Fungating Breast Cancer: Experience in Low and Middle Income Country

Abstract

Fungating breast cancer (FBC) is a rare entity in developed nations. But this occurrence is not uncommon in our country. The aim of this study was to review clinico-pathologic profile and outcomes of FBC in a developing country. This retrospective study consisted of patients with FBC managed at our institute (Jan 2005–Dec 2015). Clinico-pathologic profile, management details, and outcomes were analyzed. The Kaplan-Meier method was used to determine overall survival (OS). Log-rank test was performed to compare survival in various subgroups. Seventy-nine patients were detected to have FBC constituting 3.3% of all breast cancers and 24.8% of those having T4b lesions. Mean age of the patients was 55 + 11 years. Ninety-six percent were women and 67% belonged to rural areas. A total of 75% women were postmenopausal. Mean duration of lump was 16 + 11 months. The mean tumor size was 8+ 2 cm. Eighty-seven percent had axillary lymph node involvement and 42% distant metastases. Fifty-eight percent (n = 46) patients had stage III and 42% (n = 33) stage had IV tumors. Hormone receptor (HR) positivity was noted in 44% (n = 35) and HER2/neu overexpression in 39% (n = 31) tumors, whereas 32% (n = 25) were triple negative. Overall, 95% (n = 75) of patients received chemotherapy, 91% (n = 72) patients underwent mastectomy, and 76% (n = 60) loco-regional radiotherapy. Median duration of follow-up was 40 (2–93) months. Median survival was 36 months, and 5-year OS was 40%. Except for stage (53% vs 22%, p = 0.005), no other factor influenced OS. Multimodality therapy in FBS results in good symptom palliation and comparable survival to stage III and IV patients without fungating tumors.

Introduction

Breast cancer (BC) is the most common cancer in women not only in the developed world but also in developing countries [1]. The outcome of BC depends on multitude of variables with the stage of disease at presentation being the most important factor. The incidence of BC is increasing worldwide, while mortality has decreased in developed nations due to early detection of disease and better adjuvant systemic therapies [2].

In general, presentation of all malignancies is late and mortality is high in low and middle income countries (LMIC). Over 65% of cancer-related deaths occur in LMICs [3]. Despite low incidence of BC, more than half BC deaths occur in LMIC [4]. This could be attributed to the stigma of cancer, financial burdens, and the non-availability of specialized therapy at peripheral centers in LMIC [5]. About 50% of women in LMIC present with locally advanced breast cancer (LABC) [6]. Today, fungating breast cancer (FBC) is a rare entity in developed nations due to screening programs, better awareness of the disease, and easy access to health care but the same is not true for LMIC (Fig. 1). Fungation could be considered a more severe form of ulceration. Fungating describes what the cancer might look like, as they can grow in the shape of a fungus or cauliflower. As per National Cancer Institute (NCI) Dictionary of Cancer Terms, a fungating lesion is “A type of skin lesion that is marked by ulcerations and necrosis and that usually has a bad smell. This kind of lesion may occur in many types of cancer, including breast cancer, melanoma, and squamous cell carcinoma, and especially in advanced disease”. Factors such as presence of discharge, malodor, risk of infection, and potential social isolation complicate the comprehensive management of these patients.

Fig. 1.

a Ulcerated breast cancer. b Fungating breast cancer

Due to rare occurrence, there is not much published literature on FBC. The purpose of the current study was to share our experience of managing FBC. The specific aims were to review clinico-pathologic profile and outcomes of FBC in a developing country.

Methods

This is retrospective analysis of prospectively maintained data of BC patients who were managed in our department between January 2005 and December 2015. The study was approved by the department research forum. The case records of all the identified patients were reviewed, and following parameters were noted: age, gender, menopausal status, education level, residence, duration of breast lump, duration of fungation, and any other symptoms. The details regarding the pathology and management details including surgery, chemotherapy, radiotherapy, hormone therapy, and management of breast wound were collected from the hospital information system. Follow-up data was obtained from outpatient record registry of our department. Patients who had not been regularly coming for follow-up visits were contacted by postal mail, telephone, or email. Patients for whom sufficient data was not available were excluded from the analysis.

All patients were evaluated by standard triple assessment. Ultrasonography (USG) was preferentially used for the radiological assessment of the affected breast, and mammography could be performed only in cases with small ulcers. Diagnosis was confirmed by histological analysis of tumor, either by core needle or by incisional biopsy. Pathological evaluation was done to determine the histological type and molecular subtype of the tumor. Staging protocol included CXR and/or CT thorax, USG abdomen and/or CT abdomen, and skeletal scan to detect metastasis. Upfront chemotherapy (CT) after ruling out and/or managing systemic/local infection was the preferred initial modality unless there were specific contraindications. Upfront palliative surgery (Sx) was performed in a few patients who were either unfit for CT or required palliative Sx because of excessive/uncontrolled bleeding or infection. Decision regarding radiotherapy (RT) was individualized based on merit of each case. All hormone receptor (HR)-positive patients received letrozole/tamoxifen based on menopausal status and those with HER2/neu positive tumors, trastuzumab depending on financial affordability.

After completion of primary treatment, patients were followed at 3 monthly or as otherwise indicated intervals for initial 3 years and 6 months thereafter. During follow-up visit, clinical examination and targeted imaging was performed. All surviving patients had annual mammography (MMG), bone mineral density (BMD), and/or trans-vaginal USG for evaluation of endometrium.

Care of wound—patients/relatives were taught to apply non-adherent and absorptive dressing on domiciliary basis. No routine antibiotic was prescribed, neither systemic nor topical.

Definitions and Standards

• Standard guidelines were followed to stage BC and report HR and menopausal status [7].

• AJCC 8^thedition system was used to stage all cases. As all the patients were operated before2017; all were reclassified [8].

• The day of surgery was taken as the reference point for defining overall survival (OS) and disease-free survival (DFS).

Statistical Analysis

The SPSS software (version 22.0) was employed to perform statistical analysis. Parametric and non-parametric tests were used as indicated, and the Kaplan–Meier method was used to estimate OS. Univariate and multivariate analysis were performed by Log-rank and the multivariate Cox regression analysis respectively.

Results

A total of 2394 BC patients were managed during the study period, out of which 316 had T4b tumors. A total of 79 patients had FBC thus constituting 3.3% of all the BC and 29% of T4b tumors.

The mean age of presentation of the whole cohort was 55 years. Ninety-six percent patients were women (M:F = 1:19). Three-fourth of the women was post-menopausal. One patient each had a family history of BC and history of previously treated BC in the opposite breast. Eleven percent (n = 9) of patients had history of lumpectomy without any adjuvant therapy and presented with recurrent disease, while rest presented for the first time. Ten patients (12.6%) were nulliparous. Majority of the patients (57%) were from rural areas and 42% patients reported to have never been to school. Mean duration of breast lump was 16 months, and of fungation was 2 months. In addition to an ulcerated breast mass, complaints of pain, wound discharge, malodor, and fever were present in 23%, 34%, 15%, and 4% of the patients respectively. Mean tumor size was 7.6 cm. Eighty six percent (n = 68) patients had axillary lymphadenopathy, and 42% (n = 33) had synchronous distant metastases. Overall prevalence of distant metastasis was 65% (n = 51), and 23% (n = 18) of patients developed metastases in follow-up (metachronous metastases).Pulmonary metastasis was most common (n = 29, 37%) either alone or with other systems. Skeletal system involvement was noted in 28% (n = 22) and hepatic metastases in 14% (n = 11) patients respectively. The histology report in 92% of the patients was infiltrating ductal carcinoma, and 1 % each had infiltrating lobular carcinoma, mucinous carcinoma, infiltrating duct carcinoma (IDC) with neuroendocrine differentiation, IDC with sarcomatoid differentiation, invasive papillary carcinoma, and secretory carcinoma. HR expression and HER2/neu overexpression was seen in 44%and 40% of the tumors respectively. Thirty-two percent of tumors were triple negative. TNM stage distribution was IIIB-55.7% (n = 44), IIIC-2.5% (n = 2), and IV-41.8% (n = 33). Except for high incidence of axillary lymphadenopathy, clinico-pathologic profile of stages III and IV FBC was comparable. A comparative summary of clinical profile of stages III and IV FBC is provided in Table 1.

Table 1.

Comparative Clinico-pathologic Features of Stage III and IV patients with Fungating Breast Cancer

SL No.	Variable	All patients n=79	Stage III n=46	Stage IV n=33	p-value
1.	Age in years: mean ± SD (Range)	55 ± 11 (35-86)	55.2 ± 11 (36-86)	55.2 ± 11.0 (35-78)	0.828
2.	Male: Female	1:19	1:45	1:15	0.568
3.	Menopausal status- n (%)
	- Postmenopausal	57 (75)	35 (78)	22 (71)	0.593
	- Premenopausal	19 (25)	10 (22)	9 (29)
4.	Nulliparous: n (%)	9 (12)	6 (13)	3 (10)	0.730
5.	Residence: n (%)
	- Rural	45 (57)	21 (46)	13 (39)	0.649
	- Urban	34 (43)	25 (54)	20 (61)
6.	Education status- n (%)
	- Never went to school	33 (42)	19 (41)	14 (43)	0.857
	- Middle	15 (19)	9 (20)	6 (18)
	- Primary	26 (33)	15 (33)	11 (33)
	- High school& above	5 (6)	3 (6)	2 (6)
7.	Presentation: n (%)
	- Primary	70 (89)	39 (85)	31 (94)	0.291
	- Recurrent	9 (11)	7 (15)	2 (6)
8.	Duration of lump in months:
	Mean ± SD	16 ± 11.4	16.8 ± 12.4	1.7 ± 9.9	0.425
9.	Duration of Fungation in months:
	Mean ± SD	2.3 ± 2.0	2.2 ± 2.0	2.5 ± 2.0	0.548
10.	Multi- Focality: n (%)	7 (9)	4 (9)	3 (9)	1.000
11.	Tumor size in cm: Mean ± SD	7.6 ± 2.8	7.1 ± 2.6	8.2 ± 3.0	0.087
	- Tumor size>5cm: n (%)	62 (78)	33 (72)	29 (88)
12.	Nodal stage- n (%)
	- N0	11 (14)	10 (22)	1 (3)	0.032
	- N1	31 (39)	20 (44)	11 (33)
	- N2	30 (38)	13 (28)	17 (51)
	- N3	7 (9)	3 (6)	4 (12)
13.	Tumor Grade: n (%)
	- Grade 1	2 (3)	1 (2)	1 (3)	0.819
	- Grade 2	34 (45)	21 (49)	13 (41)
	- Grade 3	39 (52)	21 (49)	18 (56)
14.	Receptor Status: n (%)
	- HR positive	34 (45)	18 (41)	16 (50)	0.488
	- HER2/neu over-expressed	30 (40)	19 (43)	11 (34)	0.483
	- TNBC	25 (32)	15 (34)	10 (31)	0.748
15.	Histology: n (%)
	- IDC- NOS*	73 (92)	44 (96)	29 (88)	0.84
	- Infiltrating lobular	1 (1)	-	1 (3)
	- Mucinous carcinoma	1 (1)	1 (2)	-
	- IDC with neuroendocrine differentiation	1 (1)	-	1 (3)
	- IDC with sarcamatoid differentiation	1 (1)	1 (2)	-
	- Invasive papillary	1 (1)	1 (2)	-
	- Secretory carcinoma	1 (1)	1 (2)	-

*IDC-Infiltrating Duct Carcinoma, NOS- Not otherwise Specified

All patients received multimodal therapy. Chemotherapy was administered to 94% (n = 74) patients, out of which, 84% received it before and 10% after surgery. All except one patient received anthracycline-based chemotherapy with or without combination of taxanes. Complete and partial responses were observed in 9% and 65% patients respectively. Chemotoxicity requiring hospitalization was observed in 24% patients. Febrile neutropenia was the commonest (16%) chemotoxity, remaining being diarrhea and dysphagia. Three patients died of sepsis. Eighty-nine percent (n = 70) patients underwent mastectomy, whereas rest of the patients did not have any surgical intervention. Upfront surgery was performed in 17% patients. The main indications of surgery were uncontrollable bleeding from the wound and infection. Latissimus dorsi flap and split thickness skin grafting was required in three and two patients respectively to cover post-surgery defect. Seventy-five percent (n = 59) of the patients received RT; of which, 5% received neoadjuvant RT, 60% adjuvant RT, and 10% patients palliative RT. All patients with HR-positive disease (n = 33) were put on hormonal therapy. Seventy percent of those received letrozole and the remaining, tamoxifen. Only 20% of patients with HER2/neu overexpression could afford trastuzumab therapy, and none suffered from any adverse cardiac event. Fifteen percent patients received bisphosphonate therapy in form of monthly injections of 4 g of zolendronic acid, and 2 patients received samarium therapy for palliation of severe bony pain. Summary of therapeutic intervention is provided in Table 2.

Table 2.

Summary of Therapeutic Interventions in Stage III and IV patients with Fungating Breast Cancer

Sl. No	Intervention/Response	All patients n=79	Stage III n=46	Stage IV n=33	p-value
1.	Surgery: n (%)
	- No surgery	9 (11)	2 (4)	7 (21)	0.003
	- Upfront	13 (17)	12 (26)	1 (3)
	- Post-chemotherapy	57 (72)	32 (70)	25 (76)
2.	Chemotherapy: n (%)
	- No chemotherapy	5 (6)	4 (9)	1 (3)	0.001
	- Neuadjuvant	34 (43)	34 (74)	-
	- Adjuvant	8 (10)	8 (17)	0
	- Paliative	32 (41)	-	32 (97)
3.	Response: n (%)
	- Complete response	6 (9)	4 (12)	2 (6)	0.193
	- Partial response	42 (65)	24 (73)	18 (56)
	- Stable disease	8 (12)	3 (9)	5 (16)
	- Progression	9 (14)	2 (6)	7 (22)
4.	Chemotoxicity: n (%)	18 (24)	11 (26)	7 (22)	0.787
5.	Radiotherapy: n (%)
	- No radiotherapy	20 (25)	9 (19)	11 (33)	0.026
	- Adjuvant	47 (60)	33 (72)	14 (43)
	- Neoadjuvant	4 (5)	4 (9)	-
	- Palliative	8 (10)	-	8 (24)
6.	Hormonal therapy: n (%)*
	- Tamoxifen	10 (30)	5 (27)	5 (33)	1.00
	- Letrozole	23 (70)	13 (73)	10 (67)	1.00
7.	Trastuzumabn: n (%)	6 (20)	5 (11)	1 (3)	1.00

*Only HR positive cases, n=33

Median follow up of the entire cohort was 40 (2–93) months. Median survival was 36 months, and 5-year OS was 40%. OS in stage III (53%) was significantly better (p = 0.005) than stage IV (22%). None of the factors including age (p = 0.90), menopausal status (p = 0.91), grade of tumor (p = 0.18), HR positivity (p = 0.1), HEr2/neu overexpression (p = 0.43), and type of intervention were found to be significant for OS. The only factor having an impact on survival was the presence of metastasis (p = 0.001).

Discussion

Despite grotesque appearance and seemingly high potential for infection, majority of patients with FBC successfully completed chemotherapy and their ulcer responded well to chemotherapy. As is true for other breast cancers, stage of the disease remained the main determinant for the survival. Three percent of all our BC patients and one-third of those with T4b tumors had FBC. The comparable figure is not available in the published literature. The reasons for delay in seeking medical advice could be myriad and include lack of awareness, socio-economic status, and lack of economic health protection for patients.

Despite extensive literature search, we could not identify any modern series describing FBC patients and their management to which we can compare our results. Only few case reports [9, 10] could be identified, and previous largest series was reported in the year 1987, describing 30 cases of FBC [11]. All the patients included in that study were treated preoperatively by combination chemotherapy using cyclophosphamide (Endoxan), methotrexate, 5-fluorouracil, and prednisone. Mastectomy was performed after 2 cycles of preoperative chemotherapy followed by 6 more cycles postoperatively. Management of breast cancer has evolved since then, and our results cannot be directly compared with this study. The response to chemotherapy was inferior in that study than ours (59% vs 74%).This study reported only DFS (33% after 12 months), and OS was not provided.

There are other reports on management and outcome of T4b cancers, though not on FBC per se, and we tried to compare our results with them. In a review of 75 patients with T4 un-resectable disease, patients were primarily treated with RT (mean dose 58 Gy), 83% of patients achieved a response of at least 50%. Five-year loco-regional control and OS was 51 and 29%, respectively [12]. Most of our patients were treated with CT followed by surgery, with or without RT, and 5-year OS was 40%, implying that multimodality therapy yields better results as is true for any locally advanced breast cancer (LABC). In another study of 77 patients with pT4b, upfront surgery was followed by adjuvant therapy. The 5-year OS was 60%. The comparative OS in our stage III FBC was 53%. [13].

The neoadjuvant chemotheraphy (NACT) prior to definitive local therapy is advantageous for women with LABC, since NACT can render inoperable tumors to operable [14, 15]. NACT seems to be equally beneficial in cases of FBC as well. The rate of partial and complete responses observed in our study was comparable to those previously published report on LABC. Reported complete response rate 8-22% and partial response rate ranges from 55% to 65% in LABC after NACT [15–18].

In LABC, initial tumor size and lymph node involvement are two most important prognostic factors [19, 20]. In our cohort, median tumor size was quite large (8 + 2 cm), and 87% patients had axillary lymphadenopathy, and probably, there were not enough patients with smaller tumor and without lymphadenopathy to have significant statistical difference, and therefore, except for metastases (stage IV), the influence of other factors on OS was not discernible [21, 22]. There is no exclusive data on OS of FBC. The OS observed in this study was comparable to our other LABC patients [23].

This is one of the largest series on FBC. The major limitation is the retrospective nature of the study with all its inherent weaknesses. FBC is one of the problems unique to the developing world; therefore, there is lack of evidence-based management guidelines for FBC. We believe that all the patients with FBC except those with systemic sepsis and other general contraindications for chemotherapy should be managed with upfront chemotherapy. Chemotherapy is generally well tolerated by the majority of the patients and renders the tumor resectable. Further management can be individualized based on the response to chemotherapy, stage of the disease, molecular subtype of tumor, and patients’ preference.

Conclusion

Majority of the patients with FBC have satisfactory outcome following multimodality therapy. Patients with FBCs should receive chemotherapy as the initial component of therapy to enhance their chances of operability.

Poster based on part of this study was presented in the World Congress of Surgery (WCS 2017) held in Basel 13th to 17th August, 2017.

Author Contributions

Raouef Ahmed Bichoo, Sanjay Kumar Yadav, Anjali Mishra-literature search, figures, study design, data collection, data analysis, data interpretation, and writing.

Saroj Kanta Mishra, Gyan Chand, Gaurav Agarwal, Amit Agarwal, Punita Lal-revision and editing of manuscript.

Compliance with Ethical Standards

This is to declare that all authors have contributed to the study. No part of the manuscript has been sent for consideration elsewhere or published in any international or national journal. The authors clearly certify that there is no aspect of plagiarism. All the conflicts of interest have been clearly defined and the source of grant disclosed. Due ethical permission/consent has been obtained for carrying out the study. In case of any dispute, the authors will be held fully responsible for the statement disclosed in the cover letter. The authors are also aware of the copyright rules and also declare that they will not reproduce any published text without due permission from the journal.

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed written consent was obtained from the patient.