Inflammatory Carcinoma of the Breast

Symposium on Surgical Oncology

Inflammatory Carcinoma of the Breast

Guy F. Robbins, M.D.,* Jatin Shah, M.D.,** Paul Rosen, M.D.,t Florence Chu, M.D.,! and Jane Taylor, B.S.§

Inflammatory carcinoma of the breast is the most lethal form of breast cancer that we have observed at Memorial Hospital. Available therapeutic regimens have not provided a means of control of local disease frequently observed with other forms of breast carcinoma. This report represents data acquired by the review of the charts of the 186 women with inflammatory carcinoma of the breast who were treated at the Memorial Hospital during the years 1949 through 1971. Eighty-three of these women received their primary treatment for this entity at our institution. The other 103 patients had recurrent disease diagnosed as inflammatory carcinoma. Thirty of these women had received their primary treatment at Memorial Hospital. The remaining 73 women with recurrent inflammatory breast carcinoma had their primary treatment for breast carcinoma at other institutions.

PHYSICAL CHARACTERISTICS OF INFLAMMATORY BREAST CARCINOMA Primary untreated inflammatory carcinoma of the breast has three dominant clinical features-varying amounts of skin redness with a palpable erysipeloid margin or edge, increased warmth of involved skin, and induration of underlying breast tissue (Fig. 1). The recurrent type of inflammatory carcinoma is recognized by the red, warm, indurated skin with an associated erysipeloid edge (Fig. 2). Biopsies of these areas and of adjacent normal appearing skin typically reveal diffuse dilatation of lymphatics and carcinoma cells in lymphatics. Palpable, nodular skin infilFrom Memorial Sloan-Kettering Cancer Center, New York, New York "'Acting Chief, Breast Service, Department of Surgery ""Former Fellow, Department of Surgery tAssociate Attending Physician, Department of Pathology ~Attending Physician, Department of Radiology §Statistical Assistant, Breast Service

Surgical Clinics of North America- Vol. 54, No.4, August 1974

801

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ROBBINS, SHAH, ROSEN , CHU, AND TAYLOR

Figure 1. Primary inflammatory carcinoma of left breast. Note fullness of the breast indicative of edema, and darkened area of skin with sharp margins in the area of involvement.

trates of carcinomas are an infrequent finding in primary inflammatory carcinoma. Ulceration does occur, but it is usually not extensive. In general, this clinical entity occurs in women with large breasts.

Method of Study The authors reviewed the charts of all women with primary and recurrent inflammatory breast carcinoma treated at Memorial Hospital during the years 1949 through 1971. Data pertaining to each patient's age, parity, menstrual status, size of breast, presenting symptoms, clinical and laboratory findings, treatment procedures, and survival were transferred to IBM punch cards. All available histopathologic material for patients with recurrent inflammatory carcinoma was reviewed. In patients with primary inflammatory carcinoma, the diagnosis was usually made by needle biopsy or skin biopsy.

Figure 2. Recurrent carcinoma with inflammatory pattern extending over posterior thorax. Some nodularity is evident. Nodular infiltrates were present in slightly more than a third of the patients with inflammatory recurrences.

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INFLAMMATORY CARCINOMA OF THE BREAST

Patient delay before seeking treatment and the free interval of time before recurrent inflammatory carcinoma was observed were included in our study. The data relating to patients with primary inflammatory breast carcinoma and recurrent inflammatory breast carcinoma are presented as separate entities.

Determination of Stage of Disease The criteria of inoperability for cure of patients with breast carcinoma developed by members of the Breast Service nearly 35 years ago con- . tinue to be utilized. Those patients are considered as potentially incurable' , when the following exist: 1. 2, 3. 4. 5. 6. 7.

Demonstration of distant metastasis Fixation of breast and pectoral muscles to the chest wall Edema of the ipsilateral arm Fixation of axillary nodes to underlying vessels and nerves Ipsilateral metastatic supraclavicular nodes Inflammatory carcinoma Medical contraindications

CLINICAL FEATURES OF PRIMARY INFLAMMATORY CARCINOMA OF THE BREAST (83 PATIENTS) The 83 women in this group made up 1 per cent of our population of untreated women with breast carcinoma during the observed time interval (Table 1). Ten per cent of those women considered incurable had inflammatory carcinoma. Four patients were Black, the rest were Caucasian. The median age of patients under study and that of our total population were both 55 years. Thirty-six per cent of the patients (29) were nulliparous. Wynder reports 14 per cent of all women with breast cancer as nulliparous. Sixty-nine per cent were menopausal (Wynder's total group - 52 per cent). The median delay prior to treatment was 6 months, double that for our total patient population during the same time period (Table 2). The presenting clinical appearance of this disease often confuses patient and physician alike. Therapy directed toward the treatment of a breast that is warm and red presumably explains the marked delay in the instigation of treatment of the carcinoma. All of the patients had increased warmth of the breast. Most of the patients (85 per cent) had associated redness of the breast. An erysipeloid edge was always evident:' Table 1. Untreated Invasive Breast Carcinoma at Memorial Hospital, 1949 to 1971 PATIENT STATUS

Potentially curable Considered incurable Primary inflammatory carcinoma TOTAL PATIENTS

NUMBER OF PATIENTS

7535 835 83 8370

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ROBBINS, SHAH, ROSEN, CHU, AND TAYLOR

Table 2. Women with Untreated Breast Carcinoma INFLAMMATORY CARCINOMA

Age Nulliparous Menopausal Delay

55 29 69 6

yrs. per cent per cent mos.

TOTAL GROUP

55 14 48 3

yrs. per cent per cent mos.

Two-thirds of the patients had a definite palpable mass in the breast, the others had diffuse breast involvement. Twenty per cent had pain and twenty per cent had varying degrees of ulceration. Seventy per cent of the patients had large breasts. Nipple discharge was noted in three patients. Twenty-one per cent had symptoms suggestive of distant metastasis (Table 3). The majority of patients had advanced clinical involvement upon initial examination. Seven patients seemed to have the disease limited to the breast (8.4 per cent). In 37 patients (44.5 per cent) the disease involved clinically the breast and an axilla. Another group of 28 patients (33.7 per cent) had breast, axillary, and supraclavicular involvement. Disseminated disease was demonstrated initially in 11 patients (13.3 per cent). Ten of the patients had associated edema of the ipsilateral arm. The average and median survivals of these groups of patients varied, but all were of short duration regardless of treatment (Table 4). The total group had a median survival of 17 months and an average survival of 16 months. Patients with edema of the arm (11 patients) had an average survival time of 12 months with a median time of 7 months. Treatment Initial treatment attempts were dependent upon the clinical extent of disease. Radiation therapy was utilized if the disease was clinically limited to the breast and axilla. Hormonal and/or other chemotherapeutic agents provided occasional objective short-term responses. Oophorectomy alone was unsuccessful; the one exception was an objective remission which has lasted for nearly 10 years. Objective remissions lasting 6 Table 3.

Signs and Symptoms of Primary Inflammatory Carcinoma PER CENT

Erysipeloid edge Increased breast temperature Redness Definite mass Diffuse involvement of breast Ulceration Pain Distant metastasis

100 100 85 67 33

20 20 21

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INFLAMMATORY CARCINOMA OF THE BREAST

Table 4. Clinical Extent of Disease and Survival in Primary Inflammatory Carcinoma of the Breast NUMBER OF INVOLVEMENT

Breast only Breast and axilla Breast, axilla and supraclavicular Disseminated disease Associated edema of arm TOTAL

PATIENTS

7 37 28 11 11

83

AVERAGE SURVIVAL

(mos.)

35 20 16 16 12 16

months or longer were observed in 30 per cent of those patients subjected to hypophysectomy or oophorectomy plus adrenalectomy. In 1950 through 1953, four patients were subjected to radical mastectomies. All of them died within 1 year after this surgery. During this same time interval, palliative radical mastectomies were performed on several patients who were clinically free of disease shortly after they had received radiation therapy as the primary treatment. These patients did very poorly. We now consider inflammatory breast carcinoma as an absolute contraindication for the performance of a radical mastectomy initially, or following radiation therapy. Survival Regardless of the treatment or clinical stage of inflammatory breast carcinoma, patients' survivals are extremely short. Only two (3.2 per cent) of the 63 patients treated prior to 1967 were clinically free of disease longer than 5 years. One of these patients recently died with lung metastasis, the other is still free of any stigmata of breast cancer. Seven of the 20 patients treated during the last 5 years of the study (1967 to 1971) are still alive. We lost two of our 83 patients to followup. They had demonstrable disease and are assumed to be dead. One patient died of causes other than cancer shortly after initial treatment. Clinically, she was free of carcinoma.

CLINICAL FEATURES OF RECURRENT INFLAMMATORY CARCINOMA OF THE BREAST (103 PATIENTS) Thirty of the 103 patients with recurrent inflammatory breast carcinoma had received their primary treatment at Memorial Hospital. Seventy-three patients were seen first when they had inflammatory recurrences and data relevant to their symptomatology and initial clinical findings were inadequate. Eighty per cent of both subgroups had large breasts. The median age at time of primary treatment was 55 years. Two patients were Black, the rest were Caucasian. Thirty per cent of the patients were nulliparous and 90 per cent had gone through the menopause prior to initial treatment. The free interval between initial treatment and

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ROBBINS, SHAH, ROSEN, CHU, AND TAYLOR

recognition of inflammatory recurrence was identical in both the primary and recurrent groups - an average of 31 months and a median time interval of 15 months. The Memorial Hospital group (30 patients) was clinically similar'to most potentially curable patients. A dominant mass in the breast was described in all but seven patieJ?,ts who had diffuse involvement. However, histologic examination following radical mastectomy revealed that 75 per cent of the surgical specimens had metastasis in the axillary nodes. Treatment Radiation therapy was utilized if the extent of disease was limited to an area which could be inchided in reasonable ports. As in patients with primary inflammatory carcinoma, those with recurrent inflammatory carcinoma did not respond to oophorectomy. The use of estrogen, androgens, steroids, and other chemotherapeutic agents occasionally provided '~bort-term objective remissions. Those patients subjected to hypophysectomy or oophorectomy combined with adrenalectomy responded in about the same manner as observed when treating the group of patients with primary inflammatory carcinoma. Approximately 30 per cent showed remissions lasting 6 months or longer. Those patients whose recurrences were clinically localized to areas of the chest wall that could be subjected to radiation therapy obtained the longest periods of objective remission-an average of 8 months and a median time of 9 months. Sixteen patients (two-thirds of those with metastases in nodes) had metastases in apical nodes. Nodal metastases were usually apparent grossly in the axillary contents. Review of the primary lesions of patients with recurrent inflammatory carcinoma initially treated at Memorial Hospital reveals several points of interest. All of the carcinomas were ductal in origin (Table 5). An unexpected observation was the finding of ten carcinomas which were partly or completely apocrine in type. Since apocrine type carcinomas constitute much less than a third of all duct cancers, this is an unusually high incidence. A patient with Paget's disease had a palpable infiltrating carcinoma. There were isolated examples of medullary and mucinous carcinoma as well. Intralymphatic tumor cells were found in the breast parenchyma in 22 of the mastectomies. They were not seen in the limited number of sections available in the other cases, but presumably would have been found Table 5.

Histologic Classification of Primary Carcinomas in 30 Patients with Inflammatory Recurrence Infiltrating duct Apocrine duct Infiltrating duct - apocrine features Papillary Papillary with Paget's disease Medullary Mucinous Unavailable for review

13 6 4 3

1 1

INFLAMMATORY CARCINOMA OF THE BREAST

807

* Figure 3. Low power view of section of skin in patient with inflammatory recurrent carcinoma. Note tumor cells in dermal lymphatics and modest perilymphatic lymphocytic reaction (H&E X210).

by more extensive sampling. Among these patients there were nine who had groups of cancer cells in lymphatics of the nipple and/or skin of the breast at the time of mastectomy. Skin biopsies of inflammatory recurrences were available for review in 16 cases. Intralymphatic carcinomatous emboli were present in the dermis in 14 (Figs. 3 and 4). Six of these also had nodular, infiltrative lesions in the skin. Two other biopsies revealed only nodular infiltrates. An interesting feature of the cutaneous intralymphatic carcinoma was the variability of inflammatory reaction. In most cases, little or no reaction was evident in the tissue around lymphatics which contained cancer cells. In a few instances, modest accumulations of lymphocytes were evident, and in two biopsies the perilymphatic inflammatory response was strikingly intense and consisted mainly of lymphocytes and monocytes. The majority of patients (73) with inflammatory recurrent carcinoma received their initial therapy at other institutions. In most of these cases, slides are not available for review so that a detailed analysis of histopathologic findings was not possible.

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ROBBINS, SHAH, ROSEN, CHU, AND TAYLOR

Figure 4. Enlarged view of tumor cells in lymphatics in Figure 3 demonstrating prominent nucleoli and abundant granular cytoplasm typically seen in the cases of carcinoma with apocrine features. (H&E x560).

All patients treated initially at Memorial or other hospitals were subjected to prophylactic postoperative radiation therapy when axillary metastases were found at operation. Less than 10 per cent in each group were treated by prophylactic oophorectomy. Treatment regimens were similar to those instigated when confronted with primary untreated inflammatory breast carcinoma. These will be reported in detail subsequently. Local control was accomplished by surgical excision of involved areas. Oophorectomy was of no value. Radiation therapy controlled local disease, provided it was limited to areas that could be encompassed by realistic ports. Remission, however, was uniformly short in duration. Hypophysectomy or combined oophorectomy and adrenalectomy provided the most effective therapeutic approach to the problem. Hormone therapy was disappointing. Occasionally, combinations of steroids and other chemotherapeutic agents produced short-term partial objective remissions. These effects were noted if such therapy was given prior to or following deprivative surgery.

DISCUSSION This study has provided little data which will assist clinicians in treating patients with primary or recurrent inflammatory breast cancer. However, it may have highlighted several leads that may assist investigators in future studies of this type of breast carcinoma. Perhaps endocrine and immunologic factors are paramount in the development of inflammatory carcinoma. The relatively high incidence of nulliparous women

INFLAMMATORY CARCINOMA OF THE BREAST

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who develop this entity is intriguing, as is the predominance of women in the menopause who are afflicted. It is likely that inflammatory recurrence can be predicted on the basis of findings in the mastectomy. The majority of the patients had intralymphatic cancer cells within the breast, nipple, or mammary skin at the time of mastectomy. This finding seems to be associated with multiple and often large axillary lymph node metastases. This combination, if found at mastectomy, should alert the physician to the possibility that recurrent carcinoma may have inflammatory features. We cannot offer an explanation for the surprising frequency of carcinomas with apocrine or sweat gland features. This association with inflammatory recurrence has not been described previously and is worthy of further study. Although only on a speculative basis, one may postulate that host resistance to most cancers which spread in this fashion is minimal. Immunologic and steroid studies which are now being designed may shed some light on this breast cancer enigma.

SUMMARY 1. Inflammatory carcinoma of the breast is an infrequent type of carcinoma which is often misinterpreted as an infection by patients and physicians alike. 2. Recurrent carcinoma can, in rare instances, present a clinical picture resembling primary inflammatory carcinoma. The combination of bulky axillary metastases and intralymphatic carcinoma cells in the breast seems to predispose to inflammatory recurrence. There may be a significant association with primary duct carcinomas of the apocrine type. However, not all patients with this constellation of findings developed inflammatory recurrences. 3. Conventional surgical procedures are contraindicated for the treatment of primary inflammatory carcinoma. They do not provide the local control of the disease frequently observed in patients with other types of clinically localized breast carcinoma. 4. Radiation therapy and endocrine ablation, such as hypophysectomy or combined oophorectomy and adrenalectomy, provide the most effective palliation in patients afflicted with this entity. 5. Hormone and other chemotherapeutics occasionally provide short-term objective regression of disease. 6. Biochemical and immu:p.ologic research efforts may provide a better understanding of this lethal form of breast carcinoma.

SUGGESTED READING 1. Barber, K. W., Jr., Dockerty, M. B., and Clagett, O. T.: Inflammatory carcinoma of the

breast. Surg. Gynec. Obstet., 112:406, 1961. 2. Berger, S. M.: Inflammatory carcinoma of the breast. Amer. J. Roentgenol., 88:1109, 1962. 3. Byrd, B. F., Jr., and Stephenson, $. E., Jr.: Management of inflammatory breast cancer. Southern Med. J" 53:945, 1960.

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4. Chris, S. M.: Inflammatory carcinoma of the breast Brit. J. Surg., 38:163,1950. 5. Dao, T. L., and McCarthy, J. D.: Treatment of inflammatory carcinoma of the breast. Surg. Gynec. Obstet., 105:281=1, 1957. 6. Donegan, W. L: In Spratt, J. S., Jr., and Donegan, W. L: Cancer of the Breast Philadelphia, W. B. Saunders Co., 1967, p. 167. 7. Donnelly, B. A.: Primary "inflammatory" carcinoma of the breast. Ann. Surg., 128:918, 1948. 8. Haagensen, C. D.: Diseases of the Breast, 2nd ed. Philadelphia, W. B. Saunders Co., 1971, pp. 576-584. 9. Hartmann, H., Bertrand-Fontaine, T., and Guerin, P.: Les mastites et carcinomateuses et leur traitement. BulL assoc. franc. p. l'etude du cancer, 24: 137, .1935. 10. Huvos, A. G., Hutter, R. V. P., and Berg, J. W.: Significance of axillary macrometastases and micrometastases in mammary cancer. Ann. Surg., 173:44-46, 1971. 11. Lee, B. J., and Tannenbaum, N. E.: Inflammatory carcinoma of the breast. Surg. Gynec. Obstet., 39:580, 1924. 12. McDivitt, R. W., Stewart, F. W., and Berg, J. W.: Tumors of the Breast Atlas of Tumor Pathology, Washington, D.C., Armed Forces Institute of Pathology, 1968. Second Series, Fascicle 2. 13. Meyer, A. C., Dockerty, M. B., and Harrington, S. W.: Inflammatory carcinoma of the breast. Surg. Gynec. Obstet, 87:417, 1948. 14. Nichim, F. M., Goldman, L., Lapayowher, M. S., Levy, W. M., Maur, W., and Rosemond, G. P.: Inflammatory carcinoma of the breast in a twelve year old girl. Arch. Surg., 105:505, 1972. 15. Orbach, E.: Ueber Mastitis Carcinomatosa. ZentralbL f. Chir., 58:1258,1931. 16. Richards, G. J., Jr., and Lewison, E. F.: Inflammatory carcinoma of the breast. Surg., Gynec. Obstet., 113:729, 1961. 17. Rogers, C. S., and Fitts, W. T., Jr.: Inflammatory carcinoma of the breast. Surgery, 39:367, 1956. 18. Schumann, E. A.: A study of carcinoma mastitoides. Ann. Surg., 54:69, 1911. 19. Taylor, G. W., and Meltzer, A.: "Inflammatory carcinoma" of the breast. Amer. J. Cancer, 33:33, 1938. 20. Treves, N.: Castration as a therapeutic measure in cancer of the male breast. Cancer, 2: 191, 1949. 21. Treves, N.: Inflammatory carcinoma of the breast in the male patient. Surgery, 34:810, 1953. 22. Treves, N.: The in operability of inflammatory carcinoma of the breast. Surg. Gynec. Obstet., 109:240, 1952. 23. Wang, C. C., 'and Griscom, N. T.: Inflammatory carcinoma of the breast. Clin. Radiol., 15:167,1964. 24. Wynder, E. L: Current concepts of the etiology of breast cancer. In Forrest, A. P. M., and Kunkler, P. B. (eds.): Prognostic Factors in Breast Cancer. Baltimore, Williams & Wilkins Co., 1968, pp. 32-49. Memorial Sloan· Kettering Cancer Center 1275 York Avenue New York, New York 10021