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Staging laparotomy in Hodgkin's disease
Staging Laparotomy in Hodgkin’s Disease Further Evidence in Support of Its Clinical Utility
MICHAEL J. O’CONNELL, M.D.’ PETER H. WIERNIK. M.D. B. DONALD SKLANSKY,
M.D.+
WILLIAM H. GREENE, M.D.t ARTHUR B. ABT, M.D.5 ROBERT H. KIRSCHNER, M.Dj HAROLD E. RAMSEY,
M.D.
W. LINELL MURPHY, M:D. Baltimore, Maryland
From the Baltimore Cancer Research Center, National Cancer Institute. and the Departments of Pathology, Tumor Surgery and Radiology, USPHS Hospital, Baltimore, Maryland. Requests for reprints shoukl be addressed to Dr. Peter H. Wiernik, Baltimore Cancer Research Center, 3100 Wyman Park Drive, Baltimore, Maryland 21211. Manuscript accepted December 30, 1973. Present address: Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota 55901. + Present address: Department of Otolaryngology. Massachusetts Eye and Ear Infirmary, 243 Charles St., Boston, Massachusetts 02114. $ Present address: Department of Medicine, 333 Cedar St., New Haven, Connecticut 06510. 5 Present address: Department of Pathology, Mitton S. Hershey Medical Center, Hershey, Pennsylvania 17033. T- Present address: Department of Pathology, University of Chicago, 950 East 59th St., Chicago, Illinois 60637. l
86
July 1974
Records of 99 consecutive previously untreated patients with Hodgkin’s disease subjected to iaparotomy at our institution were reviewed in order to assess the frequency with which inadequate or inappropriate therapy might have been administered on the basis of clinical staging alone. Of the 88 patients judged to be candidates for aggressive radiation therapy prior to iaparotomy (clinical stage less than IIIB) unsuspected disease was found in the porta hepatis lateral to the margin of the usual para-aortic radiation field in 4, and occult liver involvement in an additional 2. On the other hand, 2 patients with clinically suspected hepatic involvement were found to be free of parenchymai disease and therefore candidates for aggressive radiotherapy. Of particular interest was the discovery of occult abdominal disease outside conventional extended field radiation ports in 3 patients with ciinicai stage IIA disease. it was not possible to reliably exclude the presence of occult disease outside standard abdominal radiation ports by previously published guidelines outlining indications for staging iaparotomy. Staging iaparotomy has been shown to improve diagnostic accuracy in assessing abdominal involvement in patients with Hodgkin’s disease [l-15]. Approximately one third of the patients in whom there is no preoperative evidence of abdominal Hodgkin’s disease will be shown to have occult disease below the diaphragm at laparotomy [3-51. However, the value of the information gained at laparotomy in planning therapy has been questioned, particularly in patients who present with apparently localized supradiaphragmatic disease and no evidence of para-aortic or spienic involvement on the basis of noninvasive diagnostic procedures [ 161. The value of laparotomy to rule out occult hepatic involvement or tumor in lymph node sites outside conventional radiotherapy ports in patients suspected of having abdominal Hodgkin’s disease preoperatively is generally accepted. However, several investigators have suggested that laparotomy need not be performed on many patients with apparently localized nodal disease [6,16-181. This view is supported by the observation that in most cases the unsuspected infradiaphragmatic tumor found at laparotomy has been located in the spleen, ceiiac axis nodes or para-aortic nodes [ 1,3,4,6,7], sites usually included in “extended field” radiotherapy ports. in addition, some investigators have noted an improvement in
The American Journal of Medicine
Volume 57
STAGING LAPAflOTOMY
the relapse and survival statistics following “prophylactic” abdominal radiotherapy to patients whose
TABLE
only known disease is limited to sites above the diaphragm without performing staging laparotomy [ 191. In a recent comprehensive review of the literature on lymphoma staging laparotomy, Desser, Moran and Ultmann [ 20) tentatively stated that “patients with unequivocal clinical stage I or II Hodgkin’s disease are very unlikely to benefit from laparotomy.” We report here our findings in 99 consecutive, unselected, previously untreated patients with Hodgkin’s disease who underwent staging laparotomy and splenectomy at the Baltimore Cancer Research Center between July 1968 and December 1972 to provide further support for the clinical value of this procedure, both in patients with apparently localized disease and in those suspected of having disseminated disease preoperatively. Previously published guidelines outlining indications for staging laparotomy are examined, and the frequency with which clearly inadequate treatment would have been given had aggressive conventional therapy been administered without performing laparotomy is estimated.
age
under
and
histologic
consideration
Hodgkin’s
of young
disease,
at our institution cused
primarily
There
were
tients
during
patients
had “B”
symptoms
teria 1211. Clinical staging criteria
male
fo-
Negro,
and
Eighteen
pa-
by the Ann Arbor
out retrospectively
using the
of biopsy
using
0
3
1
0
(1
1
5
2
23
29
13
fi
2
75
0 0
7 0
1 1
1 1
1 ;’
3 0
13 4
0 2
1 34
1 33 _
0 15
0 9
0 6
2 99
I or II) prior to laparotomy. Of this group, 15 (30 per cent) were found at surgery to have unsuspected abdominal disease limited to the spleen, splenic hilar nodes or upper para-aortic nodes. None of these patients would have been operated on had the guidelines suggested by Johnson [ 161 been employed in selecting patients for staging laparotomy. Likewise, only two of this group would have undergone surgery had Aisenberg’s suggestions [S] been followed
clinical
profiles
stage
published
All patients
underwent
staging
[ 2,7].
were
reviewed
laparotomy
have
at positive
biopsy
patients
found
at lap-
been
operated
on
had
the
guidelines
in selecting patients for staging laparotomy. Furthermore, 2 of the 37 (6 per cent) patients in this series with clinical stage IIA disbeen
employed
TABLE II
Suggested Guidelines Outlining Indications for Staging Laparotomy in Hodgkin’s Disease ClInical Presentations in which Laparotomy
stan-
Source Johnson
(161
is Advised 1. Roentgenographicatly
as outlined
in
Postoperative
abdominal
in all cases
to ascertain
demonstra-
ble involvement
01 the
lymph
upper
nodes
2. Sptenomegaty Aisenberg
et al. 161
1. Fever,
sweats
2. Positive
that nodes suspicious on lymphangiograms were removed at surgery and to identify the position of the metallic clips placed
three
were
mentioned
lumbar
communications
roentgenograms
who
arotomy to have occult disease outside the usual para-aortic and splenic radiotherapy ports are summarized in Table III. None of these ,three patients
as well as neg-
previously
of the additional
IIA disease
[ 221.
dard criteria previous
results,
Lymphocyte depleted Unclassified Total
[ 2 11.
conference
lymphangiograms
and Age (yr) at
cri-
ative lymphangiograms not confirmed at laparotomy were reviewed by a diagnostic radiologist (W.L.M.), who was unaware
Lymphocyte predominance Nodular sclerosis Mixed cellularity
would
56 female.
3 were
by the Ann Arbor
or suspicious
policies which
disease.
and
extraction.
as defined
was
ET AL.
,ClO 11-20 21-30 31-40 41-50 51-60 Total yr yr yr yr yr yr
with
sclerosing
“localized”
Caucasian,
was carried
recommended
All positive
early
or Oriental
I. There
of this study
43 were
were
of Middle-East
population
the admission
the period with
the
with nodular
reflecting
on those
of
in Table
patients
likely
99 patients;
Ninety-three 3 were
classification
are summarized
a preponderance
Histologic Classification Time of Diagnosis
(Table II). The clinical
PATIENTS AND METHODS The
I
IN HODGKIN’S DISEASE-O’CONNELL
3. Palpable A.
stage)
spleen
4. Two of the
sites during surgery.
(B
or chtls
tymphangiogram
Equivocal
following tymphangiogram
Patients with clinical stage I (A or B), II (A or B) or IllA disease were considered candidates for radiation as the
B. Enlarged
primary
C. Palpable
liver
D. Elevated
sutfobromophthalein
level E. Elevated
alkaline
therapeutic
modality.
IIIB or IV (A or B) disease
were
Patients
with
considered
clinical
for
chemotherapy. RESULTS Fifty-four
ton roentgeno-
gram
stage
candidates
spleen
phosphatase
level
patients
supradiaphragmatic
were
considered
Hodgkin’s
to have
disease
F. Mixed
localized
(clinical
cellularity
depletion
or lymphocyte
histology
stage
July 1974
The American
Journal of Medicine
Volume
57
87
STAGING LAPAROTOMY IN HODGKIN’S DISEASE-O’CONNELL
TABLE III
ET AL.
Patients with Clinical Stage IIA Disease in Whom Unsuspected Abdominal Radiation Fields Was Proved at Laparotomy
AgeW) Patient
and Sex
Histology
35,M
NS
Bilateral
MC
supraclavicular; right axillary; hilar Bilateral cervical
E.K.
13,M
B.B.
NS
28,F
L.J.
Clinically Apparent Disease
Lymphangiogram
Involvement
Spleen*
Outside Standard
Liver*
Occult Abdominal Diseaset
-
-
Porta
Left cervical;
-I
Porta
-
internal splenic Common
-
-
ease would clearly have been treated with inadequate radiotherapy due to porta hepatis involvement, even if total nodal radiotherapy administered in the usual fashion had been given. Thirty-two patients had clinical stage IIIA disease prior to laparotomy. The data on the four patients in this group who were found to have occult abdominal disease not amenable to treatment with the standard inverted “Y” radiation port with a wing extended to cover the spleen are given in Table IV. An additional nine patients in this group, as well as three patients with clinical stage IV disease, had involvement of
Histology
Clinically Apparent Disease
A. Nodal Disease Outside 14,M
25,F
B.C.
MC
Left cervical;
NS
left supraclavicular; ? para-aortic Bilateral cervical:
spleen;
inguinal; hilum iliac; spleen; hilum;
secondary
celiac
to inflam-
porta hepatic nodes but review of postoperative abdominal films indicated the surgical clips were within the boundaries of the standard para-aortic radiation field. These findings emphasize the need for careful surgical exploration of the abdomen, with particular attention to the liver and porta hepatic region in patients suspected clinically of having abdominal Hodgkin’s disease. In this series 4 of 32 patients (13 per cent) with clinical stage IIIA disease would have been treated inadequately with standard total nodal radiotherapy ports. One of these patients (S.H., Table IV) did not fulfill Johnson’s indications for laparotomy.
Lymphangiogram
AgeW
S.H.
of abnormalities
Patients with Clinical Stage IIIA Disease in Whom Disease Outside Standard Radiation Fields Was Proved at Laparotomy
and Sex
splenic
hepatist;
splenic
* Evaluated by Ann Arbor criteria. f Site underlined shown to be outside standard upper abdominal radiation field. $ Porta hepatis nodes also outside standard total nodal radiation fields. § Enlarged node in inguinal region not considered evaluable because of high incidence mation in this site.
Patient
hepatisl;
hilum
bilateral supraclavicular; mediastinum
TABLE IV
Upper
Radiation
Suspicious
Spleen*
Total Nodal
Liver*
Biopsy Proved Abdominal Diseaset
Field
-
-
Porta
hepatis;
para-aortic; -
+
-
right axillary; para-aortic
Porta
splenic
hepatis;
splenic spleen
hilum;
spleen para-aortic;
hilum,
celiac;
B. Occult Liver Involvement B.B. B.H.
24, F 29,F
NS
Bilateral
NS
para-aortic Bilateral cervical; bilateral bilateral
axillary;
-
+
+
+
supraclavicular; axillary;
88
July 1974
the standard
The American Journal of Medlclne
total
Liver;
-
para-aortic; iliac: spleen Liver: porta hepatis;
porta
hepatis;
para-aortic; splenic hilum, iliac, mesenteric, spleen
mediastinum; para-aortic * Evaluated by Ann Arborcriteria. f Site underlined shown to be outside
-
nodal
Volume 57
radiation
field.
STAGINGLAPAROTOMY IN HODGKIN’SDISEASE---O’CONNELL
In two of five patients with clinical stage IV disease prior to laparotomy (both of whom were suspected of having hepatic involvement on the basis of hepatomegaly and abnormal liver function tests), parenchymat organ involvement could not be demonstrated at surgery. There were no diagnostic abnormalities in the wedge or needle liver biopsy specimens obtained from these two patients, nor was there evidence of splenic involvement by Hodgkin’s disease in either case. Thus it seems highly unlikely that occult hepatic tumor was missed at surgery, since hepatic involvement by Hodgkin’s disease in the absence of splenic involvement is distinctly uncommon [ l-71. Although both patients had roentgenographic evidence of bulky mediastinal disease, neither had signs of vascular compromise such as the superior vena cava syndrome, ascites or peripheral edema; therefore, the hepatomegaly cannot be readily ascribed to this mechanism. Even though the pathophysiology of the hepatic enlargement was not apparent after laparotomy, these patients were considered candidates for aggressive radiotherapy rather than chemotherapy. No evidence of hepatic Hodgkin’s disease has been noted in either patient during follow-up periods of 8 and 15 months, respectively, following therapy. Mesenteric nodal involvement was documented in three cases. One patient (B.H., Table IV) had stage IIIA disease clinically but was found to have hepatic involvement at laparotomy. The other two patients had clinical stage IIIB and IVB disease, respectively. Although mesenteric involvement is important, since nodes in this region may be outside radiation ports, this information did not affect decisions regarding therapy in this series. Two of these patients would have received chemotherapy on the basis of clinical Staging. The third also had hepatic involvement documented at laparotomy and therefore was not a candidate for radiotherapy. COMMENTS Although it was possible to demonstrate incorrect clinical staging on the basis of laparotomy findings in 44 of the patients (44 per cent) under consideration, this fact in itself has little direct bearing on therapy decisions. In many patients occult disease was confined to the spleen or upper para-aortic lymph nodes, which presumably would have been treated had “prophylactic” radiation of these areas been carried out. However, 9 of the 99 patients (9 per cent) in this series would have been improperly treated had extended field radiation, including prophylactic treatment to the upper abdominal region, been employed in patients with clinical stage I or II disease; total nodal radiation for patients with clinical stage IIIA disease; and chemotherapy for patients with clinical stage IIIB or IV disease.
ET AL.
It is possible that a combination of radiation and chemotherapy would be effective in patients without parenchymal invasion whose disease is in the porta hepatis outside the usual para-aortic radiation field, thereby making discovery of the disease in this anatomic location less important. However, it has yet to be demonstrated that the risks of combined therapy are justified by an improvement in survival [23-251. Noninvasive or relatively noninvasive staging procedures as accurate as laparotomy would be highly desirable. Peritoneoscopy, recommended by some [26], is associated with perhaps less morbidity than laparotomy, but it has certain disadvantages. The spleen cannot be adequately examined or removed; visualization and biopsy of abdominal lymph nodes are not possible; and it has not yet been demonstrated in a controlled fashion that multiple needle biopsy specimens obtained through a peritoneoscope provide the same degree of diagnostic accuracy possible with open inspection and generous wedge biopsies of the liver at laparotomy. Some of these problems are illustrated by a 60 year old white woman (M.M.) with nodular sclerosing Hodgkin’s disease who was referred to us for therapy after a negative peritoneoscopy at another institution. Biopsy of the nodes in the porta hepatis and iliac regions was positive, and a 500 g spleen extensively replaced with tumor was removed at laparotomy. Although peritoneoscopy may be useful in the initial staging of Hodgkin’s disease for patients judged not to be operative candidates, or in assessing response to therapy in patients with known hepatic involvement by performing serial studies, we do not believe that peritoneoscopy should be accepted as a routine staging procedure for the reasons already discussed. We recognize that morbidity related to staging laparotomy and splenectomy may occur. In the present series of 99 consecutive laparotomies on previously untreated patients, several complications were observed. One patient required reoperation for lysis of adhesions causing small bowel obstruction. He recovered from the second surgical procedure uneventfully and is currently symptom-free 3% years after the initial laparotomy. Another patient had a persistent wound infection: After abdominal radiation therapy and chemotherapy an intestinal fistula developed which continued to be a significant clinical problem until she died with disseminated Hodgkin’s disease 19 months after laparotomy. Postoperative pulmonary infections requiring antibiotic therapy occurred in 9 patients, and in 12 patients postoperative urinary tract infections developed. In each case the infection responded completely to appropriate therapy, and there were no chronic sequelae. An additional patient died 3 weeks postoperatively of extensive
July 1974
The American
Journal of Medicine
Volume
57
89
STAGING LAPAROTOMY
IN HODGKIN’S DISEASE-O’CONNELL
ET AL
hepatic and bone marrow infiltration by lymphocytedepleted Hodgkin’s disease despite aggressive combination chemotherapy. Although his death was considered to be due to massive tumor involvement, surgery may have been a contributing factor. This potential morbidity must be carefully weighed against the long-term benefits possible by tailoring therapy for the individual patient on the basis of laparotomy findings. Thus, unnecessary exposure of the left lung and kidney to radiation may be avoided by performing splenectomy; radiation castration of menstruating women who subsequently require pelvic radiation may be avoided by performing oophoropexy [ 271; radiation therapy [ 281 and perhaps chemotherapy [29,30] may be delivered over a shorter time period with less cytopenia as a result of splenectomy: and more intelligent decisions regarding the selection of radiation therapy, chemotherapy or combinations of these therapeutic modalities may be possible if the extent and anatomic distribution of intraabdominal Hodgkin’s disease can be accurately delineated. We believe that useful information may be gained by performing laparotomy, even in patients with apparently localized, histologically favorable disease. The discovery of three patients with clinical stage IIA disease who were found to have involvement outside extended field radiation ports is not in accord with previous literature as summarized by Desser et al. [20]. However, the high incidence of porta hepatis involvement in our series is consistent with the experience of Ferguson et al. [ 151. It should be noted that many reports do not specifically state that porta hepatis nodes were routinely obtained and that their location was marked with silver clips; therefore, it is possible that occult disease in this region outside standard radiation ports was missed at laparotomy in some cases. On the basis of our experience, it would seem advisable to include the entire porta hepatis in the “prophylactic” upper abdominal radiation field by adding an extension approximately 2 cm lateral to the usual para-aortic port from the eleventh thoracic vertebra to the first lumbar vertebra in patients with clinically localized supradiaphragmatic disease in whom laparotomy is not to b& performed. It may thereby be possible to deliver effective radiotherapy to all sites of occult abdominal Hodgkin’s disease in the vast majority of this select group of patients without performing staging laparotomy, although the exposure of the liver, biliary ducts and right kidney to radiation will unavoidably be increased by adding the
lateral extension to the usual para-aortic radiation field. The long-term sequelae from this additional radiation, if any, cannot be stated at this time. Whereas the discovery of Hodgkin’s disease involving parenchymal organs or occurring in sites outside radiotherapy ports clearly necessitates alterations in therapy, a negative laparotomy does not completely, exclude the possibility of microscopic involvement of nodes not removed for histologic examination. This is particularly true of nodes in the region of the celiac axis and upper lumbar region, which may not be visualized on lymphangiography, may be difficult to expose surgically and which have frequently been shown to be the site of relapse in patients treated solely with upper mantle radiation [31]. Thus, we advise the administration of “prophylactic” upper para-aortic radiation extending from the inferior margin of the upper mantle field to the fourth lumbar vertebra in patients with known involvement in supradiaphragmatic regions functionally contiguous with the para-aortic region (low cervical, supraclavicular or mediastinal sites), even though laparotomy findings are negative. The final evaluation of the value of staging laparotomy in planning therapy for patients with early Hodgkin’s disease cannot be made until relapse rates, delayed complications from laparotomy and splenectomy, late toxicity from radiation therapy, chemotherapy or combinations thereof, and survival rates have been carefully‘analyzed after follow-up periods of at least 5 years. Whether it is possible, by performing staging laparotomy, to avoid the increased morbidity [32] and reduced bone marrow reserves [33] observed after “prophylactic” extended field radiation, without exposing the patient to an unacceptable risk of relapse in sites not radiated because of negative laparotomy findings, remains to be seen. The significant frequency of occult disease in lymph node sites outside conventional radiation ports, and the difficulty experienced in accurately predicting hepatic involvement in patients suspected clinically of having abdominal involvement with Hodgkin’s disease, further support the need to surgically stage this group of patients. ACKNOWLEDGMENT We wish to thank Dr. Arthur A. Serpick for his encouragement and advice, Mr. William L. Robinson for aiding in the analysis of the data, and Miss Margo Coady and Mrs. Delores Norris for secretarial assistance.
REFERENCES 1.
90
Glatstein E, Guernsey
JM, Rosenberg SA, et al.: The value of staging laparotomy and splenectomy in the staging of Hodgkin’s disease. Cancer 24: 709, 1969.
July 1974
The American Journal of Medicine
Volume 57
2.
Lowenbraun S. Ramsey H, Sutherland J. et al.: Diagnostic laparotomy and splenectomy for staging Hodgkin’s disease. Ann Intern Med 72: 655, 1970.
STAGING LAPAROTOMY IN HODGKIN’S DISEASE--O’CONNELL ET AL.
3
8.
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11.
12.
13.
14.
15.
16. 17. 18.
Kadin ME, Glatstein E, Dorfman RF: Clinicopathologic studies of 117 untreated patients subjected to laparotomy for the staging of Hodgkin’s disease. Cancer 27: 1277, 1970. Glatstein E, Trueblood HW, Enright LP, et al.: Surgical staging of abdominal involvement in unselected patients with Hodgkin’s disease. Radiology 97: 425, 1970. Enright LP, Trueblood HW, Nelson TS: The surgical diagnosis of abdominal Hodgkin’s disease. Surg Gynec Obstet 130: 853, 1970. Aisenberg AC, Goldman JM, Raker JW, et al.: Spleen involvement at the onset of Hodgkin’s disease. Ann Intern Med 74: 544, 1971. Zarembok I, Ramsey HE, Sutherland J, et al.: Laparotomy and splenectomy in the staging of untreated patients with Hodgkin’s disease. Radiology 102: 673, 1972. Prosnitz LR, Nuland SB, Kligerman MM: Role of laparotomy and splenectomy in the management of Hodgkin’s disease. Cancer 29: 44, 1972. Meeker WR. Richardson JD, West WO, et al.: Critical evaluation of laparotomy and splenectomy in Hodgkin’s disease. Arch Surg 105: 222, 1972. Piro AJ, Hellman S, Moloney WC: The influence of laparotomy on management decisions in Hodgkin’s disease. Arch Intern Med 130: 844, 1972. Prosnitz LR, Fischer JL, Vera R, et al.: Hodgkin’s disease treated with radiation therapy: follow-up data and the value of laparotomy. Am J Roentgen01 Radium Ther Nucl Med 114: 583, 1972. Perlin EP, Ryan TF, Ebersole JH: Diagnostic laparotomy and splenectomy in the clinical staging of Hodgkin’s disease. Milit Med 137: 97, 1972. Gutterman JU, Rodriguez V, McClure JB: Staging of malignant lymphoma by laparotomy and splenectomy: review of the literature. Milit Med 137: 251, 1972. Paglia MA, Lather MJ, Hertz RE, et al.: Surgical aspects and results of laparotomy and splenectomy in Hodgkin’s disease. Am J Roentgen01 Radium Ther Nucl Med 117: 12. 1973. Ferguson DJ. Allen LW. Griem ML, et al.: Surgical experience with staging laparotomy in 125 patients with lymphoma. Arch Intern Med 131: 356, 1973. Johnson RE: Is laparotomy routinely indicated in Hodgkin’s disease? Ann Intern Med 75: 459, 1971. Goldman JM: Laparotomy for staging of Hodgkin’s disease. Lancet 1: 125, 1971. Smith J, Pasmantier MW, Silver RT, et al.: The staging of Hodgkin’s disease, selective vs routine laparotomy. JAMA 224: 1026, 1973.
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33.
Johnson RE, Thomas LB, Schneiderman M, et al.: Preliminary experience with total nodal irradiation in Hodgkin’s disease. Radiology 96: 603, 1970. Desser RK, Moran EM, Ultmann JE: Slaging of Hodgkin’s disease and lymphoma. Med Clin North Am 57: 479, 1973. Carbone PP, Kaplan HS, Musshoff K, et al.: Report of the committee on Hodgkin’s disease staging classification. Cancer Res 31: 1860, 1971. Abrams HL, Takahashi M, Adams DF: IJsefulness and accuracy of lymphangiography in lymphoma. Cancer Chemother Rep 52: 157, 1968. Bull JM, Jones SE, Rosenberg SA, et al.: Sequential radiotherapy and chemotherapy in the treatment of Hodgkin’s disease. Ann Intern Med 77: 1, 1972. Brace K. Serpick AA, Block JB, et al.: Combination radiotherapy and chemotherapy in the treatment of early Hodgkin’s disease. Oncology 27: 484, 1973. Rosenberg SA, Moore MR, Bull JM. et al.: Combination chemotherapy and radiotherapy for Hodgkin’s disease. Cancer 30: 1505, 1972. Bagley CM Jr, Thomas LB, Johnson RE, et al.: Diagnosis of liver involvement by lymphoma: results in 96 consecutive peritoneoscopies. Cancer 31: 840. 1973. Ray GR, Trueblood HW, Enright LP, et al.: Oophoropexy: a means of preserving ovarian function following pelvic megavoltage radiotherapy for Hodgkin’s disease. Radiology 96: 175, 1970. Salzman JR, Kaplan HS: Effect of prior splenectomy on hematological tolerance during total lymphoid radiotherapy of patients with Hodgkin’s disease. Cancer 27: 471, 1971. Lowenbraun S, Ramsey HE, Serpick A.A: Splenectomy in Hodgkin’s disease for splenomegaly, cytopenias and intolerance to myelosuppressive chemotherapy. Am J Med 50: 49, 1971. Panettiere F, Coltman CA: Splenectomy effects on chemotherapy in Hodgkin’s disease. Arch Intern Med 131: 362, 1973. Johnson RE, Glover MK, Marshall SK: Results of radiation therapy and implications for the clinical staging of Hodgkin’s disease. Cancer Res 31: 1834. 1971. Nickson JJ. Hutchinson GB: Extensions of disease, complications of therapy, and deaths in localized Hodgkin’s disease; preliminary report of a clinical trial. Am J Roentgenol Radium Ther Nucl Med 114: 564, 1972. Curran RE, Johnson RE: Tolerance to chemotherapy after prior irradiation for Hodgkin’s disease. Ann Intern Med 72: 505, 1970.
July 1974
The American Journal of Medicine
Volume 57
91
MICHAEL J. O’CONNELL, M.D.’ PETER H. WIERNIK. M.D. B. DONALD SKLANSKY,
M.D.+
WILLIAM H. GREENE, M.D.t ARTHUR B. ABT, M.D.5 ROBERT H. KIRSCHNER, M.Dj HAROLD E. RAMSEY,
M.D.
W. LINELL MURPHY, M:D. Baltimore, Maryland
From the Baltimore Cancer Research Center, National Cancer Institute. and the Departments of Pathology, Tumor Surgery and Radiology, USPHS Hospital, Baltimore, Maryland. Requests for reprints shoukl be addressed to Dr. Peter H. Wiernik, Baltimore Cancer Research Center, 3100 Wyman Park Drive, Baltimore, Maryland 21211. Manuscript accepted December 30, 1973. Present address: Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota 55901. + Present address: Department of Otolaryngology. Massachusetts Eye and Ear Infirmary, 243 Charles St., Boston, Massachusetts 02114. $ Present address: Department of Medicine, 333 Cedar St., New Haven, Connecticut 06510. 5 Present address: Department of Pathology, Mitton S. Hershey Medical Center, Hershey, Pennsylvania 17033. T- Present address: Department of Pathology, University of Chicago, 950 East 59th St., Chicago, Illinois 60637. l
86
July 1974
Records of 99 consecutive previously untreated patients with Hodgkin’s disease subjected to iaparotomy at our institution were reviewed in order to assess the frequency with which inadequate or inappropriate therapy might have been administered on the basis of clinical staging alone. Of the 88 patients judged to be candidates for aggressive radiation therapy prior to iaparotomy (clinical stage less than IIIB) unsuspected disease was found in the porta hepatis lateral to the margin of the usual para-aortic radiation field in 4, and occult liver involvement in an additional 2. On the other hand, 2 patients with clinically suspected hepatic involvement were found to be free of parenchymai disease and therefore candidates for aggressive radiotherapy. Of particular interest was the discovery of occult abdominal disease outside conventional extended field radiation ports in 3 patients with ciinicai stage IIA disease. it was not possible to reliably exclude the presence of occult disease outside standard abdominal radiation ports by previously published guidelines outlining indications for staging iaparotomy. Staging iaparotomy has been shown to improve diagnostic accuracy in assessing abdominal involvement in patients with Hodgkin’s disease [l-15]. Approximately one third of the patients in whom there is no preoperative evidence of abdominal Hodgkin’s disease will be shown to have occult disease below the diaphragm at laparotomy [3-51. However, the value of the information gained at laparotomy in planning therapy has been questioned, particularly in patients who present with apparently localized supradiaphragmatic disease and no evidence of para-aortic or spienic involvement on the basis of noninvasive diagnostic procedures [ 161. The value of laparotomy to rule out occult hepatic involvement or tumor in lymph node sites outside conventional radiotherapy ports in patients suspected of having abdominal Hodgkin’s disease preoperatively is generally accepted. However, several investigators have suggested that laparotomy need not be performed on many patients with apparently localized nodal disease [6,16-181. This view is supported by the observation that in most cases the unsuspected infradiaphragmatic tumor found at laparotomy has been located in the spleen, ceiiac axis nodes or para-aortic nodes [ 1,3,4,6,7], sites usually included in “extended field” radiotherapy ports. in addition, some investigators have noted an improvement in
The American Journal of Medicine
Volume 57
STAGING LAPAflOTOMY
the relapse and survival statistics following “prophylactic” abdominal radiotherapy to patients whose
TABLE
only known disease is limited to sites above the diaphragm without performing staging laparotomy [ 191. In a recent comprehensive review of the literature on lymphoma staging laparotomy, Desser, Moran and Ultmann [ 20) tentatively stated that “patients with unequivocal clinical stage I or II Hodgkin’s disease are very unlikely to benefit from laparotomy.” We report here our findings in 99 consecutive, unselected, previously untreated patients with Hodgkin’s disease who underwent staging laparotomy and splenectomy at the Baltimore Cancer Research Center between July 1968 and December 1972 to provide further support for the clinical value of this procedure, both in patients with apparently localized disease and in those suspected of having disseminated disease preoperatively. Previously published guidelines outlining indications for staging laparotomy are examined, and the frequency with which clearly inadequate treatment would have been given had aggressive conventional therapy been administered without performing laparotomy is estimated.
age
under
and
histologic
consideration
Hodgkin’s
of young
disease,
at our institution cused
primarily
There
were
tients
during
patients
had “B”
symptoms
teria 1211. Clinical staging criteria
male
fo-
Negro,
and
Eighteen
pa-
by the Ann Arbor
out retrospectively
using the
of biopsy
using
0
3
1
0
(1
1
5
2
23
29
13
fi
2
75
0 0
7 0
1 1
1 1
1 ;’
3 0
13 4
0 2
1 34
1 33 _
0 15
0 9
0 6
2 99
I or II) prior to laparotomy. Of this group, 15 (30 per cent) were found at surgery to have unsuspected abdominal disease limited to the spleen, splenic hilar nodes or upper para-aortic nodes. None of these patients would have been operated on had the guidelines suggested by Johnson [ 161 been employed in selecting patients for staging laparotomy. Likewise, only two of this group would have undergone surgery had Aisenberg’s suggestions [S] been followed
clinical
profiles
stage
published
All patients
underwent
staging
[ 2,7].
were
reviewed
laparotomy
have
at positive
biopsy
patients
found
at lap-
been
operated
on
had
the
guidelines
in selecting patients for staging laparotomy. Furthermore, 2 of the 37 (6 per cent) patients in this series with clinical stage IIA disbeen
employed
TABLE II
Suggested Guidelines Outlining Indications for Staging Laparotomy in Hodgkin’s Disease ClInical Presentations in which Laparotomy
stan-
Source Johnson
(161
is Advised 1. Roentgenographicatly
as outlined
in
Postoperative
abdominal
in all cases
to ascertain
demonstra-
ble involvement
01 the
lymph
upper
nodes
2. Sptenomegaty Aisenberg
et al. 161
1. Fever,
sweats
2. Positive
that nodes suspicious on lymphangiograms were removed at surgery and to identify the position of the metallic clips placed
three
were
mentioned
lumbar
communications
roentgenograms
who
arotomy to have occult disease outside the usual para-aortic and splenic radiotherapy ports are summarized in Table III. None of these ,three patients
as well as neg-
previously
of the additional
IIA disease
[ 221.
dard criteria previous
results,
Lymphocyte depleted Unclassified Total
[ 2 11.
conference
lymphangiograms
and Age (yr) at
cri-
ative lymphangiograms not confirmed at laparotomy were reviewed by a diagnostic radiologist (W.L.M.), who was unaware
Lymphocyte predominance Nodular sclerosis Mixed cellularity
would
56 female.
3 were
by the Ann Arbor
or suspicious
policies which
disease.
and
extraction.
as defined
was
ET AL.
,ClO 11-20 21-30 31-40 41-50 51-60 Total yr yr yr yr yr yr
with
sclerosing
“localized”
Caucasian,
was carried
recommended
All positive
early
or Oriental
I. There
of this study
43 were
were
of Middle-East
population
the admission
the period with
the
with nodular
reflecting
on those
of
in Table
patients
likely
99 patients;
Ninety-three 3 were
classification
are summarized
a preponderance
Histologic Classification Time of Diagnosis
(Table II). The clinical
PATIENTS AND METHODS The
I
IN HODGKIN’S DISEASE-O’CONNELL
3. Palpable A.
stage)
spleen
4. Two of the
sites during surgery.
(B
or chtls
tymphangiogram
Equivocal
following tymphangiogram
Patients with clinical stage I (A or B), II (A or B) or IllA disease were considered candidates for radiation as the
B. Enlarged
primary
C. Palpable
liver
D. Elevated
sutfobromophthalein
level E. Elevated
alkaline
therapeutic
modality.
IIIB or IV (A or B) disease
were
Patients
with
considered
clinical
for
chemotherapy. RESULTS Fifty-four
ton roentgeno-
gram
stage
candidates
spleen
phosphatase
level
patients
supradiaphragmatic
were
considered
Hodgkin’s
to have
disease
F. Mixed
localized
(clinical
cellularity
depletion
or lymphocyte
histology
stage
July 1974
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57
87
STAGING LAPAROTOMY IN HODGKIN’S DISEASE-O’CONNELL
TABLE III
ET AL.
Patients with Clinical Stage IIA Disease in Whom Unsuspected Abdominal Radiation Fields Was Proved at Laparotomy
AgeW) Patient
and Sex
Histology
35,M
NS
Bilateral
MC
supraclavicular; right axillary; hilar Bilateral cervical
E.K.
13,M
B.B.
NS
28,F
L.J.
Clinically Apparent Disease
Lymphangiogram
Involvement
Spleen*
Outside Standard
Liver*
Occult Abdominal Diseaset
-
-
Porta
Left cervical;
-I
Porta
-
internal splenic Common
-
-
ease would clearly have been treated with inadequate radiotherapy due to porta hepatis involvement, even if total nodal radiotherapy administered in the usual fashion had been given. Thirty-two patients had clinical stage IIIA disease prior to laparotomy. The data on the four patients in this group who were found to have occult abdominal disease not amenable to treatment with the standard inverted “Y” radiation port with a wing extended to cover the spleen are given in Table IV. An additional nine patients in this group, as well as three patients with clinical stage IV disease, had involvement of
Histology
Clinically Apparent Disease
A. Nodal Disease Outside 14,M
25,F
B.C.
MC
Left cervical;
NS
left supraclavicular; ? para-aortic Bilateral cervical:
spleen;
inguinal; hilum iliac; spleen; hilum;
secondary
celiac
to inflam-
porta hepatic nodes but review of postoperative abdominal films indicated the surgical clips were within the boundaries of the standard para-aortic radiation field. These findings emphasize the need for careful surgical exploration of the abdomen, with particular attention to the liver and porta hepatic region in patients suspected clinically of having abdominal Hodgkin’s disease. In this series 4 of 32 patients (13 per cent) with clinical stage IIIA disease would have been treated inadequately with standard total nodal radiotherapy ports. One of these patients (S.H., Table IV) did not fulfill Johnson’s indications for laparotomy.
Lymphangiogram
AgeW
S.H.
of abnormalities
Patients with Clinical Stage IIIA Disease in Whom Disease Outside Standard Radiation Fields Was Proved at Laparotomy
and Sex
splenic
hepatist;
splenic
* Evaluated by Ann Arbor criteria. f Site underlined shown to be outside standard upper abdominal radiation field. $ Porta hepatis nodes also outside standard total nodal radiation fields. § Enlarged node in inguinal region not considered evaluable because of high incidence mation in this site.
Patient
hepatisl;
hilum
bilateral supraclavicular; mediastinum
TABLE IV
Upper
Radiation
Suspicious
Spleen*
Total Nodal
Liver*
Biopsy Proved Abdominal Diseaset
Field
-
-
Porta
hepatis;
para-aortic; -
+
-
right axillary; para-aortic
Porta
splenic
hepatis;
splenic spleen
hilum;
spleen para-aortic;
hilum,
celiac;
B. Occult Liver Involvement B.B. B.H.
24, F 29,F
NS
Bilateral
NS
para-aortic Bilateral cervical; bilateral bilateral
axillary;
-
+
+
+
supraclavicular; axillary;
88
July 1974
the standard
The American Journal of Medlclne
total
Liver;
-
para-aortic; iliac: spleen Liver: porta hepatis;
porta
hepatis;
para-aortic; splenic hilum, iliac, mesenteric, spleen
mediastinum; para-aortic * Evaluated by Ann Arborcriteria. f Site underlined shown to be outside
-
nodal
Volume 57
radiation
field.
STAGINGLAPAROTOMY IN HODGKIN’SDISEASE---O’CONNELL
In two of five patients with clinical stage IV disease prior to laparotomy (both of whom were suspected of having hepatic involvement on the basis of hepatomegaly and abnormal liver function tests), parenchymat organ involvement could not be demonstrated at surgery. There were no diagnostic abnormalities in the wedge or needle liver biopsy specimens obtained from these two patients, nor was there evidence of splenic involvement by Hodgkin’s disease in either case. Thus it seems highly unlikely that occult hepatic tumor was missed at surgery, since hepatic involvement by Hodgkin’s disease in the absence of splenic involvement is distinctly uncommon [ l-71. Although both patients had roentgenographic evidence of bulky mediastinal disease, neither had signs of vascular compromise such as the superior vena cava syndrome, ascites or peripheral edema; therefore, the hepatomegaly cannot be readily ascribed to this mechanism. Even though the pathophysiology of the hepatic enlargement was not apparent after laparotomy, these patients were considered candidates for aggressive radiotherapy rather than chemotherapy. No evidence of hepatic Hodgkin’s disease has been noted in either patient during follow-up periods of 8 and 15 months, respectively, following therapy. Mesenteric nodal involvement was documented in three cases. One patient (B.H., Table IV) had stage IIIA disease clinically but was found to have hepatic involvement at laparotomy. The other two patients had clinical stage IIIB and IVB disease, respectively. Although mesenteric involvement is important, since nodes in this region may be outside radiation ports, this information did not affect decisions regarding therapy in this series. Two of these patients would have received chemotherapy on the basis of clinical Staging. The third also had hepatic involvement documented at laparotomy and therefore was not a candidate for radiotherapy. COMMENTS Although it was possible to demonstrate incorrect clinical staging on the basis of laparotomy findings in 44 of the patients (44 per cent) under consideration, this fact in itself has little direct bearing on therapy decisions. In many patients occult disease was confined to the spleen or upper para-aortic lymph nodes, which presumably would have been treated had “prophylactic” radiation of these areas been carried out. However, 9 of the 99 patients (9 per cent) in this series would have been improperly treated had extended field radiation, including prophylactic treatment to the upper abdominal region, been employed in patients with clinical stage I or II disease; total nodal radiation for patients with clinical stage IIIA disease; and chemotherapy for patients with clinical stage IIIB or IV disease.
ET AL.
It is possible that a combination of radiation and chemotherapy would be effective in patients without parenchymal invasion whose disease is in the porta hepatis outside the usual para-aortic radiation field, thereby making discovery of the disease in this anatomic location less important. However, it has yet to be demonstrated that the risks of combined therapy are justified by an improvement in survival [23-251. Noninvasive or relatively noninvasive staging procedures as accurate as laparotomy would be highly desirable. Peritoneoscopy, recommended by some [26], is associated with perhaps less morbidity than laparotomy, but it has certain disadvantages. The spleen cannot be adequately examined or removed; visualization and biopsy of abdominal lymph nodes are not possible; and it has not yet been demonstrated in a controlled fashion that multiple needle biopsy specimens obtained through a peritoneoscope provide the same degree of diagnostic accuracy possible with open inspection and generous wedge biopsies of the liver at laparotomy. Some of these problems are illustrated by a 60 year old white woman (M.M.) with nodular sclerosing Hodgkin’s disease who was referred to us for therapy after a negative peritoneoscopy at another institution. Biopsy of the nodes in the porta hepatis and iliac regions was positive, and a 500 g spleen extensively replaced with tumor was removed at laparotomy. Although peritoneoscopy may be useful in the initial staging of Hodgkin’s disease for patients judged not to be operative candidates, or in assessing response to therapy in patients with known hepatic involvement by performing serial studies, we do not believe that peritoneoscopy should be accepted as a routine staging procedure for the reasons already discussed. We recognize that morbidity related to staging laparotomy and splenectomy may occur. In the present series of 99 consecutive laparotomies on previously untreated patients, several complications were observed. One patient required reoperation for lysis of adhesions causing small bowel obstruction. He recovered from the second surgical procedure uneventfully and is currently symptom-free 3% years after the initial laparotomy. Another patient had a persistent wound infection: After abdominal radiation therapy and chemotherapy an intestinal fistula developed which continued to be a significant clinical problem until she died with disseminated Hodgkin’s disease 19 months after laparotomy. Postoperative pulmonary infections requiring antibiotic therapy occurred in 9 patients, and in 12 patients postoperative urinary tract infections developed. In each case the infection responded completely to appropriate therapy, and there were no chronic sequelae. An additional patient died 3 weeks postoperatively of extensive
July 1974
The American
Journal of Medicine
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57
89
STAGING LAPAROTOMY
IN HODGKIN’S DISEASE-O’CONNELL
ET AL
hepatic and bone marrow infiltration by lymphocytedepleted Hodgkin’s disease despite aggressive combination chemotherapy. Although his death was considered to be due to massive tumor involvement, surgery may have been a contributing factor. This potential morbidity must be carefully weighed against the long-term benefits possible by tailoring therapy for the individual patient on the basis of laparotomy findings. Thus, unnecessary exposure of the left lung and kidney to radiation may be avoided by performing splenectomy; radiation castration of menstruating women who subsequently require pelvic radiation may be avoided by performing oophoropexy [ 271; radiation therapy [ 281 and perhaps chemotherapy [29,30] may be delivered over a shorter time period with less cytopenia as a result of splenectomy: and more intelligent decisions regarding the selection of radiation therapy, chemotherapy or combinations of these therapeutic modalities may be possible if the extent and anatomic distribution of intraabdominal Hodgkin’s disease can be accurately delineated. We believe that useful information may be gained by performing laparotomy, even in patients with apparently localized, histologically favorable disease. The discovery of three patients with clinical stage IIA disease who were found to have involvement outside extended field radiation ports is not in accord with previous literature as summarized by Desser et al. [20]. However, the high incidence of porta hepatis involvement in our series is consistent with the experience of Ferguson et al. [ 151. It should be noted that many reports do not specifically state that porta hepatis nodes were routinely obtained and that their location was marked with silver clips; therefore, it is possible that occult disease in this region outside standard radiation ports was missed at laparotomy in some cases. On the basis of our experience, it would seem advisable to include the entire porta hepatis in the “prophylactic” upper abdominal radiation field by adding an extension approximately 2 cm lateral to the usual para-aortic port from the eleventh thoracic vertebra to the first lumbar vertebra in patients with clinically localized supradiaphragmatic disease in whom laparotomy is not to b& performed. It may thereby be possible to deliver effective radiotherapy to all sites of occult abdominal Hodgkin’s disease in the vast majority of this select group of patients without performing staging laparotomy, although the exposure of the liver, biliary ducts and right kidney to radiation will unavoidably be increased by adding the
lateral extension to the usual para-aortic radiation field. The long-term sequelae from this additional radiation, if any, cannot be stated at this time. Whereas the discovery of Hodgkin’s disease involving parenchymal organs or occurring in sites outside radiotherapy ports clearly necessitates alterations in therapy, a negative laparotomy does not completely, exclude the possibility of microscopic involvement of nodes not removed for histologic examination. This is particularly true of nodes in the region of the celiac axis and upper lumbar region, which may not be visualized on lymphangiography, may be difficult to expose surgically and which have frequently been shown to be the site of relapse in patients treated solely with upper mantle radiation [31]. Thus, we advise the administration of “prophylactic” upper para-aortic radiation extending from the inferior margin of the upper mantle field to the fourth lumbar vertebra in patients with known involvement in supradiaphragmatic regions functionally contiguous with the para-aortic region (low cervical, supraclavicular or mediastinal sites), even though laparotomy findings are negative. The final evaluation of the value of staging laparotomy in planning therapy for patients with early Hodgkin’s disease cannot be made until relapse rates, delayed complications from laparotomy and splenectomy, late toxicity from radiation therapy, chemotherapy or combinations thereof, and survival rates have been carefully‘analyzed after follow-up periods of at least 5 years. Whether it is possible, by performing staging laparotomy, to avoid the increased morbidity [32] and reduced bone marrow reserves [33] observed after “prophylactic” extended field radiation, without exposing the patient to an unacceptable risk of relapse in sites not radiated because of negative laparotomy findings, remains to be seen. The significant frequency of occult disease in lymph node sites outside conventional radiation ports, and the difficulty experienced in accurately predicting hepatic involvement in patients suspected clinically of having abdominal involvement with Hodgkin’s disease, further support the need to surgically stage this group of patients. ACKNOWLEDGMENT We wish to thank Dr. Arthur A. Serpick for his encouragement and advice, Mr. William L. Robinson for aiding in the analysis of the data, and Miss Margo Coady and Mrs. Delores Norris for secretarial assistance.
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