386 Vol. 67, No. 6

California Commission Studles* Chapter VIII 'Malignant

ANGUS WRIGHT, M.D., Los Angeles

THE terms malignant lymphoma or malignant served in all types of malignancies of lymphoid lymphoblastoma are generally used to designate tissues. malignant disease of lymphoid tissues. In common The cause or causes of this group of diseases are usage these are spoken of as lymphosarcoma, leu- unknown. Theories and observations related to their kemia, and Hodgkin's Disease. The nomenclature origins are numerous. otherwise is unfortunately highly varied, controver- sial, and confusing. GENERAL CLINICAL OBSERVATION Detailed classifications are necessarily those based The symptoms which may bring the patient to a largely on morphology and are among the trade tools doctor are many and varied. of the pathologist. Such classifications are in a gen- The onset of disease of this type is usually insid- eral way of value in estimation of prognosis and ious. The process may be present in hematologically radiation sensitivity. Gall and MalloryI who have diagnosable form before there is objective or sub- made one of the most exhaustive modern studies of jective evidence that anything may be amiss. This is the subject offer a morphologic classification based illustrated infrequently in individuals undergoing on a study of some 600 cases. This is readily appli- periodic physical examination or elective surgery, cable to clinical use and has sound histologic and where a routine blood count reveals the presence of clinical correlation. The classification is tabulated . below along with the terms of more common usage 'Painless swelling of the easily observed superficial as a reference for the individual who might en- lymph nodes is the most common early symptom of counter some of the less familiar terms: the entire malignant lymphoma group. In some cases, the secondary. effect of expansive growth of deep Malignant Lymphoma lymph nodes may first call attention to the presence (Classification of Gall and Various terms commonly of the disease. Enlargement of mediastinal or bron- Mallory) used. chial lymph nodes may cause bronchial compression A. Stem cell lymphoma Lymphosarcoma group; in- with resultant cough. The development of abdominal B. Clasmatocytic lymphoma cluding reticulum cell sar- masses due to either splenic enlargement or mesen- coma and monocytic retic- teric adenopathy is relatively frequent. Tumor masses uloendotheliosis. originating in the lymphoid tissues of the stomach C. Lymphoblastic lymphoma Lymphosarcoma, Lymph- or intestine may cause mechanical obstructive symp- D. Lymphocytic lymphoma atic leukemia (acute and toms or may produce ulceration of the overlying chronic) mucosa with resultant hematemesis or melena. E. Lymphosarcoma, giant fol- As a result of involvement of , there licle type, Brill-Symmers' is usually a decrease in the number of blood platelets Disease so that hemorrhagic signs may appear. Sudden pur- F. Hodgkin's lymphoma Hodgkin's Disease puric manifestations unrelated to or disproportionate G. Hodgkin's sarcoma to trauma are relatively frequent. Severe following tooth extraction or other minor surgery The authors of this classification emphasize the may occur. Epistaxis or unusual uterine bleeding fact that leukemia of lymphatic type is of incidental may be the first indication of disease. Weakness or occurrence in malignant lymphomatous disease and asthenia are frequent early symptoms which are, in that lymph node morphology does not differentiate part, related to . between lymphosarcoma and lymphatic leukemia. Unexplained fever is a frequent early finding in Hematologic leukemic manifestations have been ob- the malignant lymphomata. Indeed, all of the pa- tient's early symptoms may suggest a low grade * Organized by the Editorial Committee of the California infection. Vague aching and pain in the extremities Cancer Commission. may be one of the subjective symptoms. CORRECTION: I The general findings may give all of the clinical Dr. John M. Kenney, whose article, "Childhood Cancer," indications of the toxemis of . There is appeared in this section of the November issue of California freqllently unexplained weight loss. Medicine, is practicing in Santa Rosa, California, not in Occasional patients have an initial complaint of Sonoma as the signature line on the article indicated. generalized pruritis. December, 1947 EXAMINE NODE BEARING AREAS 387 As previously indicated, leukemia of lymphatic clinical manifestation and microscopic appearance. type is not differentiated by lymph node morphology. Syphilis can be overlooked and misdiagnosed as The hematologic observation of leukemia is a vari- malignancy. Other inflammatory lesions have been, able phenomenon in the group of the malignant and undoubtedly will be, similarly misinterpreted. lymphomata, being observed most frequently in the The following outline is meant to illustrate in a gen- lymphocytic lymphoma and lymphoblastic lymphoma eral way the various inflammatory lymphadenopa- groups of the classification of Gall and Mallory, and thies which may masquerade as malignancies 4nd with equal rarity in their Hodgkin's lymphoma and which, therefore, should be considered: stem cell lymphoma groups. Leukemia is not re- garded, then, as a specific disease entity but rather CAUSES OF INFLAMMATORY LYMPHADENOPATHY as one of the objective findings in this general group. A. Local acute lymphadenitis: The final classification and diagnosis o/ this entire 1. Acute focal pyogenic infections. group is dependent upon histologic examination. 2. Primary specific infections. (a) Syphilis ("cryptic" chancre). LYMPHOSARCOMA-LYMPHATIC LEUKEMIA GROUP (b) Other infectious granulomas. (c) Acute lesions of lymphogranuloma venereum. Under this broad heading may be included the (d) Tularemia with occult primary lesion. stem cell, the clasmotocytic, the lymphocytic, the (e) Bubonic plague (endemic in California). lymphoblastic, and the follicular of the B. Local chronic lymphadenitis: morphologic classification. Although these different 1. Chronic pyogenic infection. J types show slight individual differences in averages, 2. Chronic specific infections. such as in age incidence, they all exhibit the same C. Acute generalized lymphadenitis: general characteristics of the malignant lymphoma. 1. . 2. Infectious . HODGKIN S DISEASE 3. Leukemoid reaction. On the basis of the morphologic classification the 4. Exanthematous infections. most commonly encountered lymphoid malignancy is 5. Infectious granulomata. Hodgkin's Disease. As in all' of the other malignant D. Chronic generalized lymphadenitis: lymphoblastomata there is a definite preponderance 1. Infectious granulomata. of males in sex incidence which 3:1. 2. Tularemia. approximated 3. Undulant fever. Commonly a generalized disease involving the 4. Glanders. superficial and deep lymphoid tissues as a dissemi- nated disease, Hodgkin's is rarely seen as an isolated As the outline indicates, the infectious granu- primary growth originating apparently in the lymph- lomata' may be the cause of lymphadenopathy, oid tissues of a viscus such as the stomach or small whether local, generalized, acute, or chronic. Some of bowel. the more obscure infections, such as glanders (b. More so than the other lymphomas, Hodgkin's mallei), tularemia, and undulant fever, are more Disease is the picture of an infection with febrile likely to be overlooked because of their infrequent manifestation (50%o-59%o ) 1 which occasionally may incidence. be accompanied by ague-like chills. The intermittent Infectious mononucleosis, even today, is mistaken fever of Pel-Ebstein type occurs with some frequency for leukemia or other of the malignant lymphomas. but is not by any means invariable. Eosinophilia al- The heterophile antibody test is not infallible in diag- though observed occasionally is not seen frequently nosis. There are certain cases which do not ever in the hematologic picture. Cutaneous lesions are of demonstrate the heterophile phenomenon. Early in infrequent occurrence although rarely seen as an ini- the disease, the test is frequently negative. Diagnosis tial manifestation. Visceral lesions as mentioned requires competent hematologic examination. above may be primary. Rare cases of primary pul- Infectious lymphocytosis .undoubtedly has been monic involvement are seen. mistaken for lymphatic leukemia as have pertussis, infectious parotitis, measles, and other of the acute DIFFERENTIAL DIAGNOSIS infections of childhood which produce lymphatic Diagnosis of disease of lymphoid tissue must con- reaction. sider inflammatory processes, as well as malignancy. Leukemoid reaction is seen occasionally, particu- The grave portent of the diagnosis of lymphatic larly in childhood, when the lymphoid tissues are malignancy should demand that consideration of all more active and labile. These tissues frequently re- other possibilities be exhausted before final classifi- spond to injury with dissemination of immature, cation is made. toxic appearing leukocytes into the peripheral blood. The lymphatic tissues, as a series of filters in the This type of reaction is undoubtedly the entire source lymphatic channels which transport particulate mat- of the "recovered" cases of leukemia. ter and substances in solution, respond readily to In patients showing lymphadenopathy, whether injury with inflammation and hyperplasia. The generalized or regional, where the process cannot be common result of such response is lymph node attributed to inflammation, the possibility of malig- enlargement. nant lymphoblastoma should be borne in mind and It is possible for any of the inflammatory lesions the use of lymph node biopsy considered, particu- of lymphoid tissue to simulate malignancy both in larly in those cases where apparent inflammatory 388 CALIFORNIA MEDICINE Vol. 67, No. 6 association is demonstrated but where the nodes fail 5. The pathologis should always be supplied with to regress. complete blood count and Wassermann reports and In any case with hemorrhiigic "manifestations, a blood smear should be sent with the biopsy examination of the blood for evidence of malignant specimen. lymphoblastoma is warranted. TREATMENT With involvement of thef deeply situated mrndiasti- nal'or abdominal lymph nodes, there inay be evidence Roentgen radiation is the .only, form of tl@rapy of the systemic effects of the malignancy'without ex- which has proved to be effective in any significant ternally demonstrable tumor. Lesions of this charac- degree as demonstrated over a period of years on ter are difficult to demonstrate by any other means large numbers of cases. The malignant lymphomata than x-ray. as a group react favorably and rapidly to relatively small amounts of radiation. It is occasionally ob- Lymphadenopathy,' particularly in the cervical re- served that radiation of a single grou,p of lymph gion, may be the result of "silent" primary car- nodes involved in a lymphomatous process will re-' cinomas of oral and nasopharyngeal origin. Less sult in coincident reduction in size of involved lymph frequently carcinoma in other situations may give nodes in other body areas. The beneficial effects of rise to distant or widespread involvement of lymph- Roentgen radiation are effective in palliation, pro- oid tissues. longation of life, and in relief of obstruction, but are not curative. Tumors may reappear in treated areas BIOPSY immediately after oompletion of a course of therapy. Diagnosis in the great majority of the cases of Initial resistance to radiation therapy was encoun- this group is dependent upon biopPy. tered in 9 per cent of all of the cases studied by In the performance of biopsy onee annot over- Gall and Mallory. Terminally, in some cases there is emphasize the importance of certain technical con- a marked resistance to irradiation. siderations which are briefly enumerated: Radio-active phosphorus has been used extensively 1. Selection of area for biopsy:. in the treatment of malignant lymphomas. The re- If there is a choice of biopsy site, lymph nodes sults have been disappointing. In general, it has from the inguinal area should be avoided. These proven to be less effective than x-ray therapy.3 The nodes commonly show chronic inflammatory changes material has been used experimentally and is not which frequently are of such severity that they are available for general distribution. not suitable for diagnosis. Nitrogen mustard therapy (the use of hyoginated akyl amines), has been the subject of recent studies 2. Selection of individual lymph nodes: and the reports are somewhat favorable. These re- It is preferable to select the largest, 'or one of'the ports indicate that some cases resistant to radiation largest, lymph nodes, rather than one which is only respond favorably to nitrogen mustards and that slightly enlarged. This statement is made on the basis following such therapy responsiveness to radiation of the fact that the larger lymph node will offer a may be increased. Goodman, et al.,2 make the follow- more representative picture of the disease process. ing comment in discussion of their recently published The small node may not even be involved.' results: "Although indications and contraindications 3. 'Avoidance of trauma to biopsy tis-ue: for the use of nitrogen mustards remain to be estab- lished definitely, it is felt that these agents are de- The biopsy is performed to obtain information by serving of further clinical trial in Hodgkin's Disease, microscopic examination. Therefore, all considera- lymphosarcoma, and leukemia. Like radiation, thev tion should be directed to the care of the biopsy not specimen. In process of removal it should not be do cure." compressed by clamps or forceps. Compression of SURGERY even slight degree causes traumatic artifacts of the The accepted concept of the malignant lymphoma- extremely delicate lymphoid tissues so that they may tous diseases is that they are the expression of a gen- be rendered unfit for examination. After removal, eralized disseminated process. There are, however, the specimen should not be palpated, incised, well authenticated, histologically verified cases where squeezed, or massaged, but given to the pathologist removal, or intensive irradiation, of a solitary local- at once. ized visceral or skeletal lesion has been curative. 4. Care of tissues when the biopsy is to be mailed: Although the number of these cases is small, the When the tissue is to be mailed to a pathologist definite character of the lesion and the possibility of and will be any time in transit, it is wise in order favorable result should justify consideration of sur- to insure fixation, to incise the tissue with -a sharp gery where there is a demonstrated solitary lesion. knife in its midline long axis and from one of the Lesions of the tonsil and gastro-intestinal tract are pieces cut a slice of tissue measuring no more than the ones most likely to be cured by radical treatment. 4 mm. in thickness. The tissues should then be placed immediately in a volume of fixative at least 10 times PROGNOSIS that of the tissue. Choice of fixatives varies as do Prognosis in the average case in this disease group pathologists. For general purposes, readily available is most doleful. It is possible, on the basis of histo- 10 per cent formalin is satisfactory. logic classification of the lesion, to determine prog- December, 1947 BIOPSY CHRONIC LYMPH NODES 389

nosis in a general way insofar as survival period is REFERENCES concerned. The less differentiated lymphoblastic lym- 1. Gall, E. A. and Mallory, T. B.: Malignant lymphoma; phomas, the stem cell lymphomas, and the clasmoto- clinico-pathologic survey of 618 cases, American Journal of cytic lymphomas show a very small percentage of Pathology, 18:381 (May), 1942. 2. Goodman, L. S., Wintrobe, M. M., Gilmon, A. and Mc- cases with five-year survival. The more differentiated Kennon, M. T.: J.A.M.A., 132:126, 1946. follicular lymphoma and lymphocytic lymphoma 3. Rinehart, J. F., et al.: Journal of Laboratory and Clinical show approximately 50 per cent of the total number Medicine, 31:107, 1946. which survive for five years after diagnosis. Hodg- "Cancer of the Lip" by Ian Macdonald, M.D., Chapter XI kin's sarcoma which represents only a small percent- of the California Cancer Commission Studies will appear in . age of the total is a much more malignant form of the this section of the January issue of CALIFORNIA MEDICINE. disease than Hodgkin's lymphoma which shows five- Chapters IX and X on "Cancer of the Skin" will be published years survivals in roughly one-third of the cases. later.

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