Clinicopathological Conference
HODGKIN'S DISEASE WITH IDIOPATHIC HEMOCHROMATOSIS Lt Col GU DESHPANDE·, Lt Col AC ANAND Col RAMJI RAI+
VSl\l
#,
MJAF11998,54 : 247-252 KEY WORDS: Hodgkin's disease; Idiopathic hemochromatosis
Clinical History
A
47-years-old male presented to a Military hospital in December 1989 with six weeks history of easy fatiguability, palpitation, dyspnoea and giddiness and two weeks history of intermittent bleeding per anum. Past medical history revealed that he had felt a soft mass protruding per anum for previous one year but had never noted bleeding till two weeks back. In addition, five years back he was found to have tender hepatomegaly and was given some oral treatment with a provisional diagnosis of hepatic amoebiasis. Family history did not reveal any significant illness in parents, siblings or children. Clinical examination at the time of hospitalisation showed marked pallor and palpable lymph nodes in right axilla, posterior triangle and inguinal areas. Fundus exam ination showed few soft exudates and flame shaped haemorrhages. He was afebrile and normotensive. Cardiovascular, respiratory and central nervous system examination was within normal limits. Liver was palpable 4 cm below costal margin and was soft with smooth surface. Spleen was not palpable and there was no shifting dullness. Investigation results at this stage showed Hb 6.8 gm% , TLC 32000/cu mm, DLC P 18%, L 80%, M 1%, E 1%, platelet count 2 lac/cu mm, bleeding time 2' 5", clotting time 5'-30". Peripheral blood smear showed marked anisocytosis & poikilocytosis. Majority of cells appeared microcytic with numerous ovalocytes, schistocytes and acanthocytes & a few target cells and about 20 % smudge cells. Coomb's test was negative, reticulocyte count 2.7 % (corrected 1.3%), PCV 20%, MCH 30pg, MCHC 34% and MCV 91 fl. Serum Iron 8! ug/dl. Test for total iron binding capacity was not done. Serum bilirubin 0.5 mg/dl, SGOTISGPT 26/20 lUlL. Serum alkaline phosphatase 63 lUlL, serum proteins 6.3 gm/d1. AG ratio 4.7/1.6, Urine routine examination was normal, urine specific gravity 1022, blood urea 30
mg/dl, serum creatinine 1.2 mg/dl, serum uric acid 5.3 mg/dl, blood sugar (random) 92 mg/dl, stool for occult blood was negative. Electrocardiogram was normal and so was X-ray chest (PA view). Ultrasound of abdomen showed enlarged para-aortic nodes and hepatosplenomegaly. Montoux test showed 7 mm induration after 72 hours. Lymph node biopsy showed feaof Hodgkin's disease (Lymphocyte tures predominance) and the patient was transferred to this hospital. Further investigations showed that haemoglobin had not changed much inspite of over 5 units of blood transfusion within 5 days. Bone marrow examination (aspiration and biopsy) showed hypercellular marrow with focal infiltration with Hodgkin's disease. Sigmoidoscopy confirmed clinical suspicion of hamorrhoids which were not bleeding but were ligated. A clinical diagnosis of Hodgkin's disease (lymphocyte predominance) stage IV B (due to weight loss) was made. His weight was 70 kg, height 167 cm & performance status 60 %. He was advised standard chemotherapeutic regimen COPP alternating with VAD. Over next 18 months he received 8 cycles ofCOPP, 4 cycles of VAD and imperically levamesol therapy. He was also given 37 units of blood transfusion to maintain his haemoglobin level within reasonable limit. By the end of 1991 he became asymptomatic, lymphnodes were no more palpable, performance status improved to 90 %. Haemoglobin now was 13 gmldl. TLC and DLC were now normal though bone marrow continued to show focus of Hodgkin's disease. He was now HbsAg positive and S. bilirubin was 1.5 mg/dl (delayed positive van den bergh reaction). He remained stable during 19n but in May 1993 he again presented with severe anaemia. Clinically lymph nodes were not palpable, though liver was palpable 14 cm below costal margin. Haemoglobin was
'Reader, +Profcssor and Head. Department of Pathology. #Reader. Department of Medicine. Anned Forces Medical College. Punc-40.
Deshpande, Anand and Rai
248
found to be 7 gm/dl and tests for liver and renal function were normal. Electrocardiogram done at this stage showed increase in LV size, and impaired LV function (ejection fraction was 56%). Bone marrow examination showed presence of Hodgkin's deposits. With clinical diagnosis of relapsed Hodgkin's disease, he was treated with blood transfusions and cycles of COPP + ABV. With this salvage chemotherapy (5 cycles) he again improved. Bone marrow biopsy at the end of therapy was free of Hodgkin's disease. He was diagnosed to have achieved remission again. He remained stable for about 8 months and again presented in late 1994 with severe anaemia (Haemoglobin 4 gm/dl). Hepatomegaly was persisting' as 'before and bone marrow biopsy showed infiltration with Hodgkin's disease. He continued to be HbsAg positive. With a clinical impression of relapsed disease he was again started on salvage chemotherapy cycles of CEP (CCNU 3 capsules on day I, etoposide 200 mg on day I to 3 and 100 mg on day 4, prednisolone 4 mg 8 hrly and chlorambucil I mg BD) on day I to 5. He required blood transfusions to support his haemoglobin levels. After 3 cycles of chemotherapy he was noted to have hyperglycaemia (blood sugar fasting 232 mg/dl, post-prandial 513 mg/dl). In response to this development, steroids were withdrawn and oral hypoglycaemic agents were added.' He continued to require blood transfusions/packed cells for his anaemia. After 5 cycles of CEP, he again became stable and bone marrow biopsy sho~ed no evidence of Hodgkin's disease (July/Aug95). Lastly, he reported on 25 Sep with severe anaemia, breathlessness and fainting episode. He died within one hour of coming to the hospital. During this one hour only test done showed haemoglobin level' of 3 gm/dl, TLC 19,200/ cu mm & DLC P24, L71, M2 E2.
Clinical Discussions (Lt Col AC Anand) The clinical course of this patient can be as shown in Fig-I. There are 5 questions that need to be answered. 1. Did lie lias Hodgkin's disease? Clinical profile of this case was in favour of NonHodgkin's lymphoma in view of onset with disseminated disease, presence of predominantly extra nodal disease for most of the time, absence of mediastinal glands, presence of abdominal glands and specially two features namely bone marrow involvement and spillover into the peripheral blood [I]. However, Hodgkin's disease per se is a histological diagnosis. Histological subtype of lymphocyte predominance
10
"
Fig. I: Diagrammatic summary 111'1.:\ ellis over a period of 6 years of tollow-up. Horizontal axis shows the calendar year of the disease. Shaded bars show patient's hemoglobin levels in gldl, while clear bars indicate total leucocyte count in thousands per cu mm. The + or - signs in a circle denote if the bone marrow examination showed infiltration by the Hodgkin's lymphoma. 'Chemo' denotes the period of chemotherapy and the inverted arrows at the top of the figure represent the blood transfusions given to the patient.
which is usually a localised disease and rarely if ever involve bone marrow. Moreover the RS cells have been reported as numerous in some reports while usually they are scanty and difficult to locate in lymphocyte predominance variety.
2. Cause ofsevere anaemia in Hodgkin's disease? Anaemia is found in minority of cases with Hodgkin's disease at presentation and is generally mild and nondescript [2]. However, the bone marrow involvement is seen only in 10% cases with Hodgkin's disease and in one series (where none of patients had lymphocyte predominance Hodgkin's disease) frequency of anaemia was not affected by bone marrow involvement [3]. Anaemia of malignancy is rarely severe and is associated with low serum iron binding capacity with increase marrow iron stores. The latter two tests have not been carried out in this patient. Two additional possibilities are hemolytic anaemia and Clevelopment of a second malignancy in Hodgkin's disease. Hemolysis·.is .known to occur in about 10% patients with Hodgkin's disease. Initial peripheral blood picture was highly suggestive and serum bilirubin was reported to be marginally raised (and delayed positive for van den bergh reaction). Erythroid hyperplasia has also been reported on two bone marrow specimens and I noted on one occasion haemoglobin levels failed to rise above 6.8 gm/dl despite five units of blood transfusions over four days. AUAI·." VOl. 5-1. NO J. /991f
249
Hodgkin's Disease with Idiopathic Hemochromatosis
This kind of picture (in absence of active bleeding) strongly suggests hemolytic process. A negative report of Coomb's test in beginning does not support this diagnosis. Therapy related myelodysplastic syndrome (tMDS) and therapy related acute myeloid leukaemia (t-AML) are common complications of treated Hodgkin's disease. The average risk of 5-1 0% after 5 years may be still higher in males over 50 years of age [4]. However this diagnosis is apparent on bone marrow biopsy and not reported as late as July 95. 3. Wllat was tlte significance ofIIepatomegaly? Liver involvement in Hodgkin's disease is proportional to the splenic involvement [1]. Spleen was not palpable in this case and showed only marginal increase in size. In any case, liver involvement is uncommon in lymphocyte predominance variety. Liver biopsy was not done in this case, which was reported yield of 2-5%, though with the use of immunoperoxidase staining for CD markers (15,30,45) the yield may be higher. HBV infection may be a cause of hepatic enlargement as this individual was found to be HbsAg positive. Markers of viral replication were not tested. A liver span of 20 cm raises a possibility of iron overload. This patient was given 67 units of blood transfusion (iron content 7-10gms) and oral hematinics (approximately 18-20 gms over 6 years). So over six years period, he had positive iron balance of approximately 30 gms which can cause significant liver enlargement as well as some degree of organ damage. Serum ferritin measurements and MRI scan of liver are two non-invasive tests whicll could prove this diagnosis [8] but were not done in this case. 4. Wltat callsell caTlliomegaly? Echocardiographic studies in this case indicated significant myocardial dysfunction and terminal event appears to be cardiac failure precipitated by severe anaemia. By the time ECG was done, he had received 91 mg of cumulative adriamycin dose, which is an unlikely cause of cardiotoxity [4]. Significant cardiotoxity usually appears after 200 mg of cumulative dose has been given. An unrelated disease like coronary artery disease is not uncommon, at this age though resting ECG has not shown any significant abnormality. Transfusional iron overload or secondary hemachromatosis can also cause cardiac dysfunction and remains important possibility. Lastly, severe anaemia can rarely cause cardiac failure [5], though this patient had almost normal haemoglobin at the time when echocardiography was done. Af.I.4H
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5./, 1\'0 J. /998
5. Wllat caused Non-insulill llepellliellt lliabetes mellitus (NIDDM) ? NIDDM is a common disease which has a prevalence of 6-8% in Indian population. This patient had no family history and he was non-obese. It would be related to prednisolone therapy. However withdrawl of prednisolone did not lead to remission in this case. The possibility I will like to consider is again iron overload which can cause pancreatic damage and diabetes mellitus. Conclusion Although the clinical pattern of disease in this case was more like a Non-Hodgkin's lymphoma, I am in no position to doubt the diagnosis of Hodgkin's disease given by the histopathologists. Here again, clinical pattern of early bone marrow involvement is unusual for lymphocytic predominance variety. Repeated blood transfusions, appearance of hepatomegaly followed by cardiac dysfunction and diabetes mellitus strongly suggests, to my mind, the possibility of secondary hemochromatosis. Final diagnosis: (1) Hodgkin's disease - Lymphocyte predominance (2) Secondary Hemochromatosis Discussion Col RK Gupta: May I know the HIV status? Lt Col AC Anand replied that HIV status is not known as no investigations on these lines were carried out. Brig SK Basu: It was stated that onset of the disease was in Dec 89. May I know the basis of diagnosis in MDTC in CH(SC), Pune? Lt Col AC Anand replied that old slides of Iymphnode biopsy were reviewed and diagnosis of Hodgkin's disease (Lymphocyte predominance) was confirmed. Lt Gen R Jayaswal, AVSM, PHS: The initial diagnosis of Hodgkin's disease was based on lymph node biopsy but clinical features at the time of presentation & in the follow up period are different than the usual picture of Hodgkin's disease lymphocyte predominance, hence May I know the results of repeat lymph node biopsy if it was performed any time after the initial diagnosis? Lt Col Anand replied that as the lymph nodes disappeared after the initial chemotherapy, repeat lymph node biopsy could not be performed. Lt Col Kumud Rai: If USG abdomen was performed, what were the findings? Lt Col AC Anand replied that it was repeated several times but only
250
minimal hepatomegaly was splenomaegaly was also detected.
Deshpande, Anand and Rai
observed
and
Col RK Gupta: It was stated that the patient received 200 mg tablet of iron and hence only 20 mg iron must have been absorbed. Each iron tablet contain 40 mg of elemental iron, therefore the individual received only 4 mg of iron per day. Therefore, calculations that he received 20 mg iron per day does not stand to logic. Lt Col Anand replied that individual was given 6 tablets of iron per day hence I calculated that 20 mg of iron was given per day to the individual. Col R Rai : You have given detail calculations about the iron received by the individual since onset of disease till his death through oral iron and through blood transfusions, May I know the results of serum iron or any other iron studies which were performed.? Lt Col AC Anand replied that the serum iron was done only once initially and it does not appear to have repeated any time after that.
Fig. 2: Hemosiderin gmnulcs in hcpatocytcs. "uplli:r cells n'ce x 500
Pathology Protocol (Lt Col GU'Deshpande) A complete autopsy was performed. On external examination of the body, marked pallor, loss of body and pubic hairs and smaller and soft testes were observed. Straw coloured clear fluid was hoted in pericardiac, pleural and abdominal cavities. I. Lymph Nodes :The paratracheal, hilar and paraarotic nodes were moderately enlarged and cut surfaces were fleshy. Microscopically the architecture was effaced and there was diffuse infiltration of mature lymphocytes admixed with variable number of benign histiocytes. Occasional RS cells and Hodgkin's cells were seen. Golden brown pigment seen was detected to be hemosiderin on Perl's Prussian blue reaction and was seen in sinusoidal lining and also in macrophages lying in sinusoidal I,umen.
2. Liver : Weighed 2500 gm. External surface showed micronodules. The colour of liver was coppery red and cut surface was unremarkable. Microscopically fibrous bands connecting one portal tract to another were seen which at places were totally encircling the lobules. However no regenerative nodule was seen anywhere. Hemosiderin pigment was seen infiltrating the liver in form of fine granules as well as in aggregates. The pigment was predominantly hepatocellular and an occasional kupffer cell also showed the pigment. Few of the hepatocytes showed microvesicular fatty change. Portal tracts showed mononuclear cellular infiltration but no Hodgkin's deposits were seen (Fig 2-3).
Fig. 3: Hemosiderin in hepatocytes and kuplTcr cell in thc centre is totally free of hemosiderin x 500
3. Spleen: Weighed 325 gm. Cut surface showed marked congestion. Microscopically red pulp was suffused with blood and white pulp was obliterated. There were nodular hemosiderin deposits in capsule and sinusoids (Fig 4-5).
4. Pancreas : Weighed 150 gm. Cut surface showed dark coppery red colour. Microscopically marked fibrosis and hemosiderin deposits in acini and islets of Langerhans were seen (Fig 6). 5. Gastrointestinal Tract: Showed no abnonnality on gross examination. Microscopically hemosiderin deposits were seen in superficial mucosal epithelium of stomach and in villi of small intestines. 6. Heart and Aorta : Heart weighed 450 gm and was globular. Thickening of left ventricular wall (20 mm) and interventricular wall (12 mm) was noted. Microscopically diffuse interstitial fibrosis around the vessels and marked subendocardial fibrosis in apex of heart along with hemosiderin deposits in myocardial .\I./A/o"I. IW. 54, NO 3.
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Hodgkin's Disease with Idiopathic Hemochromatosis
251
tiny whitish nodules all over lung fields were seen. Microscopically bilateral pulmonary edema (predominantly basal), accumulation of hemosiderin laden macrophages and patchy interstitial fibrosis was seen. Fibrotic nodules with granular deposits spread all over lung fields were noted. 8. Endocrines: The gross examination of adrenals and thyroid did not reveal any abnormality but microscopically hemosiderin deposits were seen in adrenal cortex and in thyroid. 9. Kidneys: Each kidney weighed 150 gms. The surface showed fine granularity. Microscopically glomeruli showed wide spread thickening of capillary BM and increase in mesangial matrix. Few of the glomeruli showed obliterative diabetic glomerulosclerosis. Tubular basement membrane, arterioles and smaller vessels also showed thickening. ~xternal
Fig. 4: Hemosiderin granules in capsule of spleen . x 500
10 Testes: Testes were smaller and soft. Microscopically thickening of tubular basement membrane was seen. The tubules were lined by settoli cells only. No spermatozoa were seen. Patchy interstitial fibrosis was present.
1,. Bone Marrow: Showed hemosiderin and Hodgkin's deposits.
SALIENT AUTOPSY FINDINGSI. Hodgkins deposits lymph nodes, bone marrow. Fig. 5: Hemosiderm deposits in nodular form in sinusoids x 1000
2. Hemosiderin deposits - Liver, spleen. pancreas, adrenals, thyroid, heart, aorta, lungs, small intestine. 3. Marked fibrosis- liver, pancreas, lungs 4. Diabetic nephropathy 5. Cardiomyopathy (Secondary) 6. Chronic venous congestion spleen and lungs
FINAL AUTOPSY DIAGNOSIS Hodgkin's disease (Lymp.hocyte Predominance) Idiopathic hemochromatosis Immediate cause of death -CCF Other contributory factorsAnaemia Fig.
(1:
Pancreas showing fihro,j, in I.:cntre and Jjlluse hcmosiderin deposit.. x 1000
cells was seen. There was marked atherosclerosis in a,cending and abdominal aorta. Patchy hemosiderin dl 'osits in media of aortic wall were also seen.
Lungs : Left lung weighed 650 gms and right lung weighed 700 gm. Bilateral basal congestion and MJAH. VOl.. j.J. NO, 3. /9')8
Diabetes mellitus
COMMENTS : The deceased did suffer from Hodgkin's disease (Lymphocyte predominance) stage IV. Autopsy also showed evidence of hemosiderosis of marked degree in almost all the organs. The most important question however in this case was whether the massive accumulation of iron in liver and other organs was secondary to multiple blood transfusions
252
and oral iron he received during the period of six years or was he suffering from idiopathic hemochromatosis (IHC). It has been clearly mentioned in standard text books and literature [6-9] that excess iron of IHC accumulates preferentially in the cytoplasm of parenchymal cells of liver, pancreas and endocrine glands (1012). In contrast, where iron is liberated from the red cells as in hemolytic anaemia and following multiple transfusions, it is deposited largely in mononuclear phagocytic system (10-12). (n the present case the hemosiderin was seen in hepatocytes, acini of pancreas and cytoplasm of parenchymal cells of other organs. In IHC hemosiderin can be seen in kupffer cells of liver as well, but it is usually minimal and is seen in Kupffer cells which are in close proximity to foci of liver cell necrosis [II]. In view of these findings we strongly believe that the deceased did suffer from (HC, although relevant antemortem studies and HLA typing and similar studies of siblings could have been more meaningful.
Final Discussion Lt Col AC Anand: Idiopathic hemochromatosis is very rare in India as compared to western countries. I want to know the cause of persistent anaemia in the case. Col Ramji Rai replied that the cause of anaemia is due to the basic disease process of Hodgkin's disease. Lt Col Ranga Rao: Was it possible to diagnose hemochromatosis antemortem and if yes what should have beeil done? Col Ramji Rai replied that yes it could have been possible with high index of suspicion. Liver biopsy, serum ferritin and other iron studies could have given a clue to the diagnosis. Col Ramji Rai: If you go through the clinical history you will recollect that he had hepatomegaly even before he was diagnosed to have Hodgkin's disease (even five years prior to 1989). This hepatomegaly persisted even in first and second remissions. Thus he had persistent hepatomegaly at least for ten years which was progressive in nature. We have performed so many autopsies on hematological and other malignancies who had received ample blood transfusions and iron, but haven't come across any case of secondary hemochromatosis so far. In conclusion, I strongly feel that the hemochromatosis which was seen in the present case is idiopathic
Deshpande, Anand and Raj
hemochromatosis and as he had persistent and progressively increasing hepatomegaly and hemosiderin pigment was predominantly present in hepatocytes, acini of pancreas and cytoplasm of parenchymal cells of other organs. If it was suspected prior to death more meaningful iron studies, HLA typing and similar studies in family members could have conclusively proved Idiopathic Hemochromatosis.
REFERENCES I. CavaJli F, Bevnier J. Non Hodgkin's lymphoma in adults. In : Peckham M, Pinedo M, Vevonesi U. Oxford text book of Oncology Vol. 2 Oxford. Oxford University Press 1995: 1788-1809. 2. Jandle JH. Hodgkin's disease. In : Jandle JH. Blood -Text book of Hematology Boston. Little Brown and Company 1987:853-91. 3. Bartle R. Assessment of bone marrow histology in Hodgkin's disease: Correlation with clinical factors. Br J Hematol 1982: 51:345-49. 4. Kaufman D, Longo JO. Hodgkin's Disease. In : AbelotTMD. Armetag JO, Lichter AS, Niederhubcr JE. Clinical Oncology. New York, Churchill Livingstone 1995: 2075-2108. 5. Chabner BA, Myers CEo Antitumour antibiotics. In : Devita VT, Hellman S. Rosenberg SA. Cancer. 4th edition Philadelphia. JB Lippincott Company 1993:374-84
6. Sherlock Sand Dooly J. Iron overload states. In : Diseases of Liver and Biliary system. Black well seientilic publication 1989: 449-59. 7. Kanel GC and Korula J. Iron storage disorders In : Atlas of liver pathology -Bordin JM editor WB Saunders Company 1992: 153-59 8. Milder MS, Cook JD • Stray S and Finch CA. Idiopathic hemochromatosis - An interim report. Medicine. 1980: 50:3549. 9. Tavili AS, Shanna BK, Ba Con R. Iron and liver. Genetic hemochromatosis and other hepatic iron overload disorders. In : Progress in Liver disease. Hans Popper. Schan"ner editor WB Saunders Co. 1990 :281-305 10. Pacazzo JP, Lyndquist K. Mitchell D. Mitttal KR. Rapid development of Lymphoma following liver. transplantation in recipient of with hepatitis B and primary hemochromatosis Am J Gastroenterol. 1993. 88 : 102-4. II. Tinia Kos G. Williams R. Cirrhotic process liver cell careinoma and extrahepatic malignant tumour in idiopathic hemochromatosis, study of 71 patients treated with venesection therapy. App pathol. 1988.6(2): 128-38. 12 Aowell LW, Issei Bacher KJ. Hemochromatosis. In : Harrisons Principles oflntemal Medicine. Issei Bacher. Braukward Wilson. Mortin Fauci. Kasper. Editor McGrawHiII Inc. New York. 13th ed 1992: 2069-72.
AU,IN. I W. 54. NO.3. 19911
HODGKIN'S DISEASE WITH IDIOPATHIC HEMOCHROMATOSIS Lt Col GU DESHPANDE·, Lt Col AC ANAND Col RAMJI RAI+
VSl\l
#,
MJAF11998,54 : 247-252 KEY WORDS: Hodgkin's disease; Idiopathic hemochromatosis
Clinical History
A
47-years-old male presented to a Military hospital in December 1989 with six weeks history of easy fatiguability, palpitation, dyspnoea and giddiness and two weeks history of intermittent bleeding per anum. Past medical history revealed that he had felt a soft mass protruding per anum for previous one year but had never noted bleeding till two weeks back. In addition, five years back he was found to have tender hepatomegaly and was given some oral treatment with a provisional diagnosis of hepatic amoebiasis. Family history did not reveal any significant illness in parents, siblings or children. Clinical examination at the time of hospitalisation showed marked pallor and palpable lymph nodes in right axilla, posterior triangle and inguinal areas. Fundus exam ination showed few soft exudates and flame shaped haemorrhages. He was afebrile and normotensive. Cardiovascular, respiratory and central nervous system examination was within normal limits. Liver was palpable 4 cm below costal margin and was soft with smooth surface. Spleen was not palpable and there was no shifting dullness. Investigation results at this stage showed Hb 6.8 gm% , TLC 32000/cu mm, DLC P 18%, L 80%, M 1%, E 1%, platelet count 2 lac/cu mm, bleeding time 2' 5", clotting time 5'-30". Peripheral blood smear showed marked anisocytosis & poikilocytosis. Majority of cells appeared microcytic with numerous ovalocytes, schistocytes and acanthocytes & a few target cells and about 20 % smudge cells. Coomb's test was negative, reticulocyte count 2.7 % (corrected 1.3%), PCV 20%, MCH 30pg, MCHC 34% and MCV 91 fl. Serum Iron 8! ug/dl. Test for total iron binding capacity was not done. Serum bilirubin 0.5 mg/dl, SGOTISGPT 26/20 lUlL. Serum alkaline phosphatase 63 lUlL, serum proteins 6.3 gm/d1. AG ratio 4.7/1.6, Urine routine examination was normal, urine specific gravity 1022, blood urea 30
mg/dl, serum creatinine 1.2 mg/dl, serum uric acid 5.3 mg/dl, blood sugar (random) 92 mg/dl, stool for occult blood was negative. Electrocardiogram was normal and so was X-ray chest (PA view). Ultrasound of abdomen showed enlarged para-aortic nodes and hepatosplenomegaly. Montoux test showed 7 mm induration after 72 hours. Lymph node biopsy showed feaof Hodgkin's disease (Lymphocyte tures predominance) and the patient was transferred to this hospital. Further investigations showed that haemoglobin had not changed much inspite of over 5 units of blood transfusion within 5 days. Bone marrow examination (aspiration and biopsy) showed hypercellular marrow with focal infiltration with Hodgkin's disease. Sigmoidoscopy confirmed clinical suspicion of hamorrhoids which were not bleeding but were ligated. A clinical diagnosis of Hodgkin's disease (lymphocyte predominance) stage IV B (due to weight loss) was made. His weight was 70 kg, height 167 cm & performance status 60 %. He was advised standard chemotherapeutic regimen COPP alternating with VAD. Over next 18 months he received 8 cycles ofCOPP, 4 cycles of VAD and imperically levamesol therapy. He was also given 37 units of blood transfusion to maintain his haemoglobin level within reasonable limit. By the end of 1991 he became asymptomatic, lymphnodes were no more palpable, performance status improved to 90 %. Haemoglobin now was 13 gmldl. TLC and DLC were now normal though bone marrow continued to show focus of Hodgkin's disease. He was now HbsAg positive and S. bilirubin was 1.5 mg/dl (delayed positive van den bergh reaction). He remained stable during 19n but in May 1993 he again presented with severe anaemia. Clinically lymph nodes were not palpable, though liver was palpable 14 cm below costal margin. Haemoglobin was
'Reader, +Profcssor and Head. Department of Pathology. #Reader. Department of Medicine. Anned Forces Medical College. Punc-40.
Deshpande, Anand and Rai
248
found to be 7 gm/dl and tests for liver and renal function were normal. Electrocardiogram done at this stage showed increase in LV size, and impaired LV function (ejection fraction was 56%). Bone marrow examination showed presence of Hodgkin's deposits. With clinical diagnosis of relapsed Hodgkin's disease, he was treated with blood transfusions and cycles of COPP + ABV. With this salvage chemotherapy (5 cycles) he again improved. Bone marrow biopsy at the end of therapy was free of Hodgkin's disease. He was diagnosed to have achieved remission again. He remained stable for about 8 months and again presented in late 1994 with severe anaemia (Haemoglobin 4 gm/dl). Hepatomegaly was persisting' as 'before and bone marrow biopsy showed infiltration with Hodgkin's disease. He continued to be HbsAg positive. With a clinical impression of relapsed disease he was again started on salvage chemotherapy cycles of CEP (CCNU 3 capsules on day I, etoposide 200 mg on day I to 3 and 100 mg on day 4, prednisolone 4 mg 8 hrly and chlorambucil I mg BD) on day I to 5. He required blood transfusions to support his haemoglobin levels. After 3 cycles of chemotherapy he was noted to have hyperglycaemia (blood sugar fasting 232 mg/dl, post-prandial 513 mg/dl). In response to this development, steroids were withdrawn and oral hypoglycaemic agents were added.' He continued to require blood transfusions/packed cells for his anaemia. After 5 cycles of CEP, he again became stable and bone marrow biopsy sho~ed no evidence of Hodgkin's disease (July/Aug95). Lastly, he reported on 25 Sep with severe anaemia, breathlessness and fainting episode. He died within one hour of coming to the hospital. During this one hour only test done showed haemoglobin level' of 3 gm/dl, TLC 19,200/ cu mm & DLC P24, L71, M2 E2.
Clinical Discussions (Lt Col AC Anand) The clinical course of this patient can be as shown in Fig-I. There are 5 questions that need to be answered. 1. Did lie lias Hodgkin's disease? Clinical profile of this case was in favour of NonHodgkin's lymphoma in view of onset with disseminated disease, presence of predominantly extra nodal disease for most of the time, absence of mediastinal glands, presence of abdominal glands and specially two features namely bone marrow involvement and spillover into the peripheral blood [I]. However, Hodgkin's disease per se is a histological diagnosis. Histological subtype of lymphocyte predominance
10
"
Fig. I: Diagrammatic summary 111'1.:\ ellis over a period of 6 years of tollow-up. Horizontal axis shows the calendar year of the disease. Shaded bars show patient's hemoglobin levels in gldl, while clear bars indicate total leucocyte count in thousands per cu mm. The + or - signs in a circle denote if the bone marrow examination showed infiltration by the Hodgkin's lymphoma. 'Chemo' denotes the period of chemotherapy and the inverted arrows at the top of the figure represent the blood transfusions given to the patient.
which is usually a localised disease and rarely if ever involve bone marrow. Moreover the RS cells have been reported as numerous in some reports while usually they are scanty and difficult to locate in lymphocyte predominance variety.
2. Cause ofsevere anaemia in Hodgkin's disease? Anaemia is found in minority of cases with Hodgkin's disease at presentation and is generally mild and nondescript [2]. However, the bone marrow involvement is seen only in 10% cases with Hodgkin's disease and in one series (where none of patients had lymphocyte predominance Hodgkin's disease) frequency of anaemia was not affected by bone marrow involvement [3]. Anaemia of malignancy is rarely severe and is associated with low serum iron binding capacity with increase marrow iron stores. The latter two tests have not been carried out in this patient. Two additional possibilities are hemolytic anaemia and Clevelopment of a second malignancy in Hodgkin's disease. Hemolysis·.is .known to occur in about 10% patients with Hodgkin's disease. Initial peripheral blood picture was highly suggestive and serum bilirubin was reported to be marginally raised (and delayed positive for van den bergh reaction). Erythroid hyperplasia has also been reported on two bone marrow specimens and I noted on one occasion haemoglobin levels failed to rise above 6.8 gm/dl despite five units of blood transfusions over four days. AUAI·." VOl. 5-1. NO J. /991f
249
Hodgkin's Disease with Idiopathic Hemochromatosis
This kind of picture (in absence of active bleeding) strongly suggests hemolytic process. A negative report of Coomb's test in beginning does not support this diagnosis. Therapy related myelodysplastic syndrome (tMDS) and therapy related acute myeloid leukaemia (t-AML) are common complications of treated Hodgkin's disease. The average risk of 5-1 0% after 5 years may be still higher in males over 50 years of age [4]. However this diagnosis is apparent on bone marrow biopsy and not reported as late as July 95. 3. Wllat was tlte significance ofIIepatomegaly? Liver involvement in Hodgkin's disease is proportional to the splenic involvement [1]. Spleen was not palpable in this case and showed only marginal increase in size. In any case, liver involvement is uncommon in lymphocyte predominance variety. Liver biopsy was not done in this case, which was reported yield of 2-5%, though with the use of immunoperoxidase staining for CD markers (15,30,45) the yield may be higher. HBV infection may be a cause of hepatic enlargement as this individual was found to be HbsAg positive. Markers of viral replication were not tested. A liver span of 20 cm raises a possibility of iron overload. This patient was given 67 units of blood transfusion (iron content 7-10gms) and oral hematinics (approximately 18-20 gms over 6 years). So over six years period, he had positive iron balance of approximately 30 gms which can cause significant liver enlargement as well as some degree of organ damage. Serum ferritin measurements and MRI scan of liver are two non-invasive tests whicll could prove this diagnosis [8] but were not done in this case. 4. Wltat callsell caTlliomegaly? Echocardiographic studies in this case indicated significant myocardial dysfunction and terminal event appears to be cardiac failure precipitated by severe anaemia. By the time ECG was done, he had received 91 mg of cumulative adriamycin dose, which is an unlikely cause of cardiotoxity [4]. Significant cardiotoxity usually appears after 200 mg of cumulative dose has been given. An unrelated disease like coronary artery disease is not uncommon, at this age though resting ECG has not shown any significant abnormality. Transfusional iron overload or secondary hemachromatosis can also cause cardiac dysfunction and remains important possibility. Lastly, severe anaemia can rarely cause cardiac failure [5], though this patient had almost normal haemoglobin at the time when echocardiography was done. Af.I.4H
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5. Wllat caused Non-insulill llepellliellt lliabetes mellitus (NIDDM) ? NIDDM is a common disease which has a prevalence of 6-8% in Indian population. This patient had no family history and he was non-obese. It would be related to prednisolone therapy. However withdrawl of prednisolone did not lead to remission in this case. The possibility I will like to consider is again iron overload which can cause pancreatic damage and diabetes mellitus. Conclusion Although the clinical pattern of disease in this case was more like a Non-Hodgkin's lymphoma, I am in no position to doubt the diagnosis of Hodgkin's disease given by the histopathologists. Here again, clinical pattern of early bone marrow involvement is unusual for lymphocytic predominance variety. Repeated blood transfusions, appearance of hepatomegaly followed by cardiac dysfunction and diabetes mellitus strongly suggests, to my mind, the possibility of secondary hemochromatosis. Final diagnosis: (1) Hodgkin's disease - Lymphocyte predominance (2) Secondary Hemochromatosis Discussion Col RK Gupta: May I know the HIV status? Lt Col AC Anand replied that HIV status is not known as no investigations on these lines were carried out. Brig SK Basu: It was stated that onset of the disease was in Dec 89. May I know the basis of diagnosis in MDTC in CH(SC), Pune? Lt Col AC Anand replied that old slides of Iymphnode biopsy were reviewed and diagnosis of Hodgkin's disease (Lymphocyte predominance) was confirmed. Lt Gen R Jayaswal, AVSM, PHS: The initial diagnosis of Hodgkin's disease was based on lymph node biopsy but clinical features at the time of presentation & in the follow up period are different than the usual picture of Hodgkin's disease lymphocyte predominance, hence May I know the results of repeat lymph node biopsy if it was performed any time after the initial diagnosis? Lt Col Anand replied that as the lymph nodes disappeared after the initial chemotherapy, repeat lymph node biopsy could not be performed. Lt Col Kumud Rai: If USG abdomen was performed, what were the findings? Lt Col AC Anand replied that it was repeated several times but only
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minimal hepatomegaly was splenomaegaly was also detected.
Deshpande, Anand and Rai
observed
and
Col RK Gupta: It was stated that the patient received 200 mg tablet of iron and hence only 20 mg iron must have been absorbed. Each iron tablet contain 40 mg of elemental iron, therefore the individual received only 4 mg of iron per day. Therefore, calculations that he received 20 mg iron per day does not stand to logic. Lt Col Anand replied that individual was given 6 tablets of iron per day hence I calculated that 20 mg of iron was given per day to the individual. Col R Rai : You have given detail calculations about the iron received by the individual since onset of disease till his death through oral iron and through blood transfusions, May I know the results of serum iron or any other iron studies which were performed.? Lt Col AC Anand replied that the serum iron was done only once initially and it does not appear to have repeated any time after that.
Fig. 2: Hemosiderin gmnulcs in hcpatocytcs. "uplli:r cells n'ce x 500
Pathology Protocol (Lt Col GU'Deshpande) A complete autopsy was performed. On external examination of the body, marked pallor, loss of body and pubic hairs and smaller and soft testes were observed. Straw coloured clear fluid was hoted in pericardiac, pleural and abdominal cavities. I. Lymph Nodes :The paratracheal, hilar and paraarotic nodes were moderately enlarged and cut surfaces were fleshy. Microscopically the architecture was effaced and there was diffuse infiltration of mature lymphocytes admixed with variable number of benign histiocytes. Occasional RS cells and Hodgkin's cells were seen. Golden brown pigment seen was detected to be hemosiderin on Perl's Prussian blue reaction and was seen in sinusoidal lining and also in macrophages lying in sinusoidal I,umen.
2. Liver : Weighed 2500 gm. External surface showed micronodules. The colour of liver was coppery red and cut surface was unremarkable. Microscopically fibrous bands connecting one portal tract to another were seen which at places were totally encircling the lobules. However no regenerative nodule was seen anywhere. Hemosiderin pigment was seen infiltrating the liver in form of fine granules as well as in aggregates. The pigment was predominantly hepatocellular and an occasional kupffer cell also showed the pigment. Few of the hepatocytes showed microvesicular fatty change. Portal tracts showed mononuclear cellular infiltration but no Hodgkin's deposits were seen (Fig 2-3).
Fig. 3: Hemosiderin in hepatocytes and kuplTcr cell in thc centre is totally free of hemosiderin x 500
3. Spleen: Weighed 325 gm. Cut surface showed marked congestion. Microscopically red pulp was suffused with blood and white pulp was obliterated. There were nodular hemosiderin deposits in capsule and sinusoids (Fig 4-5).
4. Pancreas : Weighed 150 gm. Cut surface showed dark coppery red colour. Microscopically marked fibrosis and hemosiderin deposits in acini and islets of Langerhans were seen (Fig 6). 5. Gastrointestinal Tract: Showed no abnonnality on gross examination. Microscopically hemosiderin deposits were seen in superficial mucosal epithelium of stomach and in villi of small intestines. 6. Heart and Aorta : Heart weighed 450 gm and was globular. Thickening of left ventricular wall (20 mm) and interventricular wall (12 mm) was noted. Microscopically diffuse interstitial fibrosis around the vessels and marked subendocardial fibrosis in apex of heart along with hemosiderin deposits in myocardial .\I./A/o"I. IW. 54, NO 3.
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Hodgkin's Disease with Idiopathic Hemochromatosis
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tiny whitish nodules all over lung fields were seen. Microscopically bilateral pulmonary edema (predominantly basal), accumulation of hemosiderin laden macrophages and patchy interstitial fibrosis was seen. Fibrotic nodules with granular deposits spread all over lung fields were noted. 8. Endocrines: The gross examination of adrenals and thyroid did not reveal any abnormality but microscopically hemosiderin deposits were seen in adrenal cortex and in thyroid. 9. Kidneys: Each kidney weighed 150 gms. The surface showed fine granularity. Microscopically glomeruli showed wide spread thickening of capillary BM and increase in mesangial matrix. Few of the glomeruli showed obliterative diabetic glomerulosclerosis. Tubular basement membrane, arterioles and smaller vessels also showed thickening. ~xternal
Fig. 4: Hemosiderin granules in capsule of spleen . x 500
10 Testes: Testes were smaller and soft. Microscopically thickening of tubular basement membrane was seen. The tubules were lined by settoli cells only. No spermatozoa were seen. Patchy interstitial fibrosis was present.
1,. Bone Marrow: Showed hemosiderin and Hodgkin's deposits.
SALIENT AUTOPSY FINDINGSI. Hodgkins deposits lymph nodes, bone marrow. Fig. 5: Hemosiderm deposits in nodular form in sinusoids x 1000
2. Hemosiderin deposits - Liver, spleen. pancreas, adrenals, thyroid, heart, aorta, lungs, small intestine. 3. Marked fibrosis- liver, pancreas, lungs 4. Diabetic nephropathy 5. Cardiomyopathy (Secondary) 6. Chronic venous congestion spleen and lungs
FINAL AUTOPSY DIAGNOSIS Hodgkin's disease (Lymp.hocyte Predominance) Idiopathic hemochromatosis Immediate cause of death -CCF Other contributory factorsAnaemia Fig.
(1:
Pancreas showing fihro,j, in I.:cntre and Jjlluse hcmosiderin deposit.. x 1000
cells was seen. There was marked atherosclerosis in a,cending and abdominal aorta. Patchy hemosiderin dl 'osits in media of aortic wall were also seen.
Lungs : Left lung weighed 650 gms and right lung weighed 700 gm. Bilateral basal congestion and MJAH. VOl.. j.J. NO, 3. /9')8
Diabetes mellitus
COMMENTS : The deceased did suffer from Hodgkin's disease (Lymphocyte predominance) stage IV. Autopsy also showed evidence of hemosiderosis of marked degree in almost all the organs. The most important question however in this case was whether the massive accumulation of iron in liver and other organs was secondary to multiple blood transfusions
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and oral iron he received during the period of six years or was he suffering from idiopathic hemochromatosis (IHC). It has been clearly mentioned in standard text books and literature [6-9] that excess iron of IHC accumulates preferentially in the cytoplasm of parenchymal cells of liver, pancreas and endocrine glands (1012). In contrast, where iron is liberated from the red cells as in hemolytic anaemia and following multiple transfusions, it is deposited largely in mononuclear phagocytic system (10-12). (n the present case the hemosiderin was seen in hepatocytes, acini of pancreas and cytoplasm of parenchymal cells of other organs. In IHC hemosiderin can be seen in kupffer cells of liver as well, but it is usually minimal and is seen in Kupffer cells which are in close proximity to foci of liver cell necrosis [II]. In view of these findings we strongly believe that the deceased did suffer from (HC, although relevant antemortem studies and HLA typing and similar studies of siblings could have been more meaningful.
Final Discussion Lt Col AC Anand: Idiopathic hemochromatosis is very rare in India as compared to western countries. I want to know the cause of persistent anaemia in the case. Col Ramji Rai replied that the cause of anaemia is due to the basic disease process of Hodgkin's disease. Lt Col Ranga Rao: Was it possible to diagnose hemochromatosis antemortem and if yes what should have beeil done? Col Ramji Rai replied that yes it could have been possible with high index of suspicion. Liver biopsy, serum ferritin and other iron studies could have given a clue to the diagnosis. Col Ramji Rai: If you go through the clinical history you will recollect that he had hepatomegaly even before he was diagnosed to have Hodgkin's disease (even five years prior to 1989). This hepatomegaly persisted even in first and second remissions. Thus he had persistent hepatomegaly at least for ten years which was progressive in nature. We have performed so many autopsies on hematological and other malignancies who had received ample blood transfusions and iron, but haven't come across any case of secondary hemochromatosis so far. In conclusion, I strongly feel that the hemochromatosis which was seen in the present case is idiopathic
Deshpande, Anand and Raj
hemochromatosis and as he had persistent and progressively increasing hepatomegaly and hemosiderin pigment was predominantly present in hepatocytes, acini of pancreas and cytoplasm of parenchymal cells of other organs. If it was suspected prior to death more meaningful iron studies, HLA typing and similar studies in family members could have conclusively proved Idiopathic Hemochromatosis.
REFERENCES I. CavaJli F, Bevnier J. Non Hodgkin's lymphoma in adults. In : Peckham M, Pinedo M, Vevonesi U. Oxford text book of Oncology Vol. 2 Oxford. Oxford University Press 1995: 1788-1809. 2. Jandle JH. Hodgkin's disease. In : Jandle JH. Blood -Text book of Hematology Boston. Little Brown and Company 1987:853-91. 3. Bartle R. Assessment of bone marrow histology in Hodgkin's disease: Correlation with clinical factors. Br J Hematol 1982: 51:345-49. 4. Kaufman D, Longo JO. Hodgkin's Disease. In : AbelotTMD. Armetag JO, Lichter AS, Niederhubcr JE. Clinical Oncology. New York, Churchill Livingstone 1995: 2075-2108. 5. Chabner BA, Myers CEo Antitumour antibiotics. In : Devita VT, Hellman S. Rosenberg SA. Cancer. 4th edition Philadelphia. JB Lippincott Company 1993:374-84
6. Sherlock Sand Dooly J. Iron overload states. In : Diseases of Liver and Biliary system. Black well seientilic publication 1989: 449-59. 7. Kanel GC and Korula J. Iron storage disorders In : Atlas of liver pathology -Bordin JM editor WB Saunders Company 1992: 153-59 8. Milder MS, Cook JD • Stray S and Finch CA. Idiopathic hemochromatosis - An interim report. Medicine. 1980: 50:3549. 9. Tavili AS, Shanna BK, Ba Con R. Iron and liver. Genetic hemochromatosis and other hepatic iron overload disorders. In : Progress in Liver disease. Hans Popper. Schan"ner editor WB Saunders Co. 1990 :281-305 10. Pacazzo JP, Lyndquist K. Mitchell D. Mitttal KR. Rapid development of Lymphoma following liver. transplantation in recipient of with hepatitis B and primary hemochromatosis Am J Gastroenterol. 1993. 88 : 102-4. II. Tinia Kos G. Williams R. Cirrhotic process liver cell careinoma and extrahepatic malignant tumour in idiopathic hemochromatosis, study of 71 patients treated with venesection therapy. App pathol. 1988.6(2): 128-38. 12 Aowell LW, Issei Bacher KJ. Hemochromatosis. In : Harrisons Principles oflntemal Medicine. Issei Bacher. Braukward Wilson. Mortin Fauci. Kasper. Editor McGrawHiII Inc. New York. 13th ed 1992: 2069-72.
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