Inflammatory Breast Cancer

Special Article on Breast Cancer

Inflammatory Breast Cancer William R. Grace, MD.,* and Avram M. Cooperman, M.D.t

Of all malignancies in women, perhaps none is as lethal or as frustrating to the surgeon as inflammatory breast cancer. From its original description at the end of the nineteenth century by Billroth and von Volkman lS until recent advances in systemic therapy, it has been recognized as a fatal disease with rapid and progressive involvement of vital organs. It was, however, the surgeon Bell,4 who first recognized in 1814 the poor prognosis of a breast mass that presents in the tender, erythematous breast. Koltz,23 later in the century, coined the term "mastitis carcinomatosa," which emphasized the inflammatory characteristics of this clinical presentation. "Acute mammary carcinoma" was used to describe this disease by Leitch26 and Learmouth,24 whose papers noted the rapid and fulminant downhill course. The first clear description of inflammatory breast carcinoma was reported in 1924 by Lee and Tannenbaum 25 and then again in 1938 by Taylor and Meltzer.39 In these early papers, the aggressive, fatal, systemic characteristics of the disease were described, which categorized this entity as a unique form of breast cancer affecting all ages and not confined to the pregnant or lactating as had been described by Billroth and von Volkmann and Schumann 19 at the turn of the century. No significant progress in curing or controlling inflammatory breast cancer was made until the last decade, when investigators, noting the futility of local therapies, applied systemic therapies with some significant improvement in survival. 9.,20. 29. 44. 46 We will address these new concepts in management later. EPIDEMIOLOGY

Inflammatory breast cancer develops in 1.5 per cent to 4 per cent of patients with breast cancer and is the most lethal form of the disease.n. 32 Between 47 per cent and 67 per cent of patients develop overt metastasis within one year of diagnosis. 3. 16.33.37 The average age of patients presenting with inflammatory breast cancer is 50 years, which is identical to that of

*Chief of Oncology, St. Vincent's Hospital, New York, New York tDirector of Surgery, St. Clare's Hospital, New York; Professor of Surgery, New York Medical College, Valhalla, New York

Surgical Clinics of North America-Vol. 65, No.1, February 1985

151

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WILLIAM

R. GRACE AND AVRAM M. COOPERMAN

noninflammatory varieties. 19. 39 Pregnancy and lactation are not predisposing factors.l 9

CLINICAL SIGNS AND SYMPTOMS Inflammatory breast cancer is unique in presentation and course. A discrete breast mass is most common in most cancers, but in inflammatory breast cancers it is an infrequent sign. Diffuse swelling of the breast tissues and dermis reduces the palpable contrasts between solid tumor and fat. 19, 27 The entire breast or segment of the breast is enlarged so that a common complaint is that one of the breasts no longer fits in the bra. Tenderness in the breast or nipple often accompanies the diffuse breast swelling, and in a majority of cases the skin over the affected area is reddened and inflamed. A warm feeling is present in 10 per cent to 36 per cent of the patients, and the breast tissue is firm or hard in 15 per cent to 64 per cent of patients. 19, 27 A discoloration of the skin ranging from a pinkish hue to bright red is seen in 60 per cent to 90 per cent, with peau d'orange edema present in 13.5 per cent to 67 per cent. Both the erythema and the edema have a predilection for the most dependent areas of the breast, and this may disappear with recumbency or glucocorticoid therapy.l9, 47 With the exception of nipple retraction (13 per cent), nipple discharge and itching, axillary pain, and arm swelling (signs not specific for inflammatory breast cancer) are seen in less than 10 per cent of cases 19, 27 (Table 1). These symptoms emerge rapidly in the affiicted patient, and Table l. Symptoms and Signs in 89 Patients With Inflammatory Breast Cancer from the Haagenson Series19 Compared with the Lucas and Perez-Mesa Series2 7 Group I and II Ranked Percentage of Signs or Symptoms HAAGENSON

Localized tumor Redness of the skin Enlargement of the breast Pain in the breast Tenderness Generalized breast hardness Edema of the skin Nipple retraction Axillary mass Warmth of the skin Nipple discharge Axillary pain Itching of the nipple Swelling of the arm Bone pain

57.3 57.3 48.3 29.2 15.7 15.7 13.5 13.5 8.9 7.9 7.9 4.5 4.4 3.4 1.1

LUCAS AND PEREZMESA

1*

IIt

NS 82 59 51

NS 95 88 63

64

26 58 NS NS 63 NS NS NS NS NS

67 NS NS 36 NS NS NS NS NS

*Clinically and pathologically positive for inflammatory breast cancer tClinically positive, pathologically negative breast cancer NS = Not speCified

INFLAMMATORY BREAST CANCER

153

most patients seek medical attention earlier than those with noninflammatory breast cancers. Haagenson's series suggest a delay of 2.5 months for inflammatory breast cancer versus 5 months for noninflammatory breast cancer. 19 Despite the "inflammatory" component, there are generally no systemic symptoms and signs of inflammation, such ·as fever or leukocytosis until metastases are obvious. 19 Combining two series totaling 103 patients, 4.8 per cent had leukocytosis, 8.7 per cent had fever, and 28 per cent had soft tissue, pulmonary, bone, or brain metastasis at presentation. 19, 39

DIFFERENTIAL DIAGNOSIS A significant number of patients are initially diagnosed as having a breast infection. This may delay the correct diagnosis and therapy by weeks or months. However, most breast abscesses are usually seen in the lactating breast and are generally accompanied by fever and leukocytosis, which are rarely seen in inflammatory breast cancer.19 Ductal ectasia with or without cellulitis could be misinterpreted as inflammatory cancer, but the localization of inflammation to less than one third of the breast and its rapid response to conservative therapy easily distinguishes it from inflammatory breast cancer. Neoplasms of the breast that become large and necrotic or grow in close proximity to the skin may cause an erythematous induration that might be confused as inflammatory breast cancer, but the distinct margins of the tumor mass and the confinement of the "inflammatory" component to a small portion of the breast make this easy to distinguish. Rarely, chloromas (myelogenous leukemic infiltrations) or lymphomatous invasion of the breast can mimic inflammatory breast cancer, but other obvious abnormalities seen on physical and laboratory tests are easy to distinguish from inflammatory breast cancer.

PATHOLOGY Early pathologic descriptions of the disease were influenced by the necessity to explain the clinical findings of warmth, erythema, edema, and tenderness. Koltz, Learmouth, and Schumann23 , 24, 37 described inflammatory perilymphatic and stromal infiltrates of lymphocytes and plasma cells. The classic pathologic description of dermal lymphatic invasion by tumor emboli was made by Bryant. 8 Taylor and Meltzer confirmed these findings. 39 During the past decade, controversy17, 19, 42 arose as to the accuracy of dermal lymphatic tumor invasion in predicting the clinical signs of the disease and therefore the prognosis. Several recent reports18 found no evidence of tumor in the dermal lymphatics of eight patients, diagnosed with inflammatory cancer, after a 5-year disease-free interval. Microscopic tumor in dermal lymphatics in ordinary breast cancer was reported by Saltzstein,35 who reviewed four cases of clinically negative inflammatory breast cancer with pathologic evidence of tumor invasion of the dermal lymphat-

154

WILLIAM

R. GRACE AND

AVRAM

M. COOPERMAN

ics. All four patients had a rapid downhill course typical of inflammatory breast cancer. Lucas and Perez-Mesa addressed this controversy by reviewing a series of patients from the Ellis Fischel State Cancer Hospita1. 27 In 3600 patients with breast cancer, 39 patients had clinical and pathologic evidence of inflammatory breast cancer and had as poor a survival as 19 patients with only clinical evidence of inflammatory cancer. Fifteen other cases with only carcinomatous dermal lymphatic emboli were reviewed. They had a more indolent course but 12 patients were dead of the disease within 4 years. The 4-year survival of all groups was similar. Most physicians accept either clinical, pathologic, or both criteria for establishing the diagnosis of inflammatory breast cancer. THERAPY Several papers have indicated the limitations and futility of surgery as the primary or the sole treatment. 2, 10, 16, 19, 32, 34, 35, 39 In a collected review of more than 499 patients treated by radical mastectomy alone, there were twelve 5-year survivors (2.4 per cent) with the median survival 17.5 months (Table 2,. All reports indicate that for nearly all patients surgery was always followed by systemic disease, which invariably led to a rapid downhill course and death. Because of the poor results of surgery and the systemic nature of the disease, radiotherapy became the major palliative modality for local control, in the last two decades. However, while avoiding a mastectomy, there Table 2.

Median 5-Year Survival of Patients With Inflammatory Breast Cancer After Radical Mastectomy

REFERENCE

YEAR

PATIENTS (NO)

5-YEAR SURVIVORS (%)

SURVIVORS (%)

MEDIAN SURVIVAL (MO)

Lee and Tannenbaum25

1924

4

0

Taylor and Meltzer'9

1938

6

Haagenson l9

1968

Treves40

1952

Rodgers and Fitts34

1956

10

1

10

Barker, Dockerty and Clagett2

1961

50

5

10

25

Byrd and Stevenson lO

1960

12

0

0

16

Richards and Lewison32

1961

13

0

0

20

Donegan l6

1967

12

0

0

18.5

12

2.4%

17.5

TOTAL *NS = Not specified

0

2.4

0

0

21.3

30

1

3

19.0

262

5

2

NS*

499

NS

155

INFLAMMATORY BREAST CANCER

are few survivors at 5 years, and the median survival is no different than surgical intervention. For the collected series of 265 patients treated by radiotherapy, less than 5 per cent survived 5 years, and the mean survival was 15.3 months (similar to that of surgery) (Table 3). A combination of local therapies utilizing surgery and radiotherapy should be expected to give similar results. When the combination of mastectomy and radiotherapy was done (105 patients), there were four 5-year survivals, and the median survival was similar to radical mastectomy or radiotherapy alone at 19.3 months. Systemic therapy, (hormonal, chemotherapeutic, or both) offers the potential for systemic control with added local treatment consolidating gains potentially achieved by the hematogenous route. Attempts at hormonal control with local radiation therapy were reported by Yonemoto,45 but the overall 5-year survival and mean survival were not significantly superior to other treatment modalities with local therapies. The poor response might have been anticipated since many tumors are estrogen-receptor (ER)-negative. Harvey demonstrated only 5 of 16 patients with posTable 3.

REFERENCE

Mean and 5-Year Median Survival for Inflammatory Breast Cancer Treated by Radiotherapy

YEAR

PATIENTS (NO)

5-YEAR SURVIVORS

5-YEAR SURVIVAL (%)

MEDIAN SURVIVAL (MO)

Haagenson!·

1971

29

1

3

14.7

Wang<'

1904

23

0

0

18.5

Chris

13

1950

9

0

0

16.0

Dao and McCarthy15

1957

3

0

0

4.0

Donegan!6

1967

10

0

0

18.1

Droulias et aI.!6

1976

31

0

0

23.0

Lee and Tannenbaum""

1924

13

0

0

11.0

Richards and Lewison'!

1961

6

0

0

11.0

Rogers and Fitts"

1956

24

1

4

15.7

Stocks and Peterson""

1976

3

0

0

11.0

Taylor and Meltzer'"

1938

19

0

0

9.2

Wang and Griscom"

1964

23

0

0

14.3

Wang and Griscom43

1964

10

2

20

30.0

203

4

1.9%

15.1

TOTAL

156

WILLIAM

R. GRACE AND AVRAM M. COOPERMAN

itive receptors ranging from 20 to 83 fmol per mg of cytosol protein (median = 42.8 fmol per mg).21 All ER-positive patients were premenopausal in this series. There was only one marginal response at 3 months to oophorectomy. Given a 6 per cent response rate for a duration of only 3 months, lack of response to hormonal therapy or manipulation is easily understood. The response rates of metastatic inflammatory breast cancer to chemotherapy vary from 75 per cent to 93 per cent,5. 46 which is substantially higher than the response to any other therapies. The first report of improved survival of patients with aggressive chemotherapy in addition to mastectomy and radiotherapy indicated a mean survival of 45.5 months in seven patients. 31 Buzdar et al. 9 reported similar results in 32 patients treated by chemotherapy and radiotherapy with a median survival of 30.1 months. Interestingly, there were striking differences in the survival of pre- versus postmenopausal patients. The median survival of premenopausal patients (under age 50) was 24.0 months versus 42.0 months for postmenopausal patients (greater than 50 years of age). Patterns of relapse explained some of the survival difference with 40 per cent of those under age 50 having parenchymal brain or leptomeningeal relapse patterns. This was seen in only 18 per cent of those over the age of 50. This type of relapse might be reduced in future trials by consideration of central nervous system prophylaxis with radiotherapy and/or intrathecal therapies as has been effective for other successfully treated systemic diseases, such as acute leukemia, aggressive lymphomas, or small cell cancer of the lung. Twenty-five per cent of patients had local relapse (breast), suggesting a continuing role for local therapy now that systemic therapy is available and somewhat effective in controlling life-limiting extraregional disease. This rate of 25 per cent local relapse also reflected an improved local control, achieved by the combination of chemotherapy and radiotherapy as compared to radiotherapy alone (38 per cent). Zylberberg et al. 46 recently reported 15 patients with inflammatory breast cancer treated with chemotheray and immunotherapy with Pasteur I-BCG-F followed by surgery. The median survival of his series had not yet been reached at 57 months. All patients were clinically free of metastatic disease at presentation. Of the 15 patients, 10 were free of disease 44 to 77 months after chemotherapy and surgery. The two who relapsed locally after surgery were given radiotherapy and are disease-free at 70 to 71 months. Three patients relapsed systemically and are dead of disease at 24, 27, and 37 months. FUTURE GOALS AND PERSPECTIVES Future therapies for this disease must be designed from past failures and successes. Local therapies alone salvage only 2 per cent or less of those treated (Table 4). Systemic chemotherapy, no matter how successful in controlling microscopic disease, provides local control to a minority of patients, although it increases the local control when combined with local therapies.

157

INFLAMMATORY BREAST CANCER

Table 4.

Mean and 5-Year Survival for Inflammatory Breast Cancer Treated by Radical Mastectomy and Radiotherapy CASES (NO)

5-YEAR SURVIVAL

5-YEAR SURVIVAL

(%)

MEDIAN SURVIVAL (MO)

REFERENCE

YEAR

Chris!3

1950

7

0

0

13.3

Dao and McCarthy!5

1956

6

0

0

13.0

Donegan!6

1967

9

0

0

15.9

Droulias et al,l1

1976

5

NS*

0

29.9

Meyer et al. 27

1948

47

3

6.4

28.0

Richards and Lewison32

1967

11

0

0

14.0

Rodgers and Fitts34

1956

20

1

5.0

20.7

105

4

3.8

19.3

TOTAL *NS = Not specified

Because effective systemic therapy now exists, the proper role for surgery and of radiation remains undefined. Approximately 25 per cent of those patients treated by radiotherapy and chemotherapy will develop local relapse. In theory, when there is a high risk for a large residue of local tumor burden in a microscopically disseminated disease, effective systemic therapy increases survival and enhances the effectiveness of local therapy that ordinarily would not improve survival (Table 5). If chemotherapy prolongs survival, the question of ideal local therapy becomes more salient. Whether radiation or surgery will be more effective may depend on the tumor burden left after chemotherapy. We are less impressed with radiation for large residual cancers after chemotherapy and are uncertain whether a standard traditional mastectomy or skin-sparing is not a wiser route. Our own experience is anecdotal; a study of larger numbers of patients randomized to radiation or surgery after chemotherapy needs to be done. There are many questions, and we urge cooperative group and intergroup controlled trials. Should these trials not be available, then empiric management might include chemotherapy using Adriamycin, cyclophosphamide, 5-FU and methotrexate, and glucocorticoid-based chemotherapy. After chemotherapy (the number of cycles is unclear), responders who have no systemic disease, should then have residual tumor in the breast treated by mastectomy or radiation. Mter four cycles of chemotherapy, most of the benefits will have been achieved but we are uncertain how long it should be continued. Premenopausal patients should be considered for radiotherapy of the cranial spinal axis because there may be a need to reduce the 40 per cent central nervous system relapse rate, but no data

158

WILLIAM

R. GRi\CE AND AVRAM M. COOPERMAN

Table 5.

REFERENCE

YEAR

PATIENTS (NO)

5-YEAR SURVIVORS

5-YEAR SURVIVAL (%)

MEDIAN SURVIVAL (MO)

Chris l3

1950

7

0

0

13.3

Dao and McCarthy15

1956

6

0

0

13.0

Donegan l6

1967

9

0

0

Droulias et al. 17

1976

5

NS*

NS

15.9 29.0

Meyer et al. 27

1948

47

3

6.4

28.0

Richard and Lewison32

1961

11

0

0

14.0

Rodgers and Fitts"

1956

20

1

5

20.7

105

4

3.8%

19.1

TOTAL *NS = Not specified

are available to determine the benefits of its prophylactic use. Nonresponders to chemotherapy should receive radiotherapy and/or surgery, with the intent to palliate.

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