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Role of surgery in the treatment of inflammatory breast carcinoma
Role of Surgery in the Treatment of Inflammatory Breast Carcinoma
Richard S. Hagelberg, MD, Traverse City, Michigan Phlllp C. Jolly, MD, Seattle, Washington Richard P. Anderson, MD, Seattle, Washington
Since inflammatory carcinoma of the breast was first described over 50 years ago, treatment of this disease has been based on two major tenets: The prognosis is grim, with a life expectancy of 2 to 3 years and no role exists for surgery in its treatment. A recent textbook of oncology [I], published in 1982, devoted one paragraph to the treatment of inflammatory carcinoma of the breast: “There is no role for operation in the management of this condition other than to obtain a biopsy so as to establish the diagnosis. The use of radiotherapy in combination with chemotherapy is the treatment of choice. Despite the use of local and systemic treatment, the prognosis is poor.” The surgical extirpation of inflammatory breast carcinoma, in combination with other treatment modalities has been regularly, but not exclusively, performed at our institution for over a decade. This study, a retrospective review of our experience, was undertaken to determine whether all patients face a uniformly poor prognosis irrespective of clinical status and type of therapy and whether continued application of mastectomy is justified. Methods The Virginia Mason Cancer Registry was reviewed retrospectively from December 1,1969 through January 31, 1980. During this 122 month period, 1,658 cases of pathologically confiied breast carcinoma were listed, of which 35 (2.1 percent) were classified as inflammatory breast carcinoma. Classification was based on clinical or pathologic criteria determined by review of clinical records. Clinical criteria included diffuse erythema involving greater than a third of the breast, skin edema (peau From The Depamnent of Surgery,Virginia MasonMedlcelCenter. Seattle, WMhlll@Otl.
Requestsfor reprintsshouldbe eddressedto PhilipC. Jolly. MD, Mason Clinic, 1100 Ninth Avenue, Seattle, Washington98111. Presentedat the 56th AnnualMeetingof the Pacific Coast Sugicel A5 sociation,Newport Beach, California.February 19-22. 1984.
Vdume 148, July 1984
d’orange), tenderness, induration, and warmth, with or without a mass. Histologically, dermal lymphatic invasion by tumor cells was considered to be diagnostic of inflammatory breast carcinoma. Two patients were excluded from the study because of the presence of a second non-breast primary carcinoma. Of the remaining 33 patients, the diagnosis of inflammatory carcinoma of the breast was made by clinical criteria alone in 3 patients, by both clinical and pathologic criteria in 25 patients, and by pathologic criteria alone in 5 patients. Of the five patients diiosed by pathologic criteria alone, three were clinically class&d TsN& (stage II), and two were clinically classified TsNi& (stage II). A mass was palpable in all of these patients and ranged in size from 2 to 5 cm, and all were treated with mastectomy. Three of these patients (60 percent) survived 5 years. Compared with the other 28 patients studied, these 5 patients, who lacked clinical criteria for diagnosis, generally had less advanced disease and a better prognosis, despite meeting histologic criteria for Wlammatory breast carcinoma. Since inclusion of such patients in the study group could be controversial and would favorably bias the results, they were omitted from subsequent analysis. The remaining 28 patients were followed for a mean period of 27.7 months (range 3 to 96 months). Two patients were lost to follow-up 24 and 37 months after diagnosis. Recurrence and mortality were determined by life table analysis, using the product limit method. The statistical significance of differences between various subgroups was evaluated by the log rank test. Twelve patients were premepopauseal. Estrogen receptors were assayed in seven patienta and were positive in four. Axibary lymphadenectomy was performed in 16 patients with nodal metastases confirmed in 12 patients (75 percent). Seventeen patients had a breast mass. Table I lists the clinical characteristics, treatment modalities employed, length of follow-up, patient status at follow-up, and presence or absence of local recurrence for each patient. Treatment was initiated by various physicians according to individual preference. Radiotherapy.Twenty patients received radiotherapy. This was administered by cobalt-66 teletherapy before December 1975 and by a 4 Mev linear accelerator afterward. Tangential irradiation to the breast and chest wall
125
Hagelberg et al
TABLE I
Clinlcal Data on 28 Patients With Inflammatory Breast Carcinoma
Clinical Stage
Mass Size (cm) if Present
1
741NlMo
...
3 2 4 5 6 7 8 9
74iNlMo TdWo 74iNlMo 74iN&fo 741NlW 741NoMo 74iN IMO TUNIMO
10 11
74iNoMo 741NlMo
12 13 14 15
741NlMo 74iNoMo 741NoW 741Nlf’~to
16 17 18 19 20 21 22
74iNlM1 TQNIMO 74iNlMo 74iNlMo TUNIMO
8.X.7 3
741NlW 74iNoMo
‘id 15 x 9
23 24 25 26 27 28
74iNlMo 741NoMo 74iNoMo 74iNoMo 74iNtMo 74iNoMo
6X8
Patient
s TherPapy C
Fo;cmvrUp
Status at Follow-Up
Local Recurrence
-
+
-
3
Dead
+
...
...
-
+ -
-+
8 15 10 x 15
+ + + -
+ + + +
+
-
4 3 8 10 14 15 16 10
Dead Dead Dead Dead Dead Dead Dead
Z + + + +
...
+ + + -
+
...
--
+
+
21
Dead
:
'ii
-+ + +
+ -
-+ + +
23 24 24 27
Dead Lost Alive Alive
: -
+ + +
+ + + -
28 28
Dead Alive
-
++ + + + + + +
29 32 34 36 37
Dead Dead Alive Dead Lost
+ +
+
+ + + +
38 41 41 48 64 90
Dead Dead Alive Alive Alive Alive
+ +
‘lb’
5 8 8X
10
+ -t + + + +
5X.4 10 3 2
C = chemotherapy; R = radiotherapy; S = surgery; -I- = yes; -
was administered to all patients, and nodal tissue was irradiated if there was involvement clinically. The dosage varied, ranging from 4,606 to 6,060 rads. Surgery. Two patients underwent a simple mastectomy and 14 underwent a modified radical mastectomy. Three patients received preoperative irradiation and six received postoperative irradiation. In Table II, the characteristics of the 16 patients who underwent mastectomy are compared with those of the 12 patients who did not undergo mastectomy. Clinically documented axillary adenopathy was seen more frequently in those patients who did not undergo mastectomy. Distant metastases were present in equal proportions. Chemotherapy was utilized more fre-
: + + + -
+ -
-
= no.
quently in the surgical group, and one patient in the nonsurgical group received chemotherapy as the sole treatment modality. Chemotherapy. Eighteen patients received multiagent cytotoxic chemotherapy: 8 patients received cyclophosphamide, methotrexate, and 5-fluorouracil; and 6 patients received cyclophosphamide, adriamycin, &fluorouracil, vincristine, and prednisone. The latter regimen was used in more recently diagnosed patients. The remaining four patients received miscellaneous combinations of these agents. Of the patients who received chemotherapy, 13 were in clinical stage IIIB and 5 were in clinical stage IV. All of the patients who received no chemotherapy were in clinical stage IIIB.
Results TABLE II
Clinical stage 74iNoMo 74iN1,2Mo T4iNo.i.&& Chemotherapy Irradiation Mass Mean size Range l
(n = 16) Mastectomy
(n = 12) No Mastectomy
7 (44) 6 (38) 3 (18j 14 (87) 9 (56) 12 (75) 7.9 cm 2-15 cm
9 (75) 2 (17) 4 (33) 11 (92) 5 (42) 8.7 cm 3-15 cm
Values in parentheses are percentages.
126
Overall,
Inflammatory Breast Carcinoma*
1 (8)
the
cumulative
5 year
survival
was 25
percent, with a 2 year survival of 57 percent. Seventeen patients had a breast mass, and 11 patients did not. The survival curves for these two groups are shown in Figure 1. No patient without a mass survived past 41 months. Five year survival for those patients with a mass was 37 percent. The difference between these two groups was significant (p <0.05). Eighteen patients received multiagent cytotoxic chemotherapy, and 10 patients received no chemotherapy. In Figure 2, the survival curves for these two groups are depicted. While there was a trend toward improved survival in those patients who received The Amerkan Journal of Surgery
Inflammatory Breast Carcinoma
E S
40-
37%
n. Not significant (p X10) l----j
20
20-
p
(2) No chemo
1 No mass 10
20
I
30
I
40
,
50
10%
1
I
10
60
20
Months
30 Months
40
50
60
Flgun2.Survlwa/olpai&ntswhorecehdchwihwapyand paihnbwhodkfnd(l8pnthMdlO~,~).
Mu&ersh~irnkaiethemimberofpatknkatrkk at the ttm apecM.
chemotherapy, the difference was not significant (p >O.l). A mastectomy was performed in 16 patients with inflammatory carcinoma of the breast, and 12 patients did not undergo mastectomy. The characteristics of these two groups are shown in Table II. A variety of adjuvant treatment modalities were utilized. The survival curves for those patients who underwent mastectomy and for those who did not are shown in Figure 3. Five year survival for the surgical patients was 48 percent, whereas no patient treated without mastectomy survived more than 3 years. This difference in survival curves was highly significant (p <0.0005). The status of the chest wall in patients who had mastectomy and the breast in patients who did not undergo mastectomy was examined to ascertain the ability of treatment to obtain control of the local disease. Of the 16 patients who underwent mastectomy, control of the local disease was initially obtained in all patients. Two years after diagnosis, 75 percent of the survivors were free of local disease, and at 5 years, 64 percent were free of local disease. In comparison, of the 12 patients who did not undergo mastectomy, local control was obtained in only 2 (17percent). Within 1 year, local recurrence developed in both of these patients. Comments Previous reports have emphasized the poor prognosis of this disease [2,3]. Treves [3] reviewed 262 cases in six reports, and found only four cases (1.5 percent) in which the patients survived for 5 years. The average survival of 27 patients treated by radiotherapy alone was 10.1months from the time of diagnosis. Based on such data, many physicians believe that mastectomy is not justified. We question that conclusion. Our patients who underwent mastectomy had a significantly better prognosis than those who did not volume 148, Julr 1964
undergo mastectomy. Other factors may, in part, have contributed to differences in survival between the two groups. Axillary adenopathy without distant metastases was seen less frequently in the surgical group (38 percent versus 75 percent), and chemotherapy was more often utilized in the surgical group (87 percent versus 33 percent). Although our data do not support definite conclusions regarding the influence of nodal status or treatment combinations on survival, they do suggest that such considerations bear relevently on prognosis and merit further investigations. Mastectomy in our patients was effective treatment for local disease, and bettar long-term control was achieved when compared with radio-
100
z .$ 60: 'i 8 40-
(5)
46%
Mastectomy
G a p <0.0005 20 -
No mastectomy
8 10
20
I
I
30
40
1
50
I
60
Months
127
Hagelberg et al
therapy or chemotherapy alone or in combination. Our patients treated by radiotherapy alone received 4,000 to 6,000 rads. Chu et al [4] utilized radiotherapy as the primary treatment in 62 patients with inflammatory carcinoma of the breast. Twenty-eight of their patients received hormonal therapy or chemotherapy as well. Local control was achieved initially in 47 patients (76 percent). Of the 15 patients in whom local control was not obtained, 14 received less than 6,000 rads of radiation. At 20 months, local control was maintained in 19 of the 62 patients (30 percent). The researchers concluded that at least 6,000 rads was necessary to adequately treat local disease, and our results support this conclusion. The review of Chu et al is the most encouraging with regard to radiotherapy as the primary treatment modality, but the 30 percent local control rate at 20 months compared poorly to the 75 percent local control rate at 20 months for our patients who underwent mastectomy. Although the use of radiotherapy as an adjunct to mastectomy might improve the probability of local control, it did not do so in our patients. The nine surgical patients who received adjuvant radiotherapy fared no better in terms of local control and survival than did the seven surgical patients who did not. Our data suggest that the presence of a mass is of prognostic significance. Patients with a mass had significantly longer survival than those patients without a mass. Mastectomy was performed more frequently in those patients with a mass (71 percent) compared with those patients without a mass (36 percent). It is not clear to what extent a better prognosis may be related to the presence of a mass or may be related to the application of mastectomy in treatment. The American Joint Committee on Cancer classifies all inflammatory breast carcinomas as T4i, irrespective of the presence or absence of a mass. Our data suggest that studies of inflammatory breast carcinoma should use a classification or stratification based on the presence or absence of a mass. Could our patients with a mass have had secondary inflammatory changes superimposed on the more common varieties of breast cancer? This does not appear to be the case because dermal lymphatic invasion was demonstrated pathologically in the majority of the patients, almost certainly indicating inflammatory carcinoma of the breast. Adjuvant chemotherapy has produced dramatic changes in the treatment of breast cancer, with significant enhancement of the disease-free interval as well as the length of survival [5,6]. The role of preoperative multiagent chemotherapy in patients with locally advanced breast carcinoma is less well defined. Perloff and Lesnick [7] noted that preoperative treatment reduced the size of stage III tumors, thus facilitating the subsequent surgical procedure. A favorable influence on the primary disease and a
128
prolongation of the disease-free interval has been noted in pilot data from the Cancer and Leukemia Group B Cooperative [personal communication: Perloff M]. The frequent application of multiagent chemotherapy in our better prognosis group supports the continued use of this treatment modality for inflammatory breast carcinoma. There has been disagreement as to the criteria necessary to support a diagnosis of inflammatory carcinoma of the breast. Lucas and Perez-Mesa [9] reviewed 73 cases of inflammatory carcinoma of the breast and concluded that the diagnosis can be made clinically or histologically. Their data indicated, however, that patients with only a histologic diagnosis had a better prognosis. The five patients in our series with only a pathologic diagnosis of inflammatory carcinoma of the breast had outcomes that were more characteristic of patients with stage II breast cancer, with three of these patients alive at 5 years. Since all of these patients underwent mastectomy, their inclusion in the study group would have resulted in a significant bias toward the surgical group, and for this reason, they were excluded. The three patients without a histologic diagnosis of inflammatory carcinoma of the breast presented early in the series, before the realization that dermal lymphatic invasion is a significant histologic finding. Clinically, these three patients behaved in a manner consistent with the 25 patients in whom the diagnosis was made both clinically and histologically. At the present time, we reserve the diagnosis of inflammatory carcinoma of the breast for patients demonstrating both the clinical and pathologic criteria. Patients presenting with a clinical diagnosis of inflammatory carcinoma of the breast at our institution undergo an incisional biopsy, including a portion of overlying skin. After histologic confirmation, they receive three or four courses of cyclophosphamide, adriamycin, 5-fluorouracil, vincristine, and prednisone. A mastectomy with at least a 2 cm margin is performed, and skin grafting is utilized if necessary. Postoperatively, chemotherapy is continued until a total of 12 courses has been administered. Radiotherapy is utilized only for the treatment of local recurrence. Summary Twenty-eight patients with inflammatory carcinoma of the breast have been retrospectively reviewed. Overall 5 year survival was 25 percent. There was a trend toward improved survival in patients who received chemotherapy which did not achieve statistical significance. Sixteen patients underwent mastectomy as part of their treatment. These patients had a 48 percent 5 year survival which was significantly better than the survival in patients who did not undergo mastectomy. Furthermore, mastectomy resulted in better control of the local disease. Of 12 patients who did not undergo mastectomy, local control was initially obtained in only 2, and both
The American Journal of Surgery
Inflammatory Breast Carcinoma
of these patients suffered local recurrence within 1 year. Our data support the conclusion that mastectomy be combined with preoperative and postoperative multiagent cytotoxic chemotherapy in the treatment of inflammatory carcinoma of the breast. More precise staging may permit better prognostic stratification of patients with this highly malignant cancer.
References 1. Heliman S, Harris Jr, Caneiios GP. Fisher B. Cancer of the breast in: DeVita VT, S Heliman, SA Rosenberg eds. Cancer: principles and practices of oncology. Philadelphia: JB Lipplncott, 1982: 934. 2. Camp E. Inflammatory carcinoma of the breast: the case for conservatism. Am J Surg 1976;131:583-6. 3. Treves N. The inoperability of inflammatory carcinoma of the breast. Surgery Gynecol Obst 1959;109:240-2. 4. Chu AM, Wood WC, Doucette JA. iiitcq breast carcinoma treated by radical radiotherapy. Cancer 1980;45:2730-7. 5. Fisher B, Glass A, Redmond C, et al. L-phenylaianlne mustard (L-PAM) in the v of primary breast cancar. Cancer 1977;39:2883-903. 6. Bonnadonna G, Brusamolino E, Vaiagussa P, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engi J Med 1976;294:405-10. 7. Perloff M, Lesnick Gil. Chemotherapy before and after mastectomy in stage iii breast cancer. Arch Surgery 1982;117: 879-81. 8. Lucas FV, C Perez-Mesa. inflammatory carcinoma of the breast. Cancer 1978:41:1595-605.
Discussion Jose J. Terz, MD (Duarte, CA): Dr. Hagelberg and coworkers, after reviewing the outcome of 28 patients categorized as having inflammatory breast cancer, have suggested that mastectomy be a major therapeutic modality in their management contrary to the most accepted concept that removal of the breast does not alter the limited survival rate of these patients. Their group of 16 patients who had mastectomy had a 5 year survival of 47 percent and a local control rate of 64 percent during the same interval. On the other hand, all 12 patients who did not have a mastectomy were dead 3 years after diagnosis and all had 100 percent local recurrence within 1 year. It also seemed that radiotherapy and chemotherapy, alone or in combination, enhanced the role of mastectomy in survival. The authors raised the issue once again of the role of mastectomy in the therapy of inflammatory breast cancer after it had been disregarded for many years. In 1976, E. Camp described 10 patients who were alive 5 years after diagnosis from a total of 346 patients with inflammatory cancer. Eight of these patients had undergone radical mastectomy; however, when the clinical and histologic information was reviewed by Ellis and Teitelbaum (Cancer 1974;33:1045), seven of the patients were found not to have dermal lymphatic metastasis, and in the eighth patient the pathologic material could not be located. The reviewers then concluded that these patients did not fit the diagnosis of inflammatory breast cancer. Could we also be seeing a difference of interpretation here? Inflammatory breast cancer is a clinicohistologic diagnosis which must include redness of the skin with edema (erysipeloid appearance), concomitant demonstration of
Volume 149,Juiy 1994
tumor emboli in the subdermal lymphatic vessels, and absence of a tumor mass involving the skin. All reports that strictly adhered to this definition uniformly were associated with a 5 year survival of less than 10 percent. Using this criteria, 2 years ago we reviewed the clinical course of 20 patients diagnosed as having inflammatory breast cancer seen between 1965 and 1979, with disease localized to the breast and axilla only without distant metastasis. The median length of survival was 15 months. Eight patients had mastectomy as part of the multiple therapy protocol with only one patient surviving 56 months, at which time she died from cancer. The diagnosis of inflammatory breast cancer in this paper was based on clinical or pathologic criteria or both. We must be aware that it is not unusual for direct involvement of the skin by a tumor mass to be associated with redness and edema, with or without evidence of tumor in the dermal lymphatic vessels. However, these patients uniformly have a better prognosis. I would like to offer an explanation for the unusually good results with mastectomy in patients with this disease. The authors have broadened the definition of the diagnosis of inflammatory cancer which may have led them to include cases that do not fit the standard classification. They have shown us that none of the patients without a palpable mass survived beyond 41 months, whereas the 5 year survival of those with a palpable mass was 37 percent. Further, more than 70 percent of the patients with a mass had a mastectomy. I will venture to say that the group of patients without a mass were the true inflammatory cancer patients in these groups, as evidenced by a survival curve that fits all previous reports. The authors supported their conclusion with the significance obtained from an extensive statistical analysis. However, this information is misleading because, the entered population was heterogenous-I am sure there weren’t two similar patients in the entire group-which detracts from the interpretation of the analysis. Dr. Jolly, would you clarify the fact that 64 percent of the patients in the mastectomy group were free of local disease 5 years after diagnosis, but only 48 percent of the same group survived that long? Assuming that my interpretation of case selection is incorrect, how can you explain the significant improvement in the role of mastectomy in the overall survival of the patients with inflammatory breast cancer compared with the current experience of no survival, considering all other factors as equal? William B. Hutchinson (Seattle, WA): Many factors must be considered in a discussion of inflammatory cancer of the breast that will certainly affect statistical conclusions, particularly in a small series. As noted by the authors, there are diagnostic criteria involved: clinical observation and judgment or histological fact, neither of which necessarily occur in the same patient. A breast may look inflammatory and show no evidence of carcinomatous invasion of the dermal lymphatic vessels in the submitted material and the reverse may occur when carcinomatous invasion of dermal lymphatic vessels is seen histologically where clinically it is not suspected. The woman in her 20s with clinical evidence of a true inflammatory carcinoma and confirmed dermal lymphatic invasion is a therapeutic challenge. We have found that for such patients, breast surgery has not been the initial treatment of choice. Hormone manipulation, where applicable, seemed to be the most effective modality to use until chemotherapeutic
129
Hagelberg et al
agents became available. Initially, these drugs are extremely helpful in management. Most young patients behave quite differently from older ones, especially obese women in whom we frequently find a sizeable mass and where the pathologist finds a few clusters of invasion of the dermal lymphatic vessels. Individualization of therapeutic management is imperative until more accurate categorization of inflammatory breast carcinoma is available, otherwise we may do harm with early surgery. I urge the authors to continue to seek better diagnostic criteria and improved treatment method combinations to help us manage this difficult problem. A 25 year old woman with inflammatory breast carcinoma had a biopsy specimen that showed infiltrating duct carcinoma. The scans, workups, and so on revealed no abnormalities. She had a bilateral oophorectomy with subsequent five drug chemotherapy and eventually 5,000 rads of external irradiation and then 1,000 rads with electronic beam radiation. She later had 2,000 rads with iridium implants. I suspect that this patient, after 4.5 years, who has no detectable carcinoma may, like so many others, suddenly have the development of widespread metastases. This type of patient would not have benefited from surgery. Richard E. Robins (Vancouver, British Columbia, Canada): I support mastectomy in the role of treatment of inflammatory breast cancer. I too share the concern that some of the patients described would not be considered to have true inflammatory carcinoma. I would not accept the diagnosis unless there was histologic proof of dermal involvement. Pathologists at the Cancer Control Agency of British Columbia have noted that when biopsy of the breast is not performed, there actually are very few tumor cells to be seen and they are almost never in clusters but rather they are individual cells. In our experience, too, the vast majority of these patients are estrogen-receptor negative so hormonal manipulation does not play much of a role in their treatment. Misguided surgery early in a case of true inflammatory breast cancer may lead to disaster, but perhaps in’a planned role it can later contribute to a patient’s well-being. From my experience at the Cancer Control Agency, in a group of patients seen from 1973 to 1979, half of t&e patients had the’first recurrence in the involved breast, and so many of these people, although they may have gone on to die from generalized disease, had the problems of a large tumor and sometimes an ulcerating mass on the chest wall. Well-advised surgery earlier could have prevented this. For a period of 3 or 4 years in the early 19709, the treatment was basically radiotherapy alone, and it is obvious that this only produced isolated cures. From 1975 through 1979, multidrug chemotherapy was used alone and did not result in local control or cure. From 1979 through 1982 we administered intensive multidrug therapy, and after several courses added radiation therapy, and then in certain cases added mastectomy. In this group, for the first time we saw patients who achieved good local control. Some of them are 4 year survivors and others are living longer even though they may have disease. Our present plan of treatment, which supports that of the authors, is that when first seen, a biopsy is performed and a diagnosis is made. Patients are given a single bolus of 800 rads of external irradiation as a holding dose to the local tumor, and then are given intensive multidrug ther-
130
apy for 6 months. At the end of this period, if the patient is free of generalized disease and appears to have a reasonably good prognosis, we then recommend mastectomy. Leon Morgenstern (Los Angeles, CA): This timely and important paper points out that it is about time surgeons reexamined their role in the treatment of inflammatory breast cancer. Neither Helman nor Fischer, who have been mentioned, are noted for their surgical enthusiasm. In a patient from my clinical experience this erysipeloid reaction diffusely involved the breast away from the main tumor mass. One phenomenon that I have seen a number of times but have not seen described is what I call a “periareolar blush” well away from the tumor. I think this should have an eponym. If it already has one, I would like to hear about it because this is not inflammatory breast carcinoma. It is a dilatation of the periareolar venous plexus, and I have seen it on a number of occasions. I don’t know of it being described as a’ sign. Concerning radiotherapy, a breast specimen from a woman who refused mastectomy had lumpectomy instead. She received 5,000 rads of conventional therapy and iridium implants which increased the dosage another 2,000 rads. Two years later, she reappeared for mastectomy because of progression of the disease, and we noted a very healthy-appearing condition of the tumor cells after 7,000 rads of irradiation. We have many patients like this. Radiation fibrosis is there, but very viable tumor cells are there also. Res ipsa loquitur.
Iain G.M. Cleator (Vancouver, British Columbia, Canada): I enjoyed this paper and found it very stimulating, but my feeling is that we are all talking about different kinds of inflammatory breast carcinoma. We have looked at some slides that some might have called advanced localized carcinoma in the elderly, some slides might have been called Paget’s disease, and some slides might have been called true inflammatory carcinoma. My own understanding of inflammatory carcinoma of the breast dates back to the teaching of Professor John Bruce in Edinburgh. There I saw large numbers of carcinomas, and the kind that we called inflammatory were classically in young persons. As Dr. Hutchinson reported, someone in their early 20s. The cancer would come on almost with the speed and urgency of a breast abscess and was often confused with that. There was edema and often redness which involved most of the breast. Dr. Jolly, could you indicate the ages of the patients who you described today? We may be talking about a group of diseases that conform to our current definition of inflammatory disease but don’t carry the connotation that we were taught in our undergraduate days which we see only very rarely and when we see it, it carries a very unfortunate prognosis. I see no reason not to question the role of surgery here but would like our definition to be very exact when we discuss inflammatory breast carcinoma. James Goodnight (Sacramento, CA): We are obviously struggling to define this disease but it is perhaps worth pointing out that these very broad definitions of inflammatory carcinoma have been used in other series and used to justify other approaches to the management of the condition. One approach is to start with chemotherapy which is the mainstay of treatment for what is obviously a systemic disease. It has been recommended that we give
The American Journal of Surgery
Inflammatory
three cycles of chemotherapy then begin radiation therapy. The radiation occupies a period of 6 to 8 weeks. This treatment may reduce the amount of chemotherapy the patient can take thereafter. I believe the importance of the authors’ observation regarding surgery is that if after the first three courses of chemotherapy, the disease is operable by our usual criteria, the patient would then be off chemotherapy for a very short time, perhaps even 2 weeks. Several discussants have indicated that radiation does not control this disease locally in many cases, One would expect that surgery may be the better choice in this regard. The authors have pointed out that dermal lymphatic involvement alone does not constitute inflammatory breast carcinoma. The prognosis in this group was relatively good. It has been stated that the prognosis of inflammatory breast cancer is worse in the premenopausal woman. The authors did not mention this in their presentation, and I wonder if Dr. Jolly might elaborate on this point. Philip Jolly (closing): Inflammatory breast cancer is the most malignant and fortunately the rarest form of breast cancer. Mastectomy has not been considered appropriate treatment. Surgeons have been admonished not to perform mastectomy because of the rapid development of widespread metastases. This surgical nihilism had its origins in the poor results after radical mastectomy alone reported by Haagensen, Treves, and others in the 193Os, 194Os, and 1950s. The marked improvement in survival in our mastectomy patients must be due in part to the use of adjuvant modalities and particularly the use of combination chemotherapy. The evolution of treatment of inflammatory breast cancer may have some similarities to the evolution of treatment of oat cell cancer of the lung. Surgical resection in conjunction with chemotherapy and irradiation therapy is being applied with increasing frequency in stage I oat cell cancer of the lung. Dr. Terz questioned the diagnosis of inflammatory breast cancer in our patients and suggested that patient selection may be responsible for our improved results, All 28 patients in this report had the clinical syndrome of inflammatory breast cancer. They had erythema or skin edema (peau d’orange) over at least a third of the breast often associated with a generalized increase in firmness of the breast tissue. Some of the patients also had a mass
Volume 148, July 1984
Breast Carcinoma
which was usually very large. Twenty-five of the 28 patients had pathologic confirmation of dermal lymphatic involvement with cancer. The three without pathologically confirmed dermal lymphatic involvement were seen early in the series when our pathologists were not looking for this finding. Five patients with dermal lymphatic involvement were excluded because they did not have the clinical findings of inflammatory breast cancer. These five patients’ disease behaved more like Stage II breast cancer and three of the five were alive 5 years after diagnosis. The 28 patients in the study group represent less than 2 percent of the 1,658 patients seen at our institution with breast cancer over the span of this study. Dr. Terz also pointed out that our patients who received chemotherapy did not have a significantly increased survival over those who did not receive chemotherapy. The survival curve of the patients who received chemotherapy was better than those not receiving chemotherapy, although the difference is not significant. It should be pointed out that the bias between the two groups was in favor of the nonchemotherapy group because all of the patients with Stage IV breast cancer received chemotherapy. When the differences in the two groups are considered, the improved survival in the chemotherapy group becomes more meaningful. The percentage of patients free of local recurrence is based on the survivors. Dr. Hutchinson and Dr. Cleator suggested that inflammatory breast cancer is a disease of young women. Half of our patients were premenopausal which suggests that the disease is more common in younger patients. Others have reported, however, that inflammatory breast cancer may occur over the entire age range for breast cancer. The prognosis of inflammatory breast cancer is dismal when conventional treatment is used. Because of the poor results, it seems reasonable to try some other combinations of treatment modalities. Our results suggest that mastectomy with removal of lymph nodes improves both survival and local control of disease. Our study is retrospective and involves only a small group of patients. These shortcomings could be overcome by evaluating a larger group of patients in a prospective fashion. I hope that this report will stimulate others to define precisely the role of mastectomy with lymph node removal in the treatment of inflammatory breast cancer.
131
Richard S. Hagelberg, MD, Traverse City, Michigan Phlllp C. Jolly, MD, Seattle, Washington Richard P. Anderson, MD, Seattle, Washington
Since inflammatory carcinoma of the breast was first described over 50 years ago, treatment of this disease has been based on two major tenets: The prognosis is grim, with a life expectancy of 2 to 3 years and no role exists for surgery in its treatment. A recent textbook of oncology [I], published in 1982, devoted one paragraph to the treatment of inflammatory carcinoma of the breast: “There is no role for operation in the management of this condition other than to obtain a biopsy so as to establish the diagnosis. The use of radiotherapy in combination with chemotherapy is the treatment of choice. Despite the use of local and systemic treatment, the prognosis is poor.” The surgical extirpation of inflammatory breast carcinoma, in combination with other treatment modalities has been regularly, but not exclusively, performed at our institution for over a decade. This study, a retrospective review of our experience, was undertaken to determine whether all patients face a uniformly poor prognosis irrespective of clinical status and type of therapy and whether continued application of mastectomy is justified. Methods The Virginia Mason Cancer Registry was reviewed retrospectively from December 1,1969 through January 31, 1980. During this 122 month period, 1,658 cases of pathologically confiied breast carcinoma were listed, of which 35 (2.1 percent) were classified as inflammatory breast carcinoma. Classification was based on clinical or pathologic criteria determined by review of clinical records. Clinical criteria included diffuse erythema involving greater than a third of the breast, skin edema (peau From The Depamnent of Surgery,Virginia MasonMedlcelCenter. Seattle, WMhlll@Otl.
Requestsfor reprintsshouldbe eddressedto PhilipC. Jolly. MD, Mason Clinic, 1100 Ninth Avenue, Seattle, Washington98111. Presentedat the 56th AnnualMeetingof the Pacific Coast Sugicel A5 sociation,Newport Beach, California.February 19-22. 1984.
Vdume 148, July 1984
d’orange), tenderness, induration, and warmth, with or without a mass. Histologically, dermal lymphatic invasion by tumor cells was considered to be diagnostic of inflammatory breast carcinoma. Two patients were excluded from the study because of the presence of a second non-breast primary carcinoma. Of the remaining 33 patients, the diagnosis of inflammatory carcinoma of the breast was made by clinical criteria alone in 3 patients, by both clinical and pathologic criteria in 25 patients, and by pathologic criteria alone in 5 patients. Of the five patients diiosed by pathologic criteria alone, three were clinically class&d TsN& (stage II), and two were clinically classified TsNi& (stage II). A mass was palpable in all of these patients and ranged in size from 2 to 5 cm, and all were treated with mastectomy. Three of these patients (60 percent) survived 5 years. Compared with the other 28 patients studied, these 5 patients, who lacked clinical criteria for diagnosis, generally had less advanced disease and a better prognosis, despite meeting histologic criteria for Wlammatory breast carcinoma. Since inclusion of such patients in the study group could be controversial and would favorably bias the results, they were omitted from subsequent analysis. The remaining 28 patients were followed for a mean period of 27.7 months (range 3 to 96 months). Two patients were lost to follow-up 24 and 37 months after diagnosis. Recurrence and mortality were determined by life table analysis, using the product limit method. The statistical significance of differences between various subgroups was evaluated by the log rank test. Twelve patients were premepopauseal. Estrogen receptors were assayed in seven patienta and were positive in four. Axibary lymphadenectomy was performed in 16 patients with nodal metastases confirmed in 12 patients (75 percent). Seventeen patients had a breast mass. Table I lists the clinical characteristics, treatment modalities employed, length of follow-up, patient status at follow-up, and presence or absence of local recurrence for each patient. Treatment was initiated by various physicians according to individual preference. Radiotherapy.Twenty patients received radiotherapy. This was administered by cobalt-66 teletherapy before December 1975 and by a 4 Mev linear accelerator afterward. Tangential irradiation to the breast and chest wall
125
Hagelberg et al
TABLE I
Clinlcal Data on 28 Patients With Inflammatory Breast Carcinoma
Clinical Stage
Mass Size (cm) if Present
1
741NlMo
...
3 2 4 5 6 7 8 9
74iNlMo TdWo 74iNlMo 74iN&fo 741NlW 741NoMo 74iN IMO TUNIMO
10 11
74iNoMo 741NlMo
12 13 14 15
741NlMo 74iNoMo 741NoW 741Nlf’~to
16 17 18 19 20 21 22
74iNlM1 TQNIMO 74iNlMo 74iNlMo TUNIMO
8.X.7 3
741NlW 74iNoMo
‘id 15 x 9
23 24 25 26 27 28
74iNlMo 741NoMo 74iNoMo 74iNoMo 74iNtMo 74iNoMo
6X8
Patient
s TherPapy C
Fo;cmvrUp
Status at Follow-Up
Local Recurrence
-
+
-
3
Dead
+
...
...
-
+ -
-+
8 15 10 x 15
+ + + -
+ + + +
+
-
4 3 8 10 14 15 16 10
Dead Dead Dead Dead Dead Dead Dead
Z + + + +
...
+ + + -
+
...
--
+
+
21
Dead
:
'ii
-+ + +
+ -
-+ + +
23 24 24 27
Dead Lost Alive Alive
: -
+ + +
+ + + -
28 28
Dead Alive
-
++ + + + + + +
29 32 34 36 37
Dead Dead Alive Dead Lost
+ +
+
+ + + +
38 41 41 48 64 90
Dead Dead Alive Alive Alive Alive
+ +
‘lb’
5 8 8X
10
+ -t + + + +
5X.4 10 3 2
C = chemotherapy; R = radiotherapy; S = surgery; -I- = yes; -
was administered to all patients, and nodal tissue was irradiated if there was involvement clinically. The dosage varied, ranging from 4,606 to 6,060 rads. Surgery. Two patients underwent a simple mastectomy and 14 underwent a modified radical mastectomy. Three patients received preoperative irradiation and six received postoperative irradiation. In Table II, the characteristics of the 16 patients who underwent mastectomy are compared with those of the 12 patients who did not undergo mastectomy. Clinically documented axillary adenopathy was seen more frequently in those patients who did not undergo mastectomy. Distant metastases were present in equal proportions. Chemotherapy was utilized more fre-
: + + + -
+ -
-
= no.
quently in the surgical group, and one patient in the nonsurgical group received chemotherapy as the sole treatment modality. Chemotherapy. Eighteen patients received multiagent cytotoxic chemotherapy: 8 patients received cyclophosphamide, methotrexate, and 5-fluorouracil; and 6 patients received cyclophosphamide, adriamycin, &fluorouracil, vincristine, and prednisone. The latter regimen was used in more recently diagnosed patients. The remaining four patients received miscellaneous combinations of these agents. Of the patients who received chemotherapy, 13 were in clinical stage IIIB and 5 were in clinical stage IV. All of the patients who received no chemotherapy were in clinical stage IIIB.
Results TABLE II
Clinical stage 74iNoMo 74iN1,2Mo T4iNo.i.&& Chemotherapy Irradiation Mass Mean size Range l
(n = 16) Mastectomy
(n = 12) No Mastectomy
7 (44) 6 (38) 3 (18j 14 (87) 9 (56) 12 (75) 7.9 cm 2-15 cm
9 (75) 2 (17) 4 (33) 11 (92) 5 (42) 8.7 cm 3-15 cm
Values in parentheses are percentages.
126
Overall,
Inflammatory Breast Carcinoma*
1 (8)
the
cumulative
5 year
survival
was 25
percent, with a 2 year survival of 57 percent. Seventeen patients had a breast mass, and 11 patients did not. The survival curves for these two groups are shown in Figure 1. No patient without a mass survived past 41 months. Five year survival for those patients with a mass was 37 percent. The difference between these two groups was significant (p <0.05). Eighteen patients received multiagent cytotoxic chemotherapy, and 10 patients received no chemotherapy. In Figure 2, the survival curves for these two groups are depicted. While there was a trend toward improved survival in those patients who received The Amerkan Journal of Surgery
Inflammatory Breast Carcinoma
E S
40-
37%
n. Not significant (p X10) l----j
20
20-
p
(2) No chemo
1 No mass 10
20
I
30
I
40
,
50
10%
1
I
10
60
20
Months
30 Months
40
50
60
Flgun2.Survlwa/olpai&ntswhorecehdchwihwapyand paihnbwhodkfnd(l8pnthMdlO~,~).
Mu&ersh~irnkaiethemimberofpatknkatrkk at the ttm apecM.
chemotherapy, the difference was not significant (p >O.l). A mastectomy was performed in 16 patients with inflammatory carcinoma of the breast, and 12 patients did not undergo mastectomy. The characteristics of these two groups are shown in Table II. A variety of adjuvant treatment modalities were utilized. The survival curves for those patients who underwent mastectomy and for those who did not are shown in Figure 3. Five year survival for the surgical patients was 48 percent, whereas no patient treated without mastectomy survived more than 3 years. This difference in survival curves was highly significant (p <0.0005). The status of the chest wall in patients who had mastectomy and the breast in patients who did not undergo mastectomy was examined to ascertain the ability of treatment to obtain control of the local disease. Of the 16 patients who underwent mastectomy, control of the local disease was initially obtained in all patients. Two years after diagnosis, 75 percent of the survivors were free of local disease, and at 5 years, 64 percent were free of local disease. In comparison, of the 12 patients who did not undergo mastectomy, local control was obtained in only 2 (17percent). Within 1 year, local recurrence developed in both of these patients. Comments Previous reports have emphasized the poor prognosis of this disease [2,3]. Treves [3] reviewed 262 cases in six reports, and found only four cases (1.5 percent) in which the patients survived for 5 years. The average survival of 27 patients treated by radiotherapy alone was 10.1months from the time of diagnosis. Based on such data, many physicians believe that mastectomy is not justified. We question that conclusion. Our patients who underwent mastectomy had a significantly better prognosis than those who did not volume 148, Julr 1964
undergo mastectomy. Other factors may, in part, have contributed to differences in survival between the two groups. Axillary adenopathy without distant metastases was seen less frequently in the surgical group (38 percent versus 75 percent), and chemotherapy was more often utilized in the surgical group (87 percent versus 33 percent). Although our data do not support definite conclusions regarding the influence of nodal status or treatment combinations on survival, they do suggest that such considerations bear relevently on prognosis and merit further investigations. Mastectomy in our patients was effective treatment for local disease, and bettar long-term control was achieved when compared with radio-
100
z .$ 60: 'i 8 40-
(5)
46%
Mastectomy
G a p <0.0005 20 -
No mastectomy
8 10
20
I
I
30
40
1
50
I
60
Months
127
Hagelberg et al
therapy or chemotherapy alone or in combination. Our patients treated by radiotherapy alone received 4,000 to 6,000 rads. Chu et al [4] utilized radiotherapy as the primary treatment in 62 patients with inflammatory carcinoma of the breast. Twenty-eight of their patients received hormonal therapy or chemotherapy as well. Local control was achieved initially in 47 patients (76 percent). Of the 15 patients in whom local control was not obtained, 14 received less than 6,000 rads of radiation. At 20 months, local control was maintained in 19 of the 62 patients (30 percent). The researchers concluded that at least 6,000 rads was necessary to adequately treat local disease, and our results support this conclusion. The review of Chu et al is the most encouraging with regard to radiotherapy as the primary treatment modality, but the 30 percent local control rate at 20 months compared poorly to the 75 percent local control rate at 20 months for our patients who underwent mastectomy. Although the use of radiotherapy as an adjunct to mastectomy might improve the probability of local control, it did not do so in our patients. The nine surgical patients who received adjuvant radiotherapy fared no better in terms of local control and survival than did the seven surgical patients who did not. Our data suggest that the presence of a mass is of prognostic significance. Patients with a mass had significantly longer survival than those patients without a mass. Mastectomy was performed more frequently in those patients with a mass (71 percent) compared with those patients without a mass (36 percent). It is not clear to what extent a better prognosis may be related to the presence of a mass or may be related to the application of mastectomy in treatment. The American Joint Committee on Cancer classifies all inflammatory breast carcinomas as T4i, irrespective of the presence or absence of a mass. Our data suggest that studies of inflammatory breast carcinoma should use a classification or stratification based on the presence or absence of a mass. Could our patients with a mass have had secondary inflammatory changes superimposed on the more common varieties of breast cancer? This does not appear to be the case because dermal lymphatic invasion was demonstrated pathologically in the majority of the patients, almost certainly indicating inflammatory carcinoma of the breast. Adjuvant chemotherapy has produced dramatic changes in the treatment of breast cancer, with significant enhancement of the disease-free interval as well as the length of survival [5,6]. The role of preoperative multiagent chemotherapy in patients with locally advanced breast carcinoma is less well defined. Perloff and Lesnick [7] noted that preoperative treatment reduced the size of stage III tumors, thus facilitating the subsequent surgical procedure. A favorable influence on the primary disease and a
128
prolongation of the disease-free interval has been noted in pilot data from the Cancer and Leukemia Group B Cooperative [personal communication: Perloff M]. The frequent application of multiagent chemotherapy in our better prognosis group supports the continued use of this treatment modality for inflammatory breast carcinoma. There has been disagreement as to the criteria necessary to support a diagnosis of inflammatory carcinoma of the breast. Lucas and Perez-Mesa [9] reviewed 73 cases of inflammatory carcinoma of the breast and concluded that the diagnosis can be made clinically or histologically. Their data indicated, however, that patients with only a histologic diagnosis had a better prognosis. The five patients in our series with only a pathologic diagnosis of inflammatory carcinoma of the breast had outcomes that were more characteristic of patients with stage II breast cancer, with three of these patients alive at 5 years. Since all of these patients underwent mastectomy, their inclusion in the study group would have resulted in a significant bias toward the surgical group, and for this reason, they were excluded. The three patients without a histologic diagnosis of inflammatory carcinoma of the breast presented early in the series, before the realization that dermal lymphatic invasion is a significant histologic finding. Clinically, these three patients behaved in a manner consistent with the 25 patients in whom the diagnosis was made both clinically and histologically. At the present time, we reserve the diagnosis of inflammatory carcinoma of the breast for patients demonstrating both the clinical and pathologic criteria. Patients presenting with a clinical diagnosis of inflammatory carcinoma of the breast at our institution undergo an incisional biopsy, including a portion of overlying skin. After histologic confirmation, they receive three or four courses of cyclophosphamide, adriamycin, 5-fluorouracil, vincristine, and prednisone. A mastectomy with at least a 2 cm margin is performed, and skin grafting is utilized if necessary. Postoperatively, chemotherapy is continued until a total of 12 courses has been administered. Radiotherapy is utilized only for the treatment of local recurrence. Summary Twenty-eight patients with inflammatory carcinoma of the breast have been retrospectively reviewed. Overall 5 year survival was 25 percent. There was a trend toward improved survival in patients who received chemotherapy which did not achieve statistical significance. Sixteen patients underwent mastectomy as part of their treatment. These patients had a 48 percent 5 year survival which was significantly better than the survival in patients who did not undergo mastectomy. Furthermore, mastectomy resulted in better control of the local disease. Of 12 patients who did not undergo mastectomy, local control was initially obtained in only 2, and both
The American Journal of Surgery
Inflammatory Breast Carcinoma
of these patients suffered local recurrence within 1 year. Our data support the conclusion that mastectomy be combined with preoperative and postoperative multiagent cytotoxic chemotherapy in the treatment of inflammatory carcinoma of the breast. More precise staging may permit better prognostic stratification of patients with this highly malignant cancer.
References 1. Heliman S, Harris Jr, Caneiios GP. Fisher B. Cancer of the breast in: DeVita VT, S Heliman, SA Rosenberg eds. Cancer: principles and practices of oncology. Philadelphia: JB Lipplncott, 1982: 934. 2. Camp E. Inflammatory carcinoma of the breast: the case for conservatism. Am J Surg 1976;131:583-6. 3. Treves N. The inoperability of inflammatory carcinoma of the breast. Surgery Gynecol Obst 1959;109:240-2. 4. Chu AM, Wood WC, Doucette JA. iiitcq breast carcinoma treated by radical radiotherapy. Cancer 1980;45:2730-7. 5. Fisher B, Glass A, Redmond C, et al. L-phenylaianlne mustard (L-PAM) in the v of primary breast cancar. Cancer 1977;39:2883-903. 6. Bonnadonna G, Brusamolino E, Vaiagussa P, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engi J Med 1976;294:405-10. 7. Perloff M, Lesnick Gil. Chemotherapy before and after mastectomy in stage iii breast cancer. Arch Surgery 1982;117: 879-81. 8. Lucas FV, C Perez-Mesa. inflammatory carcinoma of the breast. Cancer 1978:41:1595-605.
Discussion Jose J. Terz, MD (Duarte, CA): Dr. Hagelberg and coworkers, after reviewing the outcome of 28 patients categorized as having inflammatory breast cancer, have suggested that mastectomy be a major therapeutic modality in their management contrary to the most accepted concept that removal of the breast does not alter the limited survival rate of these patients. Their group of 16 patients who had mastectomy had a 5 year survival of 47 percent and a local control rate of 64 percent during the same interval. On the other hand, all 12 patients who did not have a mastectomy were dead 3 years after diagnosis and all had 100 percent local recurrence within 1 year. It also seemed that radiotherapy and chemotherapy, alone or in combination, enhanced the role of mastectomy in survival. The authors raised the issue once again of the role of mastectomy in the therapy of inflammatory breast cancer after it had been disregarded for many years. In 1976, E. Camp described 10 patients who were alive 5 years after diagnosis from a total of 346 patients with inflammatory cancer. Eight of these patients had undergone radical mastectomy; however, when the clinical and histologic information was reviewed by Ellis and Teitelbaum (Cancer 1974;33:1045), seven of the patients were found not to have dermal lymphatic metastasis, and in the eighth patient the pathologic material could not be located. The reviewers then concluded that these patients did not fit the diagnosis of inflammatory breast cancer. Could we also be seeing a difference of interpretation here? Inflammatory breast cancer is a clinicohistologic diagnosis which must include redness of the skin with edema (erysipeloid appearance), concomitant demonstration of
Volume 149,Juiy 1994
tumor emboli in the subdermal lymphatic vessels, and absence of a tumor mass involving the skin. All reports that strictly adhered to this definition uniformly were associated with a 5 year survival of less than 10 percent. Using this criteria, 2 years ago we reviewed the clinical course of 20 patients diagnosed as having inflammatory breast cancer seen between 1965 and 1979, with disease localized to the breast and axilla only without distant metastasis. The median length of survival was 15 months. Eight patients had mastectomy as part of the multiple therapy protocol with only one patient surviving 56 months, at which time she died from cancer. The diagnosis of inflammatory breast cancer in this paper was based on clinical or pathologic criteria or both. We must be aware that it is not unusual for direct involvement of the skin by a tumor mass to be associated with redness and edema, with or without evidence of tumor in the dermal lymphatic vessels. However, these patients uniformly have a better prognosis. I would like to offer an explanation for the unusually good results with mastectomy in patients with this disease. The authors have broadened the definition of the diagnosis of inflammatory cancer which may have led them to include cases that do not fit the standard classification. They have shown us that none of the patients without a palpable mass survived beyond 41 months, whereas the 5 year survival of those with a palpable mass was 37 percent. Further, more than 70 percent of the patients with a mass had a mastectomy. I will venture to say that the group of patients without a mass were the true inflammatory cancer patients in these groups, as evidenced by a survival curve that fits all previous reports. The authors supported their conclusion with the significance obtained from an extensive statistical analysis. However, this information is misleading because, the entered population was heterogenous-I am sure there weren’t two similar patients in the entire group-which detracts from the interpretation of the analysis. Dr. Jolly, would you clarify the fact that 64 percent of the patients in the mastectomy group were free of local disease 5 years after diagnosis, but only 48 percent of the same group survived that long? Assuming that my interpretation of case selection is incorrect, how can you explain the significant improvement in the role of mastectomy in the overall survival of the patients with inflammatory breast cancer compared with the current experience of no survival, considering all other factors as equal? William B. Hutchinson (Seattle, WA): Many factors must be considered in a discussion of inflammatory cancer of the breast that will certainly affect statistical conclusions, particularly in a small series. As noted by the authors, there are diagnostic criteria involved: clinical observation and judgment or histological fact, neither of which necessarily occur in the same patient. A breast may look inflammatory and show no evidence of carcinomatous invasion of the dermal lymphatic vessels in the submitted material and the reverse may occur when carcinomatous invasion of dermal lymphatic vessels is seen histologically where clinically it is not suspected. The woman in her 20s with clinical evidence of a true inflammatory carcinoma and confirmed dermal lymphatic invasion is a therapeutic challenge. We have found that for such patients, breast surgery has not been the initial treatment of choice. Hormone manipulation, where applicable, seemed to be the most effective modality to use until chemotherapeutic
129
Hagelberg et al
agents became available. Initially, these drugs are extremely helpful in management. Most young patients behave quite differently from older ones, especially obese women in whom we frequently find a sizeable mass and where the pathologist finds a few clusters of invasion of the dermal lymphatic vessels. Individualization of therapeutic management is imperative until more accurate categorization of inflammatory breast carcinoma is available, otherwise we may do harm with early surgery. I urge the authors to continue to seek better diagnostic criteria and improved treatment method combinations to help us manage this difficult problem. A 25 year old woman with inflammatory breast carcinoma had a biopsy specimen that showed infiltrating duct carcinoma. The scans, workups, and so on revealed no abnormalities. She had a bilateral oophorectomy with subsequent five drug chemotherapy and eventually 5,000 rads of external irradiation and then 1,000 rads with electronic beam radiation. She later had 2,000 rads with iridium implants. I suspect that this patient, after 4.5 years, who has no detectable carcinoma may, like so many others, suddenly have the development of widespread metastases. This type of patient would not have benefited from surgery. Richard E. Robins (Vancouver, British Columbia, Canada): I support mastectomy in the role of treatment of inflammatory breast cancer. I too share the concern that some of the patients described would not be considered to have true inflammatory carcinoma. I would not accept the diagnosis unless there was histologic proof of dermal involvement. Pathologists at the Cancer Control Agency of British Columbia have noted that when biopsy of the breast is not performed, there actually are very few tumor cells to be seen and they are almost never in clusters but rather they are individual cells. In our experience, too, the vast majority of these patients are estrogen-receptor negative so hormonal manipulation does not play much of a role in their treatment. Misguided surgery early in a case of true inflammatory breast cancer may lead to disaster, but perhaps in’a planned role it can later contribute to a patient’s well-being. From my experience at the Cancer Control Agency, in a group of patients seen from 1973 to 1979, half of t&e patients had the’first recurrence in the involved breast, and so many of these people, although they may have gone on to die from generalized disease, had the problems of a large tumor and sometimes an ulcerating mass on the chest wall. Well-advised surgery earlier could have prevented this. For a period of 3 or 4 years in the early 19709, the treatment was basically radiotherapy alone, and it is obvious that this only produced isolated cures. From 1975 through 1979, multidrug chemotherapy was used alone and did not result in local control or cure. From 1979 through 1982 we administered intensive multidrug therapy, and after several courses added radiation therapy, and then in certain cases added mastectomy. In this group, for the first time we saw patients who achieved good local control. Some of them are 4 year survivors and others are living longer even though they may have disease. Our present plan of treatment, which supports that of the authors, is that when first seen, a biopsy is performed and a diagnosis is made. Patients are given a single bolus of 800 rads of external irradiation as a holding dose to the local tumor, and then are given intensive multidrug ther-
130
apy for 6 months. At the end of this period, if the patient is free of generalized disease and appears to have a reasonably good prognosis, we then recommend mastectomy. Leon Morgenstern (Los Angeles, CA): This timely and important paper points out that it is about time surgeons reexamined their role in the treatment of inflammatory breast cancer. Neither Helman nor Fischer, who have been mentioned, are noted for their surgical enthusiasm. In a patient from my clinical experience this erysipeloid reaction diffusely involved the breast away from the main tumor mass. One phenomenon that I have seen a number of times but have not seen described is what I call a “periareolar blush” well away from the tumor. I think this should have an eponym. If it already has one, I would like to hear about it because this is not inflammatory breast carcinoma. It is a dilatation of the periareolar venous plexus, and I have seen it on a number of occasions. I don’t know of it being described as a’ sign. Concerning radiotherapy, a breast specimen from a woman who refused mastectomy had lumpectomy instead. She received 5,000 rads of conventional therapy and iridium implants which increased the dosage another 2,000 rads. Two years later, she reappeared for mastectomy because of progression of the disease, and we noted a very healthy-appearing condition of the tumor cells after 7,000 rads of irradiation. We have many patients like this. Radiation fibrosis is there, but very viable tumor cells are there also. Res ipsa loquitur.
Iain G.M. Cleator (Vancouver, British Columbia, Canada): I enjoyed this paper and found it very stimulating, but my feeling is that we are all talking about different kinds of inflammatory breast carcinoma. We have looked at some slides that some might have called advanced localized carcinoma in the elderly, some slides might have been called Paget’s disease, and some slides might have been called true inflammatory carcinoma. My own understanding of inflammatory carcinoma of the breast dates back to the teaching of Professor John Bruce in Edinburgh. There I saw large numbers of carcinomas, and the kind that we called inflammatory were classically in young persons. As Dr. Hutchinson reported, someone in their early 20s. The cancer would come on almost with the speed and urgency of a breast abscess and was often confused with that. There was edema and often redness which involved most of the breast. Dr. Jolly, could you indicate the ages of the patients who you described today? We may be talking about a group of diseases that conform to our current definition of inflammatory disease but don’t carry the connotation that we were taught in our undergraduate days which we see only very rarely and when we see it, it carries a very unfortunate prognosis. I see no reason not to question the role of surgery here but would like our definition to be very exact when we discuss inflammatory breast carcinoma. James Goodnight (Sacramento, CA): We are obviously struggling to define this disease but it is perhaps worth pointing out that these very broad definitions of inflammatory carcinoma have been used in other series and used to justify other approaches to the management of the condition. One approach is to start with chemotherapy which is the mainstay of treatment for what is obviously a systemic disease. It has been recommended that we give
The American Journal of Surgery
Inflammatory
three cycles of chemotherapy then begin radiation therapy. The radiation occupies a period of 6 to 8 weeks. This treatment may reduce the amount of chemotherapy the patient can take thereafter. I believe the importance of the authors’ observation regarding surgery is that if after the first three courses of chemotherapy, the disease is operable by our usual criteria, the patient would then be off chemotherapy for a very short time, perhaps even 2 weeks. Several discussants have indicated that radiation does not control this disease locally in many cases, One would expect that surgery may be the better choice in this regard. The authors have pointed out that dermal lymphatic involvement alone does not constitute inflammatory breast carcinoma. The prognosis in this group was relatively good. It has been stated that the prognosis of inflammatory breast cancer is worse in the premenopausal woman. The authors did not mention this in their presentation, and I wonder if Dr. Jolly might elaborate on this point. Philip Jolly (closing): Inflammatory breast cancer is the most malignant and fortunately the rarest form of breast cancer. Mastectomy has not been considered appropriate treatment. Surgeons have been admonished not to perform mastectomy because of the rapid development of widespread metastases. This surgical nihilism had its origins in the poor results after radical mastectomy alone reported by Haagensen, Treves, and others in the 193Os, 194Os, and 1950s. The marked improvement in survival in our mastectomy patients must be due in part to the use of adjuvant modalities and particularly the use of combination chemotherapy. The evolution of treatment of inflammatory breast cancer may have some similarities to the evolution of treatment of oat cell cancer of the lung. Surgical resection in conjunction with chemotherapy and irradiation therapy is being applied with increasing frequency in stage I oat cell cancer of the lung. Dr. Terz questioned the diagnosis of inflammatory breast cancer in our patients and suggested that patient selection may be responsible for our improved results, All 28 patients in this report had the clinical syndrome of inflammatory breast cancer. They had erythema or skin edema (peau d’orange) over at least a third of the breast often associated with a generalized increase in firmness of the breast tissue. Some of the patients also had a mass
Volume 148, July 1984
Breast Carcinoma
which was usually very large. Twenty-five of the 28 patients had pathologic confirmation of dermal lymphatic involvement with cancer. The three without pathologically confirmed dermal lymphatic involvement were seen early in the series when our pathologists were not looking for this finding. Five patients with dermal lymphatic involvement were excluded because they did not have the clinical findings of inflammatory breast cancer. These five patients’ disease behaved more like Stage II breast cancer and three of the five were alive 5 years after diagnosis. The 28 patients in the study group represent less than 2 percent of the 1,658 patients seen at our institution with breast cancer over the span of this study. Dr. Terz also pointed out that our patients who received chemotherapy did not have a significantly increased survival over those who did not receive chemotherapy. The survival curve of the patients who received chemotherapy was better than those not receiving chemotherapy, although the difference is not significant. It should be pointed out that the bias between the two groups was in favor of the nonchemotherapy group because all of the patients with Stage IV breast cancer received chemotherapy. When the differences in the two groups are considered, the improved survival in the chemotherapy group becomes more meaningful. The percentage of patients free of local recurrence is based on the survivors. Dr. Hutchinson and Dr. Cleator suggested that inflammatory breast cancer is a disease of young women. Half of our patients were premenopausal which suggests that the disease is more common in younger patients. Others have reported, however, that inflammatory breast cancer may occur over the entire age range for breast cancer. The prognosis of inflammatory breast cancer is dismal when conventional treatment is used. Because of the poor results, it seems reasonable to try some other combinations of treatment modalities. Our results suggest that mastectomy with removal of lymph nodes improves both survival and local control of disease. Our study is retrospective and involves only a small group of patients. These shortcomings could be overcome by evaluating a larger group of patients in a prospective fashion. I hope that this report will stimulate others to define precisely the role of mastectomy with lymph node removal in the treatment of inflammatory breast cancer.
131