First Era 18451924 Recognition of CLL As a Distinct Entity

The reports of Rai (2), Galton (3), Gunz (4), Hamblin (5), Piller (6), and Videbaek (7) are useful in reconstructing this early historical period.

Gunz (4) attributes the first accurate description of a case of leukemia to Dr. Velpeau, who in 1827 (8) described a 63-yr-old florist and lemonade seller Monsieur Vernis, who had abandoned himself to the abuse of spirituous liquor and women (8). Hamblin (5) shed further light on this subject by noting that in this profession and in his former job as a florist, Vernis had been a happy, carefree individual with an eye for the ladies, yet he managed to avoid the ravages of syphilis. This florist-lemonade seller fell ill in the summer of 1825 with pronounced swelling of the abdomen, fever, weakness, and symptoms caused by urinary stones. He died soon after admission to the hospital and at autopsy was found to have an enormous liver and spleen, the latter weighing 10 pounds. The blood was thick like gruel, and Velpeau wondered if it was laudable pus mixed with a blackish colored matter. Gunz (4) notes that it was this peculiar character of the blood, as seen

From: Contemporary Hematology Chronic Lymphocytic Leukemia: Molecular Genetics, Biology, Diagnosis, and Management Edited by: G. B. Faguet © Humana Press Inc., Totowa, NJ 3

Wilhelm Hematologist

Fig. 1. Dr. A. Velpeau. Courtesy of the National Library of Medicine (http://www.nlm.nih.gov/).

at postmortem, which first attracted the attention of all the early observers. Despite Dr. Velpeau's eminence, no one else seemed interested in the disease. In 1839, Barth submitted the blood of one such postmortem examination to Donne, who performed a microscopic examination and stated that he could not distinguish the mucous globules from pus. Later, he examined the blood of a leukemic patient during life and thought that the blood was so full of colorless corpuscles that at first he thought it was pus.

In his 1963 dissertation, Galton (3) begins the history of CLL with Craigie's two recorded cases of leukemia. Rather than publishing the first case, Craigie waited to confirm his observations when another patient appeared 4 yr later in 1845. Craigie (9) then published both cases in 1845. On the following pages of the same journal, Bennett (10) presented a complete autopsy report of the last case including microscopy of the cadaver blood. Both noted the purulent matter in the blood and thought it was unrelated to infection. Based on the abnormal appearance of the blood at postmortem examinations in 37 cases with 17 followed during life, Bennett called this suppuration of the blood "leucocythemia" (reported in four papers and a monograph). In the same year, 1845, Virchow (11) described two further cases and suggested a distinction between the splenic and a lymphatic type. In the lymphatic case, besides lymph node enlargement, Virchow found large and small single "rundzellen" in the bone marrow. Using the term "veisses Blut," Virchow argued that there was no evidence of local suppuration with diffuse spread and coined the term "leukemia," of which he said there were two forms: splenic and lymphatic. Virchow was able to differentiate a leukocytosis from lymphatic leukemia again permitting him to classify leukemia, into splenic and lymphatic forms. He recognized that splenic leukemias had granular leukocytes with trefoil-like nuclei, in contrast to the agranular leukocytes with smooth round nuclei of lymphatic leukemias. He also recognized a group of conditions in which lymph nodes and spleens were enlarged without alteration of the blood picture, which he termed "lymphosarcoma" and

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Fig. 2. John Hughes Bennett. Courtesy of the National Library of Medicine (http://www.nlm.nih.gov/).
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Fig. 3. Rudolf Virchow. Courtesy of the National Library of Medicine (http://www.nlm.nih.gov/).

considered not essentially different from lymphocytic leukemia. He also noted very aggressive tumors, frequently of the neck and sometimes in the mediastinum, that metastasized to other organs. These metastases, although nodular, could easily be distinguished from other malignant tumors by their less circumscribed character and their tendency to merge with the surrounding tissues. The concepts of absolute and relative lymphocytosis were introduced rather early.

Most historical reviewers consider that the history of leukemia and therefore of CLL begins with these descriptions by John Hughes Bennett (1812-1875) and Rudolph Virchow (1821— 1902). After both men performing autopsies on their respective patients, are credited with having virtually simultaneously and entirely independently of each other discovered the pathology in 1845 that is now readily recognized as leukemia (10,11). Thus, in 1845, independent publications from Bennett, a physiologist in Scotland, and Virchow, a pathologist in Germany, made leukemia a recognized clinical entity. Much has been made of the supposed rivalry between Bennett and Virchow, but Hamblin (5) supplies details about this nonexistent rivalry and concludes that since many of the colorless corpuscles were described as cells, each containing one large nucleus, the case described by Bennett might indeed represent a case of CLL. However, Galton (3) attributes the first description of CLL to Virchow: gradual, painless enlargement of cervical, axillary, and inguinal nodes over a 2-yr period. At death the spleen was firmer than normal but not enlarged. The blood in the heart and great vessels was leukemic, with the proportions of white to red corpuscles roughly estimated as 2—3:1.

The term "pseudoleukemia" was used to describe those conditions in which enlargement of spleen, lymph nodes, and other organs was found at autopsy. The macroscopic and microscopic findings resemble the lymphatic leukemia without involvement of the blood. Because the word "pseudoleukemia" was gradually understood to refer to several unrelated conditions, the term "true pseudoleukemia" was used to indicate primary lymphoid hyperplasia, which resembled leukemia but lacked the characteristic blood picture. The term "pseudoleukemia" also took another turn in which organ involvement was consistent with a lymphoid neoplasm, but a relative lymphocytosis was present. Fortunately, the terms "pseudoleukemia and true pseudoleukemia" were gradually dropped and became synonymous with aleukemic or subleukemic lymphocytic leukemia.

Paul Ehrlich, publishing in 1877, 1880, 1887, and 1891 (12-14) developed the triacid staining method to study red and white corpuscles in thin dried films of blood. His method allowed a clear distinction among the nucleus, the cytoplasm, and other details of blood cells. The stains allowed three types of granulocytes to be distinguished: the eosinophil, the basophil, and the neutrophil (13). His work allowed leukemias to be classified into two types: myeloid (granulocytes) of the bone marrow and lymphoid (lymphocytes) from nongranular cells. By 1881, Einhorn (16) had named the lymphocyte and made a distinction without staining between small and large lymphocytes.

Kundrat, in 1893 (17), followed by Turk, in 1903 (18) provided case summaries and other clinical data to separate CLL from lymphoma systematically. Kundrat used the same term, "lymphosarcoma," recognizing that the disease spreads between different groups of lymph nodes but spares the blood and bone marrow, thus distinguishing it from leukemia. However, Turk 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 20th century, and even today there remains some difficulty in distinguishing CLL from some forms of lymphoma.

Turk (18) also devised a classification scheme for hyperplastic conditions of lymphoid tissue (lymphomatosis), based on clinical behavior, the mode of growth and spread, and hematological features. He described three chronic benign lymphomatoses, which were indistinguishable clinically and histologically but could be divided hematologically. They are: (1) alymphatic or

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Fig. 4. Paul Ehrlich. Courtesy of the National Library of Medicine (http://www.nlm.nih.gov/).

Fig. 5. Sir William Osler. Courtesy of the National Library of Medicine (http://www.nlm.nih.gov/).

alymphemic with a normal lymphocyte count throughout the course of the disease; (2) sublymphatic, in which there was a relative lymphocytosis; and (3) lymphocytic, in which there was an absolute lymphocytosis. Chronic lymphocytic leukemia was thus termed "chronic benign lymphemic lymphomatosis."

The chronic malignant lymphomatoses of Turk were referred to as chronic malignant lymphosarcoma forms. Turk also notes that large cells were more often found in the blood and associated with more rapidly advancing disease. He cited cases of leukemia with both large and small cell and transitional forms present. In other cases in which the change was from a small cell to a large cell type, they were without any change in clinical behavior or evidence of locally aggressive growth. Thus, the chronic malignant lymphomatoses were considered to be true malignant tumors that began as local tumors, and although benign for long periods eventually became locally aggressive and spread rapidly by lymphatic pathways from one group of lymph nodes to the next regional lymph node. It should be noted that a plasma cell on the blood film is often referred to as a Turk cell.

Also during this time, patients were observed for long periods with just lymphadenopathy alone. After local radiation, a rapid increase in lymphocyte count could be noted with subsequent death of the patient. Although the cells in the blood were described as being small lymphocytes, microscopic examination of lymphoid tissue at autopsy revealed both large and small lymphocytes with varying degrees of massive infiltration. Galton (3) believes that many of these have been examples of generalized follicular lymphoma. Eventually the term "lymphosarcoma cell leukemia" was added. The term "terminal blast cell leukemia of lymphosarcoma" preceded the term "lymphosarcoma cell leukemia."

Galton (13) points out that the merit of Turk's classification was that the name of each condition was a concise definition of its clinical, pathological, and hematological characteristics. Lymphomatosis was a family of conditions ranging from benign to highly malignant. Galton further points out that such confusion has arisen because the leukemia associated with lymphosarcoma has not always been differentiated from chronic lymphocytic leukemia. Galton concluded that the term "leukosarcoma" had been used in a variety of circumstances as follows: (1) infiltrating tumors developing during the course of acute lymphoblastic leukemia and perhaps chronic lymphocytic leukemia; (2) lymphosarcoma with terminal leukemia; and (3) follicular lymphoma with sarcomatous features and terminal leukemia. Thus, this term may have led to the confusion of possibly distinct conditions, and, in addition, its use appears to have been partially responsible for the confusion, whereby the terminal blast cell leukemia of lymphosarcoma has not been differentiated from CLL. With regards to the pathogenesis of CLL, Galton returns to Turk's concept of a systemic diffuse hyperplasia of the lymphoid system, in contradistinction to a focally arising lymphosarcoma. After a long discussion regarding the bone marrow as a source of lym-phocytic leukemias, Galton concludes that it seems reasonable to conclude that the bone marrow is rarely if ever the site of origin of CLL.

In his review, Rai (2) notes that in the first edition of Sir William Osler's monumental book The Principles and Practice of Medicine in 1892 until the 7th edition in 1909, there was little change in the description of CLL (19). In Osler's experience at Johns Hopkins Hospital, CLL constituted 20% of all leukemias and was associated with a generalized enlargement of lymph nodes. The confusion that arose historically between the terms "chronic lymphocytic leukemia" and "lymphosarcoma" are not all that different from present day terms: chronic lymphocytic leukemia vs a well-differentiated lymphocytic lymphoma vs small lymphocytic leukemia. Clinicians, hematologists, oncologists, surgeons, and pathologists all contribute their observations to this disease. The difficulty lies in the different clinical behavior of lesions that appear morphologically similar: a lymphadenopathy without lymphocytosis and a lymphocytosis without lym-phadenopathy. The clinical course in either case cannot be predicted without observation. It will only be by the continued observation of these two extremes that the heterogeneity of the CLL

Cll Heterogenity

—Appearance of a drop of Wood, magnified 250 diameters, taken from Tinlay's finger. —Tiie same, after the addition of acetic acid,

—A drop of blood, treated by acetic aeid 24 hours after being taken from the arm by venesection.

—Appearance of a drop of Wood, magnified 250 diameters, taken from Tinlay's finger. —Tiie same, after the addition of acetic acid,

—A drop of blood, treated by acetic aeid 24 hours after being taken from the arm by venesection.

Fig. 6. (From ref. 20, Bennett, 1852, Figs. 6, 7, and 8). With permission from Sutherland and Knox, Edinburg, UK.

Fig. 6. (From ref. 20, Bennett, 1852, Figs. 6, 7, and 8). With permission from Sutherland and Knox, Edinburg, UK.

Leucocythemia 1852

Fig. 7. Colorless blood corpuscles from a vein of the pia mater of a lunatic. (A) Examined when fresh: a, in their natural fluid; b, in water. (B) After the addition of acetic acid: a-c, cells with a singular, granular nucleus, which becomes progressively larger and is finally provided with a nucleolus; d, simple division of the nuclei; e, a more advanced stage of the division; f-h, gradual division of the nuclei into three parts; i-k, four or more nuclei. 280 diameters. (From ref. 21, Virchow, 1863, Fig. 56.)

Fig. 7. Colorless blood corpuscles from a vein of the pia mater of a lunatic. (A) Examined when fresh: a, in their natural fluid; b, in water. (B) After the addition of acetic acid: a-c, cells with a singular, granular nucleus, which becomes progressively larger and is finally provided with a nucleolus; d, simple division of the nuclei; e, a more advanced stage of the division; f-h, gradual division of the nuclei into three parts; i-k, four or more nuclei. 280 diameters. (From ref. 21, Virchow, 1863, Fig. 56.)

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    WHO classification leukemias cll?
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