Imran Siddiqui
Department of Pathology & Microbiology, The Aga Khan University, Karachi.
Multiple Myeloma: A debilitating disease, which has gained interest of Physicians and scientists for decades. This disease has probably been present for centuries as cases of possible multiple myeloma have been reported in American Indian skeletons from 200 AD1. This communication is written as an attempt to revisit the history of this disease. Robert A. Kyle, in his many articles has comprehensively described the historical background of multiple myeloma. This paper is an attempt to cover most of the interesting proceeding and advancements made in the diagnosis of this disease that extends over last 150 years.
In September 1844, Mr. Thomas Alexander McBean, aged 45, professionally tradesman and a wealthy grocer in London, was on a vacation in the countryside. While vaulting out of an underground cavern, he had instantly felt as if something had snapped or given way within the chest, and for some minutes he lay in intense agony, unable to move.
Mr. McBean, initially placed himself under the treatment of Dr. Thomas Watson2 and by then he was confined to his house by excruciating pains of the chest, back and loins.
He was treated by the removal of a pint of blood and, subsequently, the application of leeches, which might be interpreted as "maintenance therapy". This resulted in considerable weakness but alleviation of his pain. The pain abated for 6 months. In September 1845, the pain recurred and subsequently worsened.
On 30 October 1845, Dr. Thomas Watson, sought second opinion from one of his friends, Dr. William Macintyre, a 53-year-old, Harley Street consultant and physician to the Western General Dispensary (Macintyre, 1850 cited by Kyle)1.
Dr. William Macintyre, personally examined a urine specimen from Mr. McBean but found no evidence of sugar. Dr. William Macintyre and Dr. Thomas Watson sent the following note and urine samples to Dr. Henry Bence Jones, a 31-year-old physician, at St. George's Hospital, who already had established reputation as a Chemical Pathologist.
The letter was cited as:
Saturday, November 1, 1845
Dear Dr Jones,
The tube contains urine of very high specific gravity; when boiled it becomes highly opaque; on the addition of nitric acid it effervesces, assumes a reddish hue, becomes quite clear, but as it cools, assumes the consistence and appearance which you see: heat reliquifies it. What is it?
(Bence Jones H, 1847) 1-4.
Dr. Henry Bence Jones after receiving the letter and urine specimen confirmed the finding that the addition of nitric acid produced a precipitate that was re-dissolved by heat and formed again upon cooling.
Dr. Bence Jones calculated that the patient excreted 67 gm of protein per day and concluded that the protein was, specifically ‘hydrated deutoxide of albumin’ (Bence Jones H, 1848 cited by Kyle)3.
Although Macintyre described the heat properties of urine, Jones emphasized its role in the diagnosis of myeloma. Dr. Jones said, “I need hardly remark on the importance of seeking for this oxide of albumen in other cases of mollities ossium” [softening of the bone]: (Bence Jones H, 1847 cited by Kyle)1.
Thus, ‘Bence Jones protein’ was discovered. Interestingly Henry Bence Jones did not use a hyphen in his name, and it does not appear in any of his more than 40 published papers and books published during his lifetime are indexed under `Jones'. The hyphen was added by his descendants in the autobiography published more than a half-century after his death2. The Bence Jones ward still exists at St. George's Hospital3.
Meanwhile, Mr Thomas Alexander McBean became weaker and died on Jan 1, 18461.
At autopsy, the ribs were soft, readily broken and easily cut by knife. Anterior of the ribs were filled with gelatiniform substance of a blood-red colour and unctuous feel. Autopsy was performed by Dr. John Dalrymple: surgeon to the Royal Ophthalmic Hospital in Moorefield, England, noted that the disease seemed to begin in the cancellous bone and then grew and produced irregularly sized round dark-red projections that were visible through the periosteum. Nucleated cells constituted the bulk of the gelatiniform mass that filled the cancellous cavities. Most of these cells were round or oval and about half to 2 times as large as an average blood cell. The cells contained one to three nuclei, each with a bright, distinct nucleolus: Dalrymple J, 1846 cited by Kyle2. Wood engravings made from the accurate drawings rendered by Dalrymple although incomplete, are almost consistent with the appearance of malignant plasma cells with some multinucleate forms1.
One can always find an earlier example, as with many so-called ‘first cases’. It is most likely that, 39-year-old Sarah Newbury, the second patient described by Solly in 1844, had multiple myeloma. She developed severe back pain, four years before her death. She had fractures developed in her thighs, clavicles, right humerus, right radius, and right ulna. After admission to St. Thomas's Hospital in London, she was treated with an infusion of orange peel and a rhubarb pill, when necessary, as well as an opiate at night. She died on April 20, 1844 and autopsy revealed that the cancellous portion of the sternum had been replaced by a red substance, which was similar to the red substance seen in the bones of Mr. McBean: Solly, 1844 cited by Kyle1.
The other case was of a 40 year old man with myeloma and amyloidosis who had severe sternal and lumbar pain. Hermann Weber reported this case in 1867. Postmortem examination revealed that the sternum was almost entirely replaced by a greyish red substance that had the microscopic appearance of a sarcoma. The same substance as found in the sternum replaced several round defects in the skull. Many of the ribs, several vertebrae, and parts of the pelvis were also involved. Amyloid was found in the kidneys and spleen3.
The term ‘Multiple Myeloma’ was introduced by a Russian doctor, Von Rustizky in 18736, (who worked in von Recklinghausen’s laboratory). During an autopsy, he found eight separate tumours of the bone marrow, which he designated as ‘Multiple Myelomas’. Although Von Rustizky’s did not mention albuminuria (Bence Jones protein), in Russia, the term ‘Rustizky’s disease’ is often used for multiple myeloma.
One of the most striking cases of multiple myeloma was that of Dr. Loos, a 46 year old physician, whose first symptoms, noted in July 1879, consisted of sudden severe pain in the right upper thoracic area, which was aggravated by taking a deep breath. Intermittent pain, aggravated by exercise, occurred in the ribs, spine, left shoulder, upper arms, and right clavicle. Albuminuria was first noticed in September 1881 and pallor was seen in 1883. Two years later, he was seen by Dr. Otto Kahler. During this period anaemia, severe kyphosis, recurrent bronchial infections, and loss of height occurred. Dr. Kahler noticed that patient's lower ribs touched iliac crest and chin pressed sternum so hard that a decubitus ulcer developed. On August 26, 1887, Dr. Loos died. An autopsy disclosed large round cells in the masses noted in the ribs and thoracic vertebrae. Kahler recognized that the urinary protein had the same characteristics as those described by Bence Jones. Of interest, the patient had maintained a high intake of fluids and had taken sodium bicarbonate regularly. Dr. Otto Kahler reported this case in 1889: Kahler, 1889, cited by Kyle2. A lot of interest was generated in this disease after this case report.
‘Plasma Cells’ A New Terminology
Waldever introduced the term `plasma cell’ in 1875. Ramon Y Cajal accurately characterized plasma cells in 1890 in a study of syphilitic condylomas; he stated that the unstained perinuclear area (hof) contained the Golgi apparatus. In 1895, Marschalko described the essential characteristics of plasma cells, including the blocked chromatin, an eccentric position of the nucleus, a perinuclear pale area (hof) and a spherical or irregular cytoplasm3.
Herrick and Kektoen reported the first case of multiple myeloma in the United States in 1894. Six years later, in 1900 Wright described a 54-year-old man with multiple myeloma and pointed out that the tumours consisted of plasma cells5. He emphasized that the neoplasms originated not from red marrow cells collectively but from only one type of cell, the plasma cell. This patient was probably the first in whom roentgenogram revealed changes in the ribs and thus contributed to the diagnosis of multiple myeloma5.
Diagnostic Advances during last century (Early And Middle 1900’s)
In 1922, Bayne-Jones and Wilson recognized two distinct groups of Bence Jones proteins. In 1928, Perlzweig and associates reported hyperproteinemia in a patient with multiple myeloma who had 9 to 11 grams of globulin in his serum. In 1929, sternal aspiration of the bone marrow was reported by Arinkin, which considerably increased the ante-mortem recognition of multiple myeloma. Bayrd and Heck described 83 cases of histologically proven multiple myeloma in patients examined at the Mayo Clinic through December 1945. The duration of survival ranged form 1 to 84 months with a median of 15 (Bayrd E D, Heck F J, 1947 cited by Kyle)3.
In 1937, nine year later, after the discovery of hyperproteinemic states in multiple myeloma, Tiselius used an electrophoretic technique to separate serum globulins into three components, which he designated alpha, beta and gamma. Interestingly, this article, which led to a Nobel Prize and later to the Presidency of the Nobel Foundation for Tiselius, was initially rejected by the Biochemical Journal3.
Two years later, in 1939, Tiselius and Kabat localized antibody activity in the gamma globulin fraction of the plasma proteins. In the same year, 1939, Longsworth and colleagues applied electrophoresis to the study of multiple myeloma and demonstrated the tall, narrow-based, ‘church-spire’ peak. The method was cumbersome and difficult; therefore, it was not readily available until the early 1950’s, when filter paper was introduced as a supporting medium (zone electrophoresis). Cellulose acetate has since supplanted filter paper1.
In 1953, Grabar and Williams described Immuno-electrophoresis, which has facilitated the diagnosis of multiple myeloma. When the results of Immuno-electrophoresis are equivocal, Immuno-fixation is useful in the recognition of small monoclonal light chains when none are found with immuno-electrophoresis7. When combined with Immuno-fixation, high-resolution agarose gel electrophoresis is more sensitive than immuno-electrophoresis in detecting small monoclonal proteins8.
In 1956, Korngold and Lipari demonstrated a relationship between Bence Jones protein and the serum proteins of multiple myeloma. The designation of the two major classes of Bence Jones protein as Kappa and Lambda is a tribute to Korngold and Lipari1.
In 1962, one hundred seventeen years, after the description of the unique heat-related properties of Bence Jones protein, Edelman and Gally demonstrated that the light chains prepared from a serum IgG myeloma protein and the Bence Jones protein from the same patient's urine were identical3.
Since then to date, diagnosis of Multiple Myeloma has essentially become a routine procedure in clinical laboratory and especially in clinical chemistry. Beside Bence Jones protein and bone marrow aspiration, serum protein-electrophoresis, serum immuno-electrophoresis, serum Immuno-fixation and Para protein quantification are now readily available in our country as well.
REFERENCES
1. Kyle RA. Multiple Myeloma. An odyssey of discovery. Br J Haematol. 2000; 111:1035-44
2. Rosenfeld L. Henry Bence Jones (1813-1873): The Best ‘Chemical Doctor’ in London. Clin Chem 1987;33(9):1687-92
3. Kyle RA. Multiple Myeloma: How did it begin? Mayo Clin Proc. 1994; 69:680-3
4. Kahn SN. Dear Dr. [Bence] Jones... Clin Chem 1991;37(9): 155-8
5. Kyle R A. The Monoclonal Gammopathies. Clin Chem 1994; 41(1): 2154-61
6. Kyle R A. Multiple Myeloma. Review of 869 cases. Mayo Clin Proc 1975; 50:29-31
7. Whicher JT, Hawkins L, Higginsons J. Clinical application of immunofixation: a more sensitive technique for the detection of Bence Jones protein. J Clin Pathol 1980; 33:779-780
8. Reichert C M, Everett Jr. DF, Nadeler PI and Papadopoulos NM. High-resolution zone electrophoresis combined with Immunofixation, in the detection of an occult myeloma paraprotein. Clin Chem 1982; 28:2312-231
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