a 79-year-old woman with bilateral cavitating lung nodules

Postgraduate Education CornerCHEST IMAGING AND PATHOLOGY FOR CLINICIANS

CHEST

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CHEST 2014; 145 ( 6 ): 1419 – 1424

A 79-year-old woman presented with history of cough, shortness of breath, and fever of 3 months’

duration. Cough was associated with scant amount of mucoid expectoration, and fever was low grade in intensity. Shortness of breath was insidious in onset and had gradually progressed over 3 months. The patient, however, was able to carry out normal activities with-out any signifi cant symptoms. There was no history of hemoptysis, chest pain, wheezing, joint pain, weight loss, skin rash, Raynaud phenomenon, epistaxis, nasal discharge, hematuria, or photosensitivity. There were no other urinary, abdominal, or neurologic complaints. Past and personal history was unremarkable. The patient was a homemaker and a lifetime nonsmoker. There were no other addictions, occupational exposure, or history of travel. The patient had been treated with broad-spectrum antibiotics and antitussives on an out-patient basis with no symptomatic improvement.

Case Report

On physical examination, the patient’s pulse rate was 90 beats/min, BP was 110/78 mm Hg, and respira-tory rate was 16 breaths/min without any use of acces-sory muscles of respiration. There was no peripheral lymph node enlargement. Examination of the respi-

A 79-Year-Old Woman With Bilateral Cavitating Lung Nodules

Karan Madan , MD, DM ; Suvendu Purkait , MD ; Sudheer Arava , MD ; Ashu S. Bhalla , MD ; Rakesh Kumar , MD ; and Randeep Guleria , MD, DM

ratory system and abdomen revealed no abnormal fi nd-ings. The rest of the systemic examination was normal. Routine hematologic investigations showed an ele-vated erythrocyte sedimentation rate (60 mm/h). Total and differential leukocyte counts, platelets, and hemo-globin levels were within normal limits. Results of liver functions and kidney function tests, including a urine microscopic examination, were normal. Blood and urine cultures were sent and were sterile. Three sputum smear examinations for acid-fast bacilli and sputum cultures (mycobacterial and fungal) were nega-tive, and a tuberculin test was nonreactive.

Serial chest radiographs demonstrated progressively increasing bilateral variable-sized pulmonary nodules, some of which demonstrated central cavitation ( Fig 1A ). CT imaging examination of the thorax ( Figs 1B, 1C ) confi rmed the presence of multiple variable-sized, ran-domly distributed pulmonary nodules predominantly in the lower lobes and many of them demonstrated central cavitation. Most nodules were thick-walled with irregular inner margins; lung parenchyma sur-rounding these nodules was normal. There was no surrounding halo around the nodules. There was no mediastinal lymph node enlargement or pleural or pericardial effusion.

Antinuclear factor, rheumatoid factor, and antineu-trophil cytoplasmic antibody titers were not elevated.

Figure 1. A, Chest radiograph demonstrating multiple bilateral variable-sized pulmonary nodules, some of which show central cavitation (arrows). B-C, CT scan of the thorax showing multiple variable-sized, randomly distributed pulmonary nodules predominantly in the lower lobes. Many show central cavitation. There is no halo surrounding the nodules.

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Manuscript received September 3 , 2013 ; revision accepted February 1 , 2014 . Affi liations: From the Department of Pulmonary Medicine and Sleep Disorders (Drs Madan and Guleria), Department of Pathol-ogy (Drs Purkait and Arava), Department of Radiodiagnosis (Dr Bhalla), and Department of Nuclear Medicine (Dr Kumar), All India Institute of Medical Sciences, New Delhi, India. Correspondence to: Karan Madan, MD, DM, FCCP, Depart-ment of Pulmonary Medicine and Sleep Disorders, All India Insti-tute of Medical Sciences, Ansari Nagar, New Delhi, India 110029; 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.13-2081

Figure 2. Fluorodeoxyglucose (FDG)-PET/CT imaging fi ndings demonstrating multiple FDG avid cavitating pulmonary nodules. The corresponding CT scan images are also shown.

monary nodule was performed. Histopathologic exam-ination of the biopsy specimen ( Fig 3 ) demonstrated diffuse infi ltration of pulmonary parenchyma by mono-morphic large-sized atypical mononuclear cells with marked destruction of the pulmonary parenchyma. The neoplastic cells had vesicular nuclei, coarse chro-matin, and scant cytoplasm. There was no evidence of angiocentricity, angiodestruction, or necrosis. The neoplastic lymphoid cells were immunopositive for CD20 and multiple myeloma oncogene while nega-tive for CD3, CD 10, Bcl-6, and Epstein-Barr virus latent membrane protein.

Ultrasonographic examination of the abdomen and a transvaginal ultrasound were normal. Flexible bron-choscopy examination demonstrated normal bronchial anatomy with no endobronchial mucosal abnormal ity. Cytologic examination results of the BAL fl uid were negative. Bronchoscopic lung and endobronchial biopsy specimens demonstrated no signifi cant abnormality.

Whole-body fl uorodeoxyglucose (FDG) PET-CT scan examination was performed. Scan fi ndings dem-onstrated multiple cavitating nodules in both lungs with increased FDG uptake ( Fig 2 ). Multiple small FDG avid lymph nodes were observed in the cervi-cal, axillary, and inguinal locations, and focal uptake was noted around the area of duodeno-jejunal fl ex-ure. CT scan-guided fi ne-needle aspiration cytology examination from one of the lung nodules showed occasional atypical cells that could not be exactly char-acterized. As the patient was unwilling to undergo a surgical lung biopsy, CT scan-guided biopsy of the pul-


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Figure 3. Histopathologic examination fi ndings from the CT scan-guided lung biopsy. A, Diffuse infi ltration of lung parenchyma by medium- to large-sized atypical lymphoid cells with destruction of alveolar architecture (hematoxylin & eosin, magnifi cation 3 400). B, Membranous/cytoplasmic immunopositivity for CD20 (magnifi cation 3 400). C, Immunonegativity for CD3 (magnifi cation 3 400). D, Nuclear immunopositivity for MUM1 ( 3 400).

What is the diagnosis?




Diagnosis: Primary pulmonary diffuse large B-cell lymphoma

Discussion

Clinical Discussion

Primary pulmonary lymphoma (PPL) is defi ned as an extranodal clonal lymphoid neoplasm involving one or both lungs (parenchyma and/or bronchi) in a patient with no detectable extrapulmonary involve-ment at diagnosis or during the subsequent 3 months. 1 It is a rare clinical entity which accounts for 0.4% of all malignant lymphomas and , 1% of all pulmonary tumors. 2 , 3 The commonest histologic subtype of PPL (70%-90% of all cases) is the mucosa-associated lym-phoid tissue type (MALT) lymphoma (low-grade lym-phoma). 3 , 4 The primary pulmonary diffuse large B-cell lymphoma (PBL) (high-grade lymphoma), as was diag-nosed in the patient, is uncommon and is seen in up to 10% patients with PPL. 5 Most patients with PPL usually present in the sixth decade of life, and there is a slight male predominance. 6 Clinically, most patients are asymptomatic. Symptomatic disease pre-sentations (more common in high-grade lymphomas) may include dyspnea, cough, fever, loss of weight, and/or appetite and other systemic symptoms. The treatment strategy and risk stratification for pri-mary pulmonary non-Hodgkin’s lymphoma is not clearly established. Treatment strategies include a wait-and-watch approach with mild forms of disease with minimal symptoms, surgery, chemotherapy, and che-motherapy followed by radiotherapy. In the PBL subtype, anthracycline-based chemotherapy with anti-CD20 monoclonal antibody has been proposed as the optimal therapeutic strategy. 5 Isolated pulmo-nary involvement is classifi ed as stage I, according to the Ann Arbor lymphoma staging system. 7 MALT lymphoma may transform into PBL. 5 Accurate diag-nosis of PPL is often diffi cult and delayed owing to nonspecifi c clinical and radiologic features. Prognosis for high-grade or PBL is worse than low-grade lym-phomas and they are more likely to present with respi-ratory and systemic symptoms as in the index patient. PBL is more common in patients who are immune-suppressed or have underlying autoimmune disorders, and occurrence in the absence of these risk factors is rare. 8 None of these risk factors was present in the index patient. The patient presented with nonspecifi c respiratory symptoms and bilateral cavitating lung nodules leading us to clinically consider the possibil-ity of metastatic malignancy or pulmonary vasculitis (granulomatosis with polyangitis) as the fi rst differen-tial diagnosis.

Radiologic Discussion

The causes of multiple cavitating lung nodules can be broadly divided into infectious and noninfectious etiologies. Noninfective conditions include granulo-matosis with polyangitis, pulmonary metastases, lung malignancies (bronchogenic carcinoma, Kaposi sar-coma in individuals infected with HIV), lymphomatoid granulomatosis, sarcoidosis, rheumatoid arthritis, and pulmonary amyloidosis. Rarer causes of cavitating pulmonary lesions include pulmonary infarction fol-low ing pulmonary embolism, bronchiolitis obliterans with organizing pneumonia, and pulmonary Langer-hans cell histiocytosis. Infective causes include nec-rotizing pneumonias with/without lung abscess, septic pulmonary embolism, actinomycosis, nocardiosis, melioi-dosis, Rhodococcus equi , Mycobacterium tuberculosis , nontuberculous mycobacteria and fungal infections, and parasitic lung diseases (echinococcus and para-gonimiasis). 9 The presence of a pulmonary cavitary lesion allows the clinician to perform a more focused evaluation as some clinical entities are more commonly associated with cavitating lung nodular lesions. In some settings, like lung cancer, the presence of cavi-tation in the pulmonary lesion has been shown to have possible negative association with overall survival. 10 The usual radiographic features of common etiologies for cavitating pulmonary nodules are shown in Table 1 .

PPL presenting as multiple cavitating pulmonary nodules is rare but has been reported previously. Cavi-tation in the setting of PPL has been reported more frequently in the setting of HIV infection. 11 It has been proposed that pulmonary involvement by lymphoma should be considered in the differential diagnosis of multiple cavitating pulmonary nodules. 12 PBL has also been rarely reported to present as a pulmonary mass with cavitation. 8

FDG-PET CT scanning is a useful and accurate non-invasive imaging modality in the evaluation of soli-tary/multiple lung nodules but there are limitations due to the possibility of false-positive and false-negative results. In patients with malignant nodules, it provides additional information regarding disease stage. 13

Pathologic Discussion

According to the World Health Organization clas-sifi cation system, PPL can be divided into the B-cell pri mary pulmonary non-Hodgkin’s lymphoma (sub-divided into low-grade type, high-grade type, primary pulmonary plasmacytoma, and intravascular pulmo-nary lymphomas) and lymphomatoid granulomatosis. 14 Low-grade B-cell type is the most common histo-pathologic subtype, and 90% of those are composed of MALT or bronchus-associated lymphoid tissue. It



is proposed that the low incidence of high-grade type is likely an underestimate as they can spread rapidly to extrathoracic locations. In many cases, high-grade PPL can coexist with MALT-type low-grade lymphoma. 8

The diagnosis of PPL is often established with relatively smaller endobronchial, transbronchial, or transthoracic biopsy specimens (CT scan-guided trans-thoracic lung biopsy in the index patient). On micro-scopic examination in patients with large B-cell-type lymphoma, the tumor characteristically shows sheet-like infi ltration of large atypical lymphoid cells, with centroblastic and/or immunoblastic morphology and destruction of pulmonary parenchyma. Immunohis-tochemically, the tumor cells express pan-B-cell anti-gens (CD19, CD20, and CD79a), along with either germinal (Bcl-6, CD10) or non-germinal center B-cell markers (multiple myeloma oncogene). The present case showed histomorphologic and immunophenotypic features of PBL, non-germinal center type. However, based on clinical and histologic features, lymphoma-toid granulomatosis is one close differential diagnosis which was ruled out on the basis of lack of angiocen-tricity/angiodestructive architecture, polymorphous background cell population, and Epstein-Barr virus-latent membrane protein immunopositivity.

Conclusions

Differential diagnosis of multiple cavitating lung nodules is broad, including a variety of infectious and noninfectious etiologies, and it is imperative that a defi nitive diagnosis is established by performing appro-priate and relevant radiologic and pathologic/microbio-logical investigations. After confi rmation of the diagnosis, the patient was referred to the oncology services for initiation of chemotherapy. However, the patient opted

for a wait-and-watch approach and was not willing to undergo chemotherapy. On last telephonic contact (5 months postdiagnosis), the patient had experienced no clinical deterioration. The present case highlights the fact that PPL can rarely present as multiple cavi-tating pulmonary nodules in immunocompetent indi-viduals and a histopathologic confi rmation of diagnosis is necessary for ensuring appropriate management.

Acknowledgments Financial/nonfi nancial disclosures: The authors have reported to CHEST that no potential confl icts of interest exist with any companies/organizations whose products or services may be dis-cussed in this article. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

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Table 1 — Common Differential Diagnoses of Cavitating Lung Nodules With Their Characteristic Features

Disease Condition Characteristic Features

Noninfectious etiology Granulomatosis with polyangitis Pulmonary nodules and infi ltrates are frequently seen. Sinonasal involvement commonly associated.

Nodules may show cavitation in nearly one-half the cases. No lobar predilection. Hematogenous metastases Lower lobe predominance, feeding vessels frequently seen. Pulmonary embolism Pulmonary infarction and subsequent necrosis may lead to appearance of a cavitary lesion. Usually

peripheral without any specifi c lobar predilection. Lymphomatoid granulomatosis Basal predominant involvement, may be confused with lung abscess. Pulmonary Langerhans cell histiocytosis Thin-walled cysts and cavities are usually seen. Thicker-walled cavities can also be observed.

Sparing of the basal areas is usually seen. Primary bronchogenic carcinoma Cavitation more frequent in squamous cell carcinoma; multiple cavitating nodules are uncommon. Pulmonary lymphoma Cavitation more frequent in individuals infected with HIV. Sarcoidosis Cavitary lesions seen in advanced fi brotic stages of the disease with an upper lobe distribution.

Accompanying perilymphatic nodules and/or mediastinal lymphadenopathy may be seen. Infectious etiology Septic emboli Peripheral/subpleural, more likely lower lobe predominant. Typically, found in varying stages of

cavitation with some noncavitary nodules. TB Upper lobes/apices or superior segments of lower lobe predominantly involved. Echinococcosis Usually seen as homogenous rounded lung nodule/masses. Rupture can lead to appearance of

cavitating nodule. Surrounding lung is usually normal.




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a 79-year-old woman with bilateral cavitating lung nodules

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