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A FIVE YEARS (1973 - 1977) RETROSPECTIVE STUDY
AND A TW O YEARS EXPERIENCE IN THE TREATMENT
OF ADULT (OVER 15 YEARS) HODGKINS DISEASE IN
KENYATTA N A TIO N A L HOSPITAL
BY
DR. CHARLES MUSEMBI KIVIN DU. M B.CH .B. (NBI)
A THESIS SUBMITTED IN PART FULFILMENT
FOR THE DEGREE OF MASTER OF MEDICINE
IN THE UNIVERSITY OF NAIROBI MARCH 1978.
- 1 -
This thesis Is my original work and has not been presented for a degree In any other University
Sign Q YICavmXZu
This thesis has been submitted for examination with my approvalas University Supervisor
- 2 -
C O N T I NTS PAGE
Title 1
De'.lorotfor, 2
W * * ry 4
Introduction 5
Review of Utoroturo
- etiology J
- Presentation and Staging 10
- Hlstapathologicoi Diagnosis and Ciosslflcotlon 17
Treatment 24
> Relapse, Survival and Cure 31
- Immunology 32
Retrospective *ocy (1973 - \9rn )
T A I U S
Table I 35
Table II 34
Table III 37
Table IV r * 37
Table V and VI 38
Table VII 39
Table VIII 40
Appendix I 43
Acknowledgement 44
References 45
3
SUM MARY t
Literature on Hodgkin* disease I* briefly reviewed under the following
headings : (a) Aetiology (b) Clinical Presentation and Staging
(c) Hlstlpathologlcal diagnosis and Classification (d) Treatment
(e) Relapse Survival and Cure (f) Immunology.
Records of 49 adult (> 15 yean) patients diagnosed and treated In Kenyatta
Notional Hoqplto! between January 1973 and December 1977 were
analysed. The mean age was 31 yean and the male-female ratio was 3:1.
A ll the patients had Lymphadenopathyas a main presenting feature, and
94.5% complained of fever at the time of presentation. The mean dura
tion of Illness before presentation was 11 months. 70% of the patients
were clinically In stage III and IV at the time of presentation. Histologi
cal classification showed a predominance of the more malignant mixed
eellulanty (37%) and Lymphocyte depleted (23%).
Multiple drug chemotherapy achieved a complete remission rate of 76%
while the complete remission rate In the group treated with radiotherapy
wdJ71 % . Side effects In both groups were minimal.
4 -
INTRODUCTION ;
Malignant Lymphomas form 8 .5 # of all malignancies in Kenya (1 ).
Hodgkin's disease as one of the maligna it lymphomas has been studied
w idely. It is no surprise therefore that a lot of epidemiological work has
been done. A lot of literature has been published on aetiology (2-15) ;
presentation and spread (16-19); clinical staging (20 40) ; histopatho •
logical classification (41-49) ; treatment (50 6 3 ); relapse, survival and
cure (64-67) and most recently Immunology of the disease (68*78).
Kenyatta National Hospital is the referal hospital for the whole of Kenya.
Within the hospital complex are the departments of Surgery, Medicine,
Po*drIatrlcs, Pathology, Radiology and •'Radiotherapy. It will be obvious
after all the literature Is reviewed, that iiallgnant lymphomas, particularly
Hodgkin's disease w ill require the cooperation of the afore mentioned
departments. It was noted before by Ogoda In 1974 (1 ), "There is a great
need for an integrated Centre In Nairobi to treat malignant lymphomas, as
at the moment being treated by Surgeons, Paedriatri d a ns and Physicians
independently.
It is the aim of this paper them fore to : -
(a) assess the size of the problem of Hod^dn's disease In Kenyatta
National Hospital.
(b) determine the stage of presentation and histopathological features
as seen In Kenyatta National Hospital and compare this to
- 5 -
experiences elsewhere.
(c) determine the extent to which Investigations neoessary for accurate
clinical staging are done In Kenyatfa National Hospital.
(d) to assess theefficacyof administration of multiple drug chemotherapy
on outpatient basis.
To achieve the above alms, the review of relevant literature will be done
first and then the retrospective study will be presented.
REVIEW OF LITERATURE
A E T IO L O G Y
Lika mot* malignant tumours, the aetiology of Hodgkin's disease romalns
unknown. Epldomlologicol studios hovo shown both community and
familial clustorfng (2 , 3 ). It has also boon reported In marrlod couples (4 ).
Tho Incldonoo Is throe tlraos greeter In doro relatives (5) and seven rimes
In siblings (6).
An Infectious agent, environment and genetics have all been Incriminated
In the pathogenesis of Hodgkin's disease (7, 8 ). Immune dysfunction has
recently been added to the above three (9 ). MocMohon suggested that
familial association was more likely due to environment than generics (10).
The presentation with fever, chills and swoatlng tend to point to possible
Infectious agent. Vldnno suggestedthat Hodgkin's disease may be due to a
virus of low virulence and Infectlvlty which Is acquired through
respiratory tract during birth. Ho further postulates that the virus Is
barrier held by Intact nonlnvoluted lymphoid tissue and that tho charac
teristic lytqphnodo changes are as a result of Immune complexes (11). The
soma author advances that nodular sclerosing histological form is the most
likely to be caused by “Infectious agent (12)". He provides a possible
evidence of transmission by a 10 year study of caws of Hogdkln's disease
occuring In students from schools where a case of the disease (either In
student or teacher) hod bean reported (13).
So for, o viral aetiology has bean speculated but not demonstrated.
- 7
Elevated antibody tftrw to herpes typo virus has boon reported, but
Goldman In 1970 demonstrated that tho ovldonco of antlbodlos to E - ft
virus, horpos simplex and cytomegalic virus In Co m of Hodgkin's dlsoaso
was not statistically higher than In tho gensral population (14).
An ottraetlvo theory on pathogwsosls was advanced by Order and Heilmann
In 1972 (15) i -
(1) T - oeils or thymus derived lymphocytes are Infected by an oncogenic
(or tumour Inducing) virus. This causes a change In the cell surface
antigen.
(tt) Normal T -c e lls Interact with virus transformed cells.
(Ill) This Interaction Is protracted and leads to the production of
neoplastic reticulum cells.
EVIDENCE FOR THE HYPOTHESIS » -
(I) T - cells are distributed In thymus, lymphnodes and spleen cells
all primary sites of early Hodgkin's disease.
(II) Viruses are known to alter antigenic surfaces of cells I coding to
auto-lmmune phenomena.
(III) T -o e ll Involvement In Immune reaction together with viral Infec
tion of T -cells causes a T -c e ll depletion with a consequential loss
of delayed hypersensitivity - a phenomenon seen In Hodgkin's
(tv) In thymectomlsed animals there Is a T - cell depletion and plasma
cell populate the thymus dependent areas. Plasma oell Infiltrate
Is a histologic torture of HodflMn's dlsooso.
(v) Experimental T -coll depletion leads to Increased Incidence of
lymphoma •
At this stage therefore the aetiology of Hod^ln's disease remains unknown
but the search still continues.
• 9
The major presenting feature of Hodgkin's disease Is painless lymphodeno-
pothy. Kaslll (Id ) analysad 117 cares of Hodgkin's dlm o w ; 113 patients
(a 97%) presented with lymphnode enlargement and only 4 (3%) patients
presented with extranodol Involvement. The lymphadenopathy may or may
not be accompanied by systemic symptoms which Include fever, weight
lees, night sweats and pruritus. The significance of these will be discussed
later.
There Is evidence that Hodgkin's disease tpreads from a primary site to
contlgous chain of lymph nodes (17, 18). Non-contlgous distribution has
also been reported and Is attributed to vascular Invasion and spread (19).
S TA G IN G i
There are two major recaons why proper stating In Hodgkin's disease should
be done i*
(a) to facilitate communication and exchange of Information.
(b) to provide guidance on prognosis and assist In the therapeutic
decision.
CLINICAL STA G IN G t
The commonly used clinical staging is that adapted at the Rye Symposium
In New York In 1965 and reported by Rosenberg (20).
PRESENTATION AND STAGING OF HODGKIN'S DISEASE
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aiN iC A l^TA P IN G ADOPTED AT THE
ST A Q| DEFINITION
I Single node region (1.*. one anatomic alto).
•• Dl**c*# limited to 2 contfgooa or *an»contigow
mgl*m but on th* gam* aid* of th* diaphragm.
M Ola**a* on both aidoa of th* diaphragm but 11 ml tod
t* iploen, nodot andWalderyers ring,
•v Inuoluow nt of any Ham* or organ othar than nodat,
tplaon and Waldaryart ring.
N O Tf i A ll atagac ora aubelawlflad *A* or to Indloata absence or
praoanc* of ayttamlc aymptama respectively.
Slno* tha Rye rwaHng how*ver,2 thlngt iwppanad that necessitated further
modification (21, 22).
(a) Extra lymphatic localltad dlaaoaa and/or Involvomant of Haauaa
ad|ooont I* Involved lyraphnadaa did not odvoraaly affect survival
and potfanti da at wall at patient* with seme atogo without extra
lymphatic qpraad.
(b) Exploratory laparatoary and splenectomy become widely wad for
ata^ng.
Hence at th* Ann Arbor Conference In Michigan, 1271, the following
modifications war* Introduced (23).
n
CLINICAL.STAGING IN HODGKIN'S DISEASE (Ann Arbor).
st a g e D EFIN ITIO N
• Involvement of a tingle lymphnode region (I) or of
• tingle extrolymphotlc organ or tile (lg) .
^ Involvement of two or more lyn^phnode reglom on
tame tide of diaphragm (II) or local I tod Involvement
of on extralymphatlc organ or tlte and of one or more
lymphnode region on tame tide of dfaphrapn (llg)
II* Involvement of lymphnode reglom on both tides of
dophragn (III), which may alto be accompanied by
Involvement of the ipleen (III^) or by localised
Involvement of extra!ymphatle organ or site (lllg) or
both ( l l lg ) .
IV Diffuse or disseminated Involvement of one or mare
extralymphetlc organs, or tissues with or without
associated lymphnode Involvement.
N O TI_ i (a) A ll stages are again subdosslfled to 'A 1 and 'I* to Indicate
the absence or presence of systemic symptoms respectively.
(b) The tubeotegory ' I ' denote* extrdymphaHc involvement.
In the tame Symposium, the significant systemic ( 'I ' ) Synptomt were ocaepted
at t -
(I) Unexplained fever with temperature upto 38*C
(It) Unexplained weight lest (10% within 6 months)
(III) Unexplained night sweats.
(Iv ) 'Pruritus’ - dene does not constitute sufficient evidence to place a
- 12-
patient In category *B*. It occurs In 4 of the potlenti and It net
leen In children (24, 25),
The studies necasanry far accurate clinical staging Include j-
(0) Complete history with emphasis on *B’ systemic symptoms
(b) Thorough clinical examination Including all p*Hphera1 lyn^hnode
groups and any palpable dbdomlnal masses. The sixes of all
enlarged glands dtould be carefully recorded for this will be used
as a therapeutic ‘maker.
(e) Staging laparotomy and splenectomy. Multiple biopsies should be
tefcen from the liver end ell ocoeslble suspicious lyit^phglands,
(d) Laparoscopy plus biopsies from the liver
(e) Percutaneous liver biopsy.
(f) Bipedal lymphangiography .
(g) Bone Marrow examination
(h) Haematol ogled work up tnbludlng complete haemogram with
differential white cell counts and ISR.
(1) Liver function tests especially alkaline phosphdase.
(|) X-tay» of chest and skeletal survey
(k) Intravenous Pyelopam
(l) Mediastinoscopy.
It Is always not necessary to do ell the above Investigations. In patients
who present with advanced disease (Stage III or IV) end e decision Is made,
to use multiple drug chemotherapy, baseline investigations may be the only
• 13 -
Investigation required. However In patients with stage I end II oHs m m ,
md RodlotWopy Is contemplated, then further Investigations to ascertain
the staging Is very Important .
Total white cell counts with differentia!*, and alkaline phorpholoto eve
nmnpocJfle end therefore net enough evidence of Involvement of hone
marrow or the liver (respectively) by Hodgkin's disease (2d). Bono morrow
and liver (percutaneous) biopsies « e therefore nooossary procedures. But
as It will bo seen letter, biopsies from these sites ere quite difficult to
Interpret and If negative, Involvement by Hodgkin's disease Is not altogether
ruled out.
staging of Hodgkin's disease. However they do not sppaar to be as helpful
as exploratory Iqxmatamy and q>leo#ctony If used routinely.
In some centres, they hove found bipedal lymphangiography as a simple
occurote Informative technique with a minimum amount of complications
and of value In clinical staging and planning of Radiotherapy flaids. Stage
I end II of Hedgin'* disease may prove to be extensive after lyxyhmsqU ysp hy .
The Incidence of rotnquowtonlol rxxbInvolvement has been staled to he from
0 - 96% In Stage I and from 14-51% In tags II (30). The accuracy of
lymphangiography far Identification of pelvic and pore-aortic node Involve-
The u n of exploratory laparotomy and splenectomy has boon widely accepted
and adopted as the most aceurato method far the evaluation and clinical
staging of patients with Hodgkin's disease. Its major value It to provide
batter diagnostic Information primarily concerning the spleen. Only one*
l**lf of the patients who are assessed
to hove Involvement of the spleen based on Its enlargement clinically, will
have Involvement on hlstepathologled examination. Conversely one
patient In four will have demonstrable Hod^dn's disease of the spleen
without pie-operative suspicion (33).
The non-operative clinical assessment of Hodf^cfn's disease Involvement of
the liver (1.0 . liver site, liver function tests) Is unreliable and cannot be
dependent upon. As liver Involvement would alter the form of treatment,
hitopathoiogled verification Is required. This con be obtained by
percutaneous liver biopsy but bettor still at laparotomy. Since the entire
liver cannot be studied at histology as can be the spleen, false positives
cllnlcd evaluations are more difficult to determine. However this occurred
In 29 of 32 portents In Ultmann's review. False-negative* occurred In t of
33 Instances In a group of patients at Stanford (34).
Laparotomy has bean found to be superior to lymphangiography In the
diagnosis of Intro-abdominal lymphnode involvement. 20% to 29% of
lymphangiopafni cannot be Interpreted as definitely positive or negative
for Hodgkin's disease Involvement. Therefore laparotomy with biopsy
sampling of all suspicious nodes yield a more accurate evaluation.
- 1 5 -
Splenectomy has a direct advantage In the subsequent management of the
patient especially when the treatment Is radiotherapy. The fields which
are required to encompass the q>leen adequately Include the left lower
lung and pleura, and portions of the left kidney. Whe» splenectomy has
been done the radiotherapist limits his field to the splenic pedicles and
hence eliminates the risk of radiation pnoumordtls and pleurltls of left
lung base and radiation damage to the left kidney.
The acute morbidity and mortality from leparatomy and splenectomy Is now
described said Is K 1 (3$). h Is still net accurately known
to what degree patients with Hodgkin's disease who have been q>lenecto~
mlsed will have a'n Increased Incidence of Infections, well described In
other patients both children said adults who have hod qslenectansy (3d, 37).
However, SeMmmff described Infections In 92 spienectomlsed patients with
Hodgkin's disease (38). Kcwy (39) also reported two cases of
pnounoecocal anc* Influerata Infection after qjlenectomy for Hodgkin's
disease. Assigning the cause of this complication to splenectomy Is part.
icularly difficult In Hodgkin's disease because e number ef ether factors
that predispose to Infection era always present. These patients have a
defect In delayed hypersensitivity and therapy with irradiation or Intensive
chemotherapy depresses their immune mecHlhi** •van further (40).
Exploratory laparotomy and splcncttomy thoroforo eremolns the method of
choice In staging and deciding the form of therapy In Hodgkin's disease.
14 -
H IS TO fA TH O LO G IC A l DIAGNOSIS AND CLASSIFICATION OFHOD G K IN ' S P lf A S f
REED-STERNB£RG (R-S) CELLS IN THE DIAGNOSIS AND CLASSIFICATION W H 5 0 G K lh l ' S D I S I A S i W "
The diagnostic typo of R-S coll U o large cell which may bo I abated, b l-
nucleated, or muifinudeated and hat a huge* Inclusion-Ilka nuclaoll
frequently with parinuclear helot (fig. 1). The cytoplasm It abundant and
acidophilic to amphophilic end both the nucleoli and cytoplasm are vividly
pyronlnophlltc. Recent studio* by Feckham and Coopar (42) have drown
that the diagnostic cell It a nonproliferating end-stage cell In which the
huge nucleolus and anphephlllc cytoplasm are a reflection of derangement
of RNA synthesis with accumulation of cytoplasmic RNA. The Intense
pyrontnaphllla of the cytoplasm In methyl (pee pyronln- stained sections Is
useful for this reason In the search far diagnostic R-S calls. The ma|arlty
of large abnormal aells found In Hodgkin's disease are the nondiagnostic
volants of the R-S cell since they lack the huge Inclusion-1 ike neucieoius
and the abundant amphophilic cytoplasm.
The Important proliferating call In Hodgkin's disease according to the work
of Feckham and Coopar (42) is a large abnormal mononuclear call qpparent-
ly related «e the non-dlagnostlc variants bf R-S cells. The frequency of
diagnostic R-S cells with huge neucieoll Is however of a primary pro
gnostic significance, while the remaining R-S cell variants are useful only
as Indicators of the histological type of Hodgkin's disease.
There are three primary variants of R-S cell other than the diagnostic
- 1 7 -
* * • * -
to The locunoo typo of nodular sderosis. This oell has 2 distinctive
features ■-
(I) the abundant pale to water-dear appearing cytoplasm
with a sharply de»naroated peripheral margin.
(II) Hyparlabulatod with small nuclei. The latter feature Is
common but not consistently found In all cells.
The most distinctive feature, the low-density or water-dear cytoplasm
presenting a halcr-llko effect appears to be partly attributed to the artifact
of fixation (fig. 2!). In well-fixed tissue with Zenker's Solution the
cytoplasm Is abundant, finely granular and ocldaphlllc and usually only
relatively narrow peripheral space Is apparent (fig. 4)* The focunar cells
very widely In frequency and occur sJi*Jy or In cohesive dusters.
(h) The dstlnctlve polypoid type of the lymphocytic and/or histiocytic
(L & H ) ty, e . This variant has a large polypoid nucleus that Is often
twisted and overlapping, the nudecr chromatin Is extremely fine
and the nudeoll are small er Inapparent (fig. 4 ). The cytoplasm
Is pale staining and moderate In amount. The L A H variant of
R-S aell may be extremely numerous and constitute 10% to 20% of
the cellular papulation.
to Iht-ggfggpgM c variant of R-S cell or the Sarcomatous type
exhibits a wide range of bizzarre morphological expression of the
diagnostic type. They usuolly dominate the cellular proliferation
- 18 -
or In olmoot tumour nodules.
HISTOfATHOLOOICAL EVIDENCE Of H O D G KIN 'S DISEASE IN THEu v t i r — -----------------------------------------------------------------------------------------
In potlenti with Hodgkin's disease elsewhere, If m R-S coils arm soon, tho
prmmmncm of mseonucleor colls with nudecr foaturos of R-5 coll In mm of
tho chcroctoriotic cellular environment of Hodgkin's disease should bo
regarded os evidence of hepatic involvement^! A typical Mstlocytos or
retted urn eel Is whleh foil almost short of those criteria but present In
cellular environment should bo reported os suggestive of Hodgkin's disease.
HISTOfATHC tO Q lC A l iV lO E N a p F HODG K IN 'S DISEASE IN THEe j n T m a K w T
In tho prosonoe of tflsease elsewhere tho finding s f ^ or diffuse
of fibrosis which contain only Inflammatory colls charoctartlsties of
Hodgkin's disease with no ft-S cells should bo regarded as strongly
suggostluo.
I f
Criteria for Involvement in Hodgkin's Disease
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Fig. 1. The iypica! binucleated and muitinucleated cells with inclusion-like nucleoli and deeply staining cytoplasm (b, c. and d) p. - u iht features of the diagnostic R-S cel! and are compared with the diagnostically unreliable mononuclear form [a). LACH S-65 I 3924. H A. E. x 850.
Fig 2. These lacunar type R-S cells exhibit the pale cytoplasm with artifactual vacuolization and retraction, typically found in tissue fixed it formaldehyde. RJL 197-68 H A F.. X 800.
Fig. 3. An aggregate of lacunar type R-S cells in tissue fixed in Zenker’s solution have a narrow' peripheral, cleat zone: prominent granuia: cytoplasm; and a variable number of nuclei The distinctive cytoplasmic character of lacunar cells may be lost with Zenker s fixation RlL 93-, I H A E, X 800.
NOVEMBER 1971 P6:
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Fig. 4. L & H variant of R-S cell. These fragile polyploid cells have large, convoluted, twisted, overlapping nuclei with finely distributed chromatin, small nucleoli, and a small amount of pale, indistinct cytoplasm. RJL 165-71. H & E, X 800.
Fig- 5. Spleen. A minimal focus of involvement in the white pulp. Several multinucleated cells resembling R-S cells are found in a slightly enlarged Malpighian body in association with slight increase in reticulum. RJL 237-67. H & E, X 400.
1766 CANCER RESEARCH VOL. 31
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I ig. 6. A small focus ot Hodgxin s disease in the liver. Scattered iobated and multirrirEated cells are found in a discrete cellular focus exhibiting a prominent increase in connective tissue. LACH 70-5264. H & E, X 160.
Fig. 7. A focus of diffuse fibrosis in the hone marrow. Itie distinctive abnormal "precollagenous” character of the fibrous typical of this type is seen in association with R-S variants. RJL 79-71. H & E, X 500.
November 1971
- v . .
HISTOLOGICAL CLASSIFICATION :
The original classification It that of Jock ton and Parker (43) Into i -
Paragranulota
Granuloma
Sarcoma
Thlt classification It not «atldoctor/ became 90% of catet foil In the
granuloma group.
Luket and ButHer (44), Introduced a tubclanlflcatlon which wot modified
FEATURES
Abundant Lymphocytic ttroma tparte Reed-
Sternberg Cells.
Nodules of Lymphoid tissue of varying sleet,
separated by bands of collagen and contain
ing lacunar cells variant of R S Cells.
More numerous R S cells with pleomorphic
stroma rich In eosinophils, plasma cells,
fibroblasts and Lymphocytes.
Paucity of Lymphocytes, diffuse Irregular
fibrosis in some Instances bizarre anaplastic
R-S cells . usually numerous.
- 23-
at the Rye Symposium (45).
TYPE
Lymphocyte Predominant -
Nodular Sclerosis (NS)
Mixed Cetlufarlty (M C) -
lymphocyte depleted (ID )
TABLEBUTTLcK
ISON OF JACKSO N AN D PARKER (43), LUKES ANDAND RYE CLASSIFICATION (45) OF HOD G K IN S DISEASE
JACKSO N AN D PARKER LUKES AND BUTTLE* RYE
Progression of disease tends to occur from Lymphocyte prodominant to
Lymphocyte doplotod. Nodular Sderotis may represent arrest of the pro
gression related to host defence mechanism.
Lymphocyte predominance is strongly associated with clinical stage I and
II while lymphocyte depleted Is seen primarily with clinical stages III and
IV . Mixed CeJIuicrlty occurs In all clinical stages without any strong
associations. Nodular Selarosls Is associated predominantly with slogs II
and Involves mainly lower cervical nodes, mediastinum and oontlgous
structures. It occurs primarily In fe.rxdes and also has a younger age dis
tribution (46).
Best prognosis Is In lymphoeyto predominant, nodular sclerosis, mixed
- 34 -
cellularlty and lymphocyte depleted In that order (47) / ,. Absence of
clinical symptoms especially weight low and favor Is also of batter pro
gnostic value (49).
~ 25 -
TREATMENT »
Thera ore three established form* of treatment for Hodgkin1* disease
(o) Radiotherapy
(b) Multiple drug Chemotherapy
(•) Combi nod Kadiotherapy and Multlplo drug Chemotherapy*
A* discussed before, occurato staging I* aboolutoly Important for doddlng
tho farm of traatmont asocial I y In oontro* whore Radiotherapy I* avail able.
RADIOTHERAPY
This Is tho treatment of choice for stage* I, II and IILA. Previous studios
hove established the tymoffoidal ^om 1° ** between 3,500 to 4,000 rods
(50, 51). This dose was usually given over 3 -4 weeks; but recent studies
have shown administration over 6-8 weeks Is not only highly effective but
has markedly attenuated the acute end delayed normal tissue reactions to
Irradiation (52).
Radiation therapy Is often guided by and limited to the apparent extent of
Involvement clinically, followed by prophylactic extension to the contigous
areas (53). However releases often occurs on non-contigous areas. The
necessity for elective Irradiation of clinically unlnvolved contigous and
non-contigous regions was demonstrated by a prospective clinical trial par-
formed by the NaHonol Cancer Institute (54). The major advantage of
prophylactic total nodal Irradiation was the consequence of treating un
suspected disease In retreperitonial lymphnodes (which con even be missed
at laparotomy). In tho absence of prophylactic abdominal Irradiation,
extension of disease has boon documented In one third of cases (55).
- 2 6 -
Extensive prophylactic Irradiation alio Improves survival for patients with
histology othar than nodular sdarosls (54).
Total nodal Irradiation |$ howovor not roqulrod far ovary clinical present
ation, but factors such as primary sltoCs), prasonco or absonco of systomlc
symptoms, and histological classification should bo considered boforo a
decision Is made. Potlonts tolerance to Intensive Irradiation (56) has pro
mpted treatment of patients with stage IIIA and extra nodal Involvement
without evidence of generalised disease, with Radiotherapy. 70% 5 year
survival rates for stage IIIA have been reported from the National Cancer
Institute and In Stanford (54). Patients with localised extranodd Involve
ment provided It can be Included to Its full extent In the curative radiation
treatment, have same survival and cure rate os those with lymph node
Involvement of the same extent (57).
CHEMOTHERAPY
In Hodgkin's disease, chemotherapy Is ined for the treatment of the more
advanced stage IIIB and stage IV . However In centres where radiotherapy
Is not available, It Is used for all stages Including I and II.
Upto until 1963 chemotherapy consisted of single agents (either an alkylating
agent or a vinca alkaloid) complete remission however rarely exceeded
20% (19.
A pilot study with combination chemotherapy started In 1963 at the
National Cancer Institute showed that of the first 43 patients treated, all
responded but 33/43 (81 % ) achieved complete remission (59). The pro
- 2 7 -
gramme was modified slightly and began Its prsssnt farm of combination of
MusHno hydrochlorldo (or Cydaphoq»hamide), oncovlns, procarbazlno and
prod!mono MOPP or COPP (59). The rational# for using combination
chemotherapy Is that » -
(a) A|| agents used should hav# activity against tho tumour.
(b) A ll agents should hoy# dlff#r#nt mechanisms of action so as to delay
emergence of (bug resistant done.
(c) Toxicity should be dispersed among different organs and thus obviate
cumulative toxicity.
Details of the administration and toxicity are well documented (40). Table
I shows a single cyde of the combination drug progem. Each cyde Is
given ever 2 weeks followed by a 2 week rest Interval before Institution of
the next cyde. The therapy therefore consists of 6 cycles In 6 months.
Haematol ogled status of tho patient eqieddly the white blood cells and
thrombocytes should bo assessed before each cyde Is started.
TAftLEI.
DRUG DOSE ROUTE SCHEDULE
Nitrogen Mustard* 6 mg/m I.V Day 1 and Day 7
Vincristine (onoovfno) 1.4mf/m2 I.V Day 1 and Day 7
Procarbazine lOOmg/m2 P .O 14 days
PrecHnsone 40 mg/m2 P .O 14 days
Can be substituted for Cydophiqphamlde at 650 mg/n? especially In
patients who develop thrombocytopenia.
The limiting foe ton In this form of troatmont U uwolly loukaponto ond/m
thrombocytoponio (l.o . Bono Morrow doproodon), This occurred In 20}*
In Oo Vital (BO) series. Nausea and vomiting alopecia, ond neurotoxity
aro novor saver* enough to warrant stoppage of treatment. Alopecia ond
neurotoxicity aro always reversible aftar #10 potlont finishes troatmont.
Patients who rolapso aftar troatmont Ota successfully troatad with tho sam*
regimen.
Soma contra* havo mod tho sam* rogfmon but substituting Vlnblastlno
(which It mart nouro toxic) for VlncrlcHno. In ono such study, Nicholson
(B1) obtainoda complete romltslon rata of 8 6 # . It Is no doubt tharaforo
combination c ho mo tho ropy has groat! y Improved tho outcomo of potlont*
with advanced Hodgkin's d io o » .
* 29 -
COMBINED RADIOTHERAPY AND CHEMOTHERAPY
The Indications for combination of radiotherapy and chemotherapy era (52) i -
(e) Potentiation of radiation effect for better tumour shrinkage In cer
tain rad stent tumour or for those recurring within a former therapy
port.
(b) To allow lower radiation dosage during therapy of tumour In organ
easily damaged by x-rays e .g . lungs or kidneys.
(c) During Initial therapy to stage IV patient with a dominant tumour
mass In one area which can be treated locally followed by tehemo-
thorapy for the smaller disseminated foci.
(d) Before radiotherapy to shrink huge messes to allow more reasonable
X-ray port slxe e .g . mediastinal tumours.
(e) As medical decompression on an emergency bases for obstructure
synsbomes of venae cave, spinal cord or airways prior to radiation.
(f) To control systemic symptoms e .g . fever prior to radiation.
Moore (63) randomised 102 untreated patients with Hodgkin's disease stages
IB ^ HIB t one group received total - lymphoid radiation, and the second
group received total-nodal radiation followed by 6 courses MOPP. Over
4 years the group which hod received radiation alone had 10 relapses while
the combined radiation and chemotherapy group hod one relapse. The
probability of disease free survival was also significantly Improved (p<0.01)
In the combination group ; however actual survival was not significantly
Improved (p » 0.10). The MOPP was well tolerated by the patients who
had recently received total lymphoid radiation.
- 30 *
The rld< of relapse of patients with stage I and II It approximately 20/4 In
the first year. 15/ the wcond year and 5 - 10/4 In the third year. Far
patients with stage III and IV , there Is a similar sharp decrease In the rldi
of relapse from the first to the third year. For patients treated with radio
therapy, relapse If It occurs, Invariably occurs In non-Irradiated site(s).
In contra* relapse following chemotherapy occurs In tumour that has been
*---- a- -IIIVQTOO e
The relapse free Interval (In radiotherapy treated patients), may be
Influenced by the hlstapathologled type af Hodgkin's disease. Thus
Fuller (45) found lymphocyte predominant Hodgkin's disease Is cytaklnetlodly
slow moving, and late relapses Is more common than for mixed and nodular
sclerosis.
Information on survival Is largely obtained from End Results Section of
National Cancer Institute (64). The risk af death from Hodgkin's disease Is
about 15% In the first five years after treatment and 10 - 5% after 4 years.
No death occurod from Hodgkin's disease after tho 20th year. There Is there
fore a decreasing risk of death from Hodgkin's disease with time, but cure
(as defined by Easson and Russel (47) "We can peak of cure when In time -
probably a decade or so after treatment there remains a< group of dlseaee-
£e free survivors whq'progresslve death rate from oil causes Is similar to that of
a normal papulation of the seme sex and age constitution") by our daft nation
does not occur until after the 20th year.
*ELA£$E RATE, SURVIVAL AND CURE OP HODGKIN’S DISEASE (64)
-3 1 -
IMMUNOLOGY OP HODGKIN'S DISEASE «-
In 1902 Reed (68) noted tuberculin wos given In fly* (out of eight) cam
without reaction. It waa net however until 1932 when Porker (69)
suggested the negotlve tuberculin teats even In the presence of tuberculosis
wos as o result of an abnormal Immune response. It has since been shown
that patients with active Hodgkin's disease have Impaired delayed cell
mediated Immunity (70). Further It has been shown peripheral blood
lymphocytes from untreated patients ere deficient In their vivo function as
measured by their capacity to form I rosaottos with sheep erythrocytes (71).
Bcbrove (72) showed that the Impaired Immune response In patients with un
treated Hodgkin's disease could not be attributed to a quantitative deple
tion of circulating T lymphocytes and that the Impaired E cassette formation
could be restored to normal levels by Incubating overnight the peripheral
blood lymphocytes In tissue*culture medium containing fodtol serum (73).
When the restored lymphocytes were Incubated In serum of patients with
untreated Hedgfdn's disease, their E rossetfe forming capacity wos
suppressed, but when Incubated In serum from normal subjects, no rappre-
nlon was observed. This finding therefore suggested that there wos a specific
Interaction between serum factors and the surface of peripheral blood T
lymphocytes In Hod^tln's (disease (74).
Grifont (75) stated that antiymphocyte aufo- ontfbodles present In serum and
lymphnoda extracts obtained from patients with Hodgkin's disease, could be
detected on the surface of peripheral blbod lymphocytes. He further obser
- 32 -
ved that the antibodies Inhibited the response ia f' the lymphocytes to
phytohemoagglutlnln (76).
Chfsart and Edglngton (77) Isolated a low density lipoprotein from the
sorum of patients with hepatitis B virus Infection that reduced the capacity
of peripheral blood lymphocytes from normal doners to form E rossettes.
Hodgkin's disease rosette Inhibiting factors also hen boon found to bo a
component of the low-density lipoprotein fraction (74) other than In the
purified Immunoglobulins fraction of the serum as found by Longmlre 9taial (78). This field of Investigation Is new and further research is still
going on.
- 3 3 -
A FIVE YEAR (JANUARY 1973 - DECEMBER 1977) RETROSPECTIVE STUDY
AN D TW O YEAR (JANUARY 1974 - DECEMBER 1977) EXPERIENCE IN THE
TREATMENT OF ADULT ( 13 YEARS) HO D G KIN 'S DISEASE IN
KENYATTA N A TIO N A L HOSPITAL
MATERIALS AND PATIENTS
Th» Konya Canau Roglstry (leapt by the Daportmant of Pothology of the
Uni vanity of Nairobi) was scrutinised. The number of oil patients with
hltfaleglool confirmation of Hod^cln's disease was obtained. This was
divided Into portents below and above 15 years of age. The available case
notes of patients treated initially at Kenyatto National Hospital wore
obtained from the Records Office and the following parameters analysed :
age, sex, presenting symptoms, duration of symptoms prior to hospitalisation,
slte(s) of presumed tumour Involvement, treatment given and subsequent
For the clinical staging, the modified Peters Creterler (20) was used. Lukes
and Buttier classification as modified at the Rye Symposium (45), was used
far tha Mstopathologlaol classification.
During the period January 1976 and Deoambar 1977 I personally participated
In the treatment of patients who still umre attending the haematology clinic
on outpatient basis. The side effects and reqponse to combined drug chemo
therapy noted during that; period will be dlscumed later.
RESULTS
Hftfology reports of tha period between January 1973 and Deoambar 1976
34
w o t complete. These reports represent biopsies token from oil over
Kenya and sent to Kenyotta National Hospital. A ll biopsies serf from dbroad
w o t not Included.
Approximate ly 39 patients are diagnosed every year and 0 % of these ore
above 15 years of age (table I).
TABLE I
Y tA i 1973 1974 1975 1976 Average 96
A g ^ Y n . N o. * N o. % No. 96 N o. 96
^ 15 11 29.8 7 18.4 13 30.9 17 44.7 30.9
> 15 26 70.2 31 81.6 29 69.1 21 55.3 69.1
TO TA L i 37 100 38 ,00 42 100 38 100 100
Plies of 49 patients were available In Kenyotta National Hospital records
for detailed analysis. There was varying degrees of non-uniformity In Hie
patients' records, but most parameters wore recorded and available for
analysis.
Mean ago of the patients was 31 yean and the range was 15 - 74 yean.
There ware 37 male cases and 12 female oases, similar type of mole pre-
poderence Is found both In African (79) and European communities (60).
The mean duration of symptoms before presentation to hospital was I I
months. The range was 2 - 60 months.
35-
T / B ig II (Shows « Summary of Presumed Tumour Involvement)
LYMPHADENOPATWY.
SITE N O . PATIENT * OP TO TAL
N iC K * 40 •2
IN G U IN A L to 47
AXILLA V 55
EPITROCUAR % 4
MEDIASTINUM $ 10
IN TR A -A ID OM lNAL^ 5 10
EXRANQPAL
lONE(STERNUM ) 1 2
LU N G 1 2
l iv e r ’ 10 20
s p l e e n " 14 I t
NECK* * includes cervical, submandibular, supradarlcular
oach alono or in combination
IN TR A -A iO O M lN A l* -
LIVER* Js r u in I
Two patients had memos of glands around tho
caoaum with Involvement of InfosHnal nuuasa
Thrao had rolro^orlfonlal lymphadenopathy
in m d im w ifi |usf pmumKi to d# invoiwJ
without histological proof.
Among tho symptoms, favor and loos of wolght worn tho two comma
complains os dtown bolow In table lit . five of tho 49 patients had no
comment mod* on the B symptoms and therefore are not Included In the
table.
TABLE III, (Analysis of the I Symptom In 44 patients)
SYMPTOM N O . %
Fever 35 94.5
Weight loss 1* 43
Diaphoresis (night sweats) 9 20
Pruritus 4 9
Note » Anaemia of less then 10 ern% occurred In 36% of the patients at the
time of presentation to Hospital. In most cases this was not Investigated. It
Is likely therefore that It was either pert of the disease or due to underlying
la cta tio n .
Table IV shows the clinical stages In 47 of the 49 patients. Records of two
patients did not show enough Information for staging. This staging Is strictly
based on a thorough clinical examination and thorough history from tho
patient. Enlarged Liver or Spleen was presumed to be part of tho disease.
Only 6 patients (12$o) underwent <flagnostic iqparatomy. This Is an In
adequate way for accurate clinical staging as was discussed In the review of
literature
TABLE IV ( Clolnfal staging)
STAGE N O . %
1 10 21.3
II 4 8.5III 21 44.7
IV 12 25.5
- 37-
A ll the patients with stage III and IV had 'B' symptoms; while only two
patients had 'B' symptoms In stages I and li.
TABLE V (Shows the Histological Classification of Adult Hodgkin's Disease In Kenyutta National Hospital compared with some Results from Uganda and U .S .A .)
Kenyatta National Hospital Uganda U .S .A .
39 cases> 15 yrs. 18 cases > 15 yrs . Review of 377
Histological Type N o. % %
cases by Lukes &
Bottler (44)%
Lymphocyte Predominant 8 20 0 16
Nodular Sclerosis 8 20 11 40
Mixed Cellulartty 14 37 50 26
Lymphocyte Depleted 9 23 39 18
Note i 10 patients in this series (20^6 of the original 49 patients) were not
classified In any of the four classes above.
All patients with H .D stage I and II were treated with Radiotherapy while
those in stages III and IV were treated with either MOPP or COPP (59).
Table VI shows the drugs, dosages, route of admtnlstralon and schedule used
for chemotherqay. The therapeutic aim was to administer 6 courses at 4 week
Intervals.
TABLE V I.
DRUG DOSE ROUTE SCHEDULE
Nitrogen Mustard* 6mg/m^ I.V Day 1 and Day 8*
VInctrlstine (oneovine) 1 .4mg/m^ I.V . Day 1 and Day 8
Procarbazine (Methylhydrazine) 100 mg/tr? P .0 14 days
Predlnsone 40 mg/m* P .O 14 days
+When Nitrogen mustard was not available, cydophlsphamtde (650
was given.
* wcond doses of Nitrogen mustard and oncovlne whore given on Hw 7th day because haematology ailnlc Is run once In a week (on Mondays)
Predinsone was given with courses one and four*
The patients who received radiotherapy had 4,000 rads to the tumour site
plus the contfgous slta(a).
In a ll, 33 patients received chemotherapy and 14 Radiotherapy. The
results of treatment are shown In Table V II.
TA B U VII
MODE OF TREATMENT COM PUTE REMISSION PARTIAL REMISSION DIED*
No. f t N o. f t N o. ft
Chemotherapy 25 76 4 12 4 12
Radiotherapy 10 71.4 P 14.3 l 14.3
*4 patients died while on chemotherapy . 2 'died of tuberculosis > 1 of
pyogenic meningitis and 1 of disseminated disease.
2 patients dtedfavhile on Radiotherapy. I patient had mediastinal lung
Involvement and died following thoracotomy after airway obstruction.
The other had recurrence of disease on nonHrrodlated areas and died despite
being put on Chemotherapy afterwards.
The summary of the d in lc d data of the patient whom I treated bO tween
January 1976 * December 1977 Is shown In appendix I. Most of the
cllnicsd data axoept the complication has boon analysed with the other
- 3 9 -
patients studied. Table VIM shews a su< nary of the complications In the
11 patients
ta b l e vim
LEUKOPENIA* ALOPECIA4 PARA ST REDUCI LEXES
NESIAS v rD REF-
V O M ITIN G 4
N e. % N o. % No. % N « . %
1 9 3 27 8 73 3 27
The leukopenia was so severe that the treatment had to be discontinued and
patient admitted for blood transfusslons.
^These side affects were minor and treatment was continued to completion.
Patients who were vomiting were given 5 mg of stemotil 30 - BO minutes
before drugs were administered and 5 mg eight hourly for 24 hours thereafter.
No vomiting was recorded with this regimen. Alopecia el ways recovered
after the end of treatment.
• 40 -
DISCUSSION AND CONCLUSIONS
The commonest mode of presentation In Hodgkin's disease Is painless
lymphadenopathy. This has been supported by a study In Ugandan patients
(7 9 ); and an earlier study In Kenyan patients In Kenyatta National
Hospital (16). The commonest site of Involvement as shown In this study
(Table II) Is the neck (82% of the cones).
Patients In Kenya tend to present late with wide spread disease. The
average duration of disease before presentation In this study Is 11 months.
This Is similar to what Olweny (79) found In Ugandan patients. In the
Ugandan series, 83% of the patients were stage IV while In this study the
percentage of stage IV Is low (Table IV ). This discrepancy Is likely due to
the fact that more Investigations (skeletal survey, Intravenous pyelography,
cavagraphy, per cutanea* liver biopsies, bone marrow examination) were
done for clinical staging than In this series. Exploratory laparotomy was
done In 6 (4...8/0) out of the 14 patients in stages I and II.
Hlstopathologlcal analysis reveals an excess of the more malignant mixed
cellulanty and lymphocyte depleted type (Table V ) unlike the experience
reported from U .S .A .(4 4 ). Though, the pattern Is similar to that found In
Uganda (79), this series show 20% of the lymphocyte predominant type
(Table V) while there was 0% In the Ugandan series.
The results of both multiple drug chemotherapy (76% complete remission rate)
and Radiotherapy (71% complete remission rate) are encouraging. The
results are similar to the overall 76% complete remission rate obtained In
-41
Ugandan patients using multiple drug chemotherapy alone j and oomparable
to the results (84 4) of De Vita and Ms colleagues (40). It Is to be
remembered however that accurate staging leading to the correct choice of
treatment Is Invariant In determining the type of results one will get. There
fore with careful staging our results In Kenyatta National Hospital can be
definitely Improved.
The toxicity encountered In this study Is similar to that described by De Vita
(40) but bone marrow depression was less common 9% than In De Vita's
series (20/4).
To determine survival end cure rote as described In the review of literature,
protracted and careful follow up Is necesscry. The follow up of patients In
tMs study was short, but if continued long enough survival and cure rotes
may be determined later.
In conclusion I would like to point out that we have all the facilities
required to start an Integrated centre for the treatment of all malignancies
(Including Hodgkin's disease). A depart; ant of Oncology (though It r.;lght
seem an ambitious Idea) should be seriously considered. It Is my belief
that. If we pool oil our resources and ddlls together better results In the
treatment of all forms of malignancies will be realised.
-42
APPENDIX I tHAEMATOLOG1CAL STATUS C O M P L 1 C A T 1 O
----------fc-N S
Duration before Presentation in Months
. r Beginning of £ End of *Anoemiaor /ond Leuko- pema
Parosthe-
No.a 9«/Sex
ClinicalStage
SystemicSymptoms
Site(s) of Presumed Tumour
HistologyType Laparotomy
Response toCOPP/MOPP
ThiozinaSteptomy-cin Relapse
HBgms%
WBCxlO3 HBgnss%
WBCxlO3SurvivalMonths Alopecia
sthesiaDiminishedReflexes
NouseoVomit-ting
1. I9M 1113 F, NSW, WL C,A X,Sp. 7 MC YES CR N O . 14.4 14.0 14.8 7.9 18 N O N O YES N O
2. 24F 1113 F,NSW,WL C.AX.Ing 12 NS N O CR YES - 12.0 13.6 13.0 7.0 22 N O N O N O N O
3. 4GM IVB F.Pru C,AX,lng,8M
12 NS N O CR N O - 12.8 10.2 11.6 7.7 14 N O N O YES N O
4. 16F 1113 F - £ * * * & ■ 4 NS YES CR N O _ 12.8 4.3 13.4 7.7 30 N O N O N O N O5. 23P ll!B F c , i 24 LD NO CK N O . 10.0 7.1 13.2 9.1 21 N O N O YES N O
6. 22M IIIA * AX,I,RP 7 MC YES CR N O Yes after 9I l lU t l i l l k
14.9 10.4 14.8 5.5 21 N O N O YES N O
7. 2AM II1A - c , a x ,kp 3 IP YES* CR N O - 11.9 5.7 14.9 3.0 6 N O YTS YtS YTS8 . 4«M IIIR F.N9W , Wl r ,A X ,l ?/.0 1 P N O CR YTS - in l 4.4 13.7 31 NO N O YTC NO*). I V lilt F C,I,/AI) 10 1 P NO PR* NO - 11.4 7.4 - 2* N O N O N O N O!V. leJ IV& f,V/L C, AX , lug 11, *r 1 1 LI* y l :» I'K* NO - U. 1 2.0 - 4* YLS YtS YLS YL^
ii. l i f IV# F, Wl,Pru C, AX/Li/t«tsi IIUlii 2 LD N O CR YES Yo.
iiliai j14.0 8.6 3.3 5.2 12 N O YES YES YES
weak)Average 24 14 [TZ418.T 1.4 "578 "1675F*
N?JVWLPro
- r«v*r■»* Night Sweats- Weight Lots = Pruritus
C. “ (jarvicnl AX - Axillary Sp. = Spleen LI = Liver
InfjMDMC = NS -
Inguinal Mwliuinwn Mixed Ccllularity Nodular Sclorosis
nicPR
“ 1 ymj»l»ory|o Ptndniuinont 1 yinpliiv.yln D«|*ln|oc|= Complete Remission = Partial Remission
*Thi» patient Itm nut completed iho »U courses.
Patient very sensitive to MOPP/COPP. Hod frequent transfuulon*. Last seen 4 months ago. Presumed dead.
f ; remcioM : Mule
ACKNOW LEDGEMENT I
I wish to express my si homo appreciation and thanks to tho following t -
1. DR. O G A D A , T . , M .B .C H .B <EA), M .R .C .P . (UK) D .T .M . & H
(LO N D O N ) for Ms encouragement, guidance and supervision.
2. PROFESSOR K U N O U , A . , M .B .C H .B (EA ), M .R .C . PATH, for
Ms permission to uso tho Konya Cancer Registry.
3. MR. M . M UHINJA of the Konya Cancer Registry.
4. The Sister (,/c and all the nurses who help In the Hoematology Clinic
of Kenyotta Notional Hospital.
5. MRS. NDEGWA and all the staff of Kenyotta National Hospital
Mhdlcal Records Department.
6 . All the patients I was treating • for their cooperation.
- 4 4 -
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45
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