Pediatric Annals

LYMPHOSARCOMA

André D Lascari, MD

Abstract

1. Pochedly. C. Lymphosarcomas in children. NY. State J. Med. 70 0970), 543-551.

2. Jones. B. and Klingberg. W. G. Lymphosarcoma in children. J. Pediatr. 63 (1963). 11-20.

3. Schey. W.L., White, H.. Conway, J.J., and Kidd, J.M. Lymphosarcoma in children: A roentgenologic and clinical evaluation of 60 children. Am. J. Roentgenol. Radium Ther. Nucl. Med. 117 0973), 59-72.

4. Rappaport, H. Tumors of the Hematopoietic System. Atlas of Tumor Pathology, Section IllFascicle 8. Washington. D. C: Armed Forces Institute of Pathology, 1966.

5. Rundles, R.W. Lymphosarcoma. W4J. Williams, E. Beutler, A.J. Erslev, and R.W. Rundles, eds. In Hematology. New York: McGraw-Hill Co., 1972.927-936.

6. Jaffe. B. F. and Jaffe, N. Head and neck tumors in children. Pediatrics 51 (1973). 731-740.

7. Han. T. and Stutzman, L. Mode of spread in patients with localized malignant lymphoma. Arch. Intern. Med. 120 (1967), 1-7.

8. Hartsock, R.J. Postvaccinal lymphadenitis: Hyperplasia of lymphoid tissue that simulates malignant lymphomas. Cancer 21 (1968), 632-649.

9. Choovlvathanavanich, P., Wallace, E. M., and Scaglione, P.A. Pseudolymphome Induced by diphenylhydantoin. J. Pediat. 76 (1970). 621-623.

10. Gams, R. A., Neal, J. A., and Conrad, F. G. Hydantoin-induced pseudo-pseudolymphoma . Ann. Intern. Med. 69 (1968). 557-568.

11. Anthony, J.J. Malignant lymphoma associated with hydantoin drugs. Arch. Neurol. 22 (1970), 450-454.

12. Canale, V.C. and Smith. CH. Chronic lymphadenopathy simulating malignant lymphoma. J. Pediatr. 70 (1967). 891-899.

13. Gasquet, C, Schweisguth, O., Deb run, G., et al. Lymphangiography in malignant diseases of childhood. Am. J. Roentgenol. Radium Ther. Nucl. Med. 103 (1968), 1-12.

14. Alsenberg. A.C. Malignant lymphoma. New Engl. J. Med. 288 (1973), 883-941.

15. Carbone. P.P. Management of patients with non-Hodgkin's lymphoma. Arch. Intern. Med. 131 (1973), 455-459.

16. Aur, R.J.A., Hustu. H.O.. Simone. J.V.. et al. Therapy of localized and regional lymphosarcoma of childhood. Cancer 27 (1971). 1328-1331.

17. Jones, S. E., Kaplan, H. S., and Rosenberg, S.A. Non-Hodgkin's lymphomas. III. Preliminary results of radiotherapy and a proposal for new clinical trials. Radiology 103 (1972), 657-662.

18. Johnson, R. E. Radiation therapy of generalized lymphocytic lymphomas. Am. J. Roentgenol. Radium Ther. Nucl. Med. if 7 (1973), 50-53.

19. Luce. JK. , Gamble. J. F.. Wilson. H. E., et al. Combined cyclophosphamide, vincristine, and prednisone therapy of malignant lymphoma. Cancer 28 (1971), 306-317.

20. Bagley, C.M., Jr., Devita, V.T., Jr., Berard, CW.. and Canellos. G. P. Advanced lymphosarcoma: Intensive cyclical combination chemotherapy with cyclophosphamide, vincristine, and prednisone. Ann. Intern. Med. 76(1972), 227-234.

21 . Appendix. The Year Book of Cancer. 1972. Chicago: Year Book Medical Publishers, 1972, 194-196.

22. Rosenberg, S.A., Diamond, H. D., Dargeon. H. W., and Craver, L. F. Lymphosarcoma in childhood. New Engl. J. Med. 259 (1958). 505-512.

23. Carbone, P.P., Kaplan, H. S.. Musshoff. K., et al. Report of the committee on Hodgkin's disease staging classification. Cancer Res. 31 (1971). 1860-1861.

24. Watanabe, A.. Sullivan. M. P., Sutow, WW., and Wilbur, J. R. Undifferentiated lymphoma, non-Burkitt's type. Am. J. Dis. Child. 125 (1973), 57-61.

25. Weick, J. K., Kiely, J. M., Harrison. E.G.. Jr., et al. Pleural effusion in lymphoma. Cancer 31 (1973). 848-853.

26. D'Angio. G.J. . Mitus. A., and Evans, A. E. The superior mediastinal syndrome in children with cancer. Am. J. Roentgenol Radium Ther. Nucl. Med. 93 (1965). 537-544.

27. Lasca ri, A.D. Leukemia in Childhood. Springfield: Charles C Thomas, 1973.

TABLE 1. CLASSIFICATION OF MALIGNANT NON-HODGKIN'S LYMPHOMAS

TABLE 2. CLINICAL MANIFESTATIONS OF CHILDHOOD LYMPHOSARCOMA

TABLE 3. STAGING OF A LYMPHOSARCOMA*

TABLE 4. DIAGNOSTIC EVALUATION OF LYMPHOSARCOMA

TABLE 5. TREATMENT OF COMPLICATIONS OF LYMPHOSARCOMA…

Lymphosarcoma is a vicious malignancy which accounts for five per cent of childhood cancers.1 It is rare in children under one year of age; slight increases in incidence are seen in children three to five years and nine to twelve years of age.2'3 The tumor may originate in any lymphatic tissue in the body, either within or outside of the lymph nodes.

The diagnostic evaluation, histologic classification, and treatment of nonHodgkin's lymphoma have changed significantly in the last several years. Our ability to define the anatomic extent of the disease has greatly improved, and current radiotherapy and chemotherapy programs are resulting in increased survival.

Current methods of classification of non-Hodgkin's lymphoma are now based primarily on Rappaport's scheme4 (see Table 1). Lymphosarcoma is now referred to as malignant lymphoma, lymphocytic type, either poorly differentiated or well differentiated; however, the term lymphosarcoma will be used in this article.

CLINICAL MANIFESTATIONS

Cervical lymphadenopathy is the initial manifestation in one third of patients (Table 2). The involved nodes are discrete, firm, and nontender and usually are not fixed to surrounding tissue. Later, large conglomerates of nodes may be present. Nodes that enlarge rapidly, however, may be tender and may fluctuate somewhat in size but do not disappear spontaneously.5 Unilateral involvement occurs in 75 per cent of patients with cervical lymphadenopathy.6 The upper cervical and submaxillary nodes are usually involved, although occasionally lymphadenopathy may be found in the supraclavicular area. Bilateral neck nodes are present in 25 per cent of cases. Involvement of peripheral lymph nodes in the axillary and inguinal areas occurs much less frequently.

The mediastinal nodes are frequently involved (Figure 1) and may cause nonproductive cough, dyspnea, airway obstruction, or superior vena cava syndrome (Figure 2). The abdomen is also a common initial site, with involvement oí retroperitoneal or mesenteric nodes or generalized abdominal involvement. Tumor in the gastrointestinal tract, particularly the terminal ileum, can produce bleeding, intussusception, and bowel obstruction. Enlargement of the liver and spleen usually indicates the tumor has undergone general dissemination. Other sites of initial signs and symptoms include the central nervous system, nasopharynx, parotid gland, bone, kidney, ovary, testis, and skin.

Systemic symptoms usually are not present when the disease is only localized, but malaise, anorexia, weight loss, sweating, and fever may be present with more extensive disease. There are usually no significant changes in blood counts. The presence of anemia and thrombocytopenia usually indicates that the tumor has converted to a picture of acute lymphocytic leukemia.

The course of lymphosarcoma may be acute or recurrent. Occasionally, some patients fail to respond to all forms of treatment, and the disease pursues an unremitting course resulting in death of the child within a few months or even weeks.1 In other children the disease may be recurrent and require continuous treatment. Spread in Hodgkin's disease usually (64 per cent) occurs by direct extension to the next adjacent lymph node region. Lymphosarcoma, however, usually (67 per cent) spreads to distant sites or spreads generally.7

DIFFERENTIAL DIAGNOSIS

Lymphosarcoma in the cervical area may be erroneously diagnosed as cervical adenitis. Tenderness, overlying erythema, fluctuation, and onset following an upper respiratory infection would suggest bacterial adenitis. However, the typical picture of cervical adenitis is seen less frequently than in the past because of the widespread use of antibiotics. The child initially may be seen three or four weeks after the initial infection and following the use of one or more types of antibiotics. Little tenderness may be seen at this time, and erythema may not be present. The mass may also be more firm than fluctuant, and there may be a slow resolution in size. A history of prior tenderness or pain when the child moved his or her head would suggest adenitis. If the diagnosis of the cervical mass is in doubt, a trial of antibiotics can be given for a two- week period. If the mass does not start to decrease in size after that period, a biopsy is indicated for a definitive diagnosis.

Cat-scratch disease, tuberculosis, and atypical mycobacterial infections occasionally have to be considered in the differential diagnosis. Postvaccinal lymphadenitis has been misinterpreted as malignant lymphoma; history of vaccination should preclude this error.8

A pseudolymphoma syndrome, secondary to diphenylhydantoin therapy, has been described, consisting of fever, skin rash, hepatosplenomegaly, generalized or regional lymphadenopathy, leukocytosis, and eosinophilia.9 The syndrome is reversible on withdrawal of the drug. A few patients with hydantoin-induced lymphadenopathy, however, have subsequently developed a true malignant lymphoma ending in death (pseudo-pseudolymphoma).10 There also appears to be an increased incidence of malignant lymphoma in epileptic patients receiving long-term hydantoin therapy.11

Table

TABLE 1. CLASSIFICATION OF MALIGNANT NON-HODGKIN'S LYMPHOMAS

TABLE 1. CLASSIFICATION OF MALIGNANT NON-HODGKIN'S LYMPHOMAS

Table

TABLE 2. CLINICAL MANIFESTATIONS OF CHILDHOOD LYMPHOSARCOMA

TABLE 2. CLINICAL MANIFESTATIONS OF CHILDHOOD LYMPHOSARCOMA

A bizarre syndrome has been described that consists of generalized lymphadenopathy, hepatosplenomegaly, variable lymph node histology, and a chronic course; 12 onset of the illness was between one month and two years of age. The lymphadenopathy of this syndrome decreased in size during infections and immunosuppressive therapy. Some patients developed a positive Coombs test and several had a serum-sickness-like illness with transient swelling of the large joints associated with an erythema multiforme-like rash. Anemia, reticulocytosis, and thrombocytopenia were also present in most of these patients.

DIAGNOSIS

The definitive diagnostic study is a properly performed biopsy. The specimen must be obtained carefully in order to avoid artifact and crush distortion of the node or tumor tissue. Diagnosis of lymphomas is often difficult even under the best of circumstances, and efforts should be made to avoid increasing the pathologist's problems with a poor tissue specimen.

Anemia and thrombocytopenia usually are present only if the lymphosarcoma has converted to a leukemic phase identical to acute lymphocytic leukemia. The white blood count usually is normal but may be low or increased if leukemic conversion has occurred. Bone marrow examination is always indicated and may occasionally reveal leukemic conversion when the peripheral blood counts are normal. A hemolytic anemia with a positive Coombs test is very unusual in children with lymphosarcoma.

Roentgenographic studies may reveal chest, nasopharyngeal, bone, kidney, or gastrointestinal tract involvement.3 Thoracic lesions may be found in the anterior or superior mediastinum or in a paratracheal distribution. Pleural effusion may be present. The combination of a mediastinal mass and pleural effusion strongly suggests the diagnosis of lymphosarcoma.3 Intravenous pyelogram and inferior venocavagram (Figure 3) should be done if abdominal involvement is suspected.

Figure 1. Chest x-ray film of a child with lymphosarcoma showing a large mass in the upper mediastinum. Enlargement of the spleen is also evident.

Figure 1. Chest x-ray film of a child with lymphosarcoma showing a large mass in the upper mediastinum. Enlargement of the spleen is also evident.

Figure 2. Child with mediastinal lymphosarcoma (Figure 1) showing signs of acute superior vena cava syndrome; a. edema and fullness of the neck, respiratory obstruction, and venous distension ; b. x-ray therapy to the chest gave relief.

Figure 2. Child with mediastinal lymphosarcoma (Figure 1) showing signs of acute superior vena cava syndrome; a. edema and fullness of the neck, respiratory obstruction, and venous distension ; b. x-ray therapy to the chest gave relief.

Figure 3. Inferior venacavagram of a child with lymphosarcoma showing displacement and compression of the inferior vena cava by enlarged lymph nodes (arrow).

Figure 3. Inferior venacavagram of a child with lymphosarcoma showing displacement and compression of the inferior vena cava by enlarged lymph nodes (arrow).

Table

TABLE 3. STAGING OF A LYMPHOSARCOMA*

TABLE 3. STAGING OF A LYMPHOSARCOMA*

STAGING

Once the diagnosis of lymphosarcoma is confirmed by biopsy, the anatomic stage of the disease should be determined (Table 3). The liver, spleen, lymph nodes, and Waldeyer's ring should receive careful evaluation on the physical examination. It should be remembered that moderate cervical lymphadenopathy and enlarged tonsillar nodes are seen in many normal children; these should not be misinterpreted. A list of diagnostic studies usually required for staging of lymphosarcoma is presented in Table 4. The most helpful studies in defining the extent of the disease are the chest x-ray, lymphangiogram (Figure 4), and bone marrow aspiration. Lymphangiography may be difficult in children under five years of age, but it has been successful in a child as young as 17 months.13

The staging work-up for lymphosarcoma differs somewhat from the evaluation of Hodgkin's disease. Dividing each stage into "A" or "B" by the absence or presence, respectively, of systemic manifestations (fever, night sweats, weight loss) is not useful in nonHodgkin's lymphoma.14 Bone marrow aspiration is usually adequate for evaluating lymphosarcoma in children, but a bone marrow biopsy is required in Hodgkin's disease. The incidence of gastrointestinal tract involvement is significant in lymphosarcoma, unlike Hodgkin's disease, and justifies radiologic studies in the staging evaluation.

Laparotomy and splenectomy are now performed in most centers to more accurately determine the presence and location of Hodgkin's disease in the abdomen in patients with stage I, II, or III disease. The value, however, of laparotomy and splenectomy has not been defined for non-Hodgkin's lymphomas.15 The procedure is not without risks, and it appears that the potential value is much less in nonHodgkin's lymphomas than it is in Hodgkin's disease. The results of a laparotomy in Hodgkin's disease may permit selection among alternative curative therapies. Such a choice of curative therapies does not exist for lymphosarcoma.14 This author, therefore, does not use routine laparotomy for the staging of lymphosarcoma.

TREATMENT

The prognosis for childhood lymphosarcoma has been dismal. A recent review of 221 patients in various series showed that the over-all fiveyear survival rate was only nine per cent.16 The incidence of leukemic transformation in several recent series has ranged from 50 to 73 per cent.3,16 In the past, treatment usually consisted of surgery, radiation therapy, and chemotherapy. Although localized radiation therapy can occasionally result in longterm survivals, the majority of patients have disseminated disease. Recent studies have stressed more aggressive radiation treatment or more intensive chemotherapy or both.

Patients with stage I and II disease are being treated in some centers with total nodal irradiation, and some patients with stage III disease are receiving total nodal irradiation in addition to combined chemotherapy with cyclophosphamide, vincristine, and prednisone.17 Total body irradiation and total node irradiation has resulted in a 93 per cent remission rate and a five-year survival rate of 72 per cent of adults with stage III and stage IV (with only bone marrow involvement).18

It has been shown that the incidence and durations of remissions in lymphomas are much greater when combinations of effective drugs are used than when the agents are used singly. The combination of cyclophosphamide, vincristine, and prednisone has produced remissions in 50 to 60 per cent of adult patients with lymphosarcoma.19,20 The mean duration of maintained remissions was 49 weeks in one study,19 and 89 per cent of the complete remissions lasted more than one year in another series.20 New drugs that have shown effectiveness against lymphosarcoma include adriamycin, bleomycin, and nitrosourea (BCNU).

Figure 4. Lymphangiogram showing marked enlargement of pelvic and lower abdominal lymph nodes. (Same child as Figure 3.)

Figure 4. Lymphangiogram showing marked enlargement of pelvic and lower abdominal lymph nodes. (Same child as Figure 3.)

Table

TABLE 4. DIAGNOSTIC EVALUATION OF LYMPHOSARCOMA

TABLE 4. DIAGNOSTIC EVALUATION OF LYMPHOSARCOMA

A recently described program uses chemotherapy and radiation therapy to attempt to improve the quality and duration of remission, reduce the incidence of leukemic conversion, and increase the cure rate.16 Clinically involved areas are treated with cobalt60 radiation in doses of 1,600 to 3,500 rads. Patients also receive combination chemotherapy (prednisone, vincristine, 6-mercaptopurine, methotrexate, cyclophosphamide) similar to that used for acute lymphocytic leukemia in the St. Jude program. Six of 10 patients treated in the series have remained in continuous complete remission for 4 to 49 months.21 Of these, five had treatment stopped after two years of continuous complete remission, while four continued to be free of tumor for 43 to 49 months.

We can easily conclude from the current number of treatment studies that we presently do not know the best way to treat lymphosarcoma. The author presently favors the St. Jude approach with localized radiotherapy and combination chemotherapy.16 Complications of lymphosarcoma are frequent; the management of them is listed in Table 5.

SUMMARY

Lymphosarcoma is a highly malignant tumor that may originate in any lymphatic tissue in the body, either in lymph nodes or in extra-nodal sites. The disease most frequently occurs in the neck, mediastinum, or abdomen. The involved nodes are discrete, firm, non-tender and are usually not fixed to surrounding tissue. Lymphosarcoma involving the cervical nodes frequently must be differentiated from bacterial adenitis.

The definitive diagnosis is made by a properly performed biopsy, and the anatomic stage of the disease is then defined. The most helpful studies for staging are the chest x-ray, lymphangiogram, and bone marrow aspiration. Results of treatment have been dismal in the past, but recently instituted aggressive radiotherapy and chemotherapy programs have resulted in improved survival.

Table

TABLE 5. TREATMENT OF COMPLICATIONS OF LYMPHOSARCOMA

TABLE 5. TREATMENT OF COMPLICATIONS OF LYMPHOSARCOMA

BIBLIOGRAPHY

1. Pochedly. C. Lymphosarcomas in children. NY. State J. Med. 70 0970), 543-551.

2. Jones. B. and Klingberg. W. G. Lymphosarcoma in children. J. Pediatr. 63 (1963). 11-20.

3. Schey. W.L., White, H.. Conway, J.J., and Kidd, J.M. Lymphosarcoma in children: A roentgenologic and clinical evaluation of 60 children. Am. J. Roentgenol. Radium Ther. Nucl. Med. 117 0973), 59-72.

4. Rappaport, H. Tumors of the Hematopoietic System. Atlas of Tumor Pathology, Section IllFascicle 8. Washington. D. C: Armed Forces Institute of Pathology, 1966.

5. Rundles, R.W. Lymphosarcoma. W4J. Williams, E. Beutler, A.J. Erslev, and R.W. Rundles, eds. In Hematology. New York: McGraw-Hill Co., 1972.927-936.

6. Jaffe. B. F. and Jaffe, N. Head and neck tumors in children. Pediatrics 51 (1973). 731-740.

7. Han. T. and Stutzman, L. Mode of spread in patients with localized malignant lymphoma. Arch. Intern. Med. 120 (1967), 1-7.

8. Hartsock, R.J. Postvaccinal lymphadenitis: Hyperplasia of lymphoid tissue that simulates malignant lymphomas. Cancer 21 (1968), 632-649.

9. Choovlvathanavanich, P., Wallace, E. M., and Scaglione, P.A. Pseudolymphome Induced by diphenylhydantoin. J. Pediat. 76 (1970). 621-623.

10. Gams, R. A., Neal, J. A., and Conrad, F. G. Hydantoin-induced pseudo-pseudolymphoma . Ann. Intern. Med. 69 (1968). 557-568.

11. Anthony, J.J. Malignant lymphoma associated with hydantoin drugs. Arch. Neurol. 22 (1970), 450-454.

12. Canale, V.C. and Smith. CH. Chronic lymphadenopathy simulating malignant lymphoma. J. Pediatr. 70 (1967). 891-899.

13. Gasquet, C, Schweisguth, O., Deb run, G., et al. Lymphangiography in malignant diseases of childhood. Am. J. Roentgenol. Radium Ther. Nucl. Med. 103 (1968), 1-12.

14. Alsenberg. A.C. Malignant lymphoma. New Engl. J. Med. 288 (1973), 883-941.

15. Carbone. P.P. Management of patients with non-Hodgkin's lymphoma. Arch. Intern. Med. 131 (1973), 455-459.

16. Aur, R.J.A., Hustu. H.O.. Simone. J.V.. et al. Therapy of localized and regional lymphosarcoma of childhood. Cancer 27 (1971). 1328-1331.

17. Jones, S. E., Kaplan, H. S., and Rosenberg, S.A. Non-Hodgkin's lymphomas. III. Preliminary results of radiotherapy and a proposal for new clinical trials. Radiology 103 (1972), 657-662.

18. Johnson, R. E. Radiation therapy of generalized lymphocytic lymphomas. Am. J. Roentgenol. Radium Ther. Nucl. Med. if 7 (1973), 50-53.

19. Luce. JK. , Gamble. J. F.. Wilson. H. E., et al. Combined cyclophosphamide, vincristine, and prednisone therapy of malignant lymphoma. Cancer 28 (1971), 306-317.

20. Bagley, C.M., Jr., Devita, V.T., Jr., Berard, CW.. and Canellos. G. P. Advanced lymphosarcoma: Intensive cyclical combination chemotherapy with cyclophosphamide, vincristine, and prednisone. Ann. Intern. Med. 76(1972), 227-234.

21 . Appendix. The Year Book of Cancer. 1972. Chicago: Year Book Medical Publishers, 1972, 194-196.

22. Rosenberg, S.A., Diamond, H. D., Dargeon. H. W., and Craver, L. F. Lymphosarcoma in childhood. New Engl. J. Med. 259 (1958). 505-512.

23. Carbone, P.P., Kaplan, H. S.. Musshoff. K., et al. Report of the committee on Hodgkin's disease staging classification. Cancer Res. 31 (1971). 1860-1861.

24. Watanabe, A.. Sullivan. M. P., Sutow, WW., and Wilbur, J. R. Undifferentiated lymphoma, non-Burkitt's type. Am. J. Dis. Child. 125 (1973), 57-61.

25. Weick, J. K., Kiely, J. M., Harrison. E.G.. Jr., et al. Pleural effusion in lymphoma. Cancer 31 (1973). 848-853.

26. D'Angio. G.J. . Mitus. A., and Evans, A. E. The superior mediastinal syndrome in children with cancer. Am. J. Roentgenol Radium Ther. Nucl. Med. 93 (1965). 537-544.

27. Lasca ri, A.D. Leukemia in Childhood. Springfield: Charles C Thomas, 1973.

TABLE 1. CLASSIFICATION OF MALIGNANT NON-HODGKIN'S LYMPHOMAS

TABLE 2. CLINICAL MANIFESTATIONS OF CHILDHOOD LYMPHOSARCOMA

TABLE 3. STAGING OF A LYMPHOSARCOMA*

TABLE 4. DIAGNOSTIC EVALUATION OF LYMPHOSARCOMA

TABLE 5. TREATMENT OF COMPLICATIONS OF LYMPHOSARCOMA

10.3928/0090-4481-19740501-07

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