Friday, February 15, 2008

History of CLL (part 1)


In the beginning

As far as we know, leukaemia has always existed. Probably the first patient noticed by a doctor as exhibiting the symptoms was a Monsieur Vernis, a 63-year-old Parisian lemonade salesman (Velpeau, 1827). We know that in this profession and in his former job as a florist he had been a happy, carefree individual with an eye for the ladies; yet he had managed to avoid the ravages of syphilis. Alas, despite Dr Velpeau's eminence, nobody else seemed interested in the disease. It took a controversy over precedence for leukaemia to reach the medical agenda in earnest. In the same issue of the Edinburgh Medical and Surgical Journal in October 1845, two case reports (Bennett, 1845; Craigie,1845) described patients who probably had leukaemia. Craigie's patient, a 30-year-old man whose illness began in 1841, had a spleen that weighed seven pounds three and a half ounces and `pink, wine-lee-coloured, groumous blood mixed with whitish-coloured masses of purulent lymph'. ‘Groumous' means viscous or jelly like. The patient survived for 1 year with deteriorating fatigue, weakness and increasing abdominal girth and pain. It is quite likely that this was the first reported case of chronic myeloid leukaemia.

We do not know for sure what type of leukaemia John Hughes Bennett, the Englishman later to become Professor of Medicine in Edinburgh, reported. His patient, John Menteith, a 28-year-old slater from Edinburgh, had been aware of a mass in the left side of his abdomen for 8 months before he died. At post-mortem examination, he had massive enlargement of his liver, spleen and lymph nodes. Examination of his blood revealed `the existence of true pus, formed universally within the vascular system, independent of any local purulent collection from which it could be derived'. Although the involvement of the lymph nodes suggests chronic lymphocytic leukaemia (CLL), it is more likely that a patient of this age would have had a spill-over lymphoma.

We cannot fully diagnose the case of Marie Straide, reported only 6 weeks later by Rudolph Virchow in Berlin (Virchow, 1845), either. Marie was a 50-year-old cook, who ied with a huge spleen 6 months after presentation. In her blood, the ratio of pigmented to colourless corpuscles was reversed. As she developed furuncles and suppurations of the skin and had several nosebleeds during her short illness, she may well have had acute leukaemia.

The word `leukaemia' (leukaemie) was coined by Virchow (1847a), and by that time he had already published a further nine cases (Virchow, 1846, 1847b). Meanwhile, Bennett preferred the term `leucocythaemia' and collected a further 35 cases that he salami-sliced into four papers and a monograph (Bennett et al, 1851a,b,c,d, 1852). Most of the early cases had splenomegaly as a major feature, although at least one of Virchow's cases had generalized lymphadenopathy without splenomegaly (Virchow, 1846), perhaps the first true case of CLL. Thereafter, Virchow classified leukaemia into `splenic' and `lymphatic' forms, recognizing that splenic leukaemias had granular leucocytes with trefoil-like nuclei in contrast to the agranular leucocytes with smooth round nuclei of the lymphatic leukaemias (Virchow, 1851). It is important to grasp the atmosphere as the two competing doctors strove for pre-eminence in the field of leukaemia. Even the name of the condition was acrimoniously disputed.

Bennett was 33 years old in 1845. He had graduated from Edinburgh after a brilliant student career. He was apprenticed to a surgeon in Maidstone and he then spent 2 years in Paris under the great microscopist Donné, who himself has some claim to have described the pathological features of leukaemia before either Virchow or Bennett (Donne, 1844). This case had presented clinically in 1839, and it is easy to believe it had been much talked about by the doctors there. After Paris, where he founded and was first President of the Parisian Medical Society, Bennett spent a further 2 years in Germany and then returned to Edinburgh. Here, he gathered a reputation as an outstanding teacher. By 1845, he was already a Fellow of the Royal Society of Edinburgh, and in 1848 was elected to the Chair at the Institutes of Medicine. That he never achieved the much more prestigious Chair of Physic at Edinburgh University has been attributed to his short temper, pugnacious attitude and certainty of his own virtues. Even the writer of his obituary had to admit that `his tendency to indulge freely in critical and sarcastic remarks upon the works of others did not make him a general favourite with some of his professional brethren' (McKendrick, 1875).

Virchow was only 24 in 1845 and just 2 years out of medical school. The Berlin Army Medical School (Friedrich-Wilhelms Institut) must have been a very much more disciplined establishment than Edinburgh, but Virchow was just as opinionated as Bennett. Part of the requirements for his entry to medical school was an undertaking to serve in the army on qualifying. When sent to report on an epidemic of typhus in 1847, his experiences led him to become a politically active radical and his part in the uprising in 1848 caused his expulsion from the Charité where he held his academic position. He was elected to the Berlin City Council in 1859, where he instituted many public health improvements. Later, as a member of the Prussian Lower House, he opposed Bismarck and became famous for his radical views and polemical speeches. In the Franco-Prussian war, he organized the ambulance service of the German army. Incontrovertibly the greatest pathologist of his generation, perhaps of all time, Virchow became assistant to Professor Froriep at the Charité in Berlin and was given the task of investigating the inflammation of veins. Froriep had been in Paris at the same time as Bennett, so might well have known of Donné’s case.

The first ante-mortem diagnosis of leukaemia was made by Fuller (1846). Both Virchow and Bennett made their discoveries at the autopsy table. How sad it is that so few young doctors are to be found there these days. Despite their dispute, both Bennett and Virchow agreed that the main trouble lay in the enormous number of colourless corpuscles in the blood. Without the ability to stain blood cells, their ideas on pathogenesis were exotic. Bennett believed that the red cells were the extruded nuclei of white cells and that a failure of this process led to the reversal of the ratio of the two types of cell. Virchow believed that the leukaemic cells came from the lymph, although he conceded that the spleen was an alternative source.

The bone marrow.

Ernst Neumann first recognized the central role of the bone marrow in leukaemia (Neumann, 1870). Neumann, like Immanuel Kant a century before, was a lifelong citizen of Konigsberg. He gave us our conception of the marrow as the source of the blood cells, eventually achieving fame as a visionary man of science and a writer of impeccable German. Meanwhile, he had to endure 20 years of ridicule by the medical establishment, who clung to the outmoded ideas of the previous generation. Nothing changes. Neumann recognized two patterns of bone marrow involvement in leukaemia: pyoid hyperplasia, dominated by highly granular cells, and lymphadenoid hyperplasia, where the cells had pale homogeneous nuclei and were almost devoid of cytoplasm (Neumann, 1878).

Stained cells.

Paul Ehrlich (Fig 4) developed a tri-acid stain that allowed the clear definition of nucleus, cytoplasm and other cytoplasmic detail (Ehrlich, 1891). His cousin, Carl Weigert, already a master at staining tissues, guided him. The German chemical industry had recently discovered the aniline dyes ± a prime example of technology driving science. Ehrlich was a man obsessed with his studies. His skin and clothing were stained from his experiments, as was his billiard table where he regularly conducted them. He frequently moved his base; from Leipzig to the Charité in Berlin, to Koch's Institute, to Steglitz and to Frankfurt. Although he was showered with honours, including the Nobel Prize in 1908, his last years were unhappy as he was involved in controversy over his introduction of the arsenicals for the treatment of syphilis. Nevertheless, Erhlich's stains allowed the leukaemias to be more clearly separated, and by the turn of the century Turk (1903) published criteria for the diagnosis of CLL.

Overlap with lymphoma.

In this same publication, Turk stressed the resemblance between CLL and lymphoma. Thomas Hodgkin had first described fatal tumours of the lymph nodes, although in retrospect we now know that only three of his seven patients actually had Hodgkin's disease (Hodgkin, 1832). Virchow (1863) described lymphosarcoma as a malignant tumour of the lymphoid tissue distinct from leukaemia and tuberculosis. Kundrat (1893) used the same term, recognizing that the disease spread between different groups of lymph nodes but spared the blood and bone marrow, thus distinguishing it from leukaemia. However, Turk (1903) pointed out that transitions between lymphosarcoma and CLL did occur and he regarded them as part of a family of diseases. A lively debate between these two extreme positions continued well into the twentieth century and even today there remains some difficulty in distinguishing CLL from some forms of lymphoma


merle said...

loved your descriptions of these early geniuses...imagine the dedication and stubbornness of these early doctors. their personal lives must have been chaotic... i love books about medical beliefs and catastrophes...the years of wonders by geraldine brooks, was about the 1660's plague in derbyshire. the making of monsters was about the imprinting of events on pregnant women. i know you will have time to read; actually that's what i've been induldging in since my mini mud ...keeps me away from people with colds and flu. enjoy your new found time and thanks for YOUR dedication to the list.

sincerely...merle pollack

Anonymous said...

In some respects it is amazing that earlier anatomists/physicians had not described patients with splenomegaly and lymphadenopathy as it seems intuitive that the blood/lymphatic dyscrasias have always been with us.

I trained at an academic US institutuion in the early 1970s and vividly recall the first patient that we encountered with what would later become to be known as AIDS.

because of the strong Internal medicine Dept and the particularly strong Infectious Disease Dept this man (who was hospitalized more than once with unusual infections and wasting disease) was didcussed on many occasions.

Several years late, when I was in practice and HIV?AIDS had been described it seemed obvious that that is almost certainly what this man had died from.

The other amazing thing that this recollection brings to mind is that no one had described or suggested the use of "Universal precautions" at that time...think of how many house officers were exposed to countless infectious situations.

I am anxious to read more of your book.