Br. J. Cancer (1975) 31, Suppl. II, 362

STAGING PROCEDURES IN MYCOSIS FUNGOIDES M. L. GRIEM, E. M. MORAN, D. J. FERGUSON, F. A. METTLER AND S. F. GRIEM From the Departments of Radiology, Medicine and Surgery of the University of Chicago and the Franklin McLean Memorial Research Institute (operated by the University of Chicago for the United States Atomic Energy Commission), Chicago, Illinois 60637

Summary.-Mycosis fungoides (MF) in deep-seated lymph nodes, spleen or liver

appears to be associated with a lack of response of the disease to topical external therapy. Fourteen patients with mycosis fungoides were clinically staged and had a staging laparotomy. Mycosis fungoides was found in the lymph nodes of 3 of these patients, in the spleen in 4 and in the liver in 2 cases. Patients with adenopathy, or with splenomegaly or abnormal spleen scans, should be considered for surgical staging to determine the extent of extracutaneous disease. The documentation of extracutaneous MF becomes necessary in the development of new therapeutic approaches.

MYCOSIS FUNGOIDES (MF) is an uncommon skin disease which is characterized clinically by progression from an erythematous lesion to infiltrative plaques, and finally to tumour lesions. It is considered to be a form of malignant lymphoma with primary manifestation in the skin (Block et al., 1963; Rappaport, Edgcomb and Thomas, 1968). As the disease progresses, involvement of lymph nodes, spleen, lungs, heart, gut, liver and bone marrow may occur. Autopsy findings have revealed significant visceral involvement which was often undetected before death (Epstein et al., 1972). In addition, a peculiar cell, the Sezary cell, is sometimes seen in the peripheral blood, especially in patients with a diffuse erythematous form of the disease (Clendenning, Brecher and Van Scott, 1964). The usefulness of surgical staging to determine the extent of Hodgkin's disease (HD) and of other malignant lymphomata led to the investigation of similar staging procedures in MF, intended to help determine the extent of disease and thus the appropriate form of therapy. This paper summarizes the results obtained when the clinical, radiographic

and scintigraphic diagnostic procedures used in the staging of HD and other malignant lymphomata were applied to patients with MF. These results are correlated with the laparotomy findings in lymph nodes, spleen and liver. MATERIALS AND METHODS

Since 1969 we have performed a staging laparotomy similar to that introduced in HD and other lymphomata (Moran et al., 1973, 1975) in 14 patients with MF who underwent clinical staging procedures (Table I). Of the 14 patients, 7 were male and 7 female; 12 patients were Caucasians and 2 were Blacks. The age at onset of the disease ranged from 22 to 72 years. Mycosis fungoides had been present clinically for i- year to 7 years before staging. All patients had been treated with topical steroids, topical nitrogen mustard, regional superficial irradiation, systemic single-drug chemotherapy (cyclophosphamide or methotrexate), or a combination of these, for 1-2 years before admission for the staging procedures. In all patients, the disease had progressed on previous management. Erythematous lesions, localized or generalized plaques, tumours or a combination of these forms of involvement were present in all patients (Table II). Plaques were con-

This work was supported in part by the National Cancer Institute Research Training Grant No. 5-TO 1CA 05204.

363

STAGING PROCEDURES IN MYCOSIS FUNGOIDES

T.ABLE I.-Mycosis Fungoides, Clinical and by radioactive isotope scanning procedures, as well as with the findings at staging Staging Procedures laparotomy. Liver function tests were also Complete physical Note type of skin lesions obtained. Eight patients had biopsies of examination: Routine, including liver and enlarged superficial lymph nodes, and in Laboratory 5 patients bone marrow biopsies had been renal function tests studies: Aspiration and core biopsy Bone marrow: obtained before surgical staging. From area draining skin lesions Lymph node The surgical staging procedure consisted biopsy: of an exploratory laparotomy with removal Chest Radiological of the spleen, needle and wedge biopsies of Inferior venacavagram studies: Bipedal lymphangiogram the liver, a bone marrow biopsy, and excisScintigraphic studies: *

67Ga (whole body scan) 99mTc sulphur colloid (liver, spleen and bone marrow) 99rnTc EHDP* (bone scan) EHDP Ethane, hydroxy, diphosphonate.

sidered to be generalized when they involved more than 20% of the body surface area. Tumours were defined as prominent nodular lesions at least 1 cm in height. The description of the clinical lesions as " infiltrative " (Variakojis, Rosas-Uribe and Rap-

ional biopsies of para-aortic, iliac, splenic hilar, porta hepatis and coeliac axis lymph nodes (Ferguson et al., 1973). RESULTS

In Table II the clinical and prelaparotomy histological observations, as well as the results of radiographic examinations of the lymph nodes, are correlated with the laparotomy findings. Before laparotomy, biopsies of enlarged lymph

TABLE II.-Mycosis Fungoides, Lymph Nodes, Findings at Clinical and Surgical Staging Interval between clinical Histology of diagnosis lymph Age and Type of nodes Inferior Patient and staging skin Clinical (prevenasex No. (years) lesions( 1) adenopathy( 2) laparotomy)( 3) cavagram 1 45 F 10/12 LP MF NP + 2 66 F 4 E DL 3 46M 6/12 E, LP DL + 4 5 72M E, GP MF 5 1 9/12 56M GP, T MF + 6 2 6/12 72M E, LP NP + 7 54M 6/12 E, GP NP 8 35M 5 GP, T NP 61 M 9 3 6/12 E NP NP 62 F 10 2 E, LP DL 11 5 58 F E NP 12 67 F 5 E DL 13 22M 7 GP, T NP 14 51 F 5 E, LP, T DL (1) E (2) Localized erythema + = Present or abnormal (3) MF = LP = Localized plaques = Absent or normal DL= = GP Generalized plaques = T Tumours NP = U = -

paport, 1974) has been avoided in this report since plaques as well as tumours are

MF in

lymph

nodes at

Lymphlaparoangiogram( 3) tomy( 2) NP U ±

±

+

+

NP NP

±

NP

+ ± Mycosis fungoides Dermatophatic lymphadenopathy Not performed Unsuccessful.

nodes were performed in 8 patients. Mycosis fungoides was diagnosed in 3 of considered by different observers as infiltra- these, whereas 5 patients with clinical tive in nature. adenopathy had dermatopathic lymphaIn the course of this study, we correlated denitis. At laparotomy, MF was found the findings on physical examination with the in the abdominal nodes in 3 patients: 2 observations made by contrast x-ray studies had had clinical adenopathy and positive

364

M. L. GRIEM ET AL.

lymph node biopsies; the third patient had adenopathy but the lymph nodes had not been biopsied. Contrast studies included intravenous pyelogram, inferior venacavagram and bipedal lymphangiogram. In one patient who was allergic to iodides, these studies were not performed. Three patients did not have lymphangiograms because of advanced age. The intravenous pyelogram was normal in the remaining 13 individuals. The inferior venacavagram

and the lymphangiogram demonstrated enlarged nodes in the iliac and paraaortic regions in 4 patients. Mycosis fungoides was found in the abdominal lymph nodes in 2 of the 4 patients with abnormal inferior venacavagrams and in 2 patients with abnormal lymphangiograms. Table III correlates the results of the staging laparotomy and splenectomy with the form of cutaneous disease and the pre-surgical examinations of the spleen.

TABLE III.-Mycosis Fungoides, Spleen Findings at Clinical and Surgical Staging Interval between Age clinical diagnosis Type of Patiient and and staging skin MF Spleen N o. sex (years) lesions(M) Splei rnomegaly( 2) Spleen scan(2) in spleen weight (g) 1 45 F 10/12 LP + 115 2 66 F 4 E 95 3 46 M 6/12 E, LP 155 + 4 72M 5 E, GP 480 + + 5 56M 19/12 GP,T 305 + 6 72M 26/12 E,LP 65 7 54M 6/12 E, GP 114 8 35M 5 GP,T + 280 + 9 61 M 3 6/12 E + 250 + 10 62 F 2 E, LP - 90 [1 58 F 5 E 115 12 67 F 5 E 141 3 22M 7 GP,T - 110 14 51 F 5 E, LP, T 99 (1) E = Localized erythema (2) + = Present or abnormal LP = Localized plaques Absent or normal. GP= Generalized plaques T = Tumours -

-

=

TABLE IV.-Mycosis Fungoides, Liver Findings at Clinical and Surgical Staging Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Age and

Interval between clinical diagnosis and staging (years) 10/12 4 6/12

Type of skin sex lesionsM1) 45 F LP 66 F E 46 M E, LP 72 M 5 E, GP 56 M 1 9/12 GP, T 72 M 2 6/12 E, LP 54 M 6/12 E, GP 35M 5 GP, T 61 M 3 6/12 E 62 F 2 E, LP 58 F 5 E 67 F 5 E 22 M 7 GP,T 51 F 5 E, LP, T (1) E = Localized erythema LP = Localized plaques GP = Generalized plaques T = Tumours

Hepatomegaly( 2) Liver scan(2) +

+

+

+

MF in liver biopsy

+

(2)

+ = Present

=

or

abnormal

Absent or normal.

STAGING PROCEDURES IN MYCOSIS FUNGOIDES

N

i t5B3,++ + g+ ~

.~~~~~

~

~ ~ 4

~~~~0~ ~

.0±II

0

0~~~~~~~~~~~~~~~~~~0 0~~~~~~~~~

be ._

r

++ ++

W

O;

00.

o

e

o

C t oo

11 1

NO

0

*

*Co>

Qs

° 0

-,4

8 ^^

04

0

0"-m4 " 14 0d

a)) .1 11 11 1

Z,3

4

0-

II4

0tCo PI)

I

PA

Id

00

¢

coz~~

b

CO

-4

r4

u:

-

365

3S 6(6

AI . L.

GRIEM YT AL.

No patient had splenomegaly on physical examination. Five had abnormal spleen scans; MF was found in the spleen in 3 of these. Of 4 spleens weighing 250 g or more, all showed involvement by MIF. The largest normal spleen weighed 155 g. Table IV shows the correlations between the pre-surgical examination and the results of liver biopsy at the time of laparotomy. Alkaline phosphatase determinations were normal in all cases. One patient had an abnormal bromsulphalein (BSP) retention test, but no hepatic MF was present. Hepatomegaly and abnormal liver scans occurred in 3 patients but no liver involvement was found at laparotomy. However, MF was documented histologically in 2 patients without hepatomegaly, who had normal liver function tests and normal scans. The peripheral smear of only one patient (No. 4) contained Sezary cells (76% of the total white blood cells). This patient had MF in generalized plaque form, with generalized lymphadenopathy, and MF in lymphnodes and spleen. Haemoglobin and platelet counts were normal in all patients. Each patient had a bone marrow bopsy; no MF was found in the marrow. Bone scans were normal in 12 patients tested. All patients had normal gastrointestinal x-ray examinations. No involvement of the gastrointestinal tract was found at laparotomy. Table V correlates the findings of the pre-laparotomy work-up with those of the laparotomy in the 6 patients who had involved lymph nodes, spleen or liver. Two patients with lymph node involvement (Nos. 4 and 5) had spleen involvement, and one (No. 5) also had hepatic involvement. Of the 4 patients with MF in the spleen (Nos. 4, 5, 8, and 9) one (No. 5) had liver involvenment. In another patient (No. 14), with tumour lesions but no MF in the lymph nodes (biopsied before and at laparotomy) or in the spleen, MF was found in the liver biopsy.

DISCUSSION

Although a number of patients with MF showed excellent clearing of the skin following administration of up to 4000 rad of total skin irradiation with electrons according to a technique described by Bagshaw- and Eltringham (1968) and by Fuks and Bagshaw (1971), most patients develop recurrent disease within weeks to months following this therapy. At this stage of the disease it is essential to document the presence of MF in areas that cannot be treated with superficial irradiation. If staging procedures, including laparotomy and splenectomy, reveal involvement of lymph nodes and internal organs, deep radiotherapy or chemotherapy in addition to total skin electron beam irradiation might be more succ-ssful in the cure of this disease. An evaluation of such an approach is now in progress at this institution.

Recommendations In a patient with biopsy proven cutaneous MF a " blind " biopsy of a lymph node from the area draining the skin lesion should be obtained during the initial work-up. When palpable adenopathy is present, an excisional lymph node biopsy should be performed. If the lymph node shows MF, further staging, including laparotomy, may reveal abdominal lymph node or visceral involvement. Patients with splenomegaly or abnormal spleen scans should be considered for surgical staging. We would like to acknowledge the consultations and valuable suggestions of Drs Henry Rappaport and Daina Variakojis from the Department of Pathology, and of Drs Stanford Lamberg, Allan Lorincz, Fred Malkinson, John Ultmann and Dorothy Windhorst, from the Department of Medicine, University of Chicago. The editorial assistance of Mrs Elisabeth Lanzl and the secretarial help of Mrs Sandra Morgan in the preparation of the manuscript are appreciated.

STAGING PROCEDURES IN MYCOSIS FUNGOIDES REFERENCES BAGSHAW, M. A. & ELTRINGHAM, J. R. (1968) Observations on the Electron Beam Therapy of Mycosis Fungoides. In Frontier8 of Radiation Therapy and Oncology, Vol. 2, Ed. J. M. Vaeth. New York and Basel: Karger. p. 163. BLOCK, J. B., EDGCOMB, J., EISEN, A. & VAN SCOTT, E. J. (1963) Mycosis Fungoides. Natural History and Aspects of its Relationship to Other Malignant Lymphomas. Am. J. Med., 34, 228. CLENDENNING, W. E., BRECHER, G. & VAN SCOTT, E. J. (1964) Mycosis Fungoides. Relationship to Malignant Cutaneous Reticulosis and the Sezary Syndrome. Archs Derm., 89, 785. EPSTEIN, E. H., LEVIN, D. L., CROFT, J. D. & LUTZNER, M. A. (1972) Mycosis Fungoides: Survival, Prognostic Features, Response to Therapy, and Autopsy Findings. Medicine, Baltimore, 15, 61. FERGUSON, D. J., ALLEN, L. W., GRIEM, M. L., MORAN, M. E., RAPPAPORT, H. & ULTMANN, J. E. (1973) Surgical Experience with Staging Laparo-

367

tomy in 125 Patients with Lymphoma. Archs intern. Med., 131, 356. FUKS, Z. & BAGSHAW, M. A. (1971) Total-Skin Electron Treatment of Mycosis Fungoides. Radiology, 100, 145. MORAN, E. M., HOFFER, P. B., FERGUSON, D. J., RANNIGER, K., RAPPAPORT, H. & ULTMANN, J. E. (1973) Staging of Lymphoma: A Clinical, Radiographic, Scintigraphic and Histologic Correlation. Ann. intern. Med., 78, 824. MORAN, E. M., ULTMANN, J. E., FERGUSON, D. J., HOFFER, P. B., RANNIGER, K. & RAPPAPORT, H.

(1975) Staging Laparotomy in Non-Hodgkin's Lymphomas. Br. J. Cancer, 31, Suppl. II, 228. RAPPAPORT, H., EDGCOMB, J. & THOMAS, L. (1968) Mycosis Fungoides: A Re-evaluation of its Position in the Scheme of Lymphoreticular Neoplasms. Am. J. clin. Path., 50, 625. VARIAKOJIS, D., ROSAS-URIBE, A. & RAPPAPORT, H. (1974) Mycosis Fungoides: Pathological Findings in Staging Laparotomies. Cancer, N. Y., 33, 1589.