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

• GMF (Granulomatous Mycosis Fungoides)
• Granuloma Fungoides
• Granulomatous MF

What is Granulomatous Mycosis Fungoides? (Definition/Background Information)

• Granulomatous Mycosis Fungoides (GMF) is a rare variant of Mycosis Fungoides, which is a cutaneous T-cell non-Hodgkin’s lymphoma. In this condition, granulomatous inflammation, including many giant cells, is prominent when the biopsy of GMF-affected skin is examined by a pathologist under the microscope
• GMF primarily originates in the skin, and is a type of primary cutaneous non-Hodgkin lymphoma. When other parts of the body such as the lymph nodes and bone marrow are affected, it is called Systemic Granulomatous Mycosis Fungoides
• Skin rashes and lesions (papules and plaques), most commonly on the arms and legs, are the primary symptoms of GMF.  However, the skin lesions can ulcerate and develop secondary infections. Once the condition spreads to other organs, the symptoms depend on the specific organ(s) affected. Additionally, systemic symptoms, such as weight loss, fatigue, anemia, fever, and night sweats, have been reported
• Granulomatous Mycosis Fungoides is typically diagnosed through biopsy of the involved skin, or of swollen lymph nodes or affected organs. Other tests may be conducted to assess the severity or spread of the condition
• The treatment depends upon the stage of Granulomatous Mycosis Fungoides. If the condition is restricted to the skin, treatment options might include topical medications, phototherapy, or local radiation therapy. On the other hand, when the disease has already spread,  systemic therapy (treatment with one or more of chemotherapy, radiation therapy, and surgery) is often prescribed
• In general, the prognosis of Granulomatous Mycosis Fungoides depends on many factors and is assessed on a case-by-case basis

General information on lymphoma and lymphocytes:

• Lymphoma is a type of cancer stemming from uncontrolled division of lymphocytes, which are a type of white blood cells (WBCs). 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. T-cells mature in the thymus; Granulomatous Mycosis Fungoides arises from cancerous T-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 Granulomatous Mycosis Fungoides? (Age and Sex Distribution)

• Granulomatous Mycosis Fungoides (GMF) is a rare disorder that generally affects adults
• Individuals of both genders, all races and ethnicities can be affected by GMF

What are the Risk Factors for Granulomatous Mycosis Fungoides? (Predisposing Factors)

Individuals reported to be at a higher risk for contracting Granulomatous Mycosis Fungoides are those belonging to the following categories:

• Have smoked cigarettes for a prolonged time (40 years or longer)
• Have certain skin conditions (for example eczema)
• Have a family history of multiple myeloma
• Are involved in certain occupations such as painting, carpentry, farming, and pottery and ceramics
• Have had certain viral infections

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones 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 Granulomatous Mycosis Fungoides? (Etiology)

As explained previously, 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. Abnormal growth or proliferation of the lymphocytes could lead to a condition called lymphoma, a common type of cancer. There are 2 categories of lymphoma:

• Hodgkin lymphoma
• Non-Hodgkin lymphoma

The exact cause for Granulomatous Mycosis Fungoides, a non-Hodgkin lymphoma, is not known at the present time. It is believed that it may be caused by a viral infection. Additionally, certain genetic defects, such as translocation (a juxtaposition of regions of the chromosomes) may be involved. A translocation may lead to:

• Changes in how certain cancer-causing genes (oncogenes) are regulated. For example, reduced regulation could lead to increased production of an oncogene’s mRNA (overexpression), consequently their protein levels, resulting in erratic growth
• Exchange of protein coding regions of gene, giving rise to new proteins that can stimulate the inappropriate growth of cells

Additionally, an abnormal development of lymphocytes is believed to give rise to cancerous cells, leading to GMF. However, the way this occurs and the factors leading up to it are being researched.

Note: Granulomatous Mycosis Fungoides is non-contagious and is not transmitted from one individual to another. One cannot contract the condition through close physical interaction with the affected individuals.

What are the Signs and Symptoms of Granulomatous Mycosis Fungoides?

The signs and symptoms of Granulomatous Mycosis Fungoides (GMF) involving the skin include:

• Skin nodule, patch, or rash (that may or may not itch)
• As skin manifestations progress, they can ulcerate and extend to other parts of the body
• Any skin region may be affected, but the common locations include the arms and legs
• The lesions can grow, ulcerate, and spread to other parts of the body

When the lymphoma spreads beyond the skin, the entire body may be affected and the symptoms would depend upon the organs involved. In such cases, the following may be noted:

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

Some specific symptoms pertinent to particular affected organs may be:

• Lymph nodes: Non-painful swelling of lymph nodes in the neck, armpits, or groin
• Associated autoimmune disorders
• Joint and muscle pain
• Heat intolerance
• Recurrent rashes
• Abdominal pain
• Generally feeling ill
• Neurological symptoms (if the brain gets affected)
  • Confusion
  • Tinnitus (ringing in the ears)
  • Hearing and visual impairment
• GI tract symptoms (when the GI tract is affected by GMF)
  • Ulcers
  • Diarrhea
  • Inflammation
  • GI bleeding
• Liver and spleen: Enlargement of the organs
• Joints
• Inflammation
• Fluid accumulation (effusions)

How is Granulomatous Mycosis Fungoides Diagnosed?

Granulomatous Mycosis Fungoides (GMF) is generally diagnosed by biopsy of the affected region. The following are some of the methods, including biopsy, which may be employed for diagnosis of the condition as well as to determine the extent of disease spread:

• A physical examination and assessment of personal and family medical history
• Blood tests:
  • Complete blood cell count (CBC) blood test
  • Absolute lymphocyte count on peripheral blood
  • Liver function blood test (LFT)
  • Lactate dehydrogenase (LDH) blood test
• Skin biopsy from the affected area:
  • A biopsy of the tumor is performed and sent to a laboratory for a pathological examination. Examination of the biopsy under a microscope by a pathologist is considered the gold standard for 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
• Biopsies of enlarged lymph nodes are taken when the disease spreads to the lymph nodes. The samples are examined to determine if the cells are malignant or benign. The biopsies may be performed under general or local anesthesia. Normally, the entire lymph node is removed to help determine the subtype of lymphoma
• Radiological imaging of the affected region/s to determine the extent of lymphoma in the body:
  • X-ray
  • Ultrasound scan
  • Computerized tomography (CT) scan
  • 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 (if neurological symptoms are present), to help determine if the cancer has spread to the brain, or to tissues that cover the brain
• Bone marrow aspiration and biopsy 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) on the blood or bone marrow cells to detect chromosome changes (cytogenetic analysis) in blood cancer cells. The test helps identify 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) in order 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
• Lumbar puncture to determine if the central nervous system is involved
• Examination of cerebrospinal spinal fluid (CSF) (which may be collected by inserting a needle in the spine) - microscopic, flow cytometric, PCR, and biochemical analysis, to diagnose central nervous system (CNS) involvement, if any
• Exploratory laparoscopy (diagnostic laparoscopy) 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 used frequently

Note:

• Differential diagnoses, to eliminate other tumor types, are often considered before arriving at a definitive diagnosis
• In many cases, because of the granulomatous inflammation noted on the biopsy specimen that is present along with the tumor cells, the diagnosis is delayed

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 Granulomatous Mycosis Fungoides?

An individual diagnosed with Granulomatous Mycosis Fungoides may potentially have the following complications:

• Loss of function of the organ/area to which cancer has spread
• A weakened immune system (or immunosuppression) that could become more severe during treatment. As a consequence, patients are rendered vulnerable to infections and subsequent serious complications
• Transformation of Granulomatous Mycosis Fungoides into a more aggressive form of lymphoma

Spread of the disease from the lymph nodes to other parts of the body may result in:

• Brain
  • Inflammation of the meninges or brain (that can be fatal)
  • Headache
  • Vision changes
  • Facial numbness
• Abdomen: Intestinal obstruction that results in
  • Urine outflow obstruction
  • Kidney damage

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

• Side effects such as dizziness, vomiting, appetite loss, mouth ulcers, and hair loss
• By damaging healthy cells, making the patient more prone to secondary infections
• Possibility of infertility in men and women. Hence, measures to protect the individual’s fertility must be considered, before starting chemotherapy

Note: Some treatment measures can also give rise to secondary cancers such as skin cancer.

How is Granulomatous Mycosis Fungoides Treated?

Once a definitive diagnosis of Granulomatous Mycosis Fungoides has been made, staging is used to describe how far the cancer has spread. The staging process helps determine:

• The number of lymph nodes affected
• The location of affected lymph nodes
• Spread of disease to other locations

In other words, staging of GMF determines the extent of disease, which dictates treatment regimens. The staging of Granulomatous Mycosis Fungoides is as follows:

Stage I Granulomatous Mycosis Fungoides: Presence of non-cancerous, but abnormal lymphocytes in blood.

• Stage IA: The skin lesions (patches, papules, plaques) cover less than 10% of the body area
• Stage IB: The skin lesions cover more than 10% of the body area

Stage II Granulomatous Mycosis Fungoides: Presence of non-cancerous, but abnormal lymphocytes in blood.

• Stage IIA: The skin lesions (patches, papules, plaques) can cover any percentage of the body area. The cancer has not affected the lymph nodes, but they are enlarged
• Stage IIB: The presence of single or multiple tumors, over 1 cm in size (or larger), on the skin. The cancer has not affected the lymph nodes, but they may be enlarged

Stage III Granulomatous Mycosis Fungoides:

• Presence of non-cancerous, but abnormal lymphocytes in blood
• The skin is red and the skin lesions (patches, papules, plaques) may be found almost on the entire body
• The cancer has not affected the lymph nodes, but they may be enlarged

Stage IV Granulomatous Mycosis Fungoides: The skin is red on most part of the body surface; the skin lesions (patches, papules, plaques) or tumors can cover any percentage of the body area.

• Stage IVA: Additionally -
  • The cancer has affected the lymph nodes and there may be a presence of cancerous lymphocytes in blood, OR
  • The cancer has not affected the lymph nodes, but it may be enlarged; and there are cancerous lymphocytes in blood
• Stage IVB: Additionally -
  • There is the involvement of other body organs
  • The cancer may have affected the lymph nodes, which may be enlarged
  • There may be the presence of cancerous lymphocytes in blood

As mentioned above, treatment is dependent upon the stage and location of the tumor. The two main treatment protocols for Granulomatous Mycosis Fungoides are:

• Skin-directed therapy
• Systemic therapy

The following skin-directed therapies may be used alone or in combination:

• Phototherapy, with or without psoralens (UVB or PUVA)
• Use of topical steroids, topical nitrogen mustard, or topical retinoids
• Systemic chemotherapy
• Radiation therapy to affected (local) skin area
• Other systemic treatment measures, such as the use of interferons, retinoids, etc.
• Biological therapy

Systemic therapy is generally used for higher or advanced stage tumors. A combination of treatment measures may be effectively used to treat the condition. It 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 Granulomatous Mycosis Fungoides. Chemotherapy could be administered as a pill, liquid, shot, or intravenously. The following points are noteworthy about chemotherapy:
  • As elaborated in the “Complications” section, chemotherapy could have 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. Chemotherapy is also known to damage healthy cells

Note: Men and women in their fertile years would greatly benefit from counseling regarding fertility issues. Some chemotherapy agents can cause infertility in both men and women. Since permanent damage to the testicles and ovaries are a potential possibility, alternate options could be explored. For example, men could consider sperm banking before initiating therapy. In women, if there is sufficient time prior to chemotherapy, ovum banking may be an alternative. The healthcare provider may help assess the risk-benefit analysis, depending upon each individual’s specific circumstances.

• Radiation: Radiation therapy uses high-energy radiation waves to destroy the DNA and therefore, kill the cancer cells
  • 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 (this form is not used in GMF)
  • 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: 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
  • 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

If Granulomatous Mycosis Fungoides is not fully responsive to treatment, or if the chance of recurrence is high, then bone marrow transplantation or stem cell transplantation could be considered.

• Bone marrow transplantation: Typically, systemic cases of Granulomatous MF could be treated with high doses of chemotherapy or radiotherapy. However, high doses of chemotherapy drugs could also damage the bone marrow, preventing it from making any blood cells
  • Autologous bone marrow transplant: Before starting high-dose chemotherapy, the healthcare specialist may aspirate the patient’s bone marrow and freeze/preserve it. Collecting the bone marrow is called a bone marrow harvest. Following high dose chemotherapy or radiation, the bone marrow is thawed and injected back into patient through a drip (transfusion).
  • Allogeneic 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
• 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. The transplantation could be
  • Autologous stem cell transplantation - where stem cells are harvested from patients before chemotherapy and transplanted back into the patient after treatment
  • Allogeneic stem cell transplantation - where stem cells donated by another matching person (usually a brother or sister) are used, if the condition recurs after stem cell transplant using one’s own cell

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.

• The patient is recommended to be kept in an isolated ward and treated with antibiotics, in order to prevent infections from compromised immunity (as a result of the disease itself or due to treatment methods)
• Nowadays, targeted therapies are being developed that could selectively kill the cancer cells. Many of them are in various stages of clinical trials. There may be some newer treatment options, currently on clinical trials, which could be considered for some patients, depending on their respective risk factors

You 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 Granulomatous Mycosis Fungoides be Prevented?

Currently, the cause of Granulomatous Mycosis Fungoides is unknown. Therefore, there are no known guidelines available for the prevention of GMF. Eliminating some risk factors by changing some habits may help in preventing the condition. The following factors may be considered:

• Smoking cessation
• Undertaking appropriate and prompt treatment for skin conditions, such as eczema, or viral infections
• Using suitable protective wear (face masks, hand gloves, protective clothing) and adhering to proper safety practices, especially if you are a painter, carpenter, farmer, or working in the ceramics industry
• Adhering to a healthy diet and regular exercise, as well as avoidance of unnecessary exposure to chemicals
• Maintaining records of the entire diagnosis, treatment process, drugs administered, etc., to enable efficient treatment, in case a relapse occurs

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 Granulomatous Mycosis Fungoides? (Outcomes/Resolutions)

• The prognosis of Granulomatous Mycosis Fungoides (GMF) depends on several factors: 
  • 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 in lymphomas
  • Whether the tumor is occurring for the first time or is a recurrent tumor. Recurrent 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 Granulomatous Mycosis Fungoides)
• An early diagnosis and prompt treatment of the tumor generally yields better outcomes than a late diagnosis and/or delayed treatment
• The combination chemotherapy drugs used may have some severe side effects (such as cardio-toxicity). This chiefly impacts 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
• In general, the prognosis of  Granulomatous Mycosis Fungoides compared to classical Mycosis Fungoides is unknown; some studies have shown a better prognosis, while some have shown a worse prognosis

Additional and Relevant Useful Information for Granulomatous Mycosis Fungoides:

• There are many variants of Mycosis Fungoides and they include the following:
  • Pagetoid Reticulosis
  • Syringotropic Mycosis Fungoides
  • Folliculotropic Mycosis Fungoides
  • Granulomatous Mycosis Fungoides
• T-cell lymphomas are less common than B-cell lymphomas
• Treatment for Granulomatous Mycosis Fungoides 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/