A 55-Year-Old Man with HIV Infection and a Mass on the Right Side of the Face

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Case Records of the Massachusetts General Hospital

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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.

Presentation of Case

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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current evaluation, an excisional biopsy of a negative. Chest radiography revealed minimal mass on the right side of the neck had been linear and reticular opacities in the right middle performed. Histopathological examination of the lobe, lingula, and left lower lobe; these findings biopsy specimen revealed an enlarged lymph had not changed from previous examinations. node with florid follicular and paracortical hy- A follow-up appointment was arranged for the perplasia. following week. The patient took diazepam and had no One week after this evaluation, repeat exami- known allergies to medications. He resided in nation in the infectious diseases clinic revealed an urban area of New England. He was retired that the size of the mass on the right side of the and had previously worked for the government. face had increased to 1 cm in diameter. One He did not smoke tobacco, drink alcohol, or use week later, the size of the mass had increased to illicit drugs. He reported that he had never had 1.5 cm in diameter, and numbness of the right sex but that he had been assaulted in the past. pinna had developed. Imaging studies were ob- His mother had had lung cancer, and his father tained. had had congestive heart failure. Dr. Hillary R. Kelly: Computed tomography (CT) On examination in the clinic, the patient ap- of the neck (Fig. 1A and 1B) revealed asymmetric peared anxious. The vital signs were normal, enlargement of the right parotid gland, with no and the weight was 75.7 kg; 2 years earlier, the surrounding inflammatory change. There was weight had been 93.2 kg. The maxilla was eden- an ill-defined, central focus of hypoattenuation tulous, and the few remaining mandibular teeth in the right parotid gland, a finding that raised appeared carious. The abdomen was scaphoid, concerns about a fluid collection or mass lesion. with an ostomy in the right lower quadrant, and Scattered cervical lymph nodes were seen through- the skin on the face and chest was erythematous out the neck; these nodes were thought to be and peeling; the remainder of the examination larger and more numerous than expected for an was normal. The anion gap and blood levels of otherwise healthy 55-year-old patient but did not glucose, calcium, alanine aminotransferase, as- meet the size criteria for enlargement due to partate aminotransferase, alkaline phosphatase, cancer. CT of the head revealed enlargement of

total bilirubin, direct bilirubin, vitamin B12, folic the prepontine and premedullary cisterns and acid, testosterone, and glycated hemoglobin were of the fourth ventricle, a finding that reflected normal, as were the results of renal-function disproportionate volume loss in the brain stem tests; other laboratory test results are shown in relative to the cerebral hemispheres. Magnetic Table 1. Topical ketoconazole–based shampoo, resonance imaging (MRI) was recommended for trimethoprim–sulfamethoxazole, and a fixed- further characterization of the facial mass. dose formulation of elvitegravir, cobicistat, em- MRI of the neck was performed after the tricitabine, and tenofovir alafenamide were pre- administration of intravenous contrast material scribed. (Fig. 1C through 1F). A large, multilobulated One week later, the patient returned to the mass or confluent cluster of nodules occupied infectious diseases clinic for follow-up (the cur- most of the deep and superficial lobes of the rent evaluation) and reported that a lump had right parotid gland, extending through and wid- developed on the right side of his face. He had ening the stylomandibular tunnel. There was a adhered to the prescribed regimen, and his ap- small rind of normal parotid parenchyma sur- petite had increased during the past week. On rounding this mass. The mass had an isointense

examination, the vital signs were normal, and signal on T1-weighted imaging, restricted diffu- the weight was 76.7 kg. At the angle of the right sion on diffusion-weighted imaging, and hetero- mandible, there was a firm, fixed, tender mass geneous enhancement on contrast-enhanced im- measuring 0.5 cm in diameter, with no overlying aging. There was a central focus of hypointense

erythema or warmth. The erythema of the skin signal on T2-weighted imaging that correspond- on the face and chest had decreased; the re- ed to the focus of hypoattenuation that had been mainder of the examination was unchanged. An seen on the CT scan of the neck. The maximum interferon-γ release assay for a cell-mediated im- dimensions of the mass were 4.2 cm transverse mune response to Mycobacterium tuberculosis was by 3.3 cm anteroposterior by 5.6 cm craniocaudal;

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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 Platelet count (per mm3) 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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A B the parotid gland was more enlarged than it had been on the CT scan. The lesion bowed the external 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, findings consistent with those seen on the CT scan of the neck. C D Dr. Goldstein: A diagnostic procedure was performed.

Differential Diagnosis 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 therapy (ART). I have participated in the care of E F this patient and am aware of the diagnosis in this case. There are several possible causes of parotid- gland enlargement, including infection, anatomical 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, Figure 1. Imaging Studies. the abrupt onset and rapid progression of parotid- Coronal and axial CT scans of the neck (Panels A and B, respectively), ob‑ gland enlargement favor infection, anatomical tained after the administration of intravenous iodinated contrast material, causes, and cancer over autoimmune processes show asymmetric enlargement of the right parotid gland (Panel A, arrow‑ heads) as compared with the left parotid gland (Panel A, arrow), with no and benign neoplasms. Third, the imaging stud- surrounding inflammatory change. There is an ill-defined, central focus of ies showed a solid lesion with no stones and hypoattenuation (Panel B, arrows) in the right parotid gland, a finding that therefore ruled out a cyst of the branchial cleft, raises concerns about an underlying fluid collection or mass lesion. An axial sialocele, and sialolithiasis. Finally, the timing T1-weighted MRI of the neck (Panel C), obtained after the administration of intravenous gadolinium, shows a large mass (arrowheads) that replaces most between the initiation of ART and the develop- the deep and superficial lobes of the right parotid gland, extending through ment of the mass raises concerns about the im- and widening the stylomandibular tunnel. A T2-weighted image (Panel D) mune reconstitution inflammatory syndrome shows a central focus of hypointense signal (arrows) that corresponds to (IRIS) and cancer. the focus of hypoattenuation seen in Panel B. The lesion bows the external carotid artery anteriorly and abuts the posterior border of the mandibular Infection ramus; there is no evidence of cortical erosion or abnormal signal in the marrow. A diffusion-weighted image and an apparent-diffusion-coefficient Viral and bacterial infections can cause rapidly map (Panels E and F, respectively) show restricted diffusion (arrows). enlarging parotid masses. The classic viral cause is mumps. However, mumps is unlikely in this

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Case Records of the Massachusetts General Hospital case because of the unilateral nature of the was taken by this patient), rapidly reduces vire- symptoms, absence of associated fever and myal- mia and is associated with a higher incidence of gias, and month-long duration of illness with no IRIS than the incidence with other ART regi- improvement.1 Other viruses that can cause par- mens.6 There are numerous possible causes of otitis, such as adenovirus, cytomegalovirus, influ- IRIS, but in this patient, I am most concerned enza virus, and parainfluenza virus, are unlikely about IRIS due to mycobacterial infection, which for the same reasons. can cause localized lymphadenitis and could be Acute suppurative bacterial parotitis, which is compatible with this patient’s presentation. How- commonly caused by Staphylococcus aureus, strepto- ever, IRIS tends to occur weeks after the initia- cocci, gram-negative bacilli, or anaerobic bacte- tion of ART7; in one prospective study, the me- ria,2 can result in rapid, unilateral parotid-gland dian time from the initiation of ART to the enlargement and abscess formation. This con- development of IRIS was 33 days.8 In this pa- dition must be considered in this patient, who tient, symptoms developed less than 1 week after had undergone a dental procedure approximately the initiation of ART, which would be uncom- 2 weeks before the current presentation. Redness, monly rapid for IRIS. pain, and fever are usually present, and pus can often be expressed from Stensen’s duct; these Autoimmune Diseases features were notably absent in this case. In ad- Sjögren’s syndrome can cause both unilateral dition, MRI revealed no surrounding inflamma- and bilateral parotid-gland enlargement. The tion and no abscess, making acute suppurative patient’s dental caries and chronic orodental pain bacterial parotitis unlikely. could have been caused by xerostomia due to the Both M. tuberculosis and M. avium complex can diminished salivary function associated with this cause parotid masses in patients with advanced condition. Enlargement of the salivary gland can HIV-1 infection.3 The negative interferon-γ release wax and wane in Sjögren’s syndrome, but the assay and absence of epidemiologic risk factors sudden onset and rapid progression that were for M. tuberculosis infection decrease the likeli- seen in this patient would be unexpected. Sar- hood but do not rule out the possibility of this coidosis and IgG4-related disease can also cause diagnosis. Although tuberculosis can occur in a parotid-gland enlargement. However, parotitis due patient with HIV infection and any CD4+ T-cell to sarcoidosis usually appears alongside other, count, M. avium complex most commonly causes more typical manifestations of the disease,9,10 disease when the CD4+ T-cell count is less than and parotitis due to IgG4-related disease is usu- 50 per cubic millimeter.4 M. avium complex infec- ally bilateral.11 tion has protean manifestations, which range from fever to localized lymphadenitis. Involve- Neoplasms ment of the parotid gland is not common, but Both benign and malignant neoplasms can af- when it occurs, the infection is often unilateral fect the parotid gland. Benign lymphoepithelial and is not associated with systemic symptoms5; lesions of the parotid gland are an important these features were seen in this case. However, cause of parotid swelling in patients with HIV the typical findings of abscess and necrosis on infection. These lesions are typically indolent, imaging were not present in this patient. Never- bilateral, and manifested by cysts with thick theless, mycobacterial infection remains a key septations on imaging studies.12 The classic im- consideration in the differential diagnosis of aging features of a benign lymphoepithelial le- this patient’s illness. sion were absent in this case, and the development of the mass was more rapid than would be Immune Reconstitution Inflammatory expected with this condition. The diffuse infil- Syndrome trative lymphocytosis syndrome is a rare disorder The timing between the initiation of ART and that can cause massive parotid swelling in per- the development of parotid-gland enlargement sons with HIV infection.13 However, the parotid- raises the possibility of IRIS, a syndrome in which gland enlargement associated with the diffuse an improvement in immune function unmasks a infiltrative lymphocytosis syndrome tends to be subclinical infection in a patient with advanced bilateral and to progress more slowly than the HIV infection. Treatment with integrase strand enlargement seen in this case. Other benign neo- transfer inhibitors, such as elvitegravir (which plasms of the parotid gland, such as pleomorphic

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adenoma and Warthin’s tumor, grow slowly over reduce morbidity and mortality,19 as well as the a period of years and would not be compatible likelihood of transmission to others.20 If the final with this patient’s clinical presentation. diagnosis in this patient is an opportunistic Several features that are “red flags” for can- infection or an AIDS-associated cancer, earlier cer are present in this patient,14 including numb- diagnosis and treatment of HIV infection may ness of the pinna (which suggests neurologic have prevented the illness. impingement), rapid growth, and the fixed na- Dr. Virginia M. Pierce (Pathology): Dr. Goldstein, ture of the mass. Non-Hodgkin’s lymphoma is what was your impression when you evaluated the AIDS-associated cancer that is most likely to this patient? affect the parotid gland. Persons with HIV infec- Dr. Goldstein: When this patient, who had newly tion have a markedly higher risk of lymphoma diagnosed advanced HIV infection, presented than nonimmunosuppressed persons,15 and lym- with a tender lump on the right jaw 1 week after phomas in persons with HIV infection tend to he started ART, we first suspected an abscess be clinically aggressive.16 Diffuse large-B-cell related to his recent dental work. However, with lymphoma is the most common type of non- the rapid enlargement of the mass over the en Hodgkin’s lymphoma; the second most common suing weeks, we grew increasingly concerned type is Burkitt’s lymphoma.17 Although either about cancer. Imaging studies were obtained, type could account for the brisk parotid-gland and the patient was referred to an otolaryngolo- enlargement seen in this patient, the rapid gist. He underwent fine-needle aspiration and growth raises particular concerns about Burkitt’s biopsy of the mass. lymphoma. The incidence of lymphoma appears 18 to be highest during the first 6 months of ART, Clinical Diagnosis which would be compatible with this patient’s presentation. A diagnosis of lymphoma would High-grade lymphoma associated with human not necessarily rule out other conditions in the immunodeficiency virus infection. differential diagnosis. For example, Sjögren’s syndrome can lead to lymphoma involving the sali- Dr. Kevin L. Ard’s Diagnosis vary gland, and cases of lymphomatous transformation of benign lymphoepithelial lesions Lymphoma. have also been described.12 Several cancers that are not associated with HIV, including mucoepi- Pathological Discussion dermoid carcinoma and adenoid cystic carcinoma, can arise in the parotid gland, but they do Dr. Abner Louissaint, Jr.: Fine-needle aspiration of not tend to enlarge as quickly as the mass seen the mass was performed, and examination of the in this case. aspirate revealed numerous large, abnormal lym- In view of the underlying advanced HIV infec- phoid cells, a finding consistent with lymphoma. tion, the rapid parotid-gland enlargement, and Flow cytometric analysis of the aspirate revealed the absence of inflammatory changes on physi- a monoclonal population of CD19+, CD20+, and cal examination and imaging studies, I think CD10+ B cells, with restricted expression of that this patient’s parotid-gland enlargement is lambda immunoglobulin light chain. due to cancer, most likely an aggressive lym- A biopsy of the mass of the right parotid phoma. I would pursue a biopsy of the parotid gland was subsequently performed. The parotid gland for pathological evaluation. gland was densely infiltrated by monomorphic Regardless of the diagnosis, it is unfortunate sheets of neoplastic lymphoid cells with mod- that this patient’s HIV infection was first recog- erate amounts of cytoplasm, round-to-irregular nized at an advanced stage of disease, despite nuclei, open chromatin, and variably promi- previous contacts with the health care system. nent nucleoli (Fig. 2A). Abundant single-cell Routine HIV screening of all adults is recom- necrosis and phagocytic histiocytes were pres- mended by both the Centers for Disease Control ent in the background, imparting a “starry sky” and Prevention and the U.S. Preventive Services appearance. Immunohistochemical stains showed Task Force because early diagnosis and treatment that the neoplastic cells were CD20+PAX5+BCL6+

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

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Dr. Martin S. Hirsch (Medicine): What are your Final Diagnosis 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.35 Taken together, I 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.

References 1. Hviid A, Rubin S, Mühlemann K. stitution inflammatory syndrome in a ran- and public health burden. Int J Cancer Mumps. Lancet 2008;371: 932-44. domized study of early vs. deferred ART 1997;73: 645-50. 2. Raad II, Sabbagh MF, Caranasos GJ. during an opportunistic infection. PLoS 17. Riedel DJ, Rositch AF, Redfield RR, Acute bacterial sialadenitis: a study of 29 One 2010;5(7):e11416. Blattner WA. HIV-associated lymphoma cases and review. Rev Infect Dis 1990;12: 9. James DG, Sharma OP. Parotid gland sub-type distribution, immunophenotypes 591-601. sarcoidosis. Sarcoidosis Vasc Diffuse Lung and survival in an urban clinic popula- 3. Rangel AL, Coletta RD, Almeida OP, Dis 2000;17:27-32. tion. Leuk Lymphoma 2015 June 19 (Epub et al. Parotid mycobacteriosis is frequent- 10. Ungprasert P, Crowson CS, Matteson ahead of print). ly caused by Mycobacterium tuberculosis EL. Clinical characteristics of parotid 18. Yanik EL, Napravnik S, Cole SR, et al. in advanced AIDS. J Oral Pathol Med 2005; gland sarcoidosis: a population-based Incidence and timing of cancer in HIV- 34:407-12. study. JAMA Otolaryngol Head Neck Surg infected individuals following initiation 4. Benson CA, Williams PL, Currier JS, 2016;142:503-4. of combination antiretroviral therapy. Clin et al. A prospective, randomized trial ex- 11. Li W, Chen Y, Sun ZP, et al. Clinico- Infect Dis 2013;57:756-64. amining the efficacy and safety of clar- pathological characteristics of immuno- 19. The INSIGHT START Study Group. ithromycin in combination with etham- globulin G4-related sialadenitis. Arthritis Initiation of antiretroviral therapy in early butol, rifabutin, or both for the treatment Res Ther 2015;17:186. asymptomatic HIV infection. N Engl J Med of disseminated Mycobacterium avium 12. Del Bono V, Pretolesi F, Pontali E, et al. 2015;373: 795-807. complex disease in persons with acquired Possible malignant transformation of be- 20. Cohen MS, Chen YQ, McCauley M, immunodeficiency syndrome. Clin Infect nign lymphoepithelial parotid lesions in et al. Prevention of HIV-1 infection with Dis 2003;37:1234-43. human immunodeficiency virus-infected early antiretroviral therapy. N Engl J Med 5. Gittinger FS, Raible A, Kempf VA. patients: report of three cases. Clin Infect 2011;365:493-505. Non-tuberculous mycobacterial infection of Dis 2000;30: 947-9. 21. Pienkowska-Grela B, Rymkiewicz G, the parotid gland in an immunosuppressed 13. Ghrenassia E, Martis N, Boyer J, Burel- Grygalewicz B, et al. Partial trisomy 11, adult. J Med Microbiol 2008;57:536-9. Vandenbos F, Mekinian A, Coppo P. The dup(11)(q23q13), as a defect characteriz- 6. Dutertre M, Cuzin L, Demonchy E, et al. diffuse infiltrative lymphocytosis syn- ing lymphomas with Burkitt pathomor- Initiation of antiretroviral therapy con- drome (DILS): a comprehensive review. phology without MYC gene rearrange- taining integrase inhibitors increases the J Autoimmun 2015;59:19-25. ment. Med Oncol 2011;28:1589-95. risk of IRIS requiring hospitalization. 14. Mehanna H, McQueen A, Robinson M, 22. Salaverria I, Martin-Guerrero I, Wa- J Acquir Immune Defic Syndr 2017;76(1): Paleri V. Salivary gland swellings. BMJ gener R, et al. A recurrent 11q aberration e23-e26. 2012;345:e6794. pattern characterizes a subset of MYC- 7. Phillips P, Bonner S, Gataric N, et al. 15. Grulich AE, van Leeuwen MT, Falster negative high-grade B-cell lymphomas re- Nontuberculous mycobacterial immune MO, Vajdic CM. Incidence of cancers in sembling Burkitt lymphoma. Blood 2014; reconstitution syndrome in HIV-infected people with HIV/AIDS compared with 123:1187-98. patients: spectrum of disease and long- immunosuppressed transplant recipients: 23. Swerdlow SH, Campo E, Harris NL, term follow-up. Clin Infect Dis 2005;41: a meta-analysis. Lancet 2007;370:59-67. eds. WHO classification of tumors of 1483-97. 16. Coté TR, Biggar RJ, Rosenberg PS, hematopoietic and lymphoid tissues. 4th 8. Grant PM, Komarow L, Andersen J, et et al. Non-Hodgkin’s lymphoma among ed. Lyon, France: International Agency for al. Risk factor analyses for immune recon- people with AIDS: incidence, presentation Research on Cancer, 2016.

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24. Hernández-Ramírez RU, Shiels MS, Immune reconstitution inflammatory syn- et al. Low-intensity therapy in adults with Dubrow R, Engels EA. Cancer risk in HIV- drome-associated Burkitt lymphoma after Burkitt’s lymphoma. N Engl J Med 2013; infected people in the USA from 1996 to combination antiretroviral therapy in HIV- 369:1915-25. 2012: a population-based, registry-link- infected patients. Clin Lymphoma Myelo- 32. Howlader N, Shiels MS, Mariotto AB, age study. Lancet HIV 2017;4(11):e495- ma Leuk 2015;15(1):e23-e29. Engels EA. Contributions of HIV to non- e504. 28. Gopal S, Patel MR, Achenbach CJ, et al. Hodgkin lymphoma mortality trends in 25. Huhn GD, Badri S, Vibhakar S, et al. Lymphoma immune reconstitution inflam- the United States. Cancer Epidemiol Bio- Early development of non-Hodgkin lym- matory syndrome in the Center for AIDS markers Prev 2016;25: 1289-96. phoma following initiation of newer class Research Network of Integrated Clinical 33. Rudek MA, Flexner C, Ambinder RF. antiretroviral therapy among HIV-infected Systems cohort. Clin Infect Dis 2014;59: Use of antineoplastic agents in patients patients — implications for immune re- 279-86. with cancer who have HIV/AIDS. Lancet constitution. AIDS Res Ther 2010;7:44. 29. Wilson WH, Grossbard ML, Pittaluga Oncol 2011;12: 905-12. 26. Kranick SM, Goncalves PH, Stetler- S, et al. Dose-adjusted EPOCH chemo- 34. Torres HA, Mulanovich V. Manage- Stevenson M, et al. Paradoxical central therapy for untreated large B-cell lympho- ment of HIV infection in patients with nervous system immune reconstitution mas: a pharmacodynamic approach with cancer receiving chemotherapy. Clin In- syndrome in acquired immunodeficiency high efficacy. Blood 2002;99:2685-93. fect Dis 2014;59:106-14. syndrome-related primary central nervous 30. Dunleavy K, Little RF, Wilson WH. 35. Kemp JE, Moore JE. Syphilis of the system lymphoma. Haematologica 2015; Update on Burkitt lymphoma. Hematol salivary glands. Arch Derm Syphilol 1922; 100(1):e21-e24. Oncol Clin North Am 2016;30:1333-43. 6:57-62. 27. Vishnu P, Dorer RP, Aboulafia DM. 31. Dunleavy K, Pittaluga S, Shovlin M, Copyright © 2018 Massachusetts Medical Society.

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