CHEST
Postgraduate Education Corner PULMONARY, CRITICAL CARE, AND SLEEP PEARLS
A Woman in Her 40s With AIDS and Lung Mass Walid Hadid, MD; Dana Rifai, MD; Odile David, MD; and Ruxana T. Sadikot, MD, FCCP
CHEST 2014; 145(1):173–177
in her 40s with HIV diagnosed in 1999 Awoman was admitted to our facility with progressive dys-
pnea, fever, and productive cough for 1 week. She had been treated previously for Pneumocystis jiroveci pneumonia and herpes zoster. She was receiving highly active antiretroviral therapy and prophylaxis with dapsone and azithromycin. She was a nonsmoker and denied using illicit drugs. Physical Examination Findings Vital signs were within normal limits, other than a temperature of 38°C and oxygen saturation of 95% on room air. There was no lymphadenopathy. There was a localized wheeze in the right infraclavicular area of the chest. The rest of the examination was within normal limits. Diagnostic Studies
WBC count was 3.4 3 103, hemoglobin level was 6.4 gm/dL, CD4 count was 1 cell/UL, and viral load
Figure 1. Chest radiograph shows right upper lobe mass. journal.publications.chestnet.org
Figure 2. CT scan of the chest shows right upper lobe mass.
was 51,600 copies/mL. Chest radiograph showed a new mass measuring 6 cm in diameter in the right upper lobe (Fig 1); this was confirmed on a chest CT scan (Fig 2). The patient was treated with vancomycin and piperacillin-tazobactam, with no significant response.
Figure 3. Sectioned right upper lobectomy specimen shows region of grayish-white necrotic tissue. CHEST / 145 / 1 / JANUARY 2014
173
Figure 4. A, Overview of section of lesion demonstrating destruction of normal pulmonary architecture with replacement by cellular infiltrates with prominent perivascular distribution (darker blue-purple areas) and focal necrosis (solid pink areas). Bronchial mucosa, cartilage, and mucous glands are present at the bottom of the image. The black arrow marks an anthracotic pigment-laden intraparenchymal lymph node (hematoxylin and eosin, magnification 3 4.1). B, Dense perivascular cellular infiltrates (right) with extensive regional necrosis (left) that grossly mimics granulomatosis (hematoxylin and eosin, magnification 3 25).
Bronchoscopy showed narrowing of the right upper anterior segment bronchus with no endobronchial lesion. Histopathology of transbronchial lung biopsy specimens was suggestive of B-cell lymphoproliferative process but was not diagnostic. Microbiologic stains and cultures were negative. Video-assisted thoracoscopy was performed, which showed necrotic tissue with negative microbial cultures. Repeat chest CT scanning showed progression of the mass with necrotic features and significant destruction of the right upper lobe. Hence, a right upper lobectomy was performed. Gross examination showed the lobe was filled with grayish-white, necrotic tissue (Fig 3). Pathology showed lymphoid infiltrates with five to 20 atypical lymphocytes/high power field and large areas of necrosis. Clonal immunoglobulin heavy-chain gene rearrangement was detected by DNA polymerase chain reaction amplification. Epstein-Barr virus (EBV) early RNA was detected by in situ hybridization in the atypical lymphocytes (Figs 4-7).
Figure 5. At higher magnification, the cellular infiltrates appear lymphoid and can be seen within the wall of the vessel right up to the endothelial cell lining (angiitis) (hematoxylin and eosin, magnification 3 100).
Manuscript received June 11, 2013; revision accepted June 18, 2013. Affiliations: From the Division of Pulmonary, Critical Care and Sleep Medicine (Drs Hadid and Rifai), and the Pathology Department (Dr David), University of Illinois at Chicago, Chicago, IL; and the Division of Pulmonary, Critical Care and Sleep Medicine (Dr Sadikot), University of Florida, Gainesville, FL. Part of this article has been presented as a case presentation (Hadid W, Sadikot R. Chest. 2009;136[4_Meeting Abstracts]: 40S-e-41S). Correspondence to: Walid Hadid, MD, Department of Medicine, University of Illinois at Chicago, 840 S Wood St, MC 719, Chicago, IL 60612-7323; e-mail: [email protected] © 2014 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-1312 174
Postgraduate Education Corner
Figure 6. Leukocyte common antigen (CD45) immunostained section confirms the lymphoid nature of the infiltrates (CD45 immunostain, magnification 3 50).
Figure 7. Polymorphous lymphoid infiltrates with scattered large atypical cells (red arrows mark a few examples). These are the Epstein-Barr virus-infected B cells (hematoxylin and eosin, magnification 3 400).
What is the diagnosis?
journal.publications.chestnet.org
CHEST / 145 / 1 / JANUARY 2014
175
Diagnosis: Lymphomatoid granulomatosis, grade 2
Discussion Lymphomatoid granulomatosis (LYG) is a rare EBVassociated extranodal angiodestructive lymphoproliferative disease. To our knowledge, it was first described by Averill Liebow and colleagues in 1972 and was originally classified among diseases characterized by pulmonary angiitis and granulomatosis. Currently, it is classified as a B-cell lymphoproliferative process. The grading system is based on the number of atypical large EBV-infected B cells within the lesions, which prominently involve the lungs but also involve extrapulmonary sites including the CNS, kidneys, and skin. Grade 1 lesions demonstrate a polymorphous population of lymphoid cells with fewer than five EBVinfected cells per high-power field and usually lack necrosis. Only one-third of patients with grade 1 LYG progress to malignant lymphoma; the most common type includes grade 2 lesions that are also polymorphous but have five to 20 EBV-infected cells per highpower field and show foci of necrosis. Approximately two-thirds of patients with grade 2 LYG progress to lymphoma. Grade 3 LYG is by definition a B-cell lymphoma with sheets of EBV-infected cells and necrosis. LYG typically presents between the ages of 30 and 50 years and has a predilection for men (2:1). Most cases arise from an immune deficiency state, and it has been associated with Sjögren syndrome, chronic viral hepatitis, rheumatoid arthritis, renal transplantation, and HIV. From a pulmonary perspective, the disorder usually presents with multiple bilateral nodules with a predilection for the lower lobes, generally without hilar or mediastinal adenopathy. Large masses and occlusion of large vessels also occur. The most common presenting symptoms and signs are cough (55.6%), fever (57.7%), rash/nodules (39%), malaise (35%), weight loss (34.5%), neurologic abnormalities (30%), dyspnea (28.9%), chest pain (13.4%), and lymphadenopathy (12%). A few asymptomatic cases have been reported in the literature. Massive hemoptysis and respiratory failure have also been described. Radiographically, 80% of cases present as peripheral bilateral nodular infiltrates, with a predilection for the lower lobes. Some of the features seen on CT scan include peribronchovascular distribution of nodules, coarse irregular opacities, small thin-walled cysts, and conglomerating small nodules. Rarely, LYG may present as a mass, cavitations, atelectasis, or as a lobar obstruction as in our case. Hilar lymphadenopathy is found in 2% to 4% of cases. 176
The clinical manifestations of LYG are nonspecific. Therefore, in most cases, the diagnosis hinges on histopathology as in the case described here. The lymphoid infiltrates typically surround and then invade the walls of the pulmonary arteries and veins “angiitis.” In grade 3 lesions, large areas of necrosis that are grossly reminiscent of granulomatosis (hence, the nomenclature) may be seen; however, well-formed granulomas are typically absent. A closely resembling disease that should be differentiated from LYG is granulomatosis with polyangiitis, in which there is commonly sinus and upper-airway involvement and renal necrotizing glomerulonephritis, all rarely encountered in LYG. Histologically, granulomatosis with polyangiitis lesions demonstrate true granulomatous inflammation, not usually seen in LYG, and lack the atypical lymphocytes present in variable numbers in LYG. Treatment of LYG depends on many factors, including the presence of symptoms, the extent of extrapulmonary involvement, and the histopathologic grade. Asymptomatic patients with low-grade (grades 1 and 2) disease confined to the lungs may be followed conservatively with serial clinical and radiologic evaluations, because many of these patients may experience spontaneous remission. Otherwise, patients should be treated with steroids and cytotoxic drugs. Anecdotal reports have described promising results with interferon alfa-2b. Other proposed therapies include multiagent chemotherapy, ganciclovir, and rituximab. Clinical Course Because the patient had low-grade disease (grade 2), no systemic therapy was required after the surgery. She was followed up for 2 years, during which time she had no recurrence. She was lost to follow-up afterwards. Clinical Pearls 1. LYG is a rare, EBV-associated, systemic angiodestructive lymphoproliferative disease. The World Health Organization classifies it under the category of B-cell proliferations of uncertain malignant potential. 2. It is associated with Sjögren syndrome, chronic viral hepatitis, rheumatoid arthritis, renal transplantation, and HIV. 3. The clinical and radiologic manifestations of LYG are nonspecific. Therefore, the diagnosis hinges on histopathology. 4. Treatment depends on many factors, including the presence of symptoms, the extent of extrapulmonary involvement, and the histopathologic grade. 5. Treatment includes steroids and cytotoxic drugs, and anecdotal reports have described promising results with interferon alfa-2b. Other proposed therapies Postgraduate Education Corner
include multiagent chemotherapy, ganciclovir, and rituximab. Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: This work was performed at University of Illinois at Chicago. CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
Suggested Readings Liebow AA, Carrington CR, Friedman PJ. Lymphomatoid granulomatosis. Hum Pathol. 1972;3(4):457-558.
journal.publications.chestnet.org
Hicken P, Dobie JC, Frew E. The radiology of lymphomatoid granulomatosis in the lung. Clin Radiol. 1979;30(6):661-664. Katzenstein AL, Carrington CB, Liebow AA. Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases. Cancer. 1979;43(1):360-373. Koss MN, Hochholzer L, Langloss JM, Wehunt WD, Lazarus AA, Nichols PW. Lymphomatoid granulomatosis: a clinicopathologic study of 42 patients. Pathology. 1986;18(3):283-288. Lee JS, Tuder R, Lynch DA. Lymphomatoid granulomatosis: radiologic features and pathologic correlations. AJR Am J Roentgenol. 2000;175(5):1335-1339. Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC Press; 2004:92-94.
CHEST / 145 / 1 / JANUARY 2014
177
Postgraduate Education Corner PULMONARY, CRITICAL CARE, AND SLEEP PEARLS
A Woman in Her 40s With AIDS and Lung Mass Walid Hadid, MD; Dana Rifai, MD; Odile David, MD; and Ruxana T. Sadikot, MD, FCCP
CHEST 2014; 145(1):173–177
in her 40s with HIV diagnosed in 1999 Awoman was admitted to our facility with progressive dys-
pnea, fever, and productive cough for 1 week. She had been treated previously for Pneumocystis jiroveci pneumonia and herpes zoster. She was receiving highly active antiretroviral therapy and prophylaxis with dapsone and azithromycin. She was a nonsmoker and denied using illicit drugs. Physical Examination Findings Vital signs were within normal limits, other than a temperature of 38°C and oxygen saturation of 95% on room air. There was no lymphadenopathy. There was a localized wheeze in the right infraclavicular area of the chest. The rest of the examination was within normal limits. Diagnostic Studies
WBC count was 3.4 3 103, hemoglobin level was 6.4 gm/dL, CD4 count was 1 cell/UL, and viral load
Figure 1. Chest radiograph shows right upper lobe mass. journal.publications.chestnet.org
Figure 2. CT scan of the chest shows right upper lobe mass.
was 51,600 copies/mL. Chest radiograph showed a new mass measuring 6 cm in diameter in the right upper lobe (Fig 1); this was confirmed on a chest CT scan (Fig 2). The patient was treated with vancomycin and piperacillin-tazobactam, with no significant response.
Figure 3. Sectioned right upper lobectomy specimen shows region of grayish-white necrotic tissue. CHEST / 145 / 1 / JANUARY 2014
173
Figure 4. A, Overview of section of lesion demonstrating destruction of normal pulmonary architecture with replacement by cellular infiltrates with prominent perivascular distribution (darker blue-purple areas) and focal necrosis (solid pink areas). Bronchial mucosa, cartilage, and mucous glands are present at the bottom of the image. The black arrow marks an anthracotic pigment-laden intraparenchymal lymph node (hematoxylin and eosin, magnification 3 4.1). B, Dense perivascular cellular infiltrates (right) with extensive regional necrosis (left) that grossly mimics granulomatosis (hematoxylin and eosin, magnification 3 25).
Bronchoscopy showed narrowing of the right upper anterior segment bronchus with no endobronchial lesion. Histopathology of transbronchial lung biopsy specimens was suggestive of B-cell lymphoproliferative process but was not diagnostic. Microbiologic stains and cultures were negative. Video-assisted thoracoscopy was performed, which showed necrotic tissue with negative microbial cultures. Repeat chest CT scanning showed progression of the mass with necrotic features and significant destruction of the right upper lobe. Hence, a right upper lobectomy was performed. Gross examination showed the lobe was filled with grayish-white, necrotic tissue (Fig 3). Pathology showed lymphoid infiltrates with five to 20 atypical lymphocytes/high power field and large areas of necrosis. Clonal immunoglobulin heavy-chain gene rearrangement was detected by DNA polymerase chain reaction amplification. Epstein-Barr virus (EBV) early RNA was detected by in situ hybridization in the atypical lymphocytes (Figs 4-7).
Figure 5. At higher magnification, the cellular infiltrates appear lymphoid and can be seen within the wall of the vessel right up to the endothelial cell lining (angiitis) (hematoxylin and eosin, magnification 3 100).
Manuscript received June 11, 2013; revision accepted June 18, 2013. Affiliations: From the Division of Pulmonary, Critical Care and Sleep Medicine (Drs Hadid and Rifai), and the Pathology Department (Dr David), University of Illinois at Chicago, Chicago, IL; and the Division of Pulmonary, Critical Care and Sleep Medicine (Dr Sadikot), University of Florida, Gainesville, FL. Part of this article has been presented as a case presentation (Hadid W, Sadikot R. Chest. 2009;136[4_Meeting Abstracts]: 40S-e-41S). Correspondence to: Walid Hadid, MD, Department of Medicine, University of Illinois at Chicago, 840 S Wood St, MC 719, Chicago, IL 60612-7323; e-mail: [email protected] © 2014 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-1312 174
Postgraduate Education Corner
Figure 6. Leukocyte common antigen (CD45) immunostained section confirms the lymphoid nature of the infiltrates (CD45 immunostain, magnification 3 50).
Figure 7. Polymorphous lymphoid infiltrates with scattered large atypical cells (red arrows mark a few examples). These are the Epstein-Barr virus-infected B cells (hematoxylin and eosin, magnification 3 400).
What is the diagnosis?
journal.publications.chestnet.org
CHEST / 145 / 1 / JANUARY 2014
175
Diagnosis: Lymphomatoid granulomatosis, grade 2
Discussion Lymphomatoid granulomatosis (LYG) is a rare EBVassociated extranodal angiodestructive lymphoproliferative disease. To our knowledge, it was first described by Averill Liebow and colleagues in 1972 and was originally classified among diseases characterized by pulmonary angiitis and granulomatosis. Currently, it is classified as a B-cell lymphoproliferative process. The grading system is based on the number of atypical large EBV-infected B cells within the lesions, which prominently involve the lungs but also involve extrapulmonary sites including the CNS, kidneys, and skin. Grade 1 lesions demonstrate a polymorphous population of lymphoid cells with fewer than five EBVinfected cells per high-power field and usually lack necrosis. Only one-third of patients with grade 1 LYG progress to malignant lymphoma; the most common type includes grade 2 lesions that are also polymorphous but have five to 20 EBV-infected cells per highpower field and show foci of necrosis. Approximately two-thirds of patients with grade 2 LYG progress to lymphoma. Grade 3 LYG is by definition a B-cell lymphoma with sheets of EBV-infected cells and necrosis. LYG typically presents between the ages of 30 and 50 years and has a predilection for men (2:1). Most cases arise from an immune deficiency state, and it has been associated with Sjögren syndrome, chronic viral hepatitis, rheumatoid arthritis, renal transplantation, and HIV. From a pulmonary perspective, the disorder usually presents with multiple bilateral nodules with a predilection for the lower lobes, generally without hilar or mediastinal adenopathy. Large masses and occlusion of large vessels also occur. The most common presenting symptoms and signs are cough (55.6%), fever (57.7%), rash/nodules (39%), malaise (35%), weight loss (34.5%), neurologic abnormalities (30%), dyspnea (28.9%), chest pain (13.4%), and lymphadenopathy (12%). A few asymptomatic cases have been reported in the literature. Massive hemoptysis and respiratory failure have also been described. Radiographically, 80% of cases present as peripheral bilateral nodular infiltrates, with a predilection for the lower lobes. Some of the features seen on CT scan include peribronchovascular distribution of nodules, coarse irregular opacities, small thin-walled cysts, and conglomerating small nodules. Rarely, LYG may present as a mass, cavitations, atelectasis, or as a lobar obstruction as in our case. Hilar lymphadenopathy is found in 2% to 4% of cases. 176
The clinical manifestations of LYG are nonspecific. Therefore, in most cases, the diagnosis hinges on histopathology as in the case described here. The lymphoid infiltrates typically surround and then invade the walls of the pulmonary arteries and veins “angiitis.” In grade 3 lesions, large areas of necrosis that are grossly reminiscent of granulomatosis (hence, the nomenclature) may be seen; however, well-formed granulomas are typically absent. A closely resembling disease that should be differentiated from LYG is granulomatosis with polyangiitis, in which there is commonly sinus and upper-airway involvement and renal necrotizing glomerulonephritis, all rarely encountered in LYG. Histologically, granulomatosis with polyangiitis lesions demonstrate true granulomatous inflammation, not usually seen in LYG, and lack the atypical lymphocytes present in variable numbers in LYG. Treatment of LYG depends on many factors, including the presence of symptoms, the extent of extrapulmonary involvement, and the histopathologic grade. Asymptomatic patients with low-grade (grades 1 and 2) disease confined to the lungs may be followed conservatively with serial clinical and radiologic evaluations, because many of these patients may experience spontaneous remission. Otherwise, patients should be treated with steroids and cytotoxic drugs. Anecdotal reports have described promising results with interferon alfa-2b. Other proposed therapies include multiagent chemotherapy, ganciclovir, and rituximab. Clinical Course Because the patient had low-grade disease (grade 2), no systemic therapy was required after the surgery. She was followed up for 2 years, during which time she had no recurrence. She was lost to follow-up afterwards. Clinical Pearls 1. LYG is a rare, EBV-associated, systemic angiodestructive lymphoproliferative disease. The World Health Organization classifies it under the category of B-cell proliferations of uncertain malignant potential. 2. It is associated with Sjögren syndrome, chronic viral hepatitis, rheumatoid arthritis, renal transplantation, and HIV. 3. The clinical and radiologic manifestations of LYG are nonspecific. Therefore, the diagnosis hinges on histopathology. 4. Treatment depends on many factors, including the presence of symptoms, the extent of extrapulmonary involvement, and the histopathologic grade. 5. Treatment includes steroids and cytotoxic drugs, and anecdotal reports have described promising results with interferon alfa-2b. Other proposed therapies Postgraduate Education Corner
include multiagent chemotherapy, ganciclovir, and rituximab. Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: This work was performed at University of Illinois at Chicago. CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
Suggested Readings Liebow AA, Carrington CR, Friedman PJ. Lymphomatoid granulomatosis. Hum Pathol. 1972;3(4):457-558.
journal.publications.chestnet.org
Hicken P, Dobie JC, Frew E. The radiology of lymphomatoid granulomatosis in the lung. Clin Radiol. 1979;30(6):661-664. Katzenstein AL, Carrington CB, Liebow AA. Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases. Cancer. 1979;43(1):360-373. Koss MN, Hochholzer L, Langloss JM, Wehunt WD, Lazarus AA, Nichols PW. Lymphomatoid granulomatosis: a clinicopathologic study of 42 patients. Pathology. 1986;18(3):283-288. Lee JS, Tuder R, Lynch DA. Lymphomatoid granulomatosis: radiologic features and pathologic correlations. AJR Am J Roentgenol. 2000;175(5):1335-1339. Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC Press; 2004:92-94.
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