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Lymphomatoid Granulomatosis

Last updated Oct. 24, 2019

Approved by: Maulik P. Purohit MD, MPH

Lymphomatoid Granulomatosis is a rare, non-Hodgkin’s B-cell lymphoma, which has shown to be associated with Epstein-Barr virus (EBV) infection in a vast majority of cases.


What are the other Names for this Condition? (Also known as/Synonyms)

  • Malignant Lymph Angiitis and Granulomatosis
  • Polymorphic Reticulosis
  • Pulmonary Lymphomatoid Granulomatosis

What is Lymphomatoid Granulomatosis? (Definition/Background Information)

  • Lymphomatoid Granulomatosis is a rare, non-Hodgkin’s B-cell lymphoma, which has shown to be associated with Epstein-Barr virus (EBV) infection in a vast majority of cases. It is a systemic condition that can involve the skin, kidney, and brain
  • However, all cases of Lymphomatoid Granulomatosis involve the lungs. Hence, it is also known as Lymphomatoid Granulomatosis of Lungs. It manifests as multiple lung nodules that may grow to large sizes. Due to this, there may be shortness of breath, cough, fever, and fatigue. The signs and symptoms depend on the specific organ involved too
  • The cause of Lymphomatoid Granulomatosis is generally unknown, but it may be related to genetic factors. The contributory factors towards development of the condition includes immunosuppression due to various reasons such as HIV infection and organ transplant
  • Systemic therapy through chemotherapy and radiation therapy may form the usual line of treating Lymphomatoid Granulomatosis. The treatment can be specific to the particular organ or body system affected
  • The prognosis depends on many factors including the type of lymphoma, progression of the condition, response to treatment, and overall health of the individual. In general, the prognosis of Lymphomatoid Granulomatosis is guarded and is evaluated on a case-to-case basis

General information on lymphoma and lymphocytes:

  • Lymphoma is a type of cancer stemming from uncontrollably dividing lymphocytes (type of white blood cells). There are two types of lymphomas:
    • Hodgkin lymphoma
    • Non-Hodgkin lymphoma
  • Lymphocytes are the main white blood cells found in the lymph, which is the fluid of the lymphatic system; just as blood is the fluid of the circulatory system
  • Lymphocytes are made in bone marrow, and can develop into either B-cells or T-cells. Lymphomatoid Granulomatosis arises from cancerous B-cells
  • Lymph results from filtration of blood as it travels to and from tissues. Lymph is colorless because it lacks red blood cells; instead, it contains lymphocytes. It is central to the immune system
  • There are 3 different kinds of lymphocytes:
    • T-lymphocytes or T cells: They help combat infections and abnormalities within the cells (cell-mediated immunity). They fight viruses and cancerous cells
    • B-lymphocytes or B cells: They produce antibodies that are bodily defense proteins, which target foreign invaders outside the cells (humoral immunity). They fight bacterial cells, cell fragments, and other immunogenic elements
    • Natural killer cells or NK cells: They perform diverse functions related to both cell-mediated and humoral immunity. They also scout for cancer cells, a process called immune surveillance

Who gets Lymphomatoid Granulomatosis? (Age and Sex Distribution)

  • Lymphomatoid Granulomatosis is a rare condition that affects middle-aged and older adults who belong to the age group 40-70 years
  • Both males and females can be affected; although there is a male predominance (male-female ratio is 2:1)
  • All races and ethnic groups can be affected

What are the Risk Factors for Lymphomatoid Granulomatosis? (Predisposing Factors)

Various studies have established the following risk factors for Lymphomatoid Granulomatosis:

  • Infection by Epstein-Barr virus (EBV), which is noted in many individuals
  • Conditions that result in immunodeficiency including X-linked severe combined immunodeficiency (SCID)
  • Organ transplantation (such as after a kidney transplant)
  • HIV infection and AIDS
  • Wiskott-Aldrich syndrome
  • Chronic viral hepatitis
  • Sjögren syndrome
  • Rheumatoid arthritis (RA)
  • Dedicator of cytokinesis 8 (DOCK8) deficiency disorder

The International Prognostic Index, for aggressive non-Hodgkin Lymphoma, lists a few factors that determine the overall risk:

  • Age over 60 years
  • Elevated level of serum lactate dehydrogenase - LDH (a type of enzyme)
  • Performance status, i.e. the overall health condition of the individual, which could range from being fully active (low risk) to being completely disabled (very high risk)
  • Individual, who have already suffered from lymphoma, or other types of blood cancers, may have a relapse or a recurrence
  • Presence of an immunodeficiency syndrome, like AIDS, is a high risk factor
  • Those infected with Epstein-Barr virus are prone to Cutaneous Lymphomatoid Granulomatosis

Note: According to some scientists, the International Prognostic Index may not be very helpful in evaluating Lymphomatoid Granulomatosis. However, some scientists believe that it is helpful in some cases, to determine the prognosis.

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one's chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Lymphomatoid Granulomatosis? (Etiology)

Lymphocytes are a type of white blood cells that are responsible for providing immunity in the human body. B-cells and T-cells are the two different types of lymphocytes. When under certain circumstances, the lymphocytes grow and multiply abnormally, it leads to a condition called as lymphoma, which is a most common type of cancer. There are 2 types of lymphoma:

  • Hodgkin lymphoma
  • Non-Hodgkin lymphoma

The exact mechanism of cause of Lymphomatoid Granulomatosis, a non-Hodgkin lymphoma, is unknown. It is seen to arise in immunocompromised individuals and those with EBV infection (in most cases). It may also occur due to certain genetic defects, such as translocation, which is a juxtaposition of regions of chromosomes that results in:

  • Change of regulatory elements of certain cancer-causing genes called as oncogenes, which can lead to increased production of their mRNA (overexpression), thus increasing their protein levels
  • Exchange of protein coding regions of gene, giving rise to new proteins that can stimulate the inappropriate growth of cells

It is believed that the abnormal development of lymphocytes gives rise to cancerous cells leading to the formation of this condition. Nevertheless, how this occurs and the factors that cause it remain under investigation.

What are the Signs and Symptoms of Lymphomatoid Granulomatosis?

Lymphomatoid Granulomatosis typically involves the lungs (almost all cases), the skin (in 50% of the cases), the central nervous system (in 35% of the cases), and the kidneys. Thus, the signs and symptoms depend on the organs involved and include:

  • Lungs: Both the lungs may be involved causing lung masses up to 10 cm in size to form; there may be multiple lung nodules. There may also be:
    • Shortness of breath
    • Cough; blood in cough
    • Weakness of lower legs with tingling sensation
  • Skin:
    • Presence of skin lesions
    • Ulceration of the lesions
    • Commonly the lower legs are involved
  • Brain and CNS:
    • Headaches
    • Convulsions
    • Varying degree of paralysis
  • Liver enlargement
  • Joint inflammation and fluid accumulation (edema) can occur, if the joints are affected

Note: The lymphoid organs and tissues (such as the spleen, thymus, and lymph nodes) are not involved. But, if they get involved, it happens much later in the disease.

The following general signs and symptoms may be observed:

  • Unintentional weight loss; changes in appetite
  • Fatigue and weakness
  • High temperatures and excessive night sweats (may be recurrent)
  • Frequent infections
  • Anemia (low red blood cell count)
  • Low lymphocyte count, established by a blood test
  • Low blood pressure
  • Back pain
  • Swelling of the legs
  • Abdominal pain and swelling; constipation
  • Frequent urination

How is Lymphomatoid Granulomatosis Diagnosed?

Lymphomatoid Granulomatosis diagnosis is performed by obtaining biopsy samples from the affected region and examining them under a microscope to detect the cancerous cells. Other methods to aid in the diagnostic study include:

  • A thorough physical examination and a complete medical history, which is very important
  • Blood tests that may include:
    • Complete blood cell count (CBC) blood test
    • Absolute lymphocyte count on peripheral blood: In some individuals, the malignant cells are positive for Epstein-Barr virus
    • Liver function blood test (LFT)
    • Lactate dehydrogenase (LDH) blood test
    • Chemistry panel
    • Serum calcium levels
    • Serum albumin levels
    • HIV testing
  • Pulmonary function test
  • Biopsy samples from the affected area:
    • A biopsy of the tumor is performed and sent to a laboratory for a pathological examination. A pathologist examines the biopsy under a microscope. After putting together clinical findings, special studies on tissues (if needed) and with microscope findings, the pathologist arrives at a definitive diagnosis. Examination of the biopsy under a microscope by a pathologist is considered to be gold standard in arriving at a conclusive diagnosis
    • Biopsy specimens are studied initially using Hematoxylin and Eosin staining. The pathologist then decides on additional studies depending on the clinical situation
    • Sometimes, the pathologist may perform special studies, which may include immunohistochemical stains, molecular testing, flow cytometric analysis and very rarely, electron microscopic studies, to assist in the diagnosis
  • Radiological imaging may be performed to determine the extent of lymphoma in the body including:
    • X-ray of the affected region
    • Ultrasound scan of the affected region
    • Computerized tomography (CT) scan of the affected region
    • Vascular radiological studies
    • Whole body bone scan
    • Whole body CT-PET scans to determine how far the lymphoma has spread, by checking the size and metabolic rate (a reflection of uncontrolled growth) of lymph nodes, throughout the body. This can also help determine, if the cancer has spread to other organ systems
    • Brain MRIs are used if neurological symptoms are present, which can help determine if the cancer has spread to the brain, or to tissues that cover the brain
  • Bone marrow aspiration and biopsy is performed and sent to a laboratory for a pathological examination, to determine if the bone marrow is involved. Sometimes, the pathologist may perform special studies, which may include immunohistochemical stains, histochemical stains, molecular testing, and very rarely electron microscopic studies. However, a bone marrow biopsy is not needed in the early stages of the condition
  • Flow cytometry to identify cells as they flow through an instrument, called a flow cytometer. Flow cytometry measures the number and percentage of cells in a blood sample, and cell characteristics such as size, shape, and the presence of biomarkers on the cell surface. This method helps to sub-classify the condition and also to detect residual levels of disease after treatment. This tool can help in diagnosing relapse and restart treatment as needed
  • Fluorescence in situ hybridization (FISH): It is a test performed on the blood or bone marrow cells to detect chromosome changes (cytogenetic analysis) in blood cancer cells. The test helps in identifying genetic abnormalities that may not be evident with an examination of cells under a microscope
  • Immunophenotyping to identify a specific type of cell in a sample, which can help determine the best treatment course to be followed
  • Polymerase chain reaction (PCR): It is used to measure the presence of certain biomarkers in blood or bone marrow cells. The test is ultrasensitive and detects extremely low amounts of biomarkers remaining in blood, which can be missed by cytogenetic methods, such as FISH, karyotype, or flow cytometry. PCR allows a more sensitive follow-up of patients in remission and can help determine whether additional treatment is necessary
  • GI endoscopy: It may be performed to assess the extent of tumor spread
  • Multigated acquisition (MUGA) scan or echocardiography to identify cardiotoxicity as a result of chemotherapy
  • Lumbar puncture to determine if the brain is involved
  • In addition, the cerebrospinal spinal fluid (CSF) may be collected by inserting a needle in the spine and subjected to microscopic, flow cytometric, PCR, and biochemical analysis, to diagnose central nervous system (CNS) involvement, if any
  • Exploratory laparoscopy (diagnostic laparoscopy) may be required, if gastrointestinal symptoms are present. In this procedure, the abdomen is examined using a minimally-invasive technique, and a tissue biopsy and tissue for culture obtained. Minimally-invasive approaches help decrease complications and the length of stay at the hospital. A diagnostic laparoscopy is also helpful in staging of the tumor. Nevertheless, this procedure is not very much used

Note: Differential diagnoses, to eliminate other tumor types are often considered, before arriving at a definitive diagnosis.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Lymphomatoid Granulomatosis?

The complications due to Lymphomatoid Granulomatosis may include: 

  • Involvement of vital organs of the body leading to loss of function of the organ/area to which the cancer has spread
  • Individuals who have positive EBV in malignant cells tend to progress to DLBCL (a more aggressive type of lymphoma)
  • Recurrence of the lymphoma
  • Weakened immune system (or immunosuppression) can be a complication, which can become more severe during treatment. Due to this, individuals are more vulnerable to infections; there is an increased risk of developing serious complications from such infections
  • If the brain and central nervous system is involved, it can give rise to:
    • Inflammation of the meninges or brain (that can be lethal)
    • Vision changes
    • Facial numbness
  • If the abdomen is affected, it can cause intestinal obstruction that results in urine outflow obstruction and kidney damage
  • Blood loss may occur due to frequent or heavy bleeding, giving rise to severe anemia
  • The leukemic cells can overgrow and cause clogging of vessels resulting in stroke, or blurring of vision

There may be complications related to chemotherapy used in treating the condition, which may include:

  • Side effects such as dizziness, vomiting, appetite loss, mouth ulcers, and hair loss
  • By damaging healthy cells, the individual is more open or vulnerable to secondary infections
  • The treatment can also cause infertility in men and women. Hence, measures to protect the individual’s fertility must be considered, before starting chemotherapy
  • Tumor lysis syndrome: This can occur due to chemotherapy treatment and can result in kidney failure, if not recognized promptly

How is Lymphomatoid Granulomatosis Treated?

Systemic therapy is generally used for Lymphomatoid Granulomatosis tumors. A combination of treatment measures may be tried to effectively treat the condition and this may include the following:

  • Chemotherapy: This approach uses a combination of drugs to kill the cancerous cells and can be used in patients, for all stages of the cancer
    • There can be severe side effects including fatigue, nausea, hair loss, anemia, high risk of infection, and drug-specific reactions
    • Many T-cell lymphomas can be resistant to chemotherapy. It can also damage healthy cells
    • Chemotherapy can be administered as a pill, liquid, shot, or intravenously

Note: Men and women in child-bearing age would greatly benefit from counseling regarding fertility issues. Some chemotherapy agents can cause infertility in both men and women. There can be permanent damage to the testicles and ovaries, harming their ability to produce sperms or ova. In men, sperm banking can be considered before initiating therapy. In women, in many cases, due to urgency of starting chemotherapy, it is often difficult to perform ovum banking. However, if there is sufficient time prior to chemotherapy, ovum banking may be performed. The healthcare provider may help assess the risk-benefit analysis, depending upon each individual’s specific circumstances.

  • Radiation: Radiation therapy is the use of high-energy radiation waves to kill cancer cells, by destroying their DNA
    • This treatment modality is generally used for early stage lymphomas. It is most commonly used in combination with chemotherapy
    • The radiation may be administered by a machine placed outside the body, or by placing a radioactive material inside the body
    • The side effects of radiation therapy include nausea, vomiting, fatigue, pain, risk of cancer later in life, and risk of heart disease
    • Radiation can damage healthy cells in addition to cancer cells, causing further complications
  • Surgery: After initial biopsies to diagnose the condition, surgery is a very uncommon treatment option, because lymphomas are systemic and might have already spread to more than one lymph node in most patients. Under such circumstances, removing all the affected lymph nodes would be extremely difficult
  • Skin-directed therapies are used (and often in combination) when the tumor affects the skin and presents associated signs and symptoms
  • Intrathecal chemotherapy, if there is an involvement of the brain
  • Supportive treatment: Steroids, blood transfusions, anti-nausea medications, and antibiotics, may be used as supportive therapy. In combination with other treatment measures, these can help combat the symptoms of immunodeficiency, on a case-by-case basis

If Lymphomatoid Granulomatosis is not fully responsive to treatment, or if the chance of recurrence is high, then bone marrow transplantation or stem cell transplantation can be considered.

  • Bone marrow transplantation: Typically systemic cases may be treated by administering high doses of chemotherapy or radiotherapy. But, high doses of chemotherapy drugs will also damage the bone marrow, preventing it from making any blood cells. Hence, before starting high-dose chemotherapy, the physicians may take out some of the patient’s bone marrow and freeze/preserve it. Collecting the bone marrow is called a bone marrow harvest. The bone marrow is then stored. After high dose chemotherapy or radiation, the bone marrow is thawed and injected back into patient through a drip (transfusion). This is called an autologous bone marrow transplant. Sometimes bone marrow donated by another matching person (usually a brother or sister) is used, if the condition recurs following transplant using one’s own cell. This is called as allogeneic bone marrow transplant
  • Stem cell transplantation: This procedure is similar to bone marrow transplantation and involves the transplantation of healthy blood-forming stem cells into the body. The procedure is also called hematopoietic progenitor cell transplantation. Stem cells can be collected from the bone marrow, circulating (peripheral) blood, and umbilical cord blood. It may either involve an autologous stem cell transplantation, where stem cells are harvested from individuals before treatment and transplanted back into the patient after treatment, or involve an allogeneic stem cell transplantation, where stem cells donated by another matching person (usually a brother or sister) is used, if the condition recurs after stem cell transplant using one’s own cell. This is called as allogeneic stem cell transplant

Note: Allogeneic bone marrow and allogeneic stem cell transplants may have more side effects and complications, and this treatment may not be suitable for every individual. If allogeneic transplants come from a healthy donor with no malignant cells, then the chances of recurrence of the condition may be reduced.

  • In order to prevent infections because the immune system is weakened by Lymphomatoid Granulomatosis or by its treatment, the patient is kept in an isolated ward and treated with appropriate antibiotics
  • Nowadays, targeted therapies are being developed, that can selectively kill the lymphoma cells. Many of them are in the stage of clinical trials
  • Clinical trials: There may be some newer treatment options, currently on clinical trials, which can be considered for some patients depending on their respective risk factors

Your healthcare provider will determine the best course of treatment depending on your individual circumstances. Also, follow-up care with regular screening and check-ups are important post-treatment.

How can Lymphomatoid Granulomatosis be Prevented?

Presently, the cause of Lymphomatoid Granulomatosis is unknown; hence, there are no known methods to prevent its occurrence. Eliminating the modifiable risk factors may help in preventing the condition.

  • Undertaking proper and effective treatment to address immunodeficiency conditions
  • Undertaking appropriate and prompt treatment for any viral infections or other disorders
  • Healthy diet and exercise, as well as avoidance of unnecessary exposure to chemicals, may help decrease its risk
  • Avoidance or cessation of smoking
  • In order to avoid a relapse, or be prepared for a recurrence, the entire diagnosis, treatment process, drugs administered, etc. should be well-documented and follow-up measures initiated

Regular medical screening at periodic intervals with blood tests, scans, and physical examinations, are mandatory. Often several years of active vigilance are crucial and necessary.

What is the Prognosis of Lymphomatoid Granulomatosis? (Outcomes/Resolutions)

  • Lymphomatoid Granulomatosis is a rare and malignant cancer. Some cases progress slowly, while others may develop aggressively. Hence, the prognosis of the condition is based on each individual’s specific condition and stage of the cancer
  • Nevertheless, the prognosis depends upon a set of several factors, which include:
    • Stage of tumor: With lower-stage tumors, when the tumor is confined to site of origin, the prognosis is usually excellent with appropriate therapy. In higher-stage tumors, such as tumors with metastasis, the prognosis is poor
    • Overall health of the individual: Individuals with overall excellent health have better prognosis compared with those with poor health
    • Age of the individual: Older individuals generally have poorer prognosis than younger individuals
    • The size of the tumor: Individuals with small-sized tumors fare better than those with large-sized tumors
    • Individuals with bulky disease have a poorer prognosis
    • Involvement of vital organs may complicate the condition
    • The surgical resectability of the tumor (meaning, if the tumor can be removed completely) - it is a rare option
    • Whether the tumor is occurring for the first time, or is a recurrent tumor. Recurring tumors have worse prognosis compared to tumors that do not recur
    • Response to treatment: Tumors that respond to treatment have better prognosis compared to tumors that do not respond to treatment
    • Progression of the condition makes the outcome worse (progressive Lymphomatoid Granulomatosis)
  • An early diagnosis and prompt treatment of the tumor generally yields better outcomes than a late diagnosis and delayed treatment
  • The combination chemotherapy drugs used, may have some severe side effects (such as cardio-toxicity). This chiefly impacts the elderly adults, or those who are already affected by other medical conditions. Tolerance to the chemotherapy sessions is a positive influencing factor
  • Progression to bone marrow failure is usually associated with short survival

Additional and Relevant Useful Information for Lymphomatoid Granulomatosis:

  • After small lymphocytic lymphoma, Lymphomatoid Granulomatosis is the second most common lymphoma involving the lungs
  • The reason why some cases of Lymphomatoid Granulomatosis progress rapidly/aggressively, while others show slower progression is still unknown; it is under investigation
  • T-cell lymphomas are less common than B-cell lymphomas
  • Treatment for Lymphomatoid Granulomatosis can cause physical and emotional distress; supportive care and encouragement, help positively and can bring a measure of relief to the patients

The following article link will help you understand leukemia and lymphoma (blood cancer):

https://www.dovemed.com/diseases-conditions/leukemia-and-lymphoma/

What are some Useful Resources for Additional Information?


References and Information Sources used for the Article:


Helpful Peer-Reviewed Medical Articles:


Reviewed and Approved by a member of the DoveMed Editorial Board
First uploaded: Feb. 29, 2016
Last updated: Oct. 24, 2019