of chemothera-
peutic agents.33,34 The availability of medications
that are associated with low rates of toxic effects
and drug interactions supports the continuation
of ART during chemotherapy.
Dr. Pierce: Dr. Goldstein, would you tell us
what happened with this patient?
Dr. Goldstein: Over the course of 4 months,
the patient received six cycles of dose-adjusted
EPOCH-R and intrathecal methotrexate. The
clinical course was complicated by pneumonia
and admissions for increased ostomy output.
Since he completed chemotherapy, he has had
prolonged lymphopenia and a slow rise in his
CD4+ T-cell count, but the HIV viral load has
been less than 20 copies per milliliter. Now, 1 year
after he completed chemotherapy, the lymphoma
remains in remission.
 Case Records of the Massachuset ts Gener al Hospital

Dr. Martin S. Hirsch (Medicine): What are your Fina l Di agnosis

thoughts about the positive serologic tests for
syphilis? Burkitt-like lymphoma with 11q aberrations.
Dr. Goldstein: We treated the patient for latent This case was presented at the 11th Annual Workshop on
syphilis with three doses of intramuscular peni- Advanced Clinical Care–AIDS in Durban, South Africa, organized
cillin. We did not perform a lumbar puncture to by Drs. Henry Sunpath and Mahomed-Yunus S. Moosa (Infectious
Diseases Unit, Nelson R Mandela School of Medicine, University
rule out neurosyphilis. of KwaZulu-Natal) and Dr. Rajesh T. Gandhi (Massachusetts Gen-
Dr. Ard: While I was reviewing the imaging eral Hospital and the Ragon Institute) and sponsored by the Har-
studies, I asked the radiologist whether the vard University Center for AIDS Research (NIH P30 AI060354),
the Centre for the AIDS Programme of Research in South Africa,
parotid mass could be a syphilitic gumma. We the University of KwaZulu-Natal, the South African HIV Clini-
discussed that a gumma would be expected to cians Society, and the KwaZulu-Natal Department of Health.
have a different appearance on imaging than Dr. Gandhi reports receiving grant support (paid to Massachu-
setts General Hospital) from Gilead Sciences, Merck, and ViiV
the features seen in this patient. A gumma HealthCare, and consulting fees from Theratechnologies and
often looks like an abscess, with a thick rind. EMD Serono. No other potential conflict of interest relevant to
I also found a case series published in the 1920s, this article was reported.
Disclosure forms provided by the authors are available with
in which parotid involvement among patients the full text of this article at NEJM.org.
with syphilis was very rare. Taken together, I
35
We thank Justin Alves for assistance with preparation of the
thought that the positive serologic tests for case history, Dr. William A. Mehan for assistance with the con-
ference, and Dr. Reiner Siebert (Institute of Human Genetics,
syphilis were probably not related to the parot­ University Hospital of Ulm, Ulm, Germany) for the performance
id mass. of additional molecular genetic assays.

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