A 51-year-old male, non-smoker with hemoptysis and lung nodules

A 51-year-old Caucasian male was admitted to the hospital with complaints of increasing cough for the past month with yellow-green sputum but no fevers or chills.

As an outpatient, he was treated with Zithromax (azithromycin, Pfizer), two different courses, and oral prednisone. He then developed progressively worsening shortness of breath and hemoptysis with cough.

Chest X-ray initially showed a right lower lobe infiltrate. A CT scan of the chest showed an irregular mass measuring 2.2 cm in the left upper lobe, a 2.1-cm mass in the left lower lobe, several small nodules in the left lower lobe and patchy ground-glass opacities bilaterally. A CT scan of the abdomen showed a bilobed lesion adjacent to the right adrenal gland measuring 4.4 cm and at least four hepatic lesions, the largest of which measured 4 cm.

Ramya Varadarajan

His ANA and ANCA were negative. A VIR biopsy of the right liver lesion showed inflammation and granuloma. A PET/CT scan showed abnormal increased activity near the right adrenal gland, both lobes of liver, lingula and azygoesophageal recess, all highly suggestive of malignancy with equivocal FDG activity in the left upper lung lesion seen on CT scan.

A bronchoscopy with biopsy showed suspicious cells for malignancy, along with caseating granulomas, but was nondiagnostic. Infectious Disease was consulted to rule out infectious etiology. Tests for Aspergillus, crypto and tuberculosis all were negative. A video-assisted thoracic surgery was performed with lingular wedge resection. This showed caseating granulomas, but no malignancy was found on the preliminary report.

Biopsy specimens were sent to the University of Pittsburgh for re-evaluation. The biopsy showed a large nodule, with central infarct-like necrosis associated with abundant hemorrhage and a periphery that largely consists of granulation tissue. Abundant small round lymphocytes associated with histiocytes, and intermixed large atypical lymphoid cells, were seen in the margin of the necrotic nodule. These large atypical cells stained positively for CD20 and CD30 but were negative for CD15. These cells stained positive for antibodies to Epstein–Barr virus (EBV) latent membrane protein and positive with in situ hybridization studies using the EBER probe for Epstein-Barr virus. There was an obvious necrotizing vasculitis with similar-appearing large cells admixed with both large and small lymphoid elements, destroying portions of the vascular wall, inducing thrombosis.

The morphology and immunophenotype was consistent with that of grade-2 lymphomatoid granulomatosis. He is being treated with chemotherapy consisting of rituximab (Rituxan, Genentech); cyclophosphamide (Cytoxan, Bristol-Myers Squibb); vincristine, doxorubicin (Adriamycin, Pharmacia and Upjohn); and prednisone. His symptoms improved within a couple of weeks after initiating chemotherapy.

Case Discussion

Pulmonary lymphomatoid granulomatosis (PLG) is a lymphoproliferative disorder characterized by multiple pulmonary nodular lesions with lymphocytic invasion of vascular walls on biopsy. WHO classification scheme places lymphomatoid granulomatosis under the generic heading of B-cell proliferations of uncertain malignant potential.

These lymphoproliferative disorders are in the family of EBV-associated B-cell lymphomas. In addition, PLG can be seen in patients with an underlying immunodeficiency or a lymphoproliferative disorder. Rare cases of PLG have been reported in patients being treated with azathioprine, methotrexate, and imatinib, with resolution sometimes following cessation of the medication.

Lymphomatoid granulomatosis presents between the ages of 30 and 50 years, although patients can be affected at any age. Men are affected more often than women by an estimated 2:1 ratio. The lung is the most commonly involved organ; the skin and neurologic systems may be affected separately or concurrently. Involvement of other organs occurs but is less common. The most common presenting symptoms and signs include cough, fever, rash/nodules, malaise, weight loss, neurologic abnormalities, dyspnea and chest pain.

Laboratory studies generally are nondiagnostic. The complete blood cell count generally is normal with occasional mild leukocytosis or leukopenia. Nonspecific abnormalities in immunoglobulins (usually increases in IgG and IgM) are seen in the majority of patients. In patients with evidence of neurologic disease, lumbar puncture commonly reveals pleocytosis with an elevated protein level.

Serologic evidence of previous EBV infection generally is seen. Chest radiography typically reveals multiple poorly defined masses in the mid- and lower-lung zones; diffuse reticular abnormalities sometimes are seen. CT usually shows both well- and poorly defined nodules throughout both lungs. Most lesions are less than 1 cm in diameter, but larger cavitary masses occasionally are seen. PET scanning shows variable uptake.

The histopathologic diagnosis of lymphomatoid granulomatosis requires a triad of polymorphic lymphoid infiltrates, transmural infiltration of arteries and veins by lymphoid cells, and focal areas of necrosis within the lymphoid infiltrates (well-formed granulomas are not present). Additional features include staining for EBV or in situ hybridization studies, polyclonality of T cells, and usually monoclonality of B cells. Grade-1 lesions either are devoid of or contain only scattered EBV-positive cells. It is unclear whether lesions devoid of EBV-positive B cells represent a distinct primary T-cell disorder or an exuberant response to rare EBV-positive cells. Grade-2 and grade-3 lesions have increasing numbers of EBV-positive large cells. Grade-3 lesions most closely resemble the clinical and pathologic features of other more conventional forms of diffuse large B-cell lymphoma.

Diagnosis can be delayed as the clinical manifestations are non-specific. Diagnosis relies on histopathology; needle biopsies are inadequate. Open-lung biopsies or video-assisted thoracoscopic biopsy are needed to make a diagnosis. PLG should be distinguished from granulomatosis with polyangiitis (Wegener’s), as well as other forms of malignant lymphoma, especially extranodal NK/T-cell lymphoma, which also is associated with EBV infection but rarely involves the lung.

Patients who have been taking a medication associated with PLG should stop the suspect medication. Patients without symptoms and with low-grade (grades 1 and 2) disease confined to the lungs may reasonably be followed with serial clinical and radiological evaluations, as this group of patients sometimes can experience spontaneous remission. Symptomatic patients, patients with more extensive disease and patients with high-grade lesions should be considered for treatment with chemotherapy. Chemotherapy for lymphomatoid granulomatosis follows those for diffuse large B-cell lymphoma, such as R-CHOP or CHOP-like regimens. However, a few case reports and case series have described results with the antiviral, antiproliferative cytokine interferon alfa-2b.

Ramya Varadarajan, MD, is a consultant at Regional Hematology and Oncology PA at Helen Graham Cancer Center in Newark, Del. She is a member of the HemOncToday Editorial Board. Disclosure: Dr. Varadarajan reports no relevant financial disclosures.

For more information:

• Jaffe ES. Cancer Surv. 1997;30:233.
• Jung KH. Chemotherapy. 2009;55:386-390.
• Katzenstein AL. Am J Surg Pathol. 2010:34:e35-48.
• Makol A. J Hematol Oncol. 2009:2:39.