Case Presentation

A 67-year-old woman with a medical history significant for hypertension, hyperlipidemia, type 2 diabetes mellitus, OSA, and schizophrenia was admitted multiple times the previous 3 months for generalized abdominal pain. Her most recent admission was unique for new onset bilateral upper and lower extremity weakness with paresthesia. Pertinent review of systems included malaise, fever, cough, left lower quadrant pain without weight loss, and rash. Previous evaluation included multiple CT scans of her abdomen that revealed colonic thickening. Ensuing colonoscopy revealed chronic ulcers with cytopathic changes consistent with cytomegalovirus.

Physical Examination Findings

Vital signs were unremarkable, except for a temperature of 39.2°C. Inspection revealed the patient lying uncomfortably in bed. She was alert and oriented. Heart and lung auscultation were unremarkable. Abdominal examination revealed hypoactive bowel sounds with diffuse tenderness; no rebound appreciated. Cranial nerve V demonstrated decreased gross sensation on the left side, which was coupled with left hemisensory deficit with ipsilateral pronator drift.

Diagnostic Studies

CBC count was notable for leukopenia of 2,940/mm3 with lymphocyte predominance of 46%, hemoglobin of 10.4 g/dL, hematocrit of 34.2%, and platelet count of 248/mm3. Renal and hepatic functions along with electrolytes were within normal limits. HIV antibody testing was negative along with normal levels of CD4 cells and immunoglobulins.

MRI brain scan revealed enhancing lesion in the right globus pallidus that measured 2 × 2 × 3 cm (Figs 1, 2). CT scan of the abdomen demonstrated colonic wall-thickening that was consistent with colitis (Fig 3). The liver and kidneys showed multiple cysts as large as 4.4 cm (Fig 4). The adrenal gland was notable for heterogeneous lobulated left adrenal mass that measured 2.3 × 1.9 × 1.6 cm (Fig 5). Lower lung fields, when compared with previous abdominal CT scans from 3 months earlier, revealed a new 2-cm nodule in the right lower lobe (Fig 6). Subsequent chest CT scans revealed multiple, bilateral subcentimeter lung nodules (Fig 7).

Figure 1MRI fluid-attenuated inversion recovery imaging of the brain shows a 2 × 2 × 3 cm lesion.

Figure 2T2-weighted MRI shows intercranial lesion.

Figure 3Abdominal CT scan shows colitis (blue arrow).

Figure 4A-B, Abdominal CT scan shows multiple cysts in A, bilateral kidneys and B, liver (blue arrows).

Figure 5Abdominal CT scan shows left lobulated adrenal mass (blue arrow).

Figure 6Chest CT scan shows right lower lobe nodule (blue arrow), which was undetected previously on CT scan from 3 months earlier.

Figure 7Chest CT scan shows multiple solid subcentimeter nodules (blue arrows).

BAL revealed mild lymphocyte predominance of 16%. Cultures were negative for bacterial, fungal, and nonTB Mycobacteria infections. Aspergillus antigen was negative. Cytology was negative for malignancy. Right lower lobe wedge resection was done. In situ hybridization for Epstein-Barr virus (EBV) that was obtained on the lung biopsy showed scattered positive cells among infiltrating lymphocytes (Fig 8). Immunostaining for CMV was negative.

Figure 8A-D, Images show atypical lymphoplasmacytic infiltrate in background of infarcted lung tissue with A, an angiocentric, B, angioinvasive, and C, angiodestructive pattern. (Hematoxylin-eosin stain, original magnification ×40). D, Epstein-Barr encoding region in situ hybridization shows positive atypical large lymphocytes that range from 5 to 20 per high-power field. (Original magnification ×40).

 Question

What is the diagnosis?

 Diagnosis

Diagnosis: Lymphomatoid granulomatosis

Discussion

Lymphomatoid granulomatosis (LG) is an angiocentric and angiodestructive EBV–associated B-cell lymphoproliferative disorder initially described in 1972. LG often occurs in the setting of dysregulated immune surveillance. Disease entities/therapies frequently associated with LG include HIV, chemotherapy, Wiskott–Aldrich syndrome, common variable immune deficiency syndrome, and transplant populations. Medications associated with LG include azathioprine, methotrexate, and imatinib. Risk of development is higher when associated with Sjogren's, rheumatoid arthritis, and viral hepatitis. Despite associated risk factors, diagnoses have been made in their absence. Although spontaneous remission can be as high as 20%, the mortality rate remains at approximately 50%, largely owing to conversion to malignant lymphoma.

Incidence is extremely low; so low that incidence in the general population is unknown. What is known is a 2:1 male predilection. Age of incidence varies among sources, with one source stating a median age of 46 years. Symptoms associated with LG development includes cough (most prevalent), fever, rash, weight loss, and neurologic deficits. Neurologic deficits include ataxia and hemiparesis. Asymptomatic individuals have been described with occasional presentations of incidental lung nodules. The most commonly affected system is the pulmonary system with >90% involvement at time of diagnosis, often with bilateral, lower lung field lesions. Central nervous (40%), integumentary, renal, and hepatic systems are also involved with decreasing frequency. Adrenal involvement, while uncommon, has been described on autopsy and/or imaging, with nodular adrenal lesions being described.

Given the broad differential diagnosis among those with lung nodules and nonspecific symptoms attributed to the disease, diagnosis is often delayed. Serologic studies are often of limited value; however, mild leukopenia can be noted along with renal and liver function abnormalities. CD8 lymphocytes are decreased often disproportionately when compared with CD4 cells. Positive immunohistochemistry stains for EBV are common, although nonspecific. Included in the evaluation of LG should be HIV testing and immunoglobulins, which are also nonspecific. The most common radiographic findings are nodules within the pulmonary parenchyma. Nodules are described inconsistently as being thin- or thick-walled cysts, ground glass, cavitary, or necrotic. Within the CNS ring-enhancing lesions are seen. Size of lesions are typically 1 to 5 cm, although can be larger. Gold standard for diagnosis is biopsy with angioinvasion and angiodestruction being common. CD20 and CD30 are predominant on immunohistochemistry; notably, CD15 is always negative.

LG is described by grades: grade 1 is virtually no EBV positive cells; grade 2 is positive for CD20 cells (5 to 20 cells/high-power field and some necrosis), and grade 3 lesions have inflammatory background along with >50 cells/high-power field (often extensive necrosis). Treatment is based on these grades, with grades 1 and 2 often not requiring treatment owing to occasional spontaneous remission in <20% of cases; symptomatic grades 2 and 3 are indications for treatment. Although no consistent treatment regimen is agreed on, most commonly a combination of rituximab, etoposide, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-EPOCH) is used for six cycles that achieves remission rates of approximately 60%. Monotherapy with steroids or rituximab do not produce durable results and are avoided. Five-year mortality rates range from 54% to 64% and are attributed to lymphoma conversion and respiratory failure, given the high incidence of pulmonary involvement.

 Clinical Course

Her right-sided lesions on brain MRI, which correlated with left-sided neurologic deficits and rapidly expanding lung nodules that were seen on chest CT scans, most likely led to coughing. Due to multiple lesions, biopsy was undertaken by both wedge resection of the lung and hemicraniotomy. Immunohistochemistry from biopsy sites supports the diagnosis of LG grade 2 and 3, respectively. She was started on R–EPOCH therapy with minimal improvement of her neurologic symptoms. Abdominal symptoms were accredited to cytomegalovirus colitis, which was treated with valganciclovir that led to resolution of abdomen pain. Follow-up imaging 2 months after treatment revealed resolution of her pulmonary nodules and decrease in size of basal ganglia lesion.

Clinical Pearls1.

LG is a B-cell lymphoproliferative disorder that is rare and typically found among those with compromised immune systems, which includes those with malignancy, history of chemotherapy, HIV, common variable immunodeficiency syndrome, and transplant populations.

2.

More than 90% of patients with LG have lung involvement, with varying types of nodules making its differential diagnosis broad.

3.

Patients are often found to have serologic evidence of EBV exposure. Gold standard for diagnosis remains biopsy and immunohistochemistry commonly results with positive CD20 and CD30 cells, never CD15 cells.

4.

Treatment modalities are similar to those used with diffuse B cell lymphoma, most commonly R-EPOCH.

5.

Spontaneous remission is possible; prognosis remains poor due to frequent conversion to malignant lymphoma.

Acknowledgments

Author contributions: All of the authors contributed to the content and the writing of the manuscript. S. Hadigal takes full responsibility for the content of the manuscript.

Financial/nonfinancial disclosures: None declared.

Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

Article InfoIdentification

DOI: https://doi.org/10.1016/j.chest.2021.01.037

Copyright

© 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

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