case 2-2019: a 36-year-old man with rash, abdominal pain ... clinico.pdf · dr. schiavoni: the...

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n engl j med 380;3 nejm.org January 17, 2019 275 The new england journal of medicine Presentation of Case Dr. Katherine H. Schiavoni (Medicine): A 36-year-old man was admitted to this hospi- tal because of abdominal pain, rash, and lymphadenopathy. The patient had been well until 4 years before admission, when swelling devel- oped in the right side of the neck. One year later, he was evaluated at this hospital and reported that the neck swelling had persisted but had not changed in size. He also reported that he had had no fevers, night sweats, or weight loss. On examina- tion, there was an enlarged posterior cervical lymph node (2 cm in diameter) on the right side. The node was mildly tender and freely mobile, with a rubbery tex- ture and slightly irregular shape. Results of liver-function tests were normal, as were blood levels of iron, ferritin, and total iron-binding capacity. A test for hetero- phile antibodies and a fourth-generation combination assay for human immuno- deficiency virus type 1 (HIV-1) and type 2 (HIV-2) antibodies and HIV-1 p24 anti- gen were negative; other laboratory test results are shown in Table 1. Chest radiography revealed a normal cardiac silhouette and clear lungs. Biopsy of the lymph node was recommended, but the patient elected not to undergo the procedure. Two years before admission, a diffuse, painless, erythematous, papular rash developed on the trunk and then spread to the arms, legs, scalp, and face. The papules appeared in separate crops, and over a period of 1 to 2 months, a small amount of purulent material drained from each papule, after which the lesions evolved into hyperpigmented nodules. The rash persisted, and 6 months later, the patient was evaluated at another hospital. A biopsy of the skin of the left arm was performed, and histopathological examination of the biopsy specimen revealed findings consistent with acute folliculitis. Treatment with doxycycline was initiated, but the rash persisted, with a waxing and waning pattern, during the next 8 months. Doxycycline was discontinued. Subsequent treatment with topical clobetasol resulted in only a mild decrease in the rash. Six weeks before admission, a biopsy of the skin of the right thigh was per- formed. Histopathological examination of the biopsy specimen revealed acute From the Departments of Medicine (S.T.C., E.T.R.), Dermatology (S.T.C.), Ra‑ diology (A.M.C.), and Pathology (R.K.F.), Massachusetts General Hospital, the De‑ partments of Dermatology (S.T.C.), Med‑ icine (E.T.R.), Radiology (A.M.C.), and Pathology (R.K.F.), Harvard Medical School, and the Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health (E.T.R.) — all in Boston. N Engl J Med 2019;380:275-83. DOI: 10.1056/NEJMcpc1810390 Copyright © 2019 Massachusetts Medical Society. 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 Alyssa Y. Castillo, M.D., Case Records Editorial Fellow Emily K. McDonald, Sally H. Ebeling, Production Editors Case 2-2019: A 36-Year-Old Man with Rash, Abdominal Pain, and Lymphadenopathy Steven T. Chen, M.D., M.P.H., Alexis M. Cahalane, M.D., Edward T. Ryan, M.D., and Ruth K. Foreman, M.D., Ph.D. Case Records of the Massachusetts General Hospital The New England Journal of Medicine Downloaded from nejm.org at UNIV STUDI LA SAPIENZA on June 3, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved.

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Page 1: Case 2-2019: A 36-Year-Old Man with Rash, Abdominal Pain ... clinico.pdf · Dr. Schiavoni: The patient was admitted to the hospital, and fine-needle aspiration and core biop-sy of

n engl j med 380;3 nejm.org January 17, 2019 275

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

Pr esen tation of C a se

Dr. Katherine H. Schiavoni (Medicine): A 36-year-old man was admitted to this hospi-tal because of abdominal pain, rash, and lymphadenopathy.

The patient had been well until 4 years before admission, when swelling devel-oped in the right side of the neck. One year later, he was evaluated at this hospital and reported that the neck swelling had persisted but had not changed in size. He also reported that he had had no fevers, night sweats, or weight loss. On examina-tion, there was an enlarged posterior cervical lymph node (2 cm in diameter) on the right side. The node was mildly tender and freely mobile, with a rubbery tex-ture and slightly irregular shape. Results of liver-function tests were normal, as were blood levels of iron, ferritin, and total iron-binding capacity. A test for hetero-phile antibodies and a fourth-generation combination assay for human immuno-deficiency virus type 1 (HIV-1) and type 2 (HIV-2) antibodies and HIV-1 p24 anti-gen were negative; other laboratory test results are shown in Table 1. Chest radiography revealed a normal cardiac silhouette and clear lungs. Biopsy of the lymph node was recommended, but the patient elected not to undergo the procedure.

Two years before admission, a diffuse, painless, erythematous, papular rash developed on the trunk and then spread to the arms, legs, scalp, and face. The papules appeared in separate crops, and over a period of 1 to 2 months, a small amount of purulent material drained from each papule, after which the lesions evolved into hyperpigmented nodules. The rash persisted, and 6 months later, the patient was evaluated at another hospital. A biopsy of the skin of the left arm was performed, and histopathological examination of the biopsy specimen revealed findings consistent with acute folliculitis. Treatment with doxycycline was initiated, but the rash persisted, with a waxing and waning pattern, during the next 8 months. Doxycycline was discontinued. Subsequent treatment with topical clobetasol resulted in only a mild decrease in the rash.

Six weeks before admission, a biopsy of the skin of the right thigh was per-formed. Histopathological examination of the biopsy specimen revealed acute

From the Departments of Medicine (S.T.C., E.T.R.), Dermatology (S.T.C.), Ra‑diology (A.M.C.), and Pathology (R.K.F.), Massachusetts General Hospital, the De‑partments of Dermatology (S.T.C.), Med‑icine (E.T.R.), Radiology (A.M.C.), and Pathology (R.K.F.), Harvard Medical School, and the Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health (E.T.R.) — all in Boston.

N Engl J Med 2019;380:275-83.DOI: 10.1056/NEJMcpc1810390Copyright © 2019 Massachusetts Medical Society.

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

Alyssa Y. Castillo, M.D., Case Records Editorial Fellow Emily K. McDonald, Sally H. Ebeling, Production Editors

Case 2-2019: A 36-Year-Old Man with Rash, Abdominal Pain, and Lymphadenopathy

Steven T. Chen, M.D., M.P.H., Alexis M. Cahalane, M.D., Edward T. Ryan, M.D., and Ruth K. Foreman, M.D., Ph.D.

Case Records of the Massachusetts General Hospital

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neutrophilic folliculitis, with follicular rupture in the middle dermis and associated acute and chronic inflammation. Surface bacteria and yeast were present, but there were no bacterial or fun-gal organisms in the dermis. Treatment with oral clindamycin and rifampin was begun, and the patient was instructed to wash twice daily with chlorhexidine and apply mupirocin to open papules.

One day before admission, abdominal pain developed in the right upper quadrant. The pain was sharp, constant, worsened by movement and deep breathing, and unchanged with eating. There was no nausea, vomiting, or diarrhea. The pain progressively worsened during the next 24 hours, and the patient presented to the emergency de-partment of this hospital for evaluation.

In the emergency department, the patient re-ported ongoing abdominal pain, as well as weight loss of 4.5 kg during the past year, which he attributed to increased regular exercise at a gym. Four weeks before admission, he had stopped exercising because of increased fatigue with ex-ertion. The patient reported that he had not had

fevers but had occasionally changed his pajamas at night because of sweating. He had microcytic anemia that had been attributed to β-thalassemia minor. The only medications were clindamycin and rifampin, and there were no known drug allergies.

The patient was born in Morocco and had moved to the United States 10 years before ad-mission. He visited his family in a rural village in Morocco every few years, with the last visit occurring 5 months earlier. He had never smoked tobacco, and he did not drink alcohol or use illicit drugs. He did not consume unpasteurized dairy products. His father had died of complications of emphysema.

On examination, the temperature was 37.6°C, the pulse 66 beats per minute, the blood pressure 132/82 mm Hg, the respiratory rate 16 breaths per minute, and the oxygen saturation 97% while the patient was breathing ambient air. The weight was 76.2 kg; the last recorded weight, which had been obtained 4 years earlier, was 81.8 kg. The patient did not appear to be ill but was in mild distress because of abdominal pain.

VariableReference Range,

Adults*3 Yr before Admission

On Admission

Hematocrit (%) 41–53 39.9 30.2

Hemoglobin (g/dl) 13.5–17.5 13.0 9.3

White‑cell count (per mm3) 4500–11,000 7370 9460

Differential count (%)

Neutrophils 40–70 63.1 75.8

Lymphocytes 22–44 24.4 11.2

Monocytes 4–11 11.5 11.7

Eosinophils 0–8 0.8 0.5

Basophils 0–3 0.1 0.2

Platelet count (per mm3) 150,000–400,000 167,000 301,000

Red‑cell count (per mm3) 4,500,000–5,900,000 6,760,000 5,510,000

Mean corpuscular volume (fl) 80.0–100.0 59.0 54.8

Mean corpuscular hemoglobin (pg) 26.0–34.0 19.2 16.9

Mean corpuscular hemoglobin concentration (g/dl) 31.0–37.0 32.6 30.8

Total protein (g/dl) 6.0–8.3 8.2 8.6

Albumin (g/dl) 3.3–5.0 4.9 3.3

d‑dimer (ng/ml) <500 734

* 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.

Table 1. Laboratory Data.

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Erythematous, follicular papules and hyperpig-mented nodules, some with central erosion and ulceration, were distributed on the trunk, arms, legs, face, and scalp (Fig. 1). Examination of the heart and lungs was normal. Bowel sounds were present, and the abdomen was soft, with tender-ness on palpation of the right upper quadrant, but was not distended. There was right axillary lymphadenopathy but no submandibular, cervical, supraclavicular, or inguinal lymphadenopathy. Blood levels of electrolytes, glucose, and lactate dehydrogenase were normal, as were results of renal-function and liver-function tests; other lab-oratory test results are shown in Table 1. Tests for antibodies to hepatitis B virus (HBV) surface antigen and antibodies to HBV core antigen were positive. Tests for HBV surface antigen, hepatitis C virus antibodies, and Treponema pallidum anti-bodies were negative, as was a fourth-generation combination assay for HIV-1 and HIV-2 antibod-ies and HIV-1 p24 antigen. Urinalysis revealed normal findings, and blood cultures were nega-tive. Imaging studies were obtained.

Dr. Alexis M. Cahalane: Abdominal ultrasonogra-phy revealed an ill-defined mass (9.0 cm by 5.6 cm) in the right lobe of the liver, with no evidence of dilatation of intrahepatic bile ducts. Computed tomography (CT) of the chest, performed after the administration of intravenous contrast mate-rial (Fig. 2A and 2B), revealed multiple prominent cardiophrenic lymph nodes (≤1 cm in maximal short-axis diameter) predominantly on the right side. There were also multiple enlarged axillary

lymph nodes (≤3.4 cm in maximal short-axis diameter) on the right side, including some with central necrosis. CT of the abdomen and pelvis (Fig. 2C) revealed multiple ill-defined hypoden-sities throughout the right lobe and in the fourth segment of the liver, with the largest measuring 2.7 cm by 2.0 cm. Trace perihepatic ascites and mild splenomegaly were present, with the spleen measuring 13.5 cm in craniocaudal dimension.

Magnetic resonance imaging (MRI) of the liver, performed after the administration of intrave-nous contrast material (Fig. 2D, 2E, and 2F), revealed multiple areas of abnormality in the right lobe that corresponded to the lesions seen on CT, with the largest measuring 3.1 cm by 6.3 cm by 3.5 cm. The lesions had mild peripheral hyper-intensity on T2-weighted images and restricted diffusion on diffusion-weighted images. On im-ages obtained during the portal venous phase, the lesions had peripheral enhancement with central hypoenhancement. On images obtained 4 minutes after the administration of contrast material, the lesions had a “cluster of grapes” appearance. Mild splenomegaly was also detected.

Dr. Schiavoni: The patient was admitted to the hospital, and fine-needle aspiration and core biop-sy of a right axillary lymph node were performed.

Dr. Ruth K. Foreman: Examination of the aspirate and biopsy specimen (Fig. 3) revealed benign-appearing lymph-node tissue with normal archi-tecture and associated necroinflammatory debris. There was no histologic evidence of cancer. Acid-fast, Gomori methenamine–silver, periodic acid–

Figure 1. Clinical Photographs.

Clinical photographs of the patient’s skin show erythematous, follicle‑based papules and hyperpigmented nodules on the trunk, arms, and legs (Panels A, B, and C, respectively).

A B C

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A B

DC

FE

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Schiff, Brown–Hopps, and Steiner stains for micro-organisms were negative, as was an immuno-histochemical stain for spirochetes. Tissue from the biopsy was sent to the microbiology labora-tory for culture.

Dr. Schiavoni: Additional diagnostic tests were performed, and a diagnosis was made.

Differ en ti a l Di agnosis

Dr. Steven T. Chen: This 36-year-old man had an indolent disease course that was characterized by generalized lymphadenopathy and a diffuse rash, ultimately followed by acute pain in the right upper quadrant. Imaging studies were notable for liver lesions that were suggestive of small pyogenic abscesses.

Lymphadenopathy was first detected in the neck 4 years before admission; by the time of admission, it was detected in the peridiaphrag-matic, anterior mediastinal, and axillary regions, with some nodes measuring more than 4 cm in diameter and having central necrosis. The rash, which developed 2 years before admission and involved the face, arms, legs, and torso, had been diagnosed as folliculitis and treated with multi-ple courses of antibiotics, without resolution. On examination of the clinical photographs (Fig. 1), the lesions do not appear to be accentuated in hair-bearing areas. This calls the diagnosis of folliculitis into question. However, these photo-

graphs were not taken with high enough resolu-tion to allow definitive assessment of whether the eruption is follicular, a finding that would help to narrow the differential diagnosis. The presence of lesions on the central back argues against a self-induced, prurigo-like process. The eruption is described as consisting of erythema-tous and hyperpigmented nodules and papules,

Figure 3. Lymph Node–Biopsy Specimen.

Hematoxylin and eosin staining of the core biopsy specimen of the right axillary lymph node (Panel A) shows benign‑appearing lymph‑node tissue with no apparent architectural disorder and with associated necroinflammatory debris (arrow). At higher magnifi‑cation (Panel B), the lymphocytes appear small and the necrotic debris is pauci‑inflammatory, without a substantial number of neutrophils.

A

B

Figure 2 (facing page). Imaging Studies of the Chest and Abdomen.

CT of the chest, abdomen, and pelvis was performed after the administration of intravenous contrast material. A coronal image (Panel A) shows marked right axillary lymphadenopathy (arrow), with lymph nodes measuring up to 3.4 cm in maximal short‑axis dimension; some lymph nodes have central necrosis. An additional coro‑nal image (Panel B) shows multiple prominent cardio‑phrenic lymph nodes (arrow) measuring up to 1 cm in maximal short‑axis diameter. An axial image (Panel C) shows multiple ill‑defined hypodensities (arrows) in the liver parenchyma. MRI of the liver was then per‑formed after the administration of intravenous contrast material. An axial, T2‑weighted image (Panel D) shows multiple hepatic parenchymal lesions (arrows) with mild peripheral hyperintensity. An image obtained during the portal venous phase (Panel E) shows peripheral enhance‑ment with central hypoenhancement of the lesions. An image obtained 4 minutes after the administration of contrast material (Panel F) shows a “cluster of grapes” appearance of the lesions.

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with ulceration, and the photographs show that the lesions have a brown and brawny appearance that is most consistent with a granulomatous process. Results of diascopy are not reported, but the finding of “apple jelly” nodules on this test would have provided additional support for characterization of the lesions as a manifestation of granulomatous disease.

Assuming that the generalized lymphadenopa-thy, liver abscesses, and granulomatous skin eruption can all be explained by a unifying di-agnosis, I will focus my differential diagnosis on three categories of causes. Listed in order of in-creasing likelihood, these categories are autoim-mune diseases (specifically sarcoidosis), lympho-proliferative disorders, and infections.

Sarcoidosis

Although several autoimmune diseases may have indolent progression similar to the disease course seen in this patient, the granulomatous skin eruption and liver lesions that were present in this patient specifically prompt consideration of sarcoidosis and would be atypical of other auto-immune diseases. Sarcoidosis could also explain the presence of peripheral lymphadenopathy1 and necrosis,2,3 a finding that was evident in some enlarged axillary lymph nodes on imaging. How-ever, sarcoidosis is typically associated with perihilar mediastinal lymphadenopathy, whereas this patient had anterior mediastinal lymphade-nopathy. Furthermore, 95% of cases of sarcoidosis involve the lungs,4 and the absence of pulmonary symptoms such as cough, dyspnea, and chest pain and of reticular opacities on CT makes the diagnosis of sarcoidosis unlikely. Finally, to es-tablish the diagnosis of sarcoidosis, it is neces-sary to rule out other diseases with similar pre-sentations, such as lymphoproliferative disorders and infections.

Lymphoproliferative Disorders

In this patient, the indolent disease course makes some lymphoproliferative diseases — such as Hodgkin’s lymphoma, follicular lymphoma, multi-centric Castleman’s disease, and immunoprolif-erative small intestinal disease — much more likely than the lymphoproliferative diseases that typically follow a more aggressive trajectory (e.g., diffuse large B-cell lymphoma, Burkitt’s lympho-ma, and angioimmunoblastic T-cell lymphoma).

Hodgkin’s lymphoma deserves careful consider-ation in this case, given that the average age at diagnosis in the United States is 39 years and this patient was 36 years of age, that the lymph-adenopathy began in the neck and later involved other sites, and that a variety of cutaneous erup-tions have been associated with Hodgkin’s lym-phoma, including paraneoplastic dermatoses and skin infiltration.5

Follicular lymphoma may also begin with peripheral lymphadenopathy and progress to involve mediastinal lymph nodes, and the dis-ease course may span several years6; however, it typically occurs in older patients and rarely oc-curs in persons in this patient’s age group. Multi-centric Castleman’s disease is another lymphopro-liferative disorder that can begin with generalized lymphadenopathy and can have an indolent course7; however, cutaneous involvement is rare, and fever, which was not reported by this pa-tient, is typical.

Immunoproliferative small intestinal disease is rare in the United States but is more common among young men in the Middle East and North Africa, so it merits consideration in this patient, who was born and raised in Morocco. Immuno-proliferative small intestinal disease is thought to occur in the context of a chronic infection that leads to B-cell activation and clonal prolif-eration, and affected patients usually present with abdominal pain, chronic diarrhea with malab-sorption, or an abdominal mass.8 This patient reported abdominal pain at the time of admis-sion, but the pain was acute. Furthermore, there was no diarrhea, the weight loss was less severe than would be expected with this disorder, and imaging studies did not reveal bowel-wall thick-ening or an abdominal mass. These findings make immunoproliferative small intestinal dis-ease unlikely.

Although it is reasonable to consider lympho-proliferative disorders in the differential diagno-sis for this patient, the findings on imaging studies of the liver are more consistent with an infectious process. Other findings — including the normal blood lactate dehydrogenase level and the absence of relevant findings on histo-pathological examination of the biopsy speci-mens — may not rule out lymphoproliferative disorders, but they make these diagnoses un-likely.

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Infections

Which infections could cause generalized lymph-adenopathy, a granulomatous skin eruption, and liver abscesses in an otherwise healthy young man who has lived in Morocco and New England? Among bacterial infections, brucellosis is a con-sideration, but the absence of fever and of a his-tory of exposure makes this diagnosis unlikely.9 Syphilis is ruled out by the negative screening test for T. pallidum antibodies. Cryptococcosis and endemic mycoses such as histoplasmosis can result in clinical and imaging findings similar to those seen in this patient but would not usu-ally lead to such a protracted illness in a pre-sumably immunocompetent person. Although leishmaniasis is endemic in Morocco, it is un-likely in this patient because the appearance of the skin lesions is not consistent with the cuta-neous form of this disease10 and because vis-ceral leishmaniasis would be expected to cause a more severe illness, with fever, pancytopenia, and more marked weight loss and splenomegaly. In addition, the findings on imaging studies of the liver are not typical of leishmaniasis.11

Mycobacterial infections deserve close con-sideration in this case. Although we often think of Mycobacterium leprae when considering myco-bacterial skin disease, the incidence of leprosy in Morocco is low and the appearance of the skin lesions in this patient is not consistent with this diagnosis. An infection with atypical mycobacte-ria such as M. fortuitum can cause skin lesions but would not usually involve the reticuloendo-thelial system in an immunocompetent person. M. bovis infection could account for this patient’s presentation; however, without exposure to un-pasteurized milk, this diagnosis is also unlike-ly.12 Because the patient had taken trips to Mo-rocco, where tuberculosis is endemic,13 I would focus on M. tuberculosis infection as the most likely cause of this patient’s presentation.

Tuberculosis

Cutaneous involvement is relatively uncommon in M. tuberculosis infection. Patients with cutane-ous tuberculosis can present with a variety of clinical findings, which can be classified ac-cording to the method by which mycobacteria are disseminated to the skin.14

Direct inoculation of mycobacteria from an exogenous source into a host can be manifested

by tuberculous chancre or tuberculosis verrucosa cutis. These cutaneous manifestations are local-ized to the site of inoculation,14 whereas this patient’s rash was diffuse. The spread of myco-bacteria from an endogenous source may result in scrofuloderma, a suppurative nodular process that often develops on the skin overlying affected lymph nodes and then drains, leading to sinus formation and resultant cordlike scars. Although this patient had lymph-node involvement, his cutaneous findings were more widely distributed than would be expected with scrofuloderma.

Hematogenous spread of mycobacteria, known as miliary tuberculosis, may have cutaneous manifestations, such as a generalized, mono-morphic papular, pustular, or nodular process. However, this patient’s systemic symptoms were less severe than would be expected with miliary tuberculosis, which is typically associated with fever and more marked night sweats and weight loss. In addition, miliary tuberculosis has a char-acteristic pattern on CT of the lungs, but there were no abnormal findings on CT of the lungs in this patient.

Lupus vulgaris is a chronic, scarring, and de-forming process that may occur either as a direct result of an underlying focus of M. tuberculosis infection or after hematogenous or lymphatic spread of infection. The eruption associated with lupus vulgaris classically affects the central por-tion of the face and can progress slowly over a long period of time.

The other category of cutaneous tuberculosis is tuberculids, skin eruptions that are thought to occur in reaction to an underlying, often occult, focus of M. tuberculosis infection.14 There are three main types of tuberculids: erythema induratum, lichen scrofulosorum, and papulonecrotic tuber-culid. Erythema induratum appears as red-to-violaceous nodules or plaques on the posterior calf and is localized, in contrast to the diffuse rash that was seen in this patient. Lichen scrofu-losorum appears as many discrete, often mono-morphic, 2-to-4-mm, flat-topped papules, usually on the trunk. Papulonecrotic tuberculid is usually a symmetric, recurring eruption of 2-to-8-mm, firm, inflammatory papules that can turn into pustules and become necrotic over time, scarring over a period of weeks. If papulonecrotic tuber-culid goes untreated, it may persist for years. This patient’s indolent disease course and the

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description and appearance of his rash are highly consistent with the papulonecrotic tuberculid form of cutaneous tuberculosis, and therefore, this is the most likely diagnosis in this case.

Confirming the diagnosis of papulonecrotic tuberculid is challenging. Although an inter-feron-γ release assay would be part of the labo-ratory evaluation in this patient, a positive assay would not help to discriminate between latent and active tuberculosis. Tuberculids are commonly considered to be hypersensitivity eruptions, and in patients with these disorders, acid-fast stains of smears or histopathological sections of skin-biopsy specimens would not normally be expect-ed to identify mycobacteria, although it is possible. Similarly, mycobacterial cultures of skin-biopsy specimens are unlikely to be positive, although the tuberculid reaction can be seeded by the hematogenous spread of mycobacteria and or-ganisms can be isolated from these lesions in some cases. In this patient, acid-fast stains and cultures would be more likely to be diagnostic if specimens were obtained from an underlying focus of M. tuberculosis infection, such as an af-fected lymph node or a liver abscess. Although M. tuberculosis may take several weeks to grow in culture, its isolation would allow for the perfor-mance of antimicrobial susceptibility testing, the results of which would inform the selection of a therapeutic antibiotic regimen.

Dr . S te v en T. Chen’s Di agnosis

Papulonecrotic tuberculid (cutaneous tuberculosis).

Pathol o gic a l Discussion

Dr. Foreman: A punch biopsy of the skin of the right forearm was obtained (Fig. 4). Histopatho-logical examination of the specimen revealed a superficial and deep necrotizing granulomatous inflammatory infiltrate. The necrosis surrounded naked hair shafts; this finding is suggestive of a possible folliculocentric process. Acid-fast, Fite, Gomori methenamine–silver, periodic acid–Schiff with diastase, and Brown–Hopps stains for mi-croorganisms were negative, as was an immuno-histochemical stain for spirochetes. A section of the specimen was submitted to the microbiology laboratory for mycobacterial culture.

Discussion of M a nagemen t a nd Foll ow-up

Dr. Meridale V. Baggett (Medicine): Dr. Ryan, would you tell us what happened next?

Dr. Edward T. Ryan: An enzyme-linked immuno-spot interferon-γ release assay for a cell-mediated immune response to M. tuberculosis was strongly positive. At this point, we thought that the com-plete clinical picture — including the epidemio-logic history, chronicity of the disease process, dermal manifestations, apparently necrotic axil-lary lymph nodes, hepatic lesions, markedly posi-tive interferon-γ release assay, weight loss, night sweats, and presence of necrotizing granulomas on examination of the skin-biopsy specimen —

Figure 4. Skin-Biopsy Specimen.

Hematoxylin and eosin staining of the punch biopsy specimen of the skin of the right forearm (Panel A) shows a predominantly dermal inflammatory process with some superficial scale and epidermal spongiosis. At higher magnification (Panel B), there is a necrotizing granulomatous infiltrate with free hair shafts (arrows).

A

B

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Case Records of the Massachusetts Gener al Hospital

strongly supported the diagnosis of papulone-crotic tuberculid with accompanying tubercu-lous lymphadenitis and hepatic involvement. The patient had recently begun to take oral clindamy-cin and rifampin, and we thought that the rifam-pin could have partially treated his tuberculosis.

While the results of mycobacterial culture of biopsy specimens of the axillary lymph node and skin were pending, we obtained three induced-sputum samples and a urine specimen for myco-bacterial culture, to increase the likelihood of establishing a microbiologic diagnosis and ob-taining information on susceptibility that could guide future therapy. Once these samples had been collected, antituberculous therapy consist-ing of daily rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE) was administered, along with vitamin B6.

After the empirical initiation of antitubercu-lous treatment, the patient did well and no new skin lesions developed. Approximately 4 weeks later, the culture of the axillary lymph node– biopsy specimen grew M. tuberculosis complex.

Subsequent susceptibility testing revealed that the isolate was susceptible to first-line antituber-culous agents in vitro. After 8 weeks of RIPE therapy, pyrazinamide and ethambutol were dis-continued, and treatment with isoniazid and ri-fampin was continued. Approximately 3 months after the initiation of therapy, the patient’s energy level had returned to normal, clinical examina-tion revealed that the axillary lymph nodes had decreased in size, and follow-up abdominal imag-ing revealed that the hepatic lesions had dimin-ished. A 6-to-12-month course of antituberculous therapy is planned.

Fina l Di agnosis

Papulonecrotic tuberculid (cutaneous tuberculosis).

This case was presented at the Medical Case Conference.No potential conflict of interest relevant to this article was

reported.Disclosure forms provided by the authors are available with

the full text of this article at NEJM.org.We thank Dr. Sherry H. Yu for contributing the clinical photo-

graphs.

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