Basic Information: Diagnostic tests
Diagnostic criteria of multiple myeloma
Unlike mclassant lymphoma that is diagnosed by a pathologist on the basis of a histological feature assessment, the multiple myeloma diagnosis is determined by a clinician who evaluate x-ray, biochemical, cytological and histological findings considering the standardised diagnostic criteria for the disease.
A typical presentation is initially a bone pain (chiefly acute lower back pain) with resultant confirmation of the diagnosis. If the x-ray examination reports lytic lesions, if the myelogram shows increased levels of plasma cells and if the monoclonal immunoglobulin is present in serum or urine, the diagnosis is confirmed.
Note: multiple myeloma, as well as Langerhans Cell Hystiocytosis develops osteoblast inactivity in lytic lesions, in consequence, the absorption of isotope is limited and the false-negative rate of bone scintigraphy is high. Thus, the conventional x-ray films of the skeleton is the basic method for detection of lytic lesions. The scitigraphy remains only a complementary examination, whereas MR imaging provides a more specfic information.
The manifestations of multiple myeloma can be various and that is why it is difficult to differentiate mm from benign monoclonal gammopathy, termed at the present time as monoclonal gammopathy of undetermined significance or unknown significance.
We would like to highlight the necessity to comply with the standardised criteria for the disease and to document carefully the medical findings that led to the diagnosis confirmation.
The Durie-Salmon system is the most widely used myeloma staging and diagnosing system (see the table 2 a). In the German speaking area, the clinical classification respects the Osserman criteria that we present here to provide an overall view. The diagnosis is confirmed if at least two features from three are present:
- plasmocytomas in bone marow >15 %,
- presence of monoclonal immunoglobulin in serum (IgG > 35 g/l and IgA > 20 g/l)
- finding of typical osteolytic lesions or osteoporosis at an advanced stage
We would like to emphasize that establishing the diagnosis can be extremely difficult in some patients, even when respecting the above-mentioned criteria. It is better to carefully follow up the patient in a long term before setting the diagnosis. Evaluating long term clinical and laboratory indicators is much more benefitting for the patient.
Table 2a: The multiple myeloma criteria according to Durie-Salmon, 1975
|1) plasmocytoma on tissue biopsy
||a) bone marrow plasmocytosis 10-30 %
|2) bone marrow plasmocytosis with > 30 % plasma cells
||b) concentration M-Ig is lower then in point of the major criteria
|3) concentration of monoclonal immunoglobulin in serum (M-Ig):
M-IgG > 35 g/l,
M-IgA > 20 g/l,
or light chain presence in urine 24 hr> 1 g
|c) presence of lytic lesions
|d) uninvolved immunoglobulin levels decreased (< 50 % of the standard levels )
IgM < 0,5 g/l
IgA < 1,0 g/l
IgG < 6,0 g/l
|The multiple myeloma diagnosis is confirmed if one major and one minor criterion is present or if criterion a+b and c or d are present.
Table 2b: Diagnostic criteria for multiple myeloma according to the International Myeloma Working Group, 2003
All three criteria must be present for multiple myeloma diagnosis confirmation:
1. A bone marrow sample showing > 10% plasma cells and/or a biopsy-proven plasmacytoma
2. Elevated monoclonal immunoglobulin levels in the blood or urine.
3. At least one organ injury or dysfunction due to multiple myeloma is present:
- (C - calcium) increased level of calcium in the blood > 2,8 mmol/l or is > upper limit
- (R - renal) renal insufficiency with serum creatinine value > 176,8 mmol/l (2 mg/ml)
- (A - anemia) anemia, hemoglobin value < 100 g/l or 20 g/l < lower limit of standard value
- (B - bone) lytic bone lesions or osteoporosis
These criteria define the stage IB, II and III A and B according to Durie and Salmon. Stage IA is classified, according to these criteria, into smoldering or indolent multiple myeloma..
Various kinds of organ damages may occur and demand treatment. In case of connection with multiple myeloma (gammopathy) features, they may lead to establishing MM diagnosis.
Rare forms of myeloma disease:
a) Multiple myeloma causing osteoporosis without developping lytic lesions.
Light chains myeloma (or Bence Jones myeloma) doesn´t increase sedimentation levels. Cases may occur where the disorder causes only diffuse osteoporosis without developping lytic lesions detectable in x-ray films. Only bone marrow biopsy or monoclonal immunoglobulin levels in serum and urine may lead to establishing myeloma diagnosis. Thus, every physician should exclude this form of multiple myeloma before pronouncing the diagnosis of primary osteoporosis.
b) Multiple myeloma developing multiple lytic lesion without diffuse infiltration of bone marrow
Even an inverse case than described may occur. X-ray film may reveal "punched-out" lytic lesions but bone punctures (myelogram) doesn´t show an increased number of plasmocytes. In these cases, the bone marrow contains myeloma cells conglomerated in clumps that result in lytic lesions, nevertheless, the infiltration of the bone marrow doesn´t take place and the blood collection don´t reveal any pathologic finding. The final histologic diagnosis can be established only on the basis of lytic lesion biopsy.
c) Multiple myeloma without demonstrable bone lesions
In 10-20 % patients, bone lesion symptoms aren´t present. These patients develop immunosuppression, anemia or renal damages. Renal failure can be the first manifestation of the disease.
d) Osteosclerotic myeloma, POEMS syndrome
Among the rare forms of multiple myeloma, we have to mention the existence of osteosclerotic myeloma and of POEMS syndrome. Detailed information about these rare disorders is provided in the publication: Hematologic Oncology II, Survey of mclassant hematologic diseases. Grada, Praha 2000.
Advisabilty of performing protein examinations, immunoelectrophoresis and detection of levels of monoclonal and polyclonal immunoglobulin
Imunoelectrophoresis detecting protein in serum and in urine is indicated if multiple myeloma, primary systematic Al- amyloidosis, Waldenström macroglobulinemia or disorders due to monoclonal immunoglobulin are suspected. The following symptoms, clinical and laboratory changes are indicators: weakness of unknown origin, anemia, elevated levels of sedimentation, bone pains, diffuse osteoporosis, dicreased levels of physiological polyclonal immunoglobulin, recurrent infections, hypercalcemia, renal failure, proteinuria, nephrotic syndrome, peripheral neuropathy, Fanconi syndrome, orthostatic hypotension, malabsorption, congestive heart failure of nonischemic origin, hepatomegaly and spleenomegaly of unknown origin.
Advisability of performing skeletal x-ray examination
Radiographic skeletal survey is considered to be advisable to perform if multiple myeloma is suspected because of the specific findings on examination or because of other clinical symptoms.
Patients presenting with back pain persisting over 1 month or worsening back pain should undergo radiographic spine survey (sagittal, lateral). If a new pain in a limb occurs, we perform x-ray survey immediatelly.
Advisability of performing MR survey of the skeleton and other specialised examination (MIBI and PET imaging)
MR imaging is established if mclassant damage of the skeleton is suspected and radiographic survey didn´t detect it. Furthermore, MR imaging is used to differentiate an osteoporotic compression fracture from the fracture due to osteoporosis attributed to mclassant infiltration of the skeleton. Acute MR is used in neurovascular compression syndromes because it can differentiate a compression due to mclassant soft tissue expansion from a compression due to the overlap of the fracture fragments. If the first case occurs, an urgent radiotherapy is performed, the second case demands neurosurgery or orthopaedic decompression within 24 hours after presented signs when there is still a hope of reversibility.
PET imaging is a promising new technique that has the potential to detect myeloma deposits in the skeleton and in other areas of the body whilst the deposits aren´t reported by radiography or sonography.
PET imaging is able to provide overall skeleton survey, nevertheless, the MR imaging is focused. PET imaging reveals accurate metastatic sites of the disease. It is a very costly technique that we use if its detection is necessary for the treatment process. An example of a fruitful use is the differential diagnosis between the solitary plasmocytoma and multiple myeloma. PET imaging is used in patients that can´t undergo the MR imaging because of the presence of a metal in their organism, especially if the information about the disease activity is necessary; namely in patints with non-secretory myeloma impossible to be monitored in a biochemical way. Exeptionally in these patients, the PET imaging can be ordered repeatedly.
MIBI imaging is comparable in detection performance with the PET imaging sensibility. We however consider that MIBI imaging evaluation is more difficult and the technique hadn´t been adopted widely into clinical practice.
Advisibility of the bone marrow sample analyse or of the percutaneous aspiration biopsy performed by an orthopeadist.
Sternal puncture and trepanobiopsy of the iliac crest are appropriate in patients with suspected mclassant bone marrow disease not evident on biochemical examination (monoclonal immunoglobulin) or both on X-ray and MR imaging (lytic lesions). In osteoporosis patients without findings of lytic lesions, the MR imaging reveals either the primary osteoporosis or the signs of tumor infiltration of vertebrae not evident on X- ray survey.
The prognostic value of the sternal bone marrow aspiration and of the trepanobiopsy is limited and depends on the charcteristics of the aspirate. The final assessment is influenced by the quantity of the peripheral blood asirated along with the bone marrow. The myelogram examination provides cell count. If an excess of peripheral blood is aspirated, a part of the cell count consists of peripheral blood neutrophils instaed of stem cells. Therefore, the level of plasmocytes is seemingly decreased.
The trepanobiopsy excludes this discrepancy due to the peripheral blood aspirate. The quantitative evaluation of myeloma cells in a histologic sample obtained by means of the trepanobiopsy is, nevertheless, more difficult. The clonality of plasmocytes can be revealed using the dual color determination for light chain of Ig kappa and lambda.
A situation may occur that the laboratory analyses are accurate, the histologic finding shows myeloma cell infiltration but the myelogram doesn´t still detect a significant presence of plasmocytes suggesting myeloma. We can certify the myeloma diagnosis if the myeloma cell infiltration is confirmed by myelogram. Otherwise, it is appropriate to perform the trepanobiopsy to establish the diagnosis.
In case of a lytic lesion that may provide a reason to suspect a solitary plasmocytoma (random bone marrow biopsy not proving the diagnosis), a sample from the lytic lesion taken by an orthopeadist should by hitologically analysed.