Burkitt's: Historical

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href="javascript:addbookmark()">Click here to Bookmark this site!</a>') </script>  </div> <bR> <div> <TABLE BORDER="1" CELLPADDING="1" CELLSPACING="1" WIDTH="581" HEIGHT="1%" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="BOX" RULES="ALL" HSPACE="0" VSPACE="0" BGCOLOR=#FFFBF0 > <tR> <tD VALIGN=TOP HEIGHT= 70 ><NOBR><div> Beryl Thyer</div> <div> Memorial Africa Trust</div> </NOBR></tD> </tR> </TABLE></div> <bR> <bR> <div>      </div> <bR> <div> Burkitt's Lymphoma: Historical    </div> <bR> <div> The following piece is part of an article to be submitted in 2006, to the journal called Transactions of the Royal Society of Tropical Medicine and Hygiene, London.</div> <div> Peter Hesseling has been my friend and mentor in the BL work since 2002. You can read about the circumstances of our meeting in this website.</div> <div> <B>Endemic Burkitt's Lymphoma, a Neglected Disease:</B></div> <div> <B>Historical Review, and Clinical Research from Cameroon</B><B>  </B></div> <div> Dr P A McCormick, Banso Baptist Hospital, NW Province, Cameroon. </div> <div> Professor P B Hesseling, Stellenbosch University, S Africa</div> <div> <I>Mr [Aloysius] Kisuule …probably speaks every language in Uganda. We sent him to find all the patients who hadn't reported back to the hospital - about eighty; and we knew this was a quite impossible task…Well, he found seventy-seven of them. We wanted … to find a boy who'd given his address as Msambya Hill, two miles outside Kampala. Aloysius couldn't find the boy there, so he simply sat down in a convenient spot, and whenever anybody passed he'd ask if they had seen a boy with a swollen jaw. After he'd sat there for a week a passer-by remembered the boy, and Aloyisius tracked him down to a place called Kimuli, ninety miles away. This is cancer research… This benefits humanity at large. 'The Long Safari' Bernard Glemser; 1971</I></div> <div> <B>Early Biographical background</B><B>:</B></div> <div> Denis Parsons Burkitt was born on 11<FONT SIZE="1" COLOR="#000000" FACE="Arial" >th</FONT> February 1911 in Enniskillen , Ireland. Denis was not a bright lad at school. At age 18 he entered the Engineering faculty of Trinity College Dublin, and showed no talent or promise there either; so much so that one of his professors wrote to Burkitt's father advising the young man be removed from the course, there being little likelihood that he would obtain the degree. Ironical indeed that half a century later the same university conferred their highest award on him - Honorary Fellowship of Trinity College</div> <div> Burkitt's subsequent years in medical school were happier. He was always within the top set each year, and won the coveted Hudson Prize and silver medal. His main interest after graduation was surgery, and there his problems began - for he was unable to secure a surgical post. It was likely that he was turned down on the grounds that he had but one eye. This was due to a boyhood argument at school. A fight with stone-throwing ensued, and Denis's glasses were smashed, with shards of glass entering his right eye. It had to be removed, and for the rest of his life he wore a glass eye on the right.</div> <div> The war helped him, for he was accepted into the Army Medical Corps in 1941 and joined a troopship for Mombassa - his first taste of Africa. After the war the Colonial Service finally accepted him in 1946, sending him to Kampala, Uganda as a general surgeon. Burkitt never claimed to be other than a 'bush surgeon'. Everything else that he subsequently observed and achieved was, he said, 'his hobby'. It could be argued that Burkitt observed more with his one eye than most of us do with both.</div> <div> The influence of Christianity in his life should not be omitted from any account, nor could it be overstated; he came from a devout family, and his beliefs underpinned the fabric of his life and work.</div> <div> Burkitt had observed the curious tumour in the faces of children for a number of years before submitting his first paper about them. New to him however, was to see a child with four tumours of the face - upper and lower jaws on both sides simultaneously. A few weeks later he saw another identical case himself.</div> <DIV ALIGN="LEFT"></DIV> <div> <TABLE BORDER="0" CELLPADDING="0" CELLSPACING="2" WIDTH="300" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=TOP HEIGHT= 245 ><NOBR><div> <IMG SRC="31e5eef0.jpg" border=0 width="350" height="239" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></div> </NOBR></tD> </tR> <tR> <tD VALIGN=TOP HEIGHT= 19 WIDTH="296"><div> Olive and Denis Burkitt</div> </tD> </tR> </TABLE></div> <div> <B>Historical Review</B><B>:</B></div> <div> One cannot start at a better point than with the re-reading Burkitt's original paper from Mulago Hospital, Uganda in 1958<B> </B><FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><A HREF="#references" TITLE="Burkitts: Historical"><B>1</B></A></FONT><B>.</B> The clinical simplicity, the astute observations, the epidemiological reasoning, the significant research in the absence of modern technology - carry messages for all who care for cases of Burkitt's lymphoma (BL) - and indeed for any rare, neglected or obscure disease - especially insofar as they affect children in the tropics.</div> <div> He described 38 cases of his own seen over 7 years. He reported Lilongwe (Malawi) as having 2 or 3 cases per year, and a Tanzanian hospital as receiving 6 patients in three months. Burkitt noted that the disease also occurred in Kenya and Nigeria. To these we can now add all countries in Africa lying between 10º N and 10º S of the equator. He originally suspected that the maxilla and mandible were solitary primary sites, but was puzzled - after having reviewed the case mentioned above, with Hugh Trowell in 1957 (rather poignantly this child's name was 'Africa') - about the children with initial lesions seen in the jaws on both sides; four sites simultaneously. He later recognised that lesions could first appear below the diaphragm and subsequently appear in the jaw. Hence the question of a primary site with distant metastases presented a problem. This anticipated later thinking that BL is to be regarded as a systemic disease, capable of appearing in any site at which cells of the lymphoid series can be found  <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><A HREF="#references" TITLE="Burkitts: Historical"><B>2</B></A></FONT>. He believed that though deposits were to be found in many organs, the spleen appeared not to be involved. This is quite contrary to our own experience, and perhaps is a reflection of the fact that we have ultrasound technology and he did not.  </div> <div> As to treatment, Burkitt soon recognized that surgery was not appropriate, and that since radiotherapy was not available, chemotherapy was the only option. With nitrogen mustard (military designation HN-2; designed for warfare, but never used; precursor of cyclophosphamide) he recorded remission in some cases. He thus anticipated chemotherapy as the likely treatment of choice. </div> <div> As to the aetiology of the tumour - 'by far the commonest tumour of childhood in Mulago Hospital, Uganda' - he at that time made no predictions. One can however almost see his scientific, epidemiological and tenacious mind working on the problem half a century ago, and he was to address the question of causation most directly and persuasively a few years later. What became very clear was that this tumour was hugely aggressive, rapidly growing, and invariably fatal within weeks or a few months. <A NAME="belt_large"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <DIV ALIGN="LEFT"></DIV> <div> <TABLE BORDER="0" CELLPADDING="2" CELLSPACING="1" WIDTH="298" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=TOP HEIGHT= 403 ><NOBR><div> <A HREF="id37_belt_large.htm" TARGET="_top" TITLE="Burkitts: Historical"><IMG SRC="35f228d0.jpg" border=0 width="290" height="397" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></A></div> </NOBR></tD> </tR> <tR> <tD VALIGN=TOP HEIGHT= 38 ><NOBR><div> The Lymphoma Belt </div> <div> Click on image to view in large scale</div> </NOBR></tD> </tR> </TABLE></div> <div> Twenty six years later we read of subsequent progress, as described in his oration upon receiving the Charles Stewart Mott Award - a private philanthropic society based in Michigan, USA, in 1982 <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><A HREF="#references" TITLE="Burkitts: Historical"><B>3</B></A></FONT>. Starting in 1958 Burkitt distributed a questionnaire and conducted personal interviews over a vast swathe of sub-Saharan and southern Africa (research grant: £25 [$75]), seeking information from distant colleagues as to the incidence of BL in their region. He received over 300 replies. This was followed by the epic 'Tumour Tour' (research grant: £250 [$700]) in which he and two colleagues travelled 10 000 miles (16 000 km) in a second-hand Ford pick-up truck, visiting sixty hospitals in ten weeks. From this he mapped out the areas and altitudes at which BL occurred and did not occur. So it was, that with simple logic he came to several conclusions which still hold firm today: BL does not occur in significant numbers where falciparum malaria is less than hyperendemic, but that in hyperendemic areas the disease can be found in black, Asian and European children, and it is far less common in children with sickle cell disease. BL does not occur in malarious areas if successful antimalarial interventions were in place there. BL does not occur over 3000 ft (923m) elevation  at 1000 miles (1666km) south of the equator, (even in nearby low-lying areas of intense malaria transmission) nor over 5 000 ft (1 515 metres) at the equator. The significance of the altitude data was provided by a virologist friend and colleague A J Haddow <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><A HREF="#references" TITLE="Burkitts: Historical"><B>4</B></A></FONT>, who suggested that altitude might imply a temperature gradient and barrier. BL seeming not to occur where the average temperature was less than 60ºF (15ºC). It was then realized that a rainfall pattern also emerged; the disease not being found in regions where annual precipitation was less than 20 inches (45cm). Both observations fitted very well with the suspicion of the involvement of malaria and the mosquito. The tumour was found to be virtually restricted to river valleys, lake shores and regions near the sea coast. These facts held true for all other areas of the world where <I>P falciparum</I> remains a problem - notably some areas of Papua New Guinea, and the Amazon basin. Never before had a malignant tumour been related to ambient temperature or annual rainfall, or altitude above sea level, or malaria and its vector.</div> <DIV ALIGN="LEFT"></DIV> <div> <TABLE BORDER="0" CELLPADDING="2" CELLSPACING="1" WIDTH="323" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=TOP HEIGHT= 364 ><NOBR><div> <IMG SRC="31f2c660.jpg" border=0 width="300" height="358" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></div> </NOBR></tD> </tR> <tR> <tD VALIGN=TOP HEIGHT= 57 WIDTH="317"><div> Professor Michael Anthony Epstein; Virologist, Bland Sutton Institute, Middlesex Hospital, London, UK<FONT SIZE="3" COLOR="#000000" FACE="Arial" >.</FONT></div> </tD> </tR> </TABLE></div> <div> Enter Anthony Epstein. Epstein, a virologist, had been wondering about viruses as being implicated in the causation of human cancer, as they were known to be in certain animal cancers; Burkitt had wondered about this too. Thus the meeting of the two men at a lecture given by Burkitt at Middlesex  Hospital in 1961 was mutually agreeable. Epstein asked for tissue from BL cases, Burkitt agreed. It was not long before Epstein and colleagues discovered a herpes-like virus within lymphoid cells in BL cases <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><A HREF="#references" TITLE="Burkitts: Historical"><B>5</B></A></FONT>. This was where the virus - to become known as Epstein-Barr Virus (EBV) - was first seen. A few years later Epstein and his colleagues at the Bland Sutton laboratory, Middlesex Hospital, learned how to maintain BL cells in vitro from a case in Uganda - who would die very soon after the tissue was flown to London. It therefore now appeared, on epidemiological grounds, that both malaria and EBV might be responsible for BL. Ninetyfive percent of endemic BL tumours have subsequently been shown to contain EBV <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><A HREF="#references" TITLE="Burkitts: Historical"><B>2</B></A></FONT>.</div> <div> Enter Werner Henle. Henle was the grandson of Friedrich Gustav Jacob Henle, celebrated anatomist and histologist (1809-1885), of loop, layer, membrane, sheath, fissure, and glands fame <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><A HREF="#references" TITLE="Burkitts: Historical"><B>6</B></A></FONT>. The younger Henle, in Philadelphia, was approached by Epstein to collaborate in the new EBV research. Henle agreed, and soon developed an immunofluorescent technique for detecting EBV antibodies. To everyone's surprise EBV was found wherever it was sought; Africans, Americans, Europeans, Icelanders, Brazilians. Eighty-five percent of individuals tested had been exposed to EBV at some time in their lives.</div> <div> Enter Elaine Hutkin. Elaine was nineteen, and working as a technician in Henle's laboratory. Serological tests on staff were routine. Elaine had been shown to be EBV-antibody negative. Later she became ill and was re-tested. This time she was EBV-antibody positive. A physician colleague diagnosed Glandular Fever. The world now came to know that EBV caused glandular fever; the world also became aware that EBV was ubiquitous, causing no illness in the majority of people, glandular fever in young adults in temperate zones, and BL in young children in sub-Saharan Africa. The virus having been first implicated in a tropical malignancy had now been found to be the cause of a non-malignant disease in temperate zones.   </div> <div> It is also recognized however, that whereas in the temperate zones of the world EBV is found in adolescents, in Africa it is found early in life - often before age one year <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><A HREF="#references" TITLE="Burkitts: Historical"><B>2</B></A></FONT><FONT SIZE="3" COLOR="#330000" FACE="Arial" >. </FONT>Along with the early onset of malaria, EBV infection is thus still widely agreed to be a candidate in the causation of BL.</div> <div> However, since intense malaria and EBV infection are clearly both common in children in sub-Saharan Africa, and since BL is - on the same scale - a comparatively rare disease - there must be yet more to be considered in the aetiology of BL. Burkitt himself wondered about the relevance of other vector-borne diseases; in particular he cites O'nyong-nyong (an epidemic of which he had witnessed in 1957) and yellow fever. Other workers have raised the possibility of Chikungunya and Bwamba fever; these are all arbovirus diseases, all present exclusively in the Lymphoma belt, all present in space-time clusters, and all favour the same conditions as those required for the transmission of malaria.</div> <div> <B>References</B><B> <A NAME="references"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>:</B></div> <div> <B>1.</B> D Burkitt, A sarcoma involving the jaws in African children. <I>British Journal</I> <I>of Surgery</I> 1958; 46: 218-213</div> <div> <B>2.</B> In 'Pediatric Oncology'; ch 20; IT Magrath; p415. eds Philip Pizzo, David Poplack, 1989</div> <div> <FONT SIZE="3" COLOR="#330000" FACE="Arial" ><B>3.</B><B> </B></FONT>Denis P Burkitt, The discovery of Burkitt's lymphoma. <I>Cancer</I> 1983; 51: 1777-1786</div> <div> <B>4</B><B>.</B>  In 'The Long Safari', ch 8, Bernard Glemser. Bodley Head, 1971 </div> <div> <B>5</B><B>.</B> MA Epstein, BG Achong, YM Barr. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. <I>Lancet</I>, March 28, 1964; p702-703 </div> <div> <B>6</B><B>.</B> In Dorland's Medical Dictionary, 2<FONT SIZE="1" COLOR="#000000" FACE="Arial" >nd</FONT> edn., 1957.</div> <div> <B>This review of Denis Burkitt will allow the reader to make various observations:</B></div> <div> Denis Burkitt was a remarkable man! A dedicated doctor, a hard-working bush surgeon, a keen observer, a logical thinker, an industrious researcher, a man of action, a likeable fellow, a humanitarian, a Christian gentleman. It was a privilege indeed to have met Dr Burkitt in the 1970s, when he was the guest of the late Dr Gerrard Crockett. Dr Crockett was at that time a consultant physician in Kettering General Hospital; a gentle and self-effacing doctor who for one year had, in my pre-GP days, been my boss.</div> <div> Dr Burkitt addressed the doctors of Kettering. It was a remarkable talk. There are men who just seem to be head and shoulders above all others; one cannot quantify this; one simply feels it; rather like sitting at the feet of Gamaliel as the apostle Paul did;  like having been present when Vaughan Williams was conducting his own music; like sitting in the House of Commons when Mr. Churchill was delivering a speech in 1940.</div> <div> It would have been impossible in 1970, to imagine how much this Irish physician would affect and colour the latter years of my professional life.</div> <div> Burkitt admitted that the African lymphoma was not a new disease, simply that it had not been written about; the world was unaware of it. He gives credit to Dr Albert Cook (later to become Sir Albert), a missionary doctor in a remote hospital in Uganda, for having accurately recorded a tumour of children identical to the ones he himself was seeing.</div> <div> It was unfortunate that Burkitt chose the British Journal of Surgery for his original article. It aroused very little interest. All subsequent papers appeared in journals dedicated to cancer. Thereafter the world really noticed Burkitt and his lymphoma!</div> <bR> <div> <B>(</B><B>Burkitt's: Historical)</B></div> <DIV ALIGN="LEFT"></DIV> <div>     <FONT SIZE="2" COLOR="#FF0000" FACE="Arial" ><A HREF="id12_m.htm" TITLE="Burkitts: Historical">top of the page</A></FONT></div> <div> Beryl Thyer Memorial Africa Trust, a UK registered charity  ~  1112603</div> <bR> <bR> </td> </tr></table></body>