Thymoma and Hypogammaglobulinemia (Good’s Syndrome)

Symposium on Unexpected Presentations of Surgical Disease

Thymoma and Hypogammaglobulinemia (Good's Syndrome> G. W. Brasher, M.D.,* P. H. Howard, Jr., M.D., and G. V. Brindley, Jr.

During the past 20 years, several immune deficiency syndromes have been recognized in patients with recurrent sinopulmonary infections. Congenital sex-linked agammaglobulinemia (Bruton's syndrome) was initially recognized in young males with recurrent pneumonia. The ataxia-telangiectasia syndrome in older children is associated with sinopulmonary infections caused by deficiency of immunoglobulin A or E (IgA or IgE). Respiratory infections from bacteria Or opportunistic fungi may develop in persons with acquired hypogammaglobulinemia associated with lymphoma or myeloma. The unusual association of thymoma and acquired hypo gammaglobulinemia (Good's syndrome) is illustrated by the following case report. The patient's presenting problems were sinusitis, bronchiectasis, and a mediastinal tumor. CASE REPORT A 64 year old woman was seen at Scott and White Clinic on October 28, 1969, complaining of a productive cough of 1 year's duration and fever and chills for 1 day. She had been hospitalized in her home community in March 1969 because of a respiratory infection. Roentgenograms made at that time revealed a rounded mass which was thought to be in the mediastinum or at the right hilum. In retrospect, the mass had been visible on the chest x-rays which were made at the same hospital 3 years previously. She had been treated intermittently since March 1969 for chronic sinusitis and chronic bronchitis. Her symptoms were fever and a continuous cough with purulent sputum. Weight loss of 14 pounds had occurred during the preceding 6 months. From the Departments of Pediatrics, Internal Medicine, and Thoracic Surgery, Scott and White Clinic, Temple, Texas

Surgical Clinics of North America- Vol. 52, No.2, April 1972

429

430

G. W.

BRASHER,

P.

H. HOWARD, JR., AND

G. V.

BRINDLEY, JR.

Bronchopulmonary disease had not occurred prior to the onset of the present illness. She did not use oily nose drops or medications. Surgery had not been performed previously. There was no history of pulmonary disease in her immediate family; however, a niece, age 24, was said to have bronchiectasis and chronic respiratory infections. PHYSICAL EXAMINATION. The patient was a thin, emaciated woman with mild respiratory distress and a brassy cough. Temperature was 101.6° F. Physical findings of pneumonia were evident in the right lower lung field. Lymphadenopathy was not noted. CLINICAL STUDIES. Hemoglobin was 10.4 gm. per 100 ml. with a hematocrit of 31 per cent; leukocytes, 12,600 per cu. mm., with 73 per cent neutrophils, 18 per cent lymphocytes, 8 per cent monocytes, and 1 per cent eosinophils. Roentgenograms of the paranasal sinuses revealed

Figure 1. Posteroanterior, lateral, and tomographic views of the well defined ovoid tumor in the right anteroinferior mediastinum.

THYMOMA AND HYPOGAMMAGLOBULINEMIA (GOOD'S SYNDROME)

431

air-fluid levels in both antra and bilateral clouding of the ethmoid air cells. The chest roentgenogram showed extensive infiltration in the right lower lobe and a mediastinal shadow partially obscured by the infiltrate. Subsequently, fluoroscopy and tomograms disclosed a lobulated mass (estimated to be 7 x 10 cm. in size) in the right anterior mediastinum, blending in with the heart margin (Fig. 1). A culture of the sputum contained pneumococci and Hemophilus influenzae. Cytologic studies were negative for malignant cells on several occasions. Oral erythromycin, 250 mg. every 6 hours, was prescribed and the patient gradually became afebrile. After 2 weeks of erythromycin therapy, H. influenzae was still the predominant organism in the sputum. Tetracycline, 500 mg. every 6 hours, eventually cleared the sputum. On November 19, 1969, bronchoscopy and bronchography were performed. Marked suppurative bronchitis was present bilaterally, especially in the right lung. Intraluminal masses or neoplasms were not noted. Bronchograms demonstrated moderate cylindrical bronchiectasis of all of the basal segments of the lower lobe of the right lung. The middle and upper lobe bronchi were normal (Fig. 2). Skin tests for tuberculosis, coccidioidomycosis, and histoplasmosis were negative, as were serologic tests for histoplasmosis and coccidioidomycosis. Serum protein electrophoresis deomonstrated marked hypogammaglobulinemia (Fig. 3). IgG values were 410 mg. per 100 mI., IgA was 97 mg. per 100 mI., and IgM was undetectable. Serial immunoglobulin

Figure 2. Bronchogram demonstrating bronchiectasis of the basal segments of the lower lobe of the right lung.

432

G. W.

P.

BRASHER,

H. HOWARD, JR., AND

Proteins

Gm per 100mi

Albumin

3.71

globulin ~ globulin globulin y globulin

0.20

Total

6.12

Q,

G. V.

BRINDLEY, JR.

1.03

f3

0.83 0.35

y

Albumin

Figure 3. Representative serum protein electrophoretic study demonstrating depression of the gamma globulin fraction.

quantitation is shown in Table 1. Investigation of the immune mechanism before and after thymectomy is outlined in Table 2. Antral punctures were made because of chronic purulent maxillary sinusitis. The sinuses were irrigated and antibiotic solutions instilled. After 3 weeks of hospitalization, pneumonia had cleared sufficiently from the right lower lobe to permit recommendation of exploratory thoracotomy to define the nature. of the mediastinal mass. The reported association of hypogammaglobulinemia with thymoma suggested the preoperative diagnosis of mediastinal thymoma.

Table 1.

Immunoglobulin Studies IgG'"

IgA'"

IgM'"

1969 November 17 November 24

470 410

80 98

46

1970 April 8 April 28 June 18

390 520t 470

95 135 80

32 65

1971 March 18 July 13 November 9

390 560t

135 105 94

16 24

DATE

680t

"'mg. per 1 00 mL t Following 20 mI. immune serum globulin. tWhile receiving 30 mg. per kg. per wk. immune serum globulin.

o o o

433

THYMOMA AND HYPOGAMMAGLOBULINEMIA (GOOD'S SYNDROME)

Table 2.

Immunologic Studies BEFORE

IgG IgA IgM Secretory IgA Widal Isohemagglutinins: Anti A Anti B Mumps Skin Test Monilia Skin Test C3 (Beta-I-C) C4 (Beta-1-3)

12

MONTHS

THYMECTOMY

AFTER THYMECTOMY

390 mg./IOO ml. 95 mg./IOO mI. 32 mg./IOO ml.

390 mg./IOO ml. 135 mg./IOO ml.

Negative 1:8 1:4 Positive Negative

o 4.2 Negative 1:4 1:8 Positive Normal Normal

The patient elected to defer surgical treatment and did not return to the clinic until April 3, 1970. Hemoptysis had been present for 3 days. Roentgenograms of the chest were essentially unchanged. A sputum culture contained mixed flora. Serum protein electrophoresis again demonstrated marked hypogammaglobulinemia. Immunoglobulin quantitation revealed an IgG value of 390 mg. per 100 mI., IgA of 95 mg., and IgM of 35 mg. Bronchoscopy on April 7, 1970, showed that bloody secretions were in the basilar segments of the right lower lobe, but a visible tumor or abnormality other than suppurative bronchitis was not noted. Bronchograms of the left lung did not demonstrate any abnormality. Exploratory thoracotomy on April 14, 1970, revealed a firm, well encapsulated tumor mass in the right anterior mediastinum. The lesion was removed without difficulty. The basal segments of the right lobe were resected because of extensive bronchiectatic changes. The mediastinal tumor (measuring 8 x 6.5 x 4 cm.) was covered by a fibrous capsule. On sectioning, it was composed of rather uniform, tancolored islands separated into irregular compartments by dense fibrous tissue. Microscopic examination demonstrated spindle cells with eosinophilic-like cytoplasm and fairly large reticulated nuclei arranged in whorls around small blood vessels: In other areas, the tumor was composed almost entirely of round cells, resembling small lymphocytes (Fig. 4). Pathologic diagnoses were (1) thymoma, mixed type, predominantly spindle cell and (2) bronchiectasis involving the lower lobe of the right lung. Convalescence was uncomplicated except for the continued production of thick purulent sputum. Pseudomonas, repeatedly grown from sputum, eventually was eradicated by intramuscular gentamicin. The chest appeared normal except for slight pleural effusion on the right on roentgenograms made 2 weeks after the operation (Fig. 5). During the postoperative period, 20 mI. of immune serum globulin were given intramuscularly. On April 28, 1970, the immunoglobulin values were IgG, 520 mg. per 100 mI.; IgA, 135 mg.; and IgM, none. The patient was dismissed from the hospital and was to receive 10 mI. of immune serum gamma globulin per week (30 mg. per kg. per week) in an attempt to mod-

434

G. W.

BRASHER,

P.

H. HOWARD, JR., AND

G. V.

BRINDLEY, JR.

Figure 4. Photomicrograph of the thymoma, mixed type, predominately spindle cell (x 100). Mitoses are visible.

ify her acquired hypogammaglobulinemia. She was to use antibiotics promptly at the first sign of respiratory infection and continue with nebulization therapy and rotary postural drainage. The patient did not return for observation until March 18, 1971. Her history was of almost continual cough, sputum production, and recurring fever with sinopulmonary infections. She had been taking antibiotics intermittently, but had not received gamma globulin since her dismissal from this hospital 11 months previously. Her physical condition was unchanged, with continuing evidence of bronchitis. Bilateral maxillary sinusitis was apparent on roentgenograms. Chest films were normal. A smear of the sputum revealed leukocytes and gram-positive and gram-negative cocci and gram-negative rods. Sputum cultures did not contain pathogens. The leukocyte count on admission was 15,000 per cu. mm. with neutrophils, 84 per cent, and lymphocytes, 16 per cent. Tetracycline therapy, 500 mg. every 6 hours, was begun on admission. The patient became afebrile and remained so throughout the hospital course. Immunoglobulin quantitation revealed persistent hypogammaglobulinemia with an IgG value of 390 mg. per 100 ml.; IgA, 135 mg.; and IgM, none. Pulmonary function studies showed slight improvement but again suggested a restrictive defect. A Caldwell-Luc drainage procedure recommended for palliation of her chronic maxillary sinusitis was refused at this time. She was dismissed on a regimen of immune serum globulin, 10 ml. a week, kindly provided by the American Red Cross.

THYMOMA AND HYPOGAMMAGLOBULINEMIA (GOOD'S SYNDROME)

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Figure 5. Essentially normal appearing roentgenograms 2 months after thymectomy and removal of basal segments of the lower lobe of the right lung.

436

G. W.

BRASHER,

P.

H. HOWARD, JR., AND

G. V.

BRINDLEY, JR.

The patient has now been followed for 9 months since the institution of weekly gamma globulin injections. She has been remarkably free from sinopulmonary infections. Further symptomatic sinusitis has not occurred, and only one Hareup of bronchitis responded promptly to antibiotic therapy. Serial quantitative immunoglobulin determinations (Table 1) have demonstrated definite improvement. Chest x-rays have shown clearing of the pulmonary infiltrates and no recurrence of the thymoma. There has been a weight gain of 13 pounds associated with an increase in strength and vitality. Weekly injections of gamma globulin will be continued for the foreseeable future.

DISCUSSION The association of thymoma with acquired hypogammaglobulinemia (Good's Syndrome), first recognized in 1954,7 led to extensive investigations into the nature of the immune response which have greatly expanded our knowledge in the field. These studies of the thymus have clearly demonstrated that this organ plays a critical role in the development of the immune response in the human and other mammals. 1:! However, the precise role of the thymus in the immune system following maturity has not been adequately definedY Study of this syndrome may provide us with insight into this aspect of thymic function. The unique association of thymoma and hypogammaglobulinemia has been documented by the more than 30 cases in the literature. 9 The typical clinical picture is a healthy adult in the fifth or sixth decade of life who develops repeated episodes of bronchopneumonia, chronic bronchitis, purulent sinusitis, and associated weight loss. Nonspecific symptoms include weakness, fatigue, and anorexia. Chronic diarrhea has been reported2 in addition to evidence of malabsorption and exudative enteropathy. Fungal infections may involve the skin and mucus membranes and prove recalcitrant to therapy.s Mesenchymal diseases such as rheumatoid arthritis and systemic lupus erythematosus occur with greater than expected frequency with thymoma and, in addition, myasthenia gravis has been reported. 17 , 18 An interesting variant of this syndrome includes hematologic abnormalities such as pure red cell agenesis, aplastic anemia, or pancytopenia. 14 At times, these hematologic disturbances occur in association with a thymoma but without evidence of an immune defect. Interestingly enough, a series of 160 thymomas from the Mayo Clinic indicated that this tumor is only rarely associated with aberrations of the immunologic or hematopoietic systems. 16 The typical histologic finding is a benign spindle cell thymoma, although occasional instances of lymphoepithelial,l, 6 epithelial,t5 and lymphocytic 12 thymomas have been reported. The vast majority have been benign but in one instance a spindle cell carcinoma with metastases was reported. 5 Examination of lymphoid tissue, including the spleen and lymph nodes, usually shows absence of germinal centers and plasma

THYMOMA AND HYPOGAMMAGLOBULINEMIA (GOOD'S SYNDROME)

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cells. Eosinophils in the blood and bone marrow were diminished in some reported cases. IS The major immunologic disturbances have involved the humoral antibody system. These patients are unable to adequately respond to antigen challenge with a variety of vaccines, including diphtheria, tetanus, and typhoid. Isohemagglutinins, which are primarily of the IgM class, are either absent or present in low titers. The levels of the 3 major immunoglobulins (IgG, IgA, and IgM) are p:r:esent in quantities higher than that seen in congenital sex-linked hypogammaglobulinemia with IgG in the range of from 200 to 500 mg. per 100 ml. Although the major immunologic disturbances involve humoral antibodies, some patients manifest varying degrees of cellular immune disturbances. For example, one patient could be sensitized to dinitrochlorobenzene (DNCB) but was unable to reject a skin graft. 1s Another patient's lymphocytes did not show the expected response to phytohemagglutinin stimulation, indicating a deficiency of immunocompetent lymphoid cells. 10 Total lymphocyte counts are often normal initially but lymphopenia may develop with progression of the disease. The significance of this aspect of immunity is unclear at present but a similar situation has been observed in the antibody deficiency syndromes. 4 • 19 In the case reported, cellular immunity (as measured by a positive skin test for delayed hypersensitivity to the mumps antigen) was intact before surgical treatment. The monilia skin test, however, converted from negative to positive during the 12 months' period after thymectomy. The significance of this finding is unclear. More refined tests of small lymphocyte function, such as blastogenic transformation following stimulation by phytohemagglutinin, might have shown quantitative differences. In developmental immunology, the thymus gland is intimately associated with cellular immunity.3 It would appear that an abnormal thymus may exert some as yet undefined influence on cellular immunity even following maturity in the human being. The response to exogenous gamma globulin has not been especially encouraging but most patients have been given a therapeutic trial with this agent. In one reported case, the associated chronic diarrhea showed dramatic improvement coincident with such therapy.2 Surgical extirpation of the mediastinal mass is ·mandatory in order to exclude malignancy, but unfortunately, does not lead to any striking improvement in the associated immunologic deficiency. Interestingly enough, amelioration of the hematologic disturbance has been reported following this procedure. 14 The associated chronic sinusitis and chronic bronchitis require intensive medical or surgical therapeutic management, or both. Bronchiectasis, a common finding, may necessitate segmental or lobar resection of the involved tissues. Biopsies of the thymic tumor examined at the time of operation may be indecisive regarding the presence of a malignant neoplasm. Gross evidence of invasion of. surrounding structures is the best indication of cancer. Excision of even a benign-appearing lesion should include wide removal of the adjacent pleura and pericardium.

438

G. W.

BRASHER,

P.

H. HOWARD, JR., AND

G. V.

BRINDLEY, JR.

SUMMARY Over 30 cases in the world's literature have documented Good's syndrome. The syndrome occurs in previously healthy adults who develop repeated sinopulmonary infections in association with acquired hypogammaglobulinemia and thymoma. A case is reported to illustrate the salient features of this syndrome and to point out the surgical implications of this problem.

REFERENCES 1. Barnes, R. D. S., and O'Gorman, P.: Two cases of aplastic anemia associated with tumors of the thymus. J. Clin. Path., 15:264-268 (May) 1962. 2. Conn, H. 0., and Quintilani, R.: Severe diarrhea controlled by gamma globulin in a patient with agammaglobulinemia, amyloidosis, and thymoma. Ann. Int. Med., 65:528-541 (Sept.) 1966. 3. Cooper, M. D., Peterson, R. D. A., South, M. A., et al.: The functions of the thymus system and the bursa system in the chicken. J. Exper. Med., 123:75-102 (Jan.) 1966. 4. Elves, M. W., Roath, S., and Israels, M. C. G.: Failure of lymphocytes from hypo gammaglobulinemic subjects to transform in culture. Brit. Med. J., 2:1051-1052 (Oct. 24) 1964. 5. Gafni, J., Michaeli, D., and Heller, H.: Idiopathic acquired agammaglobulinemia associated with thymoma. New Eng. J. Med., 263:536-541 (Sept. 15) 1960. 6. Godfrey, S.: Thymoma with hypogammaglobulinemia in an identical twin. Brit. Med. J., 1 :1159-1160 (May 2) 1964. 7. Good, R. A.: Agammaglobulinemia- a provocative experiment of nature. Bull. Univ. Minn. Hosp., 26:1-19, 1954. 8. Jeunet, F.: Thymome et syndrome de carence en immunoglobulines. Schweiz. Med. Wschr., 95:1419-1420 (Oct. 23) 1965. 9. Jeunet, F. S., and Good, R. A.: Thymoma, immunologic deficiencies and hematological abnormalities: Birth defects. Original Article Series, National Foundation Press, New York, 1968, vol. 4, pp. 192-206. 10. Korn, D., Gelderman, A., Cage, G., et al.: Immune deficiencies, aplastic anemia and abnormalities of lymphoid tissue in thymoma. New Eng. J. Med., 276:1333-1339 (June 15) 1967. 11. Miller, J. F. A. P.: Immunological significance of the thymus of the adult mouse. Nature (Lon.), 195:1318-1319,1966. 12. Mongan, E. S., Kern, W. A., and Terry, R.: Hypogammaglobulinemia with thymoma, hemolytic anemia and disseminated infection with cytomegalovirus. Ann. Intern. Med., 65:548-554 (Sept.) 1966. 13. Peterson, R. D. A., Cooper, M. D., and Good, R. A.: The pathogenesis of immunologic deficiency diseases. Amer. J. Med., 38:579-604 (April) 1965. 14. Rogers, B. H. G., Manaligod, J. R., and Blazek, W. V.: Thymoma associated with pancytopenia: and hypogammaglobulinemia. Amer. J. Med., 44:154-164 (Jan.) 1968. 15. Rubin, M., Straus, B., and Allen, L.: Clinical disorders associated with thymic tumors. Arch. Intern. Med., 114:389-398 (Sept.) 1964. . 16. Schmid, J. R., Kiely, J. M., Harrison, E. G., Jr., et al.: Thymoma associated with pure red cell agenesis: review of literature and four cases. Cancer, 18:216-230 (Feb.) 1965. 17. Strauss, A. J. L.,;md van der Geld, H. W. R.: Thymus and human disease with autoimmune concomitants with special reference to myasthenia gravis. In Wolstenholme, G. E. W., and Porter, R., eds.: The Thymus: Experimental and clinical studies, In honor of Sir MacFarlane Burnet. London, Churchill, 1966. pp. 416-439. 18. Velde, K. te, Huber, J., and van der Slikke, L. B.: Primary acquired hypo gammaglobulinemia, myasthenia, and thymoma. Ann. Intern. Med., 65 :554-559 (Sept.) 1966. 19. Wanderer, A. A., Ellis, E. F., and Go, S.: Late-onset hypogammaglobulinemia with cellular immune deficiency. J. Pediat., 78:278-284 (Feb.) 1971.

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