Clin. lab. Haemat. 1992 14, 179-188

Haematological splenectomy. Changing indications and complications N . J . K E T L E Y , MB, BS, M R C P , M . J . M I L L S , M B , BS, F R C P a t h , N . E . T R A U B , M B , B C h , F R C P a t h & A.A. BROWN*, M D , F R C S Departments of Haematology and Surgery*, Southend Hospital, Westcliff-on-Sea, Essex, SSO OR Y Accepted for publication 21 May 1992 Summary Review of splenectomies carried out for haematological disease over a ten-year period, at a district hospital, shows that the indications for splenectomy have changed substantially over this time. Fewer patients with idiopathic thrombocytopenic purpura now require splenectomy, however its role in the management of lymphoproliferative disorders has expanded. Splenectomy remains an important therapeutic option for a range of haematological disorders: this series shows it to be a safe and effective operation in selected patients, although it is not without both short and long-term sequelae. Keywords: splenectomy, haematological indications, complications

Splenectomy has for many years been an important option in the management of a wide range of haematological diseases, reflecting the role of the spleen in the physiology and pathophysiology of many of the components of the blood, especially the cellular elements (Bowdler 1983). Indications for splenectomy are varied, but can be usefully grouped into diagnostic, therapeutic and traumatic groups (Russell & Richards 1989); in an individual case, splenectomy may be indicated for a combination of diagnostic confirmation and therapeutic benefit. Few of the indications for splenectomy are absolute, as it forms part of an overall management strategy for each case. The role of splenectomy has therefore changed over recent years with the development of alternative options for diagnosis and treatment: staging laparotomy is now rarely practised in Hogdkin’s disease due to changes in imaging and treatment (Jelliffe & Vaughan Hudson 1987); the use of intravenous immunoglobulin (IVIG) has altered the management of idiopathic thrombocytopenic purpura (ITP), and fewer patients now need splenectomy (Newland 1988). The purpose of this study was to assess how such changes in management have affected the role of splenectomy in a district hospital haematology service, and to review the success and safety of this operation. Correspondence: Dr N.J. Ketley, Department of Haematology, Royal London Hospital, London El l B B , U K .

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Patients and methods

We identified 72 patients currently or previously under haematology follow-up, who had undergone splenectomy, from case summary cards; 68 patients were fully evaluable, with some information available on a further 4. The following information was recorded in each case: Patient details: age, sex, clinical diagnosis, age at and indication for splenectomy, spleen size pre-operatively, use of pneumococcal immunization and subsequent course. Laboratory details: full blood counts pre-op, at 10 days post-op and at most recent review. Operation details: date, surgeon, use of prophylactic antibiotics and platelets, post-operative complications and length of hospital stay. Histological detuils: size of removed spleen and histological diagnosis. Results D I A G N O S I S A N D I N D I C A T I O N FOR S P L E N E C T O M Y

Basic patient details and diagnoses are shown in Table 1. Almost half of our series had a lymphoproliferative disorder, a further third of patients had ITP and half of the remaining 20% had a myeloproliferative disorder. The change in diagnosis with time is shown in Table 2. More detailed analysis by diagnosis is presented below. OPERATIVE DETAILS

Fifty-six of 68 operations (82%) for which full notes were available were performed by one surgical firm, thus providing a close liaison between physicians and surgeons having extensive experience of splenectomy for haematological disorders. Thirty-six patients (53%) received prophylactic antibiotics, starting from anaesthetic induction and 47 (69%) received pneumococcal vaccine, from 27 days pre-op to 3 days post-op, the median being 3 days pre-operatively. For both antibiotics and vaccine, usage has increased over the decade: 8 of the first 20 cases in the series received prophylactic antibiotics, compared with 14 of the most recent 20 patients; the corresponding figures for pneumococcal vaccine are 4 and 20. All patients since 1983 have received penicillin V 250 mg bd for at least 2 years post-operatively, except 2 with penicillin sensitivity who received erythromycin prophylaxis. Thirty-eight patients (56%) received platelet transfusion peri-operatively. All those with pre-operative platelet counts below 50 x 109/1, and most with counts below 100 received platelets; the mean platelet count for those receiving platelets

18 1

Huemutological splenectomy Table 1. Patient details Male Number Age: mean range Diagnosis Idiopathic thrombocytopenie purpura (ITP) Autoimmune haemolytic anaemia (AIHA) Idiopathic non-tropical splenomegaly (INTS) Hereditary spherocytosis (HS) Chronic lymphocytic leukaemia (CLL) Splenic lymphoma with villous lymphocytes (SLVL) Prolymphocytic leukaemia (PLL) Hairy cell lcukaemia (HCL) Hairy cell leukaemia variant (HCL-V) Sezary cell leukaemia Non-Hodgkin’s lymphoma (NHL) Hodgkin’s disease (HD) Myelofibrosis (MF) Chronic myeloid leukaemia (CML) Myelodysplastic syndrome (MDS) Neutropenia cyst Uncertain

33

39

54.0 10-79

55.1 2 1--79

10

14 2 2

-

1 1 3 3 1 -

1 1

8 1

3

Table 2. Diagnosis by year of operation Year

Total

ITP

LPD

MPD

Others _.

1981 1982 1983 1984 1985 1986 I987 1988 1989 1990 1991

5 5 4 6 5 5

6 5 11 13 7

3

1

5 4

0 0 2

0 2

2 2 2 2 2 0

Female

0 0 0 2

1

1

3 2 2 7 7 5

0 0 1 0

2 0

I 0 0 2 1

0 2 0 2 2 2

Key: LPD, lymphoproliferative disorders: CLL, NHL, SLVL, PLL, HCL and HCL-V; MPD, myeloproliferative disorders: M F and CML; others-see Table 1.

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was 54 x 109/1, and for those not given platelets 174 x 10y/l; there has been no change in the usage of peri-operative platelets over the study period. The median duration of hospital stay was 11 days (range 6-51), and was shorter in those with an uncomplicated course (8 days) than in those who developed post-operative complications (1 3 days). Six patients had a stay in excess of 3 weeks, but in only 2 of these could the operation be said to have contributed to their protracted hospitalization; the remaining 4 patients had disease progressive after (NHL) or initially refractory to (ITP) splenectomy, requiring further treatment in the immediate post-operative period.

COMPLlCATIONS

Thirty-seven patients (54%) had 46 complications during the course of the peri-operative period; these are shown in Table 3. There was no association between diagnosis and complications, except for those with myeloproliferative disorders, 5 of 6 (83%) of whom developed a complication. The mean age of those with complications was 58.5 years and of those without 50.3 years. The complication rate increased with increasing weight of the diseased spleen: the mean weight for those with complications was 1376g, and for those without 819 g; those with spleens weighing more than 2000 g had a complication rate of 69%.

Table 3. Perioperative complications Deaths within SO days of splenectomy: septicaemia, died on 2nd postoperative day

1

within 3 months of splenectomy: progressive disease, PLL CML MF MDS Sezary cell leukaemia Major complications: Bleeding requiring re-exploration Pulmonary embolism Minor complications; Bleeding not requiring re-exploration Postoperative pyrexia Urinary retention, requiring prostatectomy Incisional hernia Calf pain, negative venogram For abbreviations, see Table 1.

4 I 4

24 4 2 1

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Bleeding Four of those with bleeding problems post-operatively had received platelets at the time of operation, their mean pre-operative count being 25 x 109/l; those with bleeding who had not received platelets had a mean pre-operative count of 132 x 109/l. Pre-operative platelet count and use of platelets peri-operatively thus had no association with post-operative bleeding.

Sept icaemia There was only 1 case of septicaemia post-operatively in a sixty-seven-year-old lady with chronic myelomonocytic leukaemia, who underwent splenectomy for thrombocytopenia; she died on the second post-operative day. Two of our patients have since suffered overwhelming post-splenectomy infections (OPSI): the first, a lady with sickle cell trait, underwent splenectomy for ITP refractory to steroids, in 1982; her ITP remitted, which was maintained; her compliance with penicillin prophylaxis was poor, despite advice that prolonged prophylaxis was indicated; she was admitted with septicaemia in 1986 and died shortly afterwards. The second, a man who initially presented with bronchiectasis and was found to have hypogammaglobulinaemia, has subsequently developed both autoimmune haemolytic anaemia and ITP; he underwent splenectomy when his ITP proved refractory to corticosteroids, and gained remission; 2 years later he developed abnormal liver function, with ultrasound showing intra-abdominal lymphadenopathy, and biopsy confirming NHL; 6 months into chemotherapy for this, he again became thrombocytopenic with marrow examination confirming relapse of his ITP. His ITP failed to respond to IVIG, and his chemotherapy was changed from chlorambucil to COP (cyclophosphamide, vincristine and prednisolone); following the first course of this, he developed cytopenia and septicaemia and died. Postmortem examination revealed extensive lymphomatous infiltration of the liver and para-aortic lymph nodes.

Post-operative pyrexiu The focus of infection in those with post-operative pyrexia was thought to be the chest in 18 patients, though only 5 had this adequately documented by radiology and/or appropriate cultures. The rate of post-operative pyrexia has increased in parallel with the use of prophylactic antibiotics, with 5 of the first 20, and 9 of the last 20 patients having this problem; thus the use of antibiotics at induction seems not to have prevented the rise in post-operative infections, although the changing case mix, with more patients with malignant disease, may have affected infection rates.

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RESPONSE T O S P L E N E C T O M Y

Idiopathic thrombocytopenic purpura ( I T P ) Twenty-three of the cases in our series were fully evaluable. All had received prednisolone beforehand, and 11 had also received IVIG. Twenty-two of the 23 underwent splenectomy between 1 and 6 months after presentation; the only patient to have a splenectomy in the chronic phase, did not respond and remains steroid-dependent with platelet counts below 20. Twenty-one patients responded, 17 immediately, with platelet counts at 10 days significantly increased on preoperative values (mean pre-op, 45; post-op, 361) and the other 4 patients more gradually, 3 gaining remission after 1 month and the fourth achieving adequate counts, whilst remaining treatment-dependent, at 3 months. Four patients have relapsed at between 9 months and 2 years, 6 months after splenectomy, 3 of whom remain on treatment. Thus, of 21 responders, 16 have gained lasting remission (1 to 8 years after splenectomy), 3 remain treatment-dependent, and 2 have died, 1 of unrelated cause when in remission 4 years after splenectomy, and the second following relapse of ITP during treatment for NHL.

Lymphoproliferative disorders The indications for splenectomy in patients with chronic lymphocytic leukaemia (CLL) and Non-Hodgkin’s lymphoma (NHL) are shown in Table 4.Those with hypersplenism generally required splenectomy to enable further chemotherapy to be given for progressive disease; all those with CLL had thrombocytopenia limiting further treatment and 5 of the 13 with NHL had neutropenia requiring intervention (neutrophils less than 1.O x 109/l). Splenectomy was successful in enabling further treatment in all cytopenic patients, with significant increases in previously decreased cellular elements, which have been maintained in the

Table 4. Indication for splenectomy in CLL and NHL

Indications

Number NHL CLL

H ypersplenism Hypersplenism + symptomatic Hypersplenism + confirmation of diagnosis Confirmation of diagnosis Symptomatic Other Total

2 2

3

-

2 1 2

-

1

5 ~

For abbreviations. see Table 1 .

5

~

13

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majority of patients; however, in only 4 of the NHL patients has this further treatment produced lasting remission. All six patients with splenic lymphoma with villous lymphocytes (SLVL) showed a response, although two have a persisting lymphocytosis. Only 2 patients have received chemotherapy post-operatively, these having had ‘B’ symptoms at presentation. Three of our series presented with symptomatic splenomegaly and had histological appearances characteristic of idiopathic non-tropical splenomegaly; 2 of the 3 have subsequently developed lymphoma, as has been reported elsewhere (Dad, et al. 1978). One lady developed Hodgkin’s disease 9 months after splenectomy, whilst a second was found to have NHL at post-mortem examination. The third patient remains well with no sign of disease 10 years after splenectomy.

Myeloprolferative disorders

All 6 patients with a myeloproliferative disorder had massive splenomegaly and underwent splenectomy primarily for symptomatic relief. Two patients died of progressive disease within 3 months of operation, and 3 others have subsequently died at between 2 and 4 years after splenectomy, all of whose quality of life was much improved by splenectomy. The remaining patient is well at I year postoperation, and receiving interferon treatment for thrombocytosis. Five of the 6 had peri-operative complications, probably due to the massive size of their diseased spleens, though only one of these was a major complication (bleeding requiring re-exploration).

Discussion I N D I C A T I O N FOR SPLENECTOMY

Despite changes in the diagnosis and treatment of many haematological conditions, the importance of splenectomy has remained. Thus, in ITP, although IVIG treatment has had a profound influence on the course of the disease, splenectomy is still required to gain lasting remission in the majority of adult cases; IVIG does, of course, allow optimization of platelet count pre-operatively, with more choice in timing the operation and fewer post-operative complications. Although the incidence of ITP requiring splenectomy has remained constant throughout the 10 year period, the proportion of ITP cases amongst the group as a whole has declined. This reflects both the changing management of the different conditions and the evolving interests of the department. The increasing number of cases with lymphoproliferative disorders reflects the interest of both Haematology and Oncology departments in this group of diseases. The diagnosis remained in doubt until after splenectomy in only a few patients: 3 of the patients with lymphoproliferative disorders were reclassified

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within that group with the benefit of splenic histology; the aetiology of the splenic cyst could only be determined with examination of the excised spleen. In 2 cases, even with the benefit of splenic histology, the exact diagnosis remains uncertain. Three patients had appearances characteristic of idiopathic non-tropical splenomegaly, 2 of whom have subsequently developed lymphoma; improved histological diagnosis and imaging seem to have largely removed INTS as a disease entity, with most cases being classified as NHL. COMPLICATIONS

Complications do however occur, and can be divided into immediate and delayed. Age and intercurrent disease are perhaps the most important factors determining the development of immediate post-operative complications, with younger patients having a lower rate. The size of the diseased spleen is also significant, but use of pre-operative antibiotics and peri-operative platelets do not seem to affect outcome. Close cooperation between physician and surgeon helps to keep complications to a minimum. The principal delayed complication is sepsis, which is often overwhelming, especially when due to capsulate bacteria. Pneumococcal vaccination and the long-term use of prophylactic penicillin both decrease incidence of OPSI, however it remains a significant problem. Both of our patients who developed OPSI had additional predisposing factors, namely sickle cell trait and post-chemotherapy cytopenia, although in one the lack of compliance with penicillin prophylaxis may have been significant; her septicaemia developed at 4 years post-splenectomy, however, beyond the period during which penicillin is generally continued. Alternative surgical techniques, such as partial splenectomy and auto-transplantation, have proved useful in non-haematological cases (Cooper & Williamson 1984), but would prove self-defeating in conditions such as ITP and hyperplenism due to lymphoproliferative infiltration. There is perhaps scope for improving the efficacy and administration of pneumococcal and other vaccines: the majority of patients received pneumococcal vaccine closer to splenectomy than is recommended (JAMA 1989). Only 4 patients received vaccine more than 2 weeks before their operation and 3 were not vaccinated until after their splenectomy. Thus, few of our series were vaccinated far enough pre-operatively to benefit fully, although immune response was not assessed in this study. Anticipation of the possibility of splenectomy becoming necessary in a particular case should allow vaccination at more than 14 days preoperatively, although occasionally this is impossible. If so, there is no clear evidence as to whether pneumococcal vaccine is best given immediately preoperatively or deferred until after the operation; patients certainly respond better with a spleen in situ (Di Padova et al. 1983), however animal data show that recently administered polysaccharide antigens are removed with the spleen at operation, thus blunting the response induced (Barron & Richter 1990); under these circumstances vaccination may be better left until after splenectomy, although human data on this point are lacking.

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R E S P O N S E TO S P L E N E C T O M Y

Idiopathic thrombocytopenic purpura

The majority of adults with ITP will not remit spontaneously. The introduction of intravenous immunoglobulin (IVIG) preparations and their use in children with ITP (Imbach et al. 1981), raised the hope of avoiding splenectomy in adults showing a good response. However, the response to IVIG is generally transient (Bellucci 1989) allowing only a deferment of the decision to proceed to splenectomy; a few patients will maintain adequate platelet counts with intermittent IVIG treatment, without the need for splenectomy (Newland 1985). Those who do not respond or who respond only temporarily to corticosteroids, benefit from splenectomy, with remission rates of 60-80% (Bussel 1990). About 10% of responders can be expected to relapse (Bellucci 1989) and an accessory spleen or remnant should be sought using isotopic scanning. Some of those who relapse will remit once more, often resonding better to standard treatment after splenectomy than they did beforehand (Karpatkin 1985); others will continue to require treatment to maintain a satisfactory platelet count. Our results fit broadly with these figures: a response rate of 90%, with subsequent relapse in 19% of resonders.

Lymphoprolijerative disorders

Splenic involvement may be part of extensive or late disease, as is seen in chronic lymphocytic leukaemia (CLL) and Non-Hodgkin’s lymphoma (NHL), or it may be a prominent early feature, as for example in splenic lymphoma with villous lymphocytes (SLVL) and hairy cell leukaemia (HCL). Removal of a diseased spleen may be indicated for symptomatic relief or for hypersplenism in the former group (Kehoe et al. 1985; Stein et ul. 1987), whilst in the latter it seems to be a more definitive treatment modality (Van Norman et al. 1986; Mulligan et al. 1991). In this group of patients, splenectomy has proved to be an effective treatment modality, affording symptomatic relief and enabling further chemotherapy to be given. Unfortunately, these benefits have not translated into better remission and survival rates.

Myeloproliferative disorders

The role of splenectomy in these disorders is less clear-cut than in other conditions. Selected patients with both chronic myeloid leukaemia (CML) and myelofibrosis (MF) benefit from splenectomy, although timing the operation for maximum benefit is difficult and the peri-operative complication rate is above the average for the procedure. Splenectomy, as in our 6 cases, is generally undertaken for either painful splenectomy or cytopenia, but does not seem to alter the natural

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history of either CML or MF (Ludlam 1990); in 3 cases, it has resulted in sustained symptomatic improvement.

Acknowledgements Our thanks to Dr A.C. Newland for critical appraisal of the manuscript and to Professor D. Catovsky for lymphocyte marker studies.

References BARRONP.T. & RICHTERM. (1990) Immunodeficiency following splenectomy in the early postimmunization period. Br. J. Surg. 77, 316-319 BELLUCCIS. (1989) Autoimmune thrombocytopenias. Balliere’s Clin. Haematol. 2, no. 3, 695-7 I8 BOWDLERA.J. (1983) Splenomegaly and hypersplenism. Clin. Haematol. 12, 467-488 BUSSELJ.B. (1990) Autoimmune thrombocytopenic purpura. Haematol. Oncol. Clin. North Am. 4, no. I , 179--191 COOPER M.J. & WILLIAMSON R.C.N. (1984) Splenectomy: indications, hazards and alternatives. Br. J . Surg. 71, 173-1 80 DACIE J.V., GALTON D.A.G., GORDON-SMITH E.C. & HARRISON C.V. (1978) Non-tropical idiopathic splenomegaly: a follow-up study of ten patients described in 1969. Br. J . Haemutol. 38, 185-193 DI PADOVAF., DURIGM., WADSTROM J. & HARDERF. (1983) The role of the spleen in immune response to polyvalent pncumococcal vaccine. Br. Med. J . 287, 1829-1832 IMBACHP., BARANDUN S.? D’APUZZOV. et al. (1981) High dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet i, 1228-123 1 JAMA,ANON(1989) Leads from the MMWR: Recommendations of the Immunization Practiccs Advisory Committee on Pneumococcal Polysaccharide Vaccine. J A M A 261, 1265- 1267 HUDSONG . (1987) Staging laparotomy in Hodgkin’s diseasc. In: JELLIFFEA.M. & VAUGHAN Hodgkin’s Disease (eds P. Selby & T.J. McElwain) pp. 160-180, Blackwell. Oxford KARPATKIN S. ( I 985) Autoimmune thrombocytopenic purpura. In Seminars in Huematology (eds P.K. Schick & H. Stormorken), 22, no. 4, 260-288 KEHOEJ.E., DALYJ.M., STRAUS D.J. & DECOSSEJ.J. (1985) Value of splenectomy in Non-Hodgkin’s Lymphoma. Cancer 55, 1256-1 264 LUDLAM C.A. (1 990) Chronic leukaemias and myelofibrosis. In: Clinical Haematology (ed C.A. Ludlam) pp. 156- 164, 267-270, Churchill Livingstone, Edinburgh MULLICAN S.P., MATUTESE., DEARDEN C. & CATOVSKY D. (1991) Splenic lymphoma with villous lymphocytes: natural history and response to therapy in 50 cases. Br. J. Haemutol. 78,206-209 NEWLAND A.C. (1985) Intravenous immunoglobulin therapy in adult idiopathic thrombocytopenic purpura. Royal Society of Medicine Symposium No 84, 93-99 NEWLAND A.C. (1988) Clinical use of intravenous immunoglobulin in blood disorders. Blood Rev. 2, 157-167 RUSSELL S.J. & RICHARDS J.D.M. (1989) Medical indications for splenectomy. Br. J . Hosp. Med. 42, 120- I28 STEINR.S., WEIKERT D., REYNOLDS V. et al. (1987) Splenectomy for end-stage chronic lymphocytic leukaemia. Cancer 59, 18 15-1 8 18 VAN NORMANA S . , NAGORNEY D.M., MARTINJ.K. et al. (1986) Splenectomy for hairy cell leukaemia. Cancer 57, 644-648