Primary malignant lymphoma cutis BURRELL H. WOLK, MD
Between 1934 and 1975, 16 patients with primary malignant lymphoma cutis were seen at the Ottawa clinic of the Ontario Cancer Foundation. The lesions were purplish, firm, dermal or hypodermal (or both) nodules, tumours and plaques. In all 16 the histopathologic diagnosis was diffuse non-Hodgkin's lymphoma; 12 were considered to have prognostically bad lymphomas. However, the prognosis of primary malignant lymphoma cutis is significantly more favourable than is implied by the stage IV designation that such localized extranodal involvement would have required under the Rye clinical staging classification. Entre 1934 et 1975, 16 patients atteints de lymphomes primaires maIms du derme ont ete examines a Ia clinique d'Ottawa de Ia Fondation ontarienne pour le cancer. Les nodules, les tumeurs et les plaques etaient violac.s, fermes et dermiques ou hypodermiques (ou les deux). Chez los 16 patients un diagnostic histopathologique de lymphome diffus non.Hodgkinien a ete pose; le pronostic a et6 considere comme mauvais pour 12 d'entre-eux. Toutefois, le pronostic d'un lymphome primaire maIm du derme est beaucoup plus favorable que ne laisse supposer sa classification de stade IV, ce qui est Ia designation accordee par le systeme de classification clinique Rye pour une telle atteinte extranodulaire localisee.
There are few published reports"2 on primary malignant lymphoma cutis. The purpose of this paper is to report the experience of the Ottawa clinic of the Ontario Cancer Foundation. Definition and classification
Lymphomatous disease of the skin can be defined as a heterogeneous group of skin diseases that have a dermal cellular infiltrate derived from either lymphocytes or histiocytes, or from their precursors. Some of these diseases are clearly benign; some are clearly malignant. However, at times it is not easy to distinguish, either din-
From the department of dermatology, Ottawa Civic Hospital and University of Ottawa Reprint requests to: Dr. Burrell H. Wolk, Ontario Cancer Foundation, Ottawa clinic, Ottawa Civic Hospital. 1053 Carling Ave.. Ottawa, Ont. K1Y 4E9
750
ically or histologically, a variety of sue, such as the testis or kidney, can cutaneous benign lymphoid hyper- be the primary site of a malignant plasias from true malignant lymphoma. lymphoma. Up to one third of nonRappaport' classified malignant lym- Hodgkin's lymphomas may arise in exphomas morphologically as follows: tranodal sites.6 * Monomorphous 1. Undifferentiated (stem cell) Methods lymphoma Records were reviewed for all pa2. Histiocytic (reticulum cell) tients attending the Ottawa clinic of lymphoma 3. Mixed cell lymphoma (histio- the Ontario Cancer Foundation between 1934 and 1975 with the followcytic and lymphocytic) ing diagnoses: lymphosarcoma, Hodg4. Lymphocytic lymphoma kin's disease, reticulum cell sarcoma, - poorly differentiated mycosis fungoides, parapsoriasis, lym- well differentiated phocytoma cutis, lymphocytic infiltra* Polymorphous tion of the skin and leukemia cutis. 1. Hodgkin's disease 2. Mycosis fungoides, Sezary's Specific skin lesions of malignant lymphoma were found in 39 patients, exsyndrome cluding those with mycosis fungoides, Monomorphous lymphomas are those leukemia cutis or multiple myeloma. with a proliferation largely of one cell In 23 of the 39 patients the primary type, and polymorphous lymphomas are site of involvement was extracutaneous. those with a mixed cell population. The Data for the other 16 patients, in whom pattern of malignant lymphomas can cutaneous lesions were the sole manibe nodular (follicular) or diffuse. The festation at the time of initial examinaentire classification is based on the tion, form the basis of this report. histologic findings in the lymph nodes, (Although there is a similarity bewhere the pattern of malignant lym- tween primary lymphoma cutis and myphoma is more characteristic than in cosis fungoides, the lesions of the 16 the skin. patients did not have the histopathoRecently the identification of cell logic appearance of mycosis fungoides surface markers has led to a new classi- and, in accordance with Bluefarb7 and fication. termed the functional classi- others, we try to restrict the term myfication.4 This has proved to be im- cosis fungoides to that polymorphous portant in investigative studies and in skin process that is chronic and has studies of the biologic features of these three sequential stages - dermatitis, lymphomas. However, it is still of lim- plaque and tumours.) ited usefulness to the pathologist, whose The criteria for inclusion of a padiagnosis is based primarily on morpho- tient in the group with primary maliglogic findings. nant lymphoma cutis were as follows: It has been estimated that about 1. Biopsy-proven lymphoma of skin. 50% of patients with malignant lym2. No evidence of extracutaneous phomas will have skin manifestations, either specific or nonspecific lesions, disease at the time of initial examinaat some time.' This study was con- tion as determined by (a) physical examination (lymph cerned with the specific lesions - lenodes, liver and spleen not sions in the skin composed of malignant lymphoma cells, excluding those palpable), (b) chest radiography (radiooccurring in mycosis fungoides, leukegraphs clear), mia cutis or multiple myeloma. (c) hematology (examination of Lymphoma cutis may be considered peripheral blood and, in some either primary (i.e., arising in the skin) or secondary (i.e., arising in a lymph patients, bone marrow yielded normal findings), node or viscus). Primary lymphoma cutis is uncommon. This is not difficult (d) biochemistry (normal results to understand since the dermis does of liver and renal function not possess organized lymphoid or retitests) and cular tissue. We usually think of lym(e) other procedures (lymphangiography, liver scan and intraphomas as originating in lymph nodes, venous pyelography, peryet we know that the dermis is capable of lymphoreticular hyperplasia in reformed in three patients, demsponse to various stimuli - for exonstrated no abnormalities). 3. Interval of not less than 6 months ample, insect bites. Furthermore, we know that other nonhematopoietic tis- from diagnosis to detection of extra-
CMA JOURNAL/OCTOBER 8, 1977/VOL. 117
cutaneous disease. (Considering the behaviour of lymphomas in other organs and the rapid doubling time of lymphoma cells, this seemed a reasonable interval for primary extracutaneous disease to have become apparent clinically.8) Most of the patients were seen before staging of disease with lymphangiography and exploratory laparotomy became routine; hence staging was done according to the facilities available. Follow-up information was obtained for each patient by letters to the patient when living, or to relatives or physicians.
6, 7, 8 and 14) the skin lesions (ranging in number from 10 to 30) were widespread (i.e., involving more than one body region); in one (no. 6) the disease remained confined to the skin. Pruritus was reported by only 1 of the 16 patients (no. 11). No other constitutional symptoms (e.g., unexplained fever, night sweats or loss of weight) were noted. Histopathologic type (Table I) All the lymphomas were non-Hodgkin's lymphomas of the diffuse pattern.
Findings Clinical manifestations at time of initial examination (Table I) The mean age of the 16 patients with primary malignant lymphoma cutis was 62.1 years (range, 23 to 79 years). The male:female sex ratio was 11:5. The lesions were purplish, firm, dermal or hypodermal (or both) nodules, tumours and plaques varying from 0.5 to 7.0 cm in diameter (Fig. I). Tumour ulceration occurred in one patient (no. 3) (Fig. 2). None had erythroderma. In 12 patients the skin lesions (ranging in number from one to three) were localized to one body region (stage IE) at the time of initial examination; in 5 (nos. 1 to 5) the disease remained confined to the skin and in 7 systemic disease developed eventually. In the remaining four patients (nos. FIG. 1-Tumour nodules on forehead.
(In the period under study there was no patient with Hodgkin's disease of the skin.) Diffuse histiocytic lymphoma was the most frequent type, occurring in 10 of the 16 patients. This histopathologic type still defies precise definition because there is no agreement on the cell of origin. The histopathologic diagnosis in the 10 patients was based on the presence of a monomorphous cellular infiltrate in the dermis and often the subcutaneous tissue, consisting of large, atypical cells with abundant cytoplasm and vesicular nuclei containing a small but prominent nucleolus. Diffuse well differentiated lymphocytic lymphoma was diagnosed in 4 of the 16 patients. Although there is often only a fine line dividing well differentiated lymphocytic lymphoma from
FIG. 2-Ulcerated tumour nodule.
CMA JOURNAL/OCTOBER 8, 1977/VOL. 117 751
chronic lymphocytic leukemia, the results of peripheral blood examination, including the absolute lymphocyte count, were repeatedly normal in the four patients. However, bone marrow examinations were not done.
for the patients in the study by Jones and colleagues, which indicates a significantly longer median survival time in the 10 patients.
Course and survival
The main treatment modality was radiotherapy. All 10 patients with systemic disease and 3 of the 6 (nos. 1, 4 and 5) with disease confined to the skin received x-ray treatment. Seven of the 10 patients with systemic disease (nos. 7, 8, 10 to 13 and 15) were also given chemotherapy. Two of the patients (nos. 2 and 3) with disease confined to the skin were treated solely by excision of the solitary lesion, and one (no. 6) received no treatment; his nodules and plaques resolved spontaneously.
In terms of clinical course the 16 patients could be divided into two groups: (a) those in whom the disease remained confined to the skin and (b) those in whom the lesions were only in the skin at the time of initial examination, but then became disseminated to lymph nodes or viscera, or both. There were six patients in the first group. Two died of a cerebrovascular accident, one (no. 2) 14 years after the diagnosis was made. No autopsy was done on either patient. The other four patients were, at the time of this study, alive and well and showed no evidence of extracutaneous disease, one (no. 5) at 25 years from the time of diagnosis and the others at 23, 53 and 30 months, respectively. One patient (no. 6) was not treated and the lesions resolved spontaneously. There were 10 patients in the second group, 9 of whom died. The mean interval from time of diagnosis to death was 40.3 months. One patient (no. 16) was, at the time of this study, alive 9 years and 7 months after the initial examination. The most common extracutaneous site of involvement was the peripheral lymph nodes (eight patients), and the next most common, the liver (five patients); hilar nodes, lung and spleen were involved in one patient each. The peripheral blood smear was abnormal in four patients. The interval from appearance of the initial skin lesions to documented extracutaneous involvement ranged from 6 months to 12 years (mean, 27.5 months). Patients with well differentiated lymphocytic lymphoma had a long survival, particularly when compared with the patients having other histopathologic types of lymphoma. Of the 16 patients only the group with diffuse histiocytic lymphoma was large enough for a meaningful estimate of the median survival time to be made. Survival curves computed by the method of Kaplan and Meier9 for these 10 patients and for the 26 patients with stage IVA diffuse histiocytic lymphoma in the study by Jones and colleagues'0 are shown in Fig. 3. The two populations, although different in size, approximate each other in terms of age, sex and period under study (i.e., all patients were seen initially after 1957). The survival curve for the 10 patients in this study lies consistently above the survival curve
Treatment
Discussion
A correlation between survival and histopathologic type of non-Hodgkin's lymphoma arising in extracutaneous sites has been shown in several studies.10'" Diffuse poorly differentiated lymphocytic lymphoma, diffuse mixed cell lymphoma and, particularly, diffuse histocytic lymphoma have a poor prognosis; they have a definite predilection for early dissemination. Well differentiated lymphocytic lymphomas, whether nodular or diffuse, generally have a very good prognosis. These observations hold true in this study: the 4 patients with well differentiated Jymphocytic lymphoma had a long survival time (median, 95 months), whereas the other 12 patients had a considerably shorter survival time (median, 24.5 months). Although the histomorphologic classification of malignant lymphomas based on specific cytologic features as proposed by Rappaport' has proven useful for clinicopathologic studies,
'-I
.08
.'
C006 U-.-,
.Q4 .Q2
a
1 2 3 Time in Years
4
FIG. 3-Probability of survival in 10 patients with primary malignant lymphoma cutis, diffuse histocytic type (squares), and 26 patients with stage IVA diffuse histiocytic lymphoma" (circles).
752 CMA JOURNAL/OCTOBER 8, 1977/VOL. 117
major problems of nomenclature have remained primarily because of lack of agreement as to the precise nature of the neoplastic cells in many tumours. Recent advances in immunology have led to re-examination of many of the conventional concepts regarding classification and nomenclature of the lymphomas. New immunologic and cytochemical techniques have established that malignant lymphomas are neoplasms of the immune system.4"2 Lukes and Collins4 have maintained that most so-called histiocytic lymphomas are made up not of true histiocytes but of transformed B-lymphocytes, which morphologically resemble the large, noncleaved follicular centre cell. In addition to histopathologic type, the other equally important determinant of prognosis, treatment and curability is the stage of the lymphoma. Although the Ann Arbor clinical staging classification13 remains a useful guide there are cases that defy such classification. For example, the patients in this study with widespread skin involvement but without nodal or visceral disease (nos. 6, 7, 8 and 14) do not fit into the Ann Arbor classification. The same problem exists with mycosis fungoides, indicating that the classification is not completely satisfactory, at least not for cutaneous lymphomas. This study detected 16 cases of nonHodgkin's lymphoma arising in the skin. Although lymphomas are usually considered to be tumours of lymph nodes, it is now well recognized that a substantial proportion of non-Hodgkin's lymphomas occur in extranodal sites (e.g., thyroid, lung, gastrointestinal tract and ovary)." Despite the fact that the lesions may be localized at the outset, the Rye Conference criteria'4 required an automatic stage IV designation for patients with any type of extranodal disease. Subsequent to several reports suggesting that extranodal lymphomas have a better prognosis than lymphomas arising in lymph nodes'5-'7 the Ann Arbor classification modified the widely accepted Rye system to permit separate classification (as JE or lIE) of such localized extranodal lesions.'3 To my knowledge survival figures justifying this separation for primary lymphomas of the skin have not been reported. The data from this study show that primary malignant lymphoma cutis has a prognosis that is significantly more favourable than i,s implied by the stage IV designation that such localized extranodal involvement would have required under the Rye clinical staging classification. I thank Dr. R. Jackson for his constructive suggestions and comments, Dr. T. Stoddart and the office staff of the Ottawa
Civic Hospital division of the Ontario
Cancer Foundation for their cooperation, and the audiovisual department of the Ottawa Civic Hospital for preparing the illustrations.
4. LUKES RJ, COLLINS RD: Immunologic characterization of human malignant lymphomas. Cancer 34: 1488, 1974 5. EPSTEIN E, MACEACHERN K: Dermatologic manifestations of the lymphoblastoma-leukemia group. Arch Intern Med 60: 867, 1937 6. ULTMANN JE, STEIN RS: Non-Hodgkin's lymphoma - an approach to staging and therapy. CA 25: 320, 1975 7. BLUEFARS SM: Is mycosis fungoides an entity? Arch Dermatol 71: 293, 1955
References 1. RIBEIRO GG: Primary lymphosarcoma and reticulum cell sarcoma of the skin. Clin Radiol 23: 279, 1972 2. KIM R, WILKELMANN RK, DOCKERTY M: Reticulum cell sarcoma of the skin. Cancer 16: 646, 1963 3. RAPPAPORT H: Tumors of the Hemacopojetic System, Washington, Armed Forces Institute of Pathology, 1966, pp 91-206
8. HOLLAND JE, FREt E Iii: Cancer Medicine, Philadelphia, Lea & Febiger, 1973, pp 629-49 9. KAPLAN EL, MEJER P: Non-parametric estimations from incomplete observations. Am Stat Assoc 1 453: 457, 1958 10. JONES
SE,
FUKS Z,
BULL M,
et al:
Non-
Hodgkin's lymphomas. IV. Clinicopathologic correlation in 405 cases. Cancer 31: 806, 1973 11. FREEMAN C,
BERG JW,
CUTLER SJ:
Occur-
rence and prognosis of extranodal lymphomas.
Cancer 29: 252, 1972
12. BRAYLAN RC, JAFFE ES, BERARD CW: Malig-
nant lymphomas: current classification and new observations, in Pathobiology Annual,
197S, IGAcHIM H (ed), New York, Appleton, 1975, pp 213-70 13. CARBONE PP, KAPLAN HS, MussHos'F K, ci al: Report of the Committee on Hodgkin's disease staging classification. Cancer Res 31:
1860, 1971 14. ROSENBERG SA: Report of the committee on the staging of Hodgkin's disease. Cancer Res 26: 1310, 1966 15. BANFI A, BONADONNA C, CARNEVALI G, et al: Preferential sites of involvement and spread in malignant Jymphomas. Eur J Cancer 4: 319, 1968 16. BERG JW, ScHOTTENFIELD D, HurraR RVP, et al: Histology, Epidemiology and End Results: the Memorial Hospital Cancer Registry, Washington, US Public Health Service, 1969 17. End results section, biometry branch, National Cancer Institutes: End Results in Cancer, no 3, Washington, Dept of Health, Education, and Welfare, 1968
Treatment of trophoblastic neoplasia at the Cancer Control Agency of British Columbia D.A. BOYES, MD; E. PANKRATZ, MD; B. GALLIFORD, MD; G.M. WHITE, MD; R.N. FAIREY, MD; B. Ho YUEN, MD
Over a period of 29 years 30 patients with gestational trophoblastic neoplasia were referred to the Cancer Control Agency of British Columbia. Five patients had benign disease and required no further treatment after having had dilatation and curettage. The remaining 25 patients were treated with methotrexate or hysterectomy, or both. Actuarial survival rates were 96.40/c at 1 year and 9O.60,.c at 5 years. There was a high correlation between malignancy and high titres of human chorionic gonadotropin (HCG). All cases of hydatidiform mole must be followed closely by means of estimations of HCG titre. Sur une periode de 29 ans 30 patientes presentant une neoplasie trophoblastique gestationnelle ont ete orientees vers l'Agence de contr6le du cancer de Ia Colombie Britannique. Cinq patientes avaient une maladie benigne et n'ont pas necessit6 d'autre traitement qu'une dilatation et un curetage. Les 25 autres patientes ont ete traitees aux methotrexate ou ont subi une hysterectomie, ou les deux. Les taux actuariels de survie ont ete de 96.40/c a I an et de 90.60/c & 5 ans. On a retrouv6 une forte corr6lation entre Ia malignite et de hauts titres de From the gynecologic oncology department, Cancer Control Agency of British Columbia, and the department of obstetrics and gynecology, University of British Columbia Reprint requests to: Dr. E. Pankratz, Cancer Control Agency of British Columbia, Heather St., Vancouver, BC V5Z 3J3 2656
gonadotropine chorionique humaine (GCH). Tous les cas de m6les hydatidiformes doivent .tre suivis de pres par mesure des titres de GCH.
Methods
A search of the records for the years 1938 through 1976 at the CCABC revealed 34 patients with trophoblastic neoplasia. Of the 34, 3 had nongestational choriocarcinoma of the ovary; all had died within 7 months of diagnosis despite chemotherapy. Another patient had a deciduoma and was successfully treated with cobalt irradiation. Only the 30 patients with gestational trophoblastic neoplasia are considered in the remainder of this report. Patients were referred to the CCABC for confirmation of the diagnosis or treatment, or both. The antecedent pregnancy, whether normal, abortal or molar, had been cared for in the patient's home town, and referral to the CCABC had been requested after the discovery of further symptoms. For all patients operative reports were obtained. Follow-up in all but 3 of the 30 patients was complete up to January 1977 and had consisted of regular examination at the CCABC or associated regional travelling clinics, or letters to the patient's physician. Three patients with benign disease had moved and were lost to follow-up. Clinical and histopathologic
I would go so far as to say that the combination of careful pregnancy-test supervision, a skilled clinician, and chemotherapy has made the histological examination of a hydatidiform mole, for a short-term clinical purpose, virtually superfluous. -W. Wallace Park1 A pathologist's report reading "Hydatidiform mole - benign" often engenders a feeling of relief in the minds of clinicians. The average physician is confronted with molar pregnancy so infrequently that the details of patient follow-up are not familiar to him; he recalls only that choriocarcinoma is malignant, hydatidiform mole is benign and chorioadenoma destruens lies somewhere in between. Such a pathology report only reinforces the impression that hydatidiform moles are benign. While virtually all hydatidiform moles are morphologically benign at the time of primary evaluation, the basis of successful treatment of subsequent trophoblastic disease lies in diligent follow-up of these "benign" moles. In this paper we review the results of treatment of gestational trophoblastic observations neoplasia at the Cancer Control Agency of British Columbia (CCABC), identify Age and racial origin shortcomings and apparent difficulties in the diagnosis and management of this Most of our patients were of childgroup of diseases, and explore ways of bearing age; four were over 40 years correcting the shortcomings and over- old. One patient was of Phillipine decoming the difficulties. scent, 1 was Chinese, 3 were North CMA JOURNAL/OCTOBER 8, 1977/VOL. 117 753
Between 1934 and 1975, 16 patients with primary malignant lymphoma cutis were seen at the Ottawa clinic of the Ontario Cancer Foundation. The lesions were purplish, firm, dermal or hypodermal (or both) nodules, tumours and plaques. In all 16 the histopathologic diagnosis was diffuse non-Hodgkin's lymphoma; 12 were considered to have prognostically bad lymphomas. However, the prognosis of primary malignant lymphoma cutis is significantly more favourable than is implied by the stage IV designation that such localized extranodal involvement would have required under the Rye clinical staging classification. Entre 1934 et 1975, 16 patients atteints de lymphomes primaires maIms du derme ont ete examines a Ia clinique d'Ottawa de Ia Fondation ontarienne pour le cancer. Les nodules, les tumeurs et les plaques etaient violac.s, fermes et dermiques ou hypodermiques (ou les deux). Chez los 16 patients un diagnostic histopathologique de lymphome diffus non.Hodgkinien a ete pose; le pronostic a et6 considere comme mauvais pour 12 d'entre-eux. Toutefois, le pronostic d'un lymphome primaire maIm du derme est beaucoup plus favorable que ne laisse supposer sa classification de stade IV, ce qui est Ia designation accordee par le systeme de classification clinique Rye pour une telle atteinte extranodulaire localisee.
There are few published reports"2 on primary malignant lymphoma cutis. The purpose of this paper is to report the experience of the Ottawa clinic of the Ontario Cancer Foundation. Definition and classification
Lymphomatous disease of the skin can be defined as a heterogeneous group of skin diseases that have a dermal cellular infiltrate derived from either lymphocytes or histiocytes, or from their precursors. Some of these diseases are clearly benign; some are clearly malignant. However, at times it is not easy to distinguish, either din-
From the department of dermatology, Ottawa Civic Hospital and University of Ottawa Reprint requests to: Dr. Burrell H. Wolk, Ontario Cancer Foundation, Ottawa clinic, Ottawa Civic Hospital. 1053 Carling Ave.. Ottawa, Ont. K1Y 4E9
750
ically or histologically, a variety of sue, such as the testis or kidney, can cutaneous benign lymphoid hyper- be the primary site of a malignant plasias from true malignant lymphoma. lymphoma. Up to one third of nonRappaport' classified malignant lym- Hodgkin's lymphomas may arise in exphomas morphologically as follows: tranodal sites.6 * Monomorphous 1. Undifferentiated (stem cell) Methods lymphoma Records were reviewed for all pa2. Histiocytic (reticulum cell) tients attending the Ottawa clinic of lymphoma 3. Mixed cell lymphoma (histio- the Ontario Cancer Foundation between 1934 and 1975 with the followcytic and lymphocytic) ing diagnoses: lymphosarcoma, Hodg4. Lymphocytic lymphoma kin's disease, reticulum cell sarcoma, - poorly differentiated mycosis fungoides, parapsoriasis, lym- well differentiated phocytoma cutis, lymphocytic infiltra* Polymorphous tion of the skin and leukemia cutis. 1. Hodgkin's disease 2. Mycosis fungoides, Sezary's Specific skin lesions of malignant lymphoma were found in 39 patients, exsyndrome cluding those with mycosis fungoides, Monomorphous lymphomas are those leukemia cutis or multiple myeloma. with a proliferation largely of one cell In 23 of the 39 patients the primary type, and polymorphous lymphomas are site of involvement was extracutaneous. those with a mixed cell population. The Data for the other 16 patients, in whom pattern of malignant lymphomas can cutaneous lesions were the sole manibe nodular (follicular) or diffuse. The festation at the time of initial examinaentire classification is based on the tion, form the basis of this report. histologic findings in the lymph nodes, (Although there is a similarity bewhere the pattern of malignant lym- tween primary lymphoma cutis and myphoma is more characteristic than in cosis fungoides, the lesions of the 16 the skin. patients did not have the histopathoRecently the identification of cell logic appearance of mycosis fungoides surface markers has led to a new classi- and, in accordance with Bluefarb7 and fication. termed the functional classi- others, we try to restrict the term myfication.4 This has proved to be im- cosis fungoides to that polymorphous portant in investigative studies and in skin process that is chronic and has studies of the biologic features of these three sequential stages - dermatitis, lymphomas. However, it is still of lim- plaque and tumours.) ited usefulness to the pathologist, whose The criteria for inclusion of a padiagnosis is based primarily on morpho- tient in the group with primary maliglogic findings. nant lymphoma cutis were as follows: It has been estimated that about 1. Biopsy-proven lymphoma of skin. 50% of patients with malignant lym2. No evidence of extracutaneous phomas will have skin manifestations, either specific or nonspecific lesions, disease at the time of initial examinaat some time.' This study was con- tion as determined by (a) physical examination (lymph cerned with the specific lesions - lenodes, liver and spleen not sions in the skin composed of malignant lymphoma cells, excluding those palpable), (b) chest radiography (radiooccurring in mycosis fungoides, leukegraphs clear), mia cutis or multiple myeloma. (c) hematology (examination of Lymphoma cutis may be considered peripheral blood and, in some either primary (i.e., arising in the skin) or secondary (i.e., arising in a lymph patients, bone marrow yielded normal findings), node or viscus). Primary lymphoma cutis is uncommon. This is not difficult (d) biochemistry (normal results to understand since the dermis does of liver and renal function not possess organized lymphoid or retitests) and cular tissue. We usually think of lym(e) other procedures (lymphangiography, liver scan and intraphomas as originating in lymph nodes, venous pyelography, peryet we know that the dermis is capable of lymphoreticular hyperplasia in reformed in three patients, demsponse to various stimuli - for exonstrated no abnormalities). 3. Interval of not less than 6 months ample, insect bites. Furthermore, we know that other nonhematopoietic tis- from diagnosis to detection of extra-
CMA JOURNAL/OCTOBER 8, 1977/VOL. 117
cutaneous disease. (Considering the behaviour of lymphomas in other organs and the rapid doubling time of lymphoma cells, this seemed a reasonable interval for primary extracutaneous disease to have become apparent clinically.8) Most of the patients were seen before staging of disease with lymphangiography and exploratory laparotomy became routine; hence staging was done according to the facilities available. Follow-up information was obtained for each patient by letters to the patient when living, or to relatives or physicians.
6, 7, 8 and 14) the skin lesions (ranging in number from 10 to 30) were widespread (i.e., involving more than one body region); in one (no. 6) the disease remained confined to the skin. Pruritus was reported by only 1 of the 16 patients (no. 11). No other constitutional symptoms (e.g., unexplained fever, night sweats or loss of weight) were noted. Histopathologic type (Table I) All the lymphomas were non-Hodgkin's lymphomas of the diffuse pattern.
Findings Clinical manifestations at time of initial examination (Table I) The mean age of the 16 patients with primary malignant lymphoma cutis was 62.1 years (range, 23 to 79 years). The male:female sex ratio was 11:5. The lesions were purplish, firm, dermal or hypodermal (or both) nodules, tumours and plaques varying from 0.5 to 7.0 cm in diameter (Fig. I). Tumour ulceration occurred in one patient (no. 3) (Fig. 2). None had erythroderma. In 12 patients the skin lesions (ranging in number from one to three) were localized to one body region (stage IE) at the time of initial examination; in 5 (nos. 1 to 5) the disease remained confined to the skin and in 7 systemic disease developed eventually. In the remaining four patients (nos. FIG. 1-Tumour nodules on forehead.
(In the period under study there was no patient with Hodgkin's disease of the skin.) Diffuse histiocytic lymphoma was the most frequent type, occurring in 10 of the 16 patients. This histopathologic type still defies precise definition because there is no agreement on the cell of origin. The histopathologic diagnosis in the 10 patients was based on the presence of a monomorphous cellular infiltrate in the dermis and often the subcutaneous tissue, consisting of large, atypical cells with abundant cytoplasm and vesicular nuclei containing a small but prominent nucleolus. Diffuse well differentiated lymphocytic lymphoma was diagnosed in 4 of the 16 patients. Although there is often only a fine line dividing well differentiated lymphocytic lymphoma from
FIG. 2-Ulcerated tumour nodule.
CMA JOURNAL/OCTOBER 8, 1977/VOL. 117 751
chronic lymphocytic leukemia, the results of peripheral blood examination, including the absolute lymphocyte count, were repeatedly normal in the four patients. However, bone marrow examinations were not done.
for the patients in the study by Jones and colleagues, which indicates a significantly longer median survival time in the 10 patients.
Course and survival
The main treatment modality was radiotherapy. All 10 patients with systemic disease and 3 of the 6 (nos. 1, 4 and 5) with disease confined to the skin received x-ray treatment. Seven of the 10 patients with systemic disease (nos. 7, 8, 10 to 13 and 15) were also given chemotherapy. Two of the patients (nos. 2 and 3) with disease confined to the skin were treated solely by excision of the solitary lesion, and one (no. 6) received no treatment; his nodules and plaques resolved spontaneously.
In terms of clinical course the 16 patients could be divided into two groups: (a) those in whom the disease remained confined to the skin and (b) those in whom the lesions were only in the skin at the time of initial examination, but then became disseminated to lymph nodes or viscera, or both. There were six patients in the first group. Two died of a cerebrovascular accident, one (no. 2) 14 years after the diagnosis was made. No autopsy was done on either patient. The other four patients were, at the time of this study, alive and well and showed no evidence of extracutaneous disease, one (no. 5) at 25 years from the time of diagnosis and the others at 23, 53 and 30 months, respectively. One patient (no. 6) was not treated and the lesions resolved spontaneously. There were 10 patients in the second group, 9 of whom died. The mean interval from time of diagnosis to death was 40.3 months. One patient (no. 16) was, at the time of this study, alive 9 years and 7 months after the initial examination. The most common extracutaneous site of involvement was the peripheral lymph nodes (eight patients), and the next most common, the liver (five patients); hilar nodes, lung and spleen were involved in one patient each. The peripheral blood smear was abnormal in four patients. The interval from appearance of the initial skin lesions to documented extracutaneous involvement ranged from 6 months to 12 years (mean, 27.5 months). Patients with well differentiated lymphocytic lymphoma had a long survival, particularly when compared with the patients having other histopathologic types of lymphoma. Of the 16 patients only the group with diffuse histiocytic lymphoma was large enough for a meaningful estimate of the median survival time to be made. Survival curves computed by the method of Kaplan and Meier9 for these 10 patients and for the 26 patients with stage IVA diffuse histiocytic lymphoma in the study by Jones and colleagues'0 are shown in Fig. 3. The two populations, although different in size, approximate each other in terms of age, sex and period under study (i.e., all patients were seen initially after 1957). The survival curve for the 10 patients in this study lies consistently above the survival curve
Treatment
Discussion
A correlation between survival and histopathologic type of non-Hodgkin's lymphoma arising in extracutaneous sites has been shown in several studies.10'" Diffuse poorly differentiated lymphocytic lymphoma, diffuse mixed cell lymphoma and, particularly, diffuse histocytic lymphoma have a poor prognosis; they have a definite predilection for early dissemination. Well differentiated lymphocytic lymphomas, whether nodular or diffuse, generally have a very good prognosis. These observations hold true in this study: the 4 patients with well differentiated Jymphocytic lymphoma had a long survival time (median, 95 months), whereas the other 12 patients had a considerably shorter survival time (median, 24.5 months). Although the histomorphologic classification of malignant lymphomas based on specific cytologic features as proposed by Rappaport' has proven useful for clinicopathologic studies,
'-I
.08
.'
C006 U-.-,
.Q4 .Q2
a
1 2 3 Time in Years
4
FIG. 3-Probability of survival in 10 patients with primary malignant lymphoma cutis, diffuse histocytic type (squares), and 26 patients with stage IVA diffuse histiocytic lymphoma" (circles).
752 CMA JOURNAL/OCTOBER 8, 1977/VOL. 117
major problems of nomenclature have remained primarily because of lack of agreement as to the precise nature of the neoplastic cells in many tumours. Recent advances in immunology have led to re-examination of many of the conventional concepts regarding classification and nomenclature of the lymphomas. New immunologic and cytochemical techniques have established that malignant lymphomas are neoplasms of the immune system.4"2 Lukes and Collins4 have maintained that most so-called histiocytic lymphomas are made up not of true histiocytes but of transformed B-lymphocytes, which morphologically resemble the large, noncleaved follicular centre cell. In addition to histopathologic type, the other equally important determinant of prognosis, treatment and curability is the stage of the lymphoma. Although the Ann Arbor clinical staging classification13 remains a useful guide there are cases that defy such classification. For example, the patients in this study with widespread skin involvement but without nodal or visceral disease (nos. 6, 7, 8 and 14) do not fit into the Ann Arbor classification. The same problem exists with mycosis fungoides, indicating that the classification is not completely satisfactory, at least not for cutaneous lymphomas. This study detected 16 cases of nonHodgkin's lymphoma arising in the skin. Although lymphomas are usually considered to be tumours of lymph nodes, it is now well recognized that a substantial proportion of non-Hodgkin's lymphomas occur in extranodal sites (e.g., thyroid, lung, gastrointestinal tract and ovary)." Despite the fact that the lesions may be localized at the outset, the Rye Conference criteria'4 required an automatic stage IV designation for patients with any type of extranodal disease. Subsequent to several reports suggesting that extranodal lymphomas have a better prognosis than lymphomas arising in lymph nodes'5-'7 the Ann Arbor classification modified the widely accepted Rye system to permit separate classification (as JE or lIE) of such localized extranodal lesions.'3 To my knowledge survival figures justifying this separation for primary lymphomas of the skin have not been reported. The data from this study show that primary malignant lymphoma cutis has a prognosis that is significantly more favourable than i,s implied by the stage IV designation that such localized extranodal involvement would have required under the Rye clinical staging classification. I thank Dr. R. Jackson for his constructive suggestions and comments, Dr. T. Stoddart and the office staff of the Ottawa
Civic Hospital division of the Ontario
Cancer Foundation for their cooperation, and the audiovisual department of the Ottawa Civic Hospital for preparing the illustrations.
4. LUKES RJ, COLLINS RD: Immunologic characterization of human malignant lymphomas. Cancer 34: 1488, 1974 5. EPSTEIN E, MACEACHERN K: Dermatologic manifestations of the lymphoblastoma-leukemia group. Arch Intern Med 60: 867, 1937 6. ULTMANN JE, STEIN RS: Non-Hodgkin's lymphoma - an approach to staging and therapy. CA 25: 320, 1975 7. BLUEFARS SM: Is mycosis fungoides an entity? Arch Dermatol 71: 293, 1955
References 1. RIBEIRO GG: Primary lymphosarcoma and reticulum cell sarcoma of the skin. Clin Radiol 23: 279, 1972 2. KIM R, WILKELMANN RK, DOCKERTY M: Reticulum cell sarcoma of the skin. Cancer 16: 646, 1963 3. RAPPAPORT H: Tumors of the Hemacopojetic System, Washington, Armed Forces Institute of Pathology, 1966, pp 91-206
8. HOLLAND JE, FREt E Iii: Cancer Medicine, Philadelphia, Lea & Febiger, 1973, pp 629-49 9. KAPLAN EL, MEJER P: Non-parametric estimations from incomplete observations. Am Stat Assoc 1 453: 457, 1958 10. JONES
SE,
FUKS Z,
BULL M,
et al:
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Hodgkin's lymphomas. IV. Clinicopathologic correlation in 405 cases. Cancer 31: 806, 1973 11. FREEMAN C,
BERG JW,
CUTLER SJ:
Occur-
rence and prognosis of extranodal lymphomas.
Cancer 29: 252, 1972
12. BRAYLAN RC, JAFFE ES, BERARD CW: Malig-
nant lymphomas: current classification and new observations, in Pathobiology Annual,
197S, IGAcHIM H (ed), New York, Appleton, 1975, pp 213-70 13. CARBONE PP, KAPLAN HS, MussHos'F K, ci al: Report of the Committee on Hodgkin's disease staging classification. Cancer Res 31:
1860, 1971 14. ROSENBERG SA: Report of the committee on the staging of Hodgkin's disease. Cancer Res 26: 1310, 1966 15. BANFI A, BONADONNA C, CARNEVALI G, et al: Preferential sites of involvement and spread in malignant Jymphomas. Eur J Cancer 4: 319, 1968 16. BERG JW, ScHOTTENFIELD D, HurraR RVP, et al: Histology, Epidemiology and End Results: the Memorial Hospital Cancer Registry, Washington, US Public Health Service, 1969 17. End results section, biometry branch, National Cancer Institutes: End Results in Cancer, no 3, Washington, Dept of Health, Education, and Welfare, 1968
Treatment of trophoblastic neoplasia at the Cancer Control Agency of British Columbia D.A. BOYES, MD; E. PANKRATZ, MD; B. GALLIFORD, MD; G.M. WHITE, MD; R.N. FAIREY, MD; B. Ho YUEN, MD
Over a period of 29 years 30 patients with gestational trophoblastic neoplasia were referred to the Cancer Control Agency of British Columbia. Five patients had benign disease and required no further treatment after having had dilatation and curettage. The remaining 25 patients were treated with methotrexate or hysterectomy, or both. Actuarial survival rates were 96.40/c at 1 year and 9O.60,.c at 5 years. There was a high correlation between malignancy and high titres of human chorionic gonadotropin (HCG). All cases of hydatidiform mole must be followed closely by means of estimations of HCG titre. Sur une periode de 29 ans 30 patientes presentant une neoplasie trophoblastique gestationnelle ont ete orientees vers l'Agence de contr6le du cancer de Ia Colombie Britannique. Cinq patientes avaient une maladie benigne et n'ont pas necessit6 d'autre traitement qu'une dilatation et un curetage. Les 25 autres patientes ont ete traitees aux methotrexate ou ont subi une hysterectomie, ou les deux. Les taux actuariels de survie ont ete de 96.40/c a I an et de 90.60/c & 5 ans. On a retrouv6 une forte corr6lation entre Ia malignite et de hauts titres de From the gynecologic oncology department, Cancer Control Agency of British Columbia, and the department of obstetrics and gynecology, University of British Columbia Reprint requests to: Dr. E. Pankratz, Cancer Control Agency of British Columbia, Heather St., Vancouver, BC V5Z 3J3 2656
gonadotropine chorionique humaine (GCH). Tous les cas de m6les hydatidiformes doivent .tre suivis de pres par mesure des titres de GCH.
Methods
A search of the records for the years 1938 through 1976 at the CCABC revealed 34 patients with trophoblastic neoplasia. Of the 34, 3 had nongestational choriocarcinoma of the ovary; all had died within 7 months of diagnosis despite chemotherapy. Another patient had a deciduoma and was successfully treated with cobalt irradiation. Only the 30 patients with gestational trophoblastic neoplasia are considered in the remainder of this report. Patients were referred to the CCABC for confirmation of the diagnosis or treatment, or both. The antecedent pregnancy, whether normal, abortal or molar, had been cared for in the patient's home town, and referral to the CCABC had been requested after the discovery of further symptoms. For all patients operative reports were obtained. Follow-up in all but 3 of the 30 patients was complete up to January 1977 and had consisted of regular examination at the CCABC or associated regional travelling clinics, or letters to the patient's physician. Three patients with benign disease had moved and were lost to follow-up. Clinical and histopathologic
I would go so far as to say that the combination of careful pregnancy-test supervision, a skilled clinician, and chemotherapy has made the histological examination of a hydatidiform mole, for a short-term clinical purpose, virtually superfluous. -W. Wallace Park1 A pathologist's report reading "Hydatidiform mole - benign" often engenders a feeling of relief in the minds of clinicians. The average physician is confronted with molar pregnancy so infrequently that the details of patient follow-up are not familiar to him; he recalls only that choriocarcinoma is malignant, hydatidiform mole is benign and chorioadenoma destruens lies somewhere in between. Such a pathology report only reinforces the impression that hydatidiform moles are benign. While virtually all hydatidiform moles are morphologically benign at the time of primary evaluation, the basis of successful treatment of subsequent trophoblastic disease lies in diligent follow-up of these "benign" moles. In this paper we review the results of treatment of gestational trophoblastic observations neoplasia at the Cancer Control Agency of British Columbia (CCABC), identify Age and racial origin shortcomings and apparent difficulties in the diagnosis and management of this Most of our patients were of childgroup of diseases, and explore ways of bearing age; four were over 40 years correcting the shortcomings and over- old. One patient was of Phillipine decoming the difficulties. scent, 1 was Chinese, 3 were North CMA JOURNAL/OCTOBER 8, 1977/VOL. 117 753
