granulomatous infections complicating hairy cell leukemia

Granuloma tous Infections Complicating Hairy Cell Leukemia

LAWRENCE RICE, MD, TODD SHENKENBERG, MD, EDWARD C. LYNCH, MD, AND THOMAS M. WHEELER, MD'

Of 14 patients with hairy cell leukemia (HCL), four developed opportunistic granulomatous infections: blastomycosis, coccidioidomycosis and two Mycobacrerim kansasii. The former two pathogens have not been reported with HCL, while M. kansasii infections appear to be common. While most reviews stress susceptibility to pyogenic bacteria and the predisposing role of iatrogenic factors, three of our patients were infected prior to any therapy. Thus, disease-related factors predispose to these granulomatous infections. Granulocytopenia and monocytopenia were present; the latter was not often cor- rected by splenectomy. There was impaired granuloma formation, with all infectious lesions appearing histologically as focal microabscesses containing few macrophages. Awareness of the frequency of opportunistic intracellular infections with early consideration of invasive diagnostic procedures to es- tablish specific etiologic diagnosis may greatly prolong survival for many HCL patients.

Cancer 49:1924-1928, 1982.

AIRY CELL LEUKEMIA (HCL; leukemic r e t i d o - H endotheliosis) is a distinct clinicopathologic entity characterized by pancytopenia, splenomegaly, and the appearance in the blood and bone marrow of mononuclear cells bearing prominent cytoplasmic projections. These cells have been subjected to extensive in- vestigation with regard to cytochemistry, ultrastructure, membrane properties and functional capabilities, yet the derivation of this malignant clone remains contro- versial. Studies have variably pointed to an origin from macrophages, pre-B or B-lymphocytes, or some hybrid of these cell types.'-4 T-lymphocyte markers are rarely found.'

Infections are the greatest cause of morbidity and mortality in HCL patients, accounting for as many as 80% of deaths6 From among 14 patients we have followed with HCL, we report here four cases complicated by opportunistic granulomatous infections. Unusual features of these infections provide insight into their pathogenesis. From detailed analysis of our experience emerges strategy aimed at the spectrum of infections which may complicate HCL.

From the Hematology Section, Department of Medicine, and De- partment of Pathology, Baylor College of Medicine; The Methodist Hospital, Ben Taub Hospital and St. Joseph Hospital, Houston, Texas.

* Dr. Wheeler is a 1980-1981 Fellow of the American Cancer So- ciety.

Address for reprints: Lawrence Rice, MD, Mail station 902, 6565 Fannin, Houston, TX 77030.

The authors thank their colleagues, Dr. Robert Hettig, Dr. Clarence Alfrey, and Dr. Ethan Natelson, who participated in the care of these patients.

Accepted for publication February 6, 198 1.

Report of Cases

Case I

A 49-year-old painter from rural Arkansas was hospitalized for evaluation of pancytopenia. H e had experienced fatigue and dyspnea for six months. Low-grade fever was present and the spleen was palpable 10 cm below the costal margin. He- moglobin was 4.7 g/dl, platelet count 98,000/mm3 and WBC count l,000/mm3 with 31% neutrophils, 1% monocytes, and few hairy cells. Bone marrow was 100% cellular with gross hairy cell infiltration. Chest roentgenograms showed a right hilar mass. Two bronchoscopies with transbronchial biopsies and brushings disclosed no abnormality. Splenectomy was performed.

The patient returned two months later with daily fever above 40°C and two distinct inflamed masses in the right neck, each 9 X 9 cm. Hemoglobin level was 6.2 g/dl, platelet count 192,000/mm3, and WBC count 3,400/mm3 with 37% neutrophils, no monocytes, and a moderate number of hairy cells. Chest roentgenograms revealed extensive bilateral reticulonodular infiltrates in addition to the right hilar mass. Surgical exploration of a neck mass with drainage of purulent material was not diagnostic, but a second surgical procedure yielded material containing abundant thick-walled, broad-based bud- ding yeasts diagnostic of blastomycosis. Cultures grew Blas- tomyces dermatitidis.

Therapy with amphoterin B was begun and continued to a total dose of 3 g. There was defervescence and substantial resolution of the neck lesions over several days. Subsequently, the fullness of the right hilum diminished radiographically, though pulmonary interstitial scarring remained. The patient regained 30 pounds of body weight. Three months after the diagnosis of blastomycosis, gram-negative pneumonia neces- sitated hospitalization for one month. Thereafter, the patient

0008-543X/82/0501/1924 $0.75 0 American Cancer Society

1924

No. 9 GRANULOMATOUS INFECTIONS IN HCL * Rice et al. 1925

has felt well with no medications, maintaining a hemoglobin level of 11 g/dl and normal platelet and WBC counts.

Case 2 A 6 1 -year-old cattle handler from Laredo, Texas, presented

with fatigability, fever, and cough for three months. He had received antibiotics for three supposedly distinct episodes of pneumonia. On this hospitalization, temperature was as high as 41 "C. There was no enlargement of liver, spleen, or lymph nodes. Hemoglobin level was 11.7 g/dl, platelet count 74,000/ mm', and WBC count 1,500/mm3 with 31% neutrophils, 13% bands, and 5% monocytes. Serum alkaline phosphatase was 200 IU, GOT was 220 IU, and albumin 2.5 g/dl. Roentgen- ograms of the chest disclosed interstitial infiltrates affecting mainly the left upper lobe. Bone marrow biopsy revealed diffuse infiltration by hairy cells.

Fever persisted on broad spectrum antibiotics and isoniazid. Fiberoptic bronchoscopy with biopsy was nondiagnostic. Ex- ploratory laparotomy and splenectomy revealed a 235-g spleen infiltrated with hairy cells. Spherules of Coccidioides immitis could be seen in lesions in both spleen and liver. The organism was cultured from these tissues and the bone marrow.

Postoperative complications of staphylococcal sepsis, Pro- teus sepsis, ventricular arrhythmias, and congestive heart failure were successfully treated. Amphotericin B therapy was rapidly advanced to 40 mg intravenously every other day. Nevertheless, biopsy of a skin rash on the 14th postoperative day revealed coccidiodomycosis. The patient was transferred to the M. D. Anderson Hospital, Houston, Texas, where he received leukocyte transfusions on eight occasions (absolute granulocyte count remained 400/mm3). On the 30th postoperative day, having received 570 mg of amphotericvn B, the patient was discharged to receive outpatient amphotericin in- fusions. One week later, he died. No autopsy was performed.

Case 3 A 54-year-old accountant was seen for easy bruisability and

splenomegaly in November 1974. Hemoglobin level was 13 g/dl, platelet count I 23,000/mm3, and WBC couni 12,700/ mm3, including 7% neutrophils and 49% hairy cells. Bone marrow was extensively replaced by hairy cells. Therapy was first instituted in January 1976 when splenectomy was performed for progressive anemia and thrombocytopenia. Persis- tent thrombocytopenia and hairy cell proliferation (WBC count 65,000/mm3 with 60% hairy cells) led to treatment with prednisone (20 mg daily). In April 1976, fever appeared. Bi- opsy of skin lesions disclosed hairy cell infiltration. Treatment with cyclophosphamide, vincristine and prednisone was begun. Fever continued and chest roentgenograms in May revealed an infiltrate in the left lower lobe and a pleural effusion. Thor- acentesis yielded fluid containing 1,700 hairy cells/mm3. Liver function tests became abnormal and liver biopsy revealed chronic inflammation with focal necrosis. PPD was negative.

By July 1976, bilateral large pleural effusions were present. Serum alkaline phosphatase was 762 IU, GOT 1.34 IU, albumin 2.0 g/dl and globulin 4.0 g/dl. Cultures of' liver and pleural fluid (obtained in June) grew Mycobacterium kan-

sasii. Therapy with isoniazid, rifampin, ethambutol and strep- tomycin was begun. The patient became afebrile and other signs of disease disappeared over four months. No further steroids or chemotherapy have been given and antituberculosis therapy was discontinued after two years. The patient has since felt well. In August 1980, hemoglobin was 13.5 g/dl, platelet count 300,000/mm3, and WBC count 7,600/mm3 with 38% granulocytes and 6% hairy cells.

Case 4

A 50-year-old man presented with a three-week history of intermittent fever and chills, pleuritic chest pain, weight loss, vomiting, and headache. Examination revealed temperature of 39.5"C, small cervical lymph nodes, clear lung fields, total liver span of 10 cm, and palpable spleen 11 cm below the costal margin. Hemoglobin was 1 1.1 g/dl, platelet count 130,000/mm3, and WBC count 2,000/mm3 with 22% granulocytes, 44% lymphocytes, and 34% hairy cells. Serum alkaline phosphatase was 300 IU, GOT 90 IU, albumin 2.8 g/ dl and globulin 4.0 g/dl. Chest roentgenograms showed diffuse bilateral reticulonodular infiltrates. Cerebrospinal fluid studies were normal except for 16 mononuclear cells/mm3. Bone marrow biopsy disclosed hairy cell leukemia and focal abscesses. Cultures of sputum, blood and marrow were negative. PPD skin test was negative.

Fever to 41 "C persisted on broad spectrum antibiotics. Ex- ploratory laparotomy and splenectomy were performed. Both the 1,100 gm spleen and the liver specimen were infiltrated with hairy cells and multiple focal lesions containing acid fast bacilli. Treatment with isoniazid and ethambutol was instituted. The patient remained febrile, but his postoperative course was considered satisfactory. On the 12th postoperative day, the patient died suddenly and no autopsy was performed. Cultures of spleen and liver grew M. kansasii.

Pathology

The bone marrow biopsies and spleens of each of the four cases showed the typical pattern of hairy cell infiltration. In all four cases, the mononuclear atypical cells with prominent cytoplasmic projections stained strongly positive with tartrate-resistant acid phosphatase.

Wright's-stained blood films and differential blood counts were reviewed on the four patients presented here and on ten more hairy cell leukemia patients we have seen during the last six years. On presentation, 13 of 14 patients had significant neutropenia ( 4 4 0 0 neutrophils and bands/mm3; mean 770) and 12 of 14 had extreme monocytopenia ( 4 4 monocytes/mm3; mean 16). Granulocytes and monocytes appeared morpholog- ically normal. We were interested in the response of these parameters to splenectomy, and we found that ten of our patients had splenectomy as a primary form of therapy. The mean absolute cell counts from all avail- able blood counts before splenectomy were compared

1926 CANCER May I 1982 V O l . 49

to the mean absolute counts after splenectomy (before any corticosteroid or cytotoxic therapy). The mean neu- trophil count increased by 385 cells/mm3 (P = 0.02; dependent t-test) and mean monocyte count by 92 cells/ mm3 ( P > 0.05). Closer inspection reveals that two patients had significant postsplenectomy increases in monocyte count (+324, +344), two had moderate increases (+86, +92), and the remaining six had no increases. Cases 1, 2, and 4 were among the latter group.

All tissue biopsies containing lesions related to infection were critically examined. These comprised the neck mass from Case 1, the liver and spleen from Case 2, the liver from Case 3, and liver, spleen, and bone marrow from Case 4. In each case, the lesions were characterized as focal necrosis or focal microabscesses, each showing a polymorphonuclear infiltrate around an area of central necrosis (Fig. 1). In no case was there true granuloma formation, with circumferential pali- sading of histiocytes or multinucleated giant cells. An- timuramidase immunoperoxidase staining (Dake, Co- penhagen) demonstrated the absence of macrophages in all of these lesions, in contrast to the infiltrate seen with true granuloma (Figs. 2A and 2B). Histochemical staining revealed the infectious organisms in the lesions in Cases 1, 2, and 4.

Discussion

The median survival of patients after the diagnosis of HCL has been four years, but the survival curve then plateaus such that surviving patients often live ten to 20 or more years with little morbidity.'** Infections are the limiting factor to health and longevity. Although opportunistic granulomatous infections occur with some frequency, reviews of infections in HCL have empha-

FIG. 1 . Photomicrograph of a focal necrotic lesion in the liver of Case 3, typical of the lesions seen in all cases. There is polymorphonuclear infiltrate, but no pallisading epithelioid histiocytes or multinucleated giant cells, thus no true granuloma formation ( H & E, XZOO).

sized the susceptibility to common bacterial pathogens.*~~ These reviews stress the role of iatrogenic factors, with caution urged in the use of corticosteroid and cytotoxic drug therapy. Granulocytopenia, character- istic of untreated HCL, is identified as another important factor. A decrease in infections has followed satisfactory granulocyte response to ~plenectomy.~

Our experience with 14 HCL patients emphasizes different problems. In addition to the four granulomatous infections, we have observed three serious bacterial infections: two gram-negative pneumonias (including Case 1) and one postoperative sepsis (Case 2), all successfully treated. Another patient suffered a fatal pneumonia with etiology never established. Finally, one patient had protracted fever which abated after empiric antituberculous therapy. Thus, we find mycobacterial and fungal infections as frequently as serious bacterial infections. Other recent reports corroborate the impor- tance of mycobacterial and fungal pathogens in HCL."."

Three of our patients contracted infection prior to treatment (Table 1 ), demonstrating that active disease itself predisposes to granulomatous infections. The patients were granulocytopenic and also profoundly mono- cytopenic. While sometimes overlooked, monocytopenia and monocyte functional deficiencies are consistently present in HCL.'*-I5 Mononuclear phagocytes are cru- cial defenders against pathogens capable of intracellular survival. l6 Beyond peripheral monocytopenia, we are first to demonstrate impaired granuloma formation to infectious challenge with conspicuous absence of macrophages in the focal abscesses. T-lymphocyte pro- liferative capacities and delayed hypersensitivity re- sponses are maintained with HCL, even when granulomatous infection is pre~ent. '~, ' ' This also suggests a

No. 9 GRANULOMATOUS INFECTIONS IN HCL - Rice et a/ . 1927

FIGS. 2A AND 2B. (A, top) Antimuramidase immunoperoxidase stain demonstrates the virtual absence of macrophages in a focal liver lesion from Case 3 (X200). (B, bottom) A control lesion from the liver of a patient with chronic lympho- cytic leukemia and tuberculosis shows true granuloma formation and prominent macrophage response, including multiiiucleatcd giant cells (XSOO).

role of monocytes in the cellular immune deficit because recall skin tests are unaffected in animals given selective antimonocyte antibodies.I8

Most recent evidence supports a B-cell derivation for hairy cells. The cause of monocytopenia is not known. The possibility that hairy cells exert suppressivt: influ- ences on bone marrow progenitors (perhaps with some

selectivity for monocyte progenitor^)'^**^ is under in- vestigation in our laboratory. Clinically, monocytopenia persisted after splenectomy in six of ten patients while granulocytopenia more often improved. With growing use of splenectomy to correct granulocytopenia and more selective use of corticosteroids and cytotoxic agents, monocytopenia becomes proportionately more

TABLE 1. Predisposing Factors to Granulomatous Infections

Blood Counts* Prior Treatmentt -

Splenectomy Steroids Chemotherapy Outcome$

no alive 6 mos + no no dead 37 days

no no no dead 12 days

Infecting agent Granulocytes Monocytes

B. dermatitidis 300 10 no no C. immitis 700 15 no M . kansasii 1700 0 Yes Yes Yes alive 4 years + M. kansasii 400 0

* Expressed as absolute: number per mm’ at the time immediately f Refers to treatment given prior to the onset of the infection. $ Outcome from the time of definitive diagnosis of the infection. prior to the onset of the infection.

1928 CANCER May I 1982 VOl. 49

important in predisposing to infection and nonpyogenic infections may relatively increase.

Mycobacterial infections are a serious problem in HCL. Among one series of 13 patients, seven had tuberculosis (five on initial presentation) and four others responded to empiric antituberculous therapy.6 M. kansasii is a frequent pathogen, with nine previously reported cases and four more among Lipshitz’ 33 HCl patients.“ M. intracellulare, M. gordonae, M. cheilone, M. fortuitum, and M. scrofulaceum have also complicated HCL. These mycobacteria, particularly M. kansasii, have become more common than M. tuberculosis in immunosuppressed patients.” In lymphoproliferative disorders, mycobacteria infections may cause 50% mortality.*’

Fungal infections reported in HCL were caused by Aspergillus, Candida, Cryptococcus and Histoplasma. There are no reports of HCL complicated by blastomycosis or coccidioidomycosis (Case 2 is also included among a series of HCL patients seen at M. D. Anderson Hospital”). While Blastomyces is uncommonly an opportunistic pathogen, one series documented advanced infection in five immunosuppressed patients who nevertheless responded well to amph~tericin.’~ Coccidioides is more often a problem to immunocompromised patients in endemic areas, bearing high m~r ta l i ty . ’~

Because HCL may pursue a benign course and infectious complications are most responsive to treatment early, an aggressive approach is demanded to complicating infections. Case 3 is an example that prolonged asymptomatic survival may follow eradication of a serious infection. When a patient with HCL becomes febrile, vigorous efforts are indicated to uncover possible infection (notwithstanding one report that disease-related fever may occur in 30% of patients’). When infection is evident, one must identify a specific causative agent. This required invasive procedures in all our patients, though it was sometimes possible to combine a diagnostic laparotomy with therapeutic splenectomy. Empiric antimicrobial therapy may fail because of the array of organisms which may infect these patients (pneumocystis, toxoplasmosis, strongyloides and disseminated viruses also reported). Trials of antituberculous agents are indicated for some febrile patients, with PPD skin tests not uniformly reliable. In short, aggressive evaluation of febrile illnesses with early consideration of invasive procedures should lead to prompt

specific treatment and potential long-term benefit for patients with HCL.

REFERENCES

I . LoBuglio AF. Leukemic reticuloendotheliosis: A defined syn- drome of an ill defined cell. N Engl J Med 1976; 295:218-220.

2. King GW, Hurtubise PE, Sagone AL, LoBuglio AF, Metz EN. Leukemic reticuloendotheliosis: A study of the origin of the malignant cell. Am J Med 1975; 59:411-416.

3. Cohen HJ, George ER, Kremer WB. Hairy cell leukemia: Cel- lular characteristics including surface immunoglobulin dynamics and biosynthesis. Blood 1979; 53:764-775.

4. Braylan RC, Jaffe ES, Triche TJ, et al. Structural and functional properties of “hairy” cells of leukemic reticuloendotheliosis. Cancer

5 . Naeim F, Gatti RA, Johnson CE Jr, Gossett T, Walford RL. “Hairy cell leukemia:” A heterogenous chronic lymphoproliferative disorder. Am J Med 1978; 65:479-487.

6. Marie JP, Degos L, Flandrin G. Hairy cell leukemia and tuberculosis (letter). N Engl J Med 1977; 296: 1354.

7. Golomb HM, Catovsky D, Golde DW. Hairy cell leukemia: A clinical review based on 71 cases. Ann Intern Med 1978; 89:677-683.

8 . Bouroncle BA. Leukemic reticuloendotheliosis (hairy cell leukemia). Blood 1979; 53:412-430.

9. Bouza E, Burgaleta C, Golde DW. Infections in hairy cell leukemia. Blood 1978; 51351-859.

10. Mackowiak PA, Demian SE, Sutker WL, e f al. Infections in hairy cell leukemia: Clinical evidence of a pronounced defect in cell- mediated immunity. Am J Med 1980; 68:718-724.

1 1 . Libshitz HI, Shuman LS, Gresik MV, Heaston DK. Pneumonia in hairy cell leukemia. Radiology 1981; 139: 19-23.

12. Seshadri RS, Brown EJ, Zipursky A. Leukemic reticuloendotheliosis: A failure of monocyte production. N Engl J Med 1976;

13. Yam LT, Chaudhy AA, Janckila AJ. Impaired marrow granulocyte reserve and leukocyte mobilization in leukemic reticuloendotheliosis. Ann Intern Med 1977; 87:444-446.

14. Kjeldsberg CR. Leukocyte mobilization in leukemic reticuloendotheliosis (letter). Ann Intern Med 1979; 88:268-269.

15. Weinstein RA, Gelmann E, Golomb HM. Disseminated atypical mycobacterial infection in hairy cell leukemia. Lancet 1978;

16. Youmans GO. Mechanisms of immunity in tuberculosis. Pa- thobiol Ann 1979; 9:137-162.

17. Lang JM, Oberling F, Mors R, Mayer S. Immunite cellulaire et leucemies a tricholeurocytes. Nouv Presse Med 1974; 3:2578.

18. Feldman JD, Unanue ER. Role of macrophages in delayed hypersensitivity. 11. Effects of anti-macrophage antibody. Cell Im- munol 1971; 2:275-282.

19. Branda RF. Leukemic reticuloendotheliosis and “hairy cells”. N Engl J Med 1976; 295:1015.

20. Brearley RL, Chapman RM, Brozovic B. Hairy-cell leukemia presenting as aplastic anemia. Ann Intern Med 1979; 91:228.

21. Feld R, Bodey GP, Groschel D. Mycobacteriosis in patients with malignant disease. Arch Intern Med 1976; I36:67-70.

22. Kaplan MH, Armstrong D, Rosen P. Tuberculosis complicating neoplastic disease. Cancer 1974; 332350-858.

23. Sarosi GA, Davies SF. Blastomycosis. Am Rev Respir Dis

24. Rutala PJ, Smith JW. Coccidiomycosis in potentially compro- mised hosts: The effect of immunosuppressive therapy in dissemina- tion. Am J Med Sci 1978; 275:283-295.

1978; 41~210-227.

295: 181-184.

2: 1052- 1053.

1979; 120:911-938.

granulomatous infections complicating hairy cell leukemia

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