Are You Confident of the Diagnosis?
What to be alert for in the history
Lymphomatoid granulomatosis (LYG) should be considered when a patient presents with multiple papules, plaques or nodules, constitutional symptoms (fever, fatigue, night sweats, weight loss) and pulmonary symptoms (dyspnea, sinusitis, cough). LYG is a multisystem lymphoproliferative disease due to B-lymphocytes latently infected with the Epstein Barr virus (EBV).
Characteristic findings on physical examination
Cutaneous lesions are the initial manifestation in up to one third of patients. Cutaneous LYG presents as multiple erythematous nodules, papules or plaques and can be tender, pruritic or both (Figure 1). About 30% of patients will develop ulceration. Uncommon presentations include white, atrophic plaques or tan nodules. LYG is often distributed diffusely on the extremeties with or without truncal involvement. The head and neck are involved in only 10% of patients.
Expected results of diagnostic studies
A biopsy of the skin typically demonstrates a lymphocytic or lymphohistiocytic infiltrate with a periadnexal and/or perivascular distribution involving the dermis and/or the panniculus (Figure 2). Multinucleated giant cells may or may not be present. Poorly formed granulomas may be seen in the subcutaneous tissue; well formed granulomas are rare. Angioinvasion and angiodestruction are seen in the majority of cases but are not necessary to make the diagnosis. The infiltrate of LYG can involve any or all the layers of the skin from the epidermis to the panniculus.
EBV-positive B-cells can be demonstrated on biopsies of cutaneous LYG but are often sparse in comparison to pulmonary biopsies. For example, patients with known LYG may not have demonstrable EBV-positive cells in their cutaneous biopsies. Pulmonary specimens are more commonly diagnostic and yield EBV-positive atypical cells. EBV can be demonstrated in pathologic specimens using EBER-1 (Epstein Barr virus encoded RNA) and EBER-2.
Histologic grading is done based on the number of EBV-positive B-cells with grade I containing less than 5 per high power field (HPF), grade II contains 5 to 20 per HPF, grade III greater than 20 per HPF. If sheets of atypical B-cells are seen, the diagnosis of diffuse large B-cell lymphoma should be considered rather than LYG. Polymerase chain reaction (PCR) and analysis for clonal immunoglobulin (IgH) chain rearrangement can be done, but are rarely positive.
Imaging studies should be performed to assess for systemic foci of LYG if the diagnosis has not been established. Imaging should include evaluation of the lungs and kidneys since these organs are most often involved; this is best accomplished with a computed tomographic (CT) scan. Central nervous system (CNS) involvement has been found in 50% of patients, so an MRI of the brain should also be considered, especially for symptomatic patients. If imaging demonstrates pulmonary disease, an open or transbronchial biopsy can establish the diagnosis when cutaneous biopsy is only suggestive.
The differential diagnosis includes Wegener’s granulomatosis (WG), extranodal NK/T-cell lymphoma, nasal type lymphoma, post-transplant lymphoproliferative disease (PTLD) and other various lymphomas.
Patients with WG can have similar cutaneous manifestations, also frequently present with constitutional symptoms, and a constellation of cutaneous, pulmonary, and renal disease. The histopathology of WG shows leukocytoclastic vasculitis or necrotizing granulomatous vasculitis, which are not seen in LYG. NK/T-cell lymphoma can have similar cutaneous lesions, however, pulmonary involvement is rare. In LYG the EBV-positive atypical cells are B-cells while in NK/T-cell lymphoma the EBV-positive atypical cells have an NK-cell phenotype (CD3+, CD 56+).
Who is at Risk for Developing this Disease?
LYG can affect patients of any age but most commonly affects adults 30 to 50 years old. LYG has a male-to-female ratio of 2.0 to 2.5:1. Childhood cases are rare and occur more often in children with concurrent immunodeficiency. LYG is more common in patients with immunodeficiency conditions such as the human immunodeficiency virus (HIV) infection, history of an organ transplant, other preceding lymphoproliferative disease(s), and immunosuppressive medications.
What is the Cause of the Disease?
LYG is an EBV-associated lymphoproliferative disorder. LYG may be more common in patients with immunodeficiency due to incomplete clearance of EBV and the resulting clonal proliferation of atypical EBV-infected B-cells. The EBV genome encodes a number of genes that promote cell survival following infection. These gene products include cytokines, signal transducers, and anti-apoptotic molecules that may cause malignant transformation of the infected B-cells.
Vessel damage and subsequent tissue destruction may be caused by reactive T-lymphocytes. Chemokines, including IP-10 and Mig are elevated in LYG lesions and may promote T-cell adhesion and direct injury of the endothelium.
Systemic Implications and Complications
LYG is a multisystem lymphoproliferative disease; the lungs are the most commonly affected organ. The skin is the second most commonly affected organ and is involved in 40% to 50% of cases. The kidneys, liver, CNS, and gastrointestinal tract can also be involved. In one large series, the diagnosis of cutaneous LYG occured simultaneously with the diagnosis of systemic LYG in 35% of patients, while 45% of patients had their cutaneous involvement occur following their diagnosis of systemic LYG.
LYG encompasses a disease spectrum with a variable clinical and pathologic appearance, which correlates with a variable prognosis. Spontaneous regression has been reported in 15% to 25% of cases while the mortality rate in some series has been as high as 65%. Neurologic involvement and higher numbers of atypical B-cells (higher grade) are indicators of a poorer prognosis. Common causes of death for patients with LYG include destruction of lung parenchyma, infection, CNS disease, and development of an aggressive large B-cell lymphoma.
Table I. Therapeutic Ladder for Treating Lymphomatoid Granulomatosis
|Medical Therapies||Surgical Therapies||Physical Modalities|
|Correct any underlying cause of immunosuppression if possible||None||Radiation – used for CNS disease|
|Systemic corticosteroids (prednisone orally 20 to 60mg daily or 0.5 to 1mg/kg)|
|Interferon alpha (5 million to 40 million units subcutaneously 3 times weekly)|
|Chemotherapy single agent (rituximab, cyclophosphamide)|
|Multiagent chemotherapy (R-CHOP, R-CVP)|
|Stem cell or bone marrow transplant|
R-CHOP: rituximab, cyclophosphamide, hydroxydaunorubicin (doxorubicin), oncovorin (vincristine), prednisolone
R-CVP: rituximab, cyclophosphamide, vincristine, prednisone
Optimal Therapeutic Approach for this Disease
LYG is a rare disease and there are no multicenter or controlled trials available to assist in decision making. Evidence to support use of a particular therapy is anecdotal (case reports and small case series). Treatment options are summarized in the Table.
Management should begin with correction of immunocompromise due to medication or systemic disease/infection. Low-grade disease, involving multiple systems or limited to the skin, is associated with a better prognosis, so toxicity and risks of systemic therapy should be minimized. Therapy with systemic corticosteroids, rituximab, cyclophosphamide, or interferon-alpha alone could be considered. These agents could be rotated if there was a lack of response without progression.
High-grade disease is associated with higher risk of progression to diffuse large B-cell lymphoma, so aggressive therapies with more serious side effects are reasonable to consider. Therapy should be coordinated with a hematologist-oncologist. Multiagent chemotherapy, often incorporating rituximab, could be an initial therapy. Patients with recurrent disease should be considered for an autologous stem cell transplant or bone marrow transplant.
Radiation therapy is not well studied and has been used primarily for treatment of CNS disease.
Patients should be closely monitored for relapse of their LYG or progression to B-cell lymphoma. The care of patients with LYG should be coordinated with a pulmonologist, dermatologist, and hematologist-oncologist. Clinical examination would demonstrate changes if the extent and quality of their disease were to progress. Annual or periodic imaging studies could be recommended to monitor for systemic involvement. If a patient develops a cutaneous relapse, the practitioner should consider reassessing for concurrent relapse of internal disease and order appropriate imaging studies.
Unusual Clinical Scenarios to Consider in Patient Management
Patients with skin lesions suggestive of, or diagnostic of, LYG, but without systemic disease on imaging studies should have close long-term follow-up. Biannual skin examinations and routine follow-up with hematology-oncology and pulmonology are warranted. If the disease state changes, repetition of biopsies and imaging studies is indicated.
What is the Evidence?
Beaty, MW, Toro, J, Sorbara, L, Stern, JB, Pittaluga, S, Raffeld, M. ” Cutaneous lymphomatoid granulomatosis”. Am J Surg Pathol . vol. 25. 2001. pp. 1111-20. (This is a case series of 20 patients with cutaneous LYG that includes a review of their clinical and pathologic findings as well as their treatment and outcome. Excellent photographs of the clinical and pathologic findings.)
Gitelson, E, Al-Saleem, T, Smith, MR. ” Lymphomatoid granulomatosis: Challanges in diagnosis and treatment”. Clin Adv Hematol Oncol . vol. 7. 2009. pp. 68-70. (This is an editorial comment that follows a primary report of primary CNS LYG by Martin, et al. This is a concise review of the pathogenesis, therapy and clinical findings including those of the CNS system.)
James, WD, Odom, RB, Katzenstein, AA. ” Cutaneous manifestations of lymphomatoid granulomatosis”. Arch Dermatol. vol. 117. 1981. pp. 196-202. (This is an update of the previous case series of 100 patients published in 1979 by Katzenstein, et al. A remarkable reference because it is one of the largest case series. The clinical, pathologic, and laboratory findings of 45 pateints with cutaneous LYG are reviewed.)
Lundell, RB, Weening, RH, Gibson, LE, Ansell, SM. “Lymphomatoid granulomatosis”. Rare hematological malignancies. 2008. pp. 265-72. (This is a concise review of LYG including the differential diagnosis, pathogenesis, pathologic findings (with photographs), therapy and prognosis.)
Wilson, WH, Kingma, DW, Raffeld, M, Wittes, RE, Jaffe, ES. “Association of lymphomatoid granulomatosis with Epstein-Barr viral infection of B lymphocytes and response to interferon-alpha 2b”. Blood. vol. 87. 1996. pp. 4531-7. (This is one of the first reports of the use of interferon-alpha to successfully treat LYG. Four patients were treated with doses ranging from 5 million to 40 million units 3 times weekly. The starting dose was 10 million units for 3 of the 4 patients. Three of four patients responded and went into a long-lasting remission. Interferon dose was often reduced due to side effects of the medication.)
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