Lymphomatoid granulomatosis is a rare disorder involving the uncontrolled growth of lymphocytes. These abnormal cells can form lesions or nodules within various tissues, leading to damage of blood vessels. It is a complex condition that can affect multiple organ systems, making its presentation diverse and challenging to diagnose. This condition is considered precancerous, with potential to progress into diffuse large B-cell lymphoma.
What is Lymphomatoid Granulomatosis?
Lymphomatoid granulomatosis (LYG) is a rare lymphoproliferative disorder, first identified in 1972, characterized by the overproduction of lymphocytes that infiltrate and accumulate in tissues. This accumulation leads to the formation of lesions or nodules that damage or destroy the blood vessels within these affected tissues. The disease is often linked to an underlying immune system dysfunction, although a clear cause for this dysfunction is frequently unknown.
The condition is almost always associated with the Epstein-Barr virus (EBV) infecting the malignant B cells. EBV, a common human herpesvirus, typically remains latent in B lymphocytes, controlled by the body’s immune system, specifically cytotoxic T cells. In LYG, this immune surveillance against EBV-infected B cells is defective, leading to uncontrolled proliferation.
The lesions themselves are composed of malignant B cells, which are infected with EBV, alongside a larger number of reactive, non-malignant T cells. These cellular components contribute to the distinctive angiocentric and angiodestructive nature of the lesions, meaning they are centered around and destructive to blood vessels. The World Health Organization (WHO) defines LYG as an angiocentric and angiodestructive lymphoproliferative disease involving sites outside of lymph nodes.
LYG is graded based on the number of EBV-positive malignant B cells present in the lesions, from Grade 1 (infrequent EBV-positive cells) to Grade 3 (numerous EBV-positive cells with extensive necrosis). This grading system is important because Grade 2 and Grade 3 lesions are often considered variants of T-cell rich diffuse large B-cell lymphoma. LYG is classified as a precancerous condition, with the potential to transform into an aggressive B-cell lymphoma, particularly diffuse large B-cell lymphoma.
How Lymphomatoid Granulomatosis Affects the Body
Lymphomatoid granulomatosis is a systemic disease that can involve multiple organs, with symptoms varying widely depending on the affected area. The lungs are almost universally involved, with over 90% of patients experiencing pulmonary manifestations. Common lung symptoms include a persistent cough, shortness of breath, and chest tightness. Lung lesions can lead to complications such as hemoptysis (coughing up blood).
Skin involvement is frequent, occurring in about 25% to 50% of patients. Skin lesions can present as small red bumps, lumps under the skin, ulcers, or thickened patches. While these lesions may sometimes be tender or itchy, they often do not cause discomfort. The appearance and location of these skin manifestations can vary significantly among individuals.
The central nervous system (CNS) is another commonly affected area, seen in approximately 25% to 50% of cases. CNS manifestations can be severe, including changes in mental status, unsteadiness, blurred vision, weakness, numbness in facial muscles or limbs, and seizures. In some instances, mass lesions may develop within the brain, contributing to neurological deficits.
Lesser affected organs include the liver and kidneys, which are involved in approximately 10% and 40-50% of cases, though clinically significant kidney disease is less common. When the liver is affected, symptoms might include abdominal pain or jaundice. Kidney involvement, while less frequently symptomatic, can be detected through imaging or biopsy. Other less common sites include the spleen, lymph nodes, eyes, and gastrointestinal tract, though these are typically spared until later stages.
Beyond organ-specific symptoms, individuals with lymphomatoid granulomatosis often experience systemic symptoms. These can include fever, feeling unwell, unexplained weight loss, and fatigue. The presence and severity of these systemic symptoms, along with the specific organ involvement, contribute to the overall clinical picture of the disease.
Identifying and Treating the Condition
Diagnosing lymphomatoid granulomatosis requires a detailed evaluation, often beginning with imaging studies. Chest radiographs frequently show abnormalities, such as bilateral nodules or masses in the lungs, present in 80% to 100% of cases. Further imaging with F18-FDG PET/CT scans can reveal increased metabolic activity in lesions, helping to identify multisystem disease distribution and guide biopsy sites. For central nervous system involvement, CT scans may show high-density lesions, while MRI can reveal hyperintense lesions on T2-weighted images.
A tissue biopsy is considered the most definitive diagnostic tool for lymphomatoid granulomatosis. Pathological examination of biopsy samples typically reveals a characteristic triad: a mixed lymphoid infiltrate, lymphocytes infiltrating and damaging the walls of arteries and veins (angiitis), and focal areas of cell death (necrosis). It is also crucial to test for Epstein-Barr virus (EBV) within the malignant B cells, a defining feature of the condition, often done through in situ hybridization with the EBER probe.
Transformation to diffuse large B-cell lymphoma (DLBCL), an aggressive form of non-Hodgkin lymphoma, is more likely in higher-grade LYG lesions, which contain a greater number of EBV-positive malignant B cells. The progression to DLBCL can significantly alter the disease course and prognosis.
Treatment approaches for lymphomatoid granulomatosis are tailored to the disease grade and severity, as there is no single standard treatment. For low-grade disease (Grade 1/2), interferon alfa-2b, a type of immunotherapy, has shown effectiveness by boosting the immune response against EBV.
Patients with high-grade disease (Grade 3) or those whose low-grade disease progresses typically receive combination immunochemotherapy regimens, similar to those used for aggressive lymphomas. One such regimen is DA-EPOCH-R, which includes etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab. Rituximab, a monoclonal antibody targeting CD20 on B-cells, is also used. Ongoing monitoring is routine to assess disease progression or recurrence, and treatment adjustments may be made if the disease grade changes.