Case Presentation - Fall, 2011

Patient History: 57 year old Male

Specimen type: Left Neck Mass, Cervical Lymph Node FNA

Case provided by: Milstead Pathology, Conyers, Georgia

Malignant Plasma Cell Myeloma or Multiple Myeloma (MM) is a plasma cell neoplasm where abnormal myeloma cells build up in the bone marrow, forming bone tumors. The formation of these tumors prevents the bone marrow from producing healthy blood cells, such as red blood cells, white blood cells and platelets. Lymph node involvement typically occurs late in the clinical course of the disease. Multiple myeloma is the most common lymphoreticular malignancy in blacks and rarely occurs in patients younger than 40 years old.

Patients with multiple myeloma present with an increased production of one type of immunoglobulin by a single clone of cells. This process is referred to as monoclonal gammopathy, which results in a "spike" on serum protein electrophoresis. Approximately half of the multiple myeloma cases secrete IgG, about a quarter IgA, and a fifth Bence Jones light chains. Secretion of IgM, IgD or IgE is rare.

As the abnormal myeloma cells increase, there is a decrease in the production of healthy blood cells. This can result in damaged, weakened bone. Multiple myeloma can sometimes be asymptomatic. Some potential symptoms of MM are as follows:
  • Bone pain, often in the back or ribs.
  • Bones that break easily.
  • Fever for no known reason or frequent infections.
  • Easy bruising or bleeding.
  • Trouble breathing.
  • Weakness of the arms or legs.
  • Feeling very tired.

Damage or weakening of the bone can also cause hypercalcemia, a condition in which too much calcium is present in the blood. This condition can affect many organs within the body causing serious health issues. Some of the organs that have been known to be affected included: kidneys, nerves, heart, muscles and digestive tract. Symptoms of hypercalcemia may include:

  • Loss of appetite.
  • Nausea or vomiting.
  • Feeling thirsty.
  • Frequent urination.
  • Constipation.
  • Feeling very tired.
  • Muscle weakness.
  • Restlessness.
  • Mental confusion or trouble thinking.
In some cases of multiple myeloma, cytogenetic tests performed by FISH can show a deletion of TP53 at 17p13. Rarely this mutation is identified at diagnosis. However, it becomes more frequent in more aggressive disease and human myeloma cell lines. This form of mutation is typically associated with an unfavorable prognosis.

Plasma cell myeloma can be characterized on cytology by the presence of pure plasma cell aggregates, often forming loose sheets. The plasma cells are typically mature, but in some instances may be immature or atypical in appearance. Mature plasma cell nuclei have coarse "clock face" chromatin. In contrast, the nuclear features of immature plasma cells are fine and have prominent nucleoli. Binucleation is a common feature and can serve as a clue when diagnosing plasma cell myeloma.

The cytoplasm usually stains blue or amphophilic with perinuclear clearing, or hof. The presence of flame cells with metachromatic apical cytoloplasm is typically associated with IgA secretions. Vacuolization within the cytoplasm is rare. Intranuclear (Dutcher) and intracytoplasmic (Russell) bodies can be seen. These bodies are collections of immunoglobulin. The presence of intranuclear bodies in plasma cells suggests malignancy. Crystalline intracytoplasmic inclusions rarely occur, however, these are more common in malignancy.

The differential diagnosis includes lymphoma, more specifically, lymphoplasmacytic lymphoma or immunoblastic lymphoma, and reactive hyperplasia with prominent plasma cells or lymphoplasmacytoid cells. Myeloma is rarely associated with IgM, in contrast to lymphoplasmacytic lymphoma. Additional differentials include other tumors that may have plasmacytoid cells, like malignant melanoma and adenocarcinomas.

The Durie-Salmon staging system and the International Staging System (ISS) are the two staging systems used to stage myelomas. The Durie-Salmon staging system was more commonly used in the past. It is based on the amount of monoclonal immunoglobulin found in the blood and urine, the amount of calcium and hemoglobin present in the blood, and the severity of bone damage seen on x-ray. The ISS is more commonly used today and is based on two parameters: beta 2-microglobulin and albumin. The International Staging System is thought to be more sensitive when classifying myeloma stages.

The staging is determined by the amount of disease present in the body. The more advanced the disease, the higher the staging. The three staging classifications for plasma cell myeloma/multiple myelomas are:

Stage I: A relatively small number of myeloma cells are present and there is minimal bone damage.

Durie-Salmon parameters for Stage I:
  • Slightly low hemoglobin. Your hemoglobin value is greater than 10 grams per deciliter (g/dL).
  • Normal blood calcium. Your blood calcium level is normal [12 milligrams per dL (m/dL) or less].
  • One bone lesion or less. You have no bone lesions or only a solitary (one) myeloma.
  • Relatively low level of monoclonal immunoglobulin
International Staging System (ISS) parameters for Stage I: beta 2-microglobulin is less than 3.5 mg/dL and your albumin is 3.5 g/dL or less.

Stage II: A moderate number of myeloma cells are present.

Durie-Salmon parameters for Stage II: Patients diagnosed with myeloma stage II have diagnostic tests that do not fall under either stage I or stage III. A patient with stage II may have more than one plasma cell tumor, but the disease has not progressed to advanced tumors.

International Staging System (ISS) parameters for Stage II: beta 2-microglobulin is between 3.5 and 5.5 milligrams per deciliter (mg/dL) and your albumin is less than 3.5 grams per deciliter (g/dL).

Stage III: A large number of myeloma cells are present, and the cancer is probably causing problems with your bones and kidneys

Durie-Salmon parameters for Stage III:
  • Low hemoglobin. A hemoglobin value less than 8.5 grams per deciliter (g/dL).
  • High blood calcium. A serum calcium level above 12 milligrams per dL (mg/dL)
  • Numerous bone lesions. People with myeloma stage III have multiple advanced tumors in their bones.
  • High production of monoclonal immunoglobulin. Blood or urine tests show high levels of monoclonal immunoglobulin.
International Staging System (ISS) parameters for Stage III: beta 2-microglobulin is 5.5 mg/dL or greater.

Many factors need to be considered when assessing the proper course of treatment for plasma cell myeloma. These factors include the stage of the disease, patient's symptoms, age of the patient and overall health. Conventional chemotherapy is the standard treatment for multiple myeloma and in some cases radiation therapy may also be used. High-dose chemotherapy followed by stem cell transplantation is becoming a common treatment for multiple myeloma. However, this treatment can have very serious side effects.

Alkylating agents are commonly prescribed to patients with multiple myeloma to slow or stop the growth of cancer cells in the body. Sometimes these drugs are given in combination with corticosteroids, which also helps to slow or stop the cancer cells. One common drug combination used is the oral alkylating agent melphalan (Alkaran) with the corticosteroid prednisone (Deltasone). Although this is a commonly used combination, there is no evidence that indicates that one alkylating agent is more superior to another. Each alkylating agent is absorbed differently by the body. Therefore doctors work with patients to find the best combination to fit their needs. In cases where the patient has not responded well to chemotherapy, radiation therapy may be used.

High-dose chemotherapy followed by stem cell transplantation
During this treatment option, patients receive high doses of chemotherapy in order to kill the cancerous cells. Patients will then receive a transplant of healthy stem cells through a surgically placed catheter or tube placed in a large vein either in the neck or chest. From the transplanted stem cells, new blood cells develop.

Stem cells will be collected from either a bone marrow transplant or a peripheral stem cell transplant. During a peripheral stem cell transplant, cells are collected from the circulating blood. Stem cells can be harvested from either a healthy donor whose cells match the patient's (allogenic transplant) or from the actual patient (autologous transplant). In cases of multiple myeloma, it is preferred to use autologous stem cells. Using allogenic stem cells often results in graft-versus-host disease. This complication results in the transplanted stem cells reacting against the patient's tissue.

In some cases, induction therapy may be used. Induction therapy is when conventional chemotherapy is used to reduce the number of cancer cells in the body prior to the patient undergoing high dose chemotherapy and stem cell transplantation. Some chemotherapy drugs are less deadly to stem cells than others. These drugs are used in cases where doctors plan on using autologous transplantation. Examples of some of the drugs used for induction therapy include: vincristine (Oncovin; Vincasar), doxorubicin (Adriamycin; Doxil), and the steroid dexamethasone. This combination of drugs is known as the VAD regimen. Cyclophosphamide (Cytoxan) and Leukine (sargramostim, GM-CSF) are given after the VAD regimen to help stimulate the growth of new stem cells. The stem cells taken from the patient are then frozen. Later, the patient receives high-dose chemotherapy, after which the stem cells are transplanted back into the patient via an intravenous infusion.

The prognosis of multiple myeloma is dependent on factors such as the extent of the disease, the grading of multiple myeloma, patient age, overall general health, and response to treatment. Prognosis also depends not only on the above factors but whether or not a certain immunoglobulin is present in the blood, and the degree of kidney damage and well as the response to initial treatment.

In cases of stage I multiple myeloma, life expectancy is about 5.1 years. Stage II is about 3 to 4 years and for stage III the life expectancy decreases to 2 years. Without treatment the prognosis of multiple myeloma is poor. Roughly 15% of patients who do not undergo treatment for multiple myeloma die within 6 months.

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