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Local relapse after mastectomy is sporadic for early breast cancer (stage 1 or 2) adequately treated, excepting some subtypes. The highest rates of local relapse occur in the first years. Loco-regional recurrences occurred within 2 years from primary surgery in 50-60% of patients and in 80-90% within 5 years.1-3 When lipofilling is immediately performed after cancer surgery, the development of early recurrences is already expected according to cancer profile and the relationship with the fat injections will be complex to be demonstrated through retrospective studies and with short periods of follow-up. On the contrary the unusual growth, if present, of the number of loco-regional recurrences at long-term or recurrences following delayed fat injections should be better considered as an alert.4 Two case reports published in 2014 are paradigmatic of this dual behavior of the biology of recurring breast cancer.5,6 I found very interesting the presentation of local recurrences after bilateral mastectomy for invasive ductal carcinoma and lipofilling.5 We would lay stress on the time intervals between mastectomy (2006), two sets of lipofilling (2011-2012) and the skin recurrence after 10 months (2013). The histological analysis of the mastectomy scar is also paradigmatic showing extensive and multifocal tumor recurrence associated with subcutaneous remnants of fat necrosis, in particular oil cysts. The primary tumour is described as ductal invasive carcinoma, grade 2, in a breast related cancer antigen type 2 patient. No information was displayed on staging, nodal status, estrogen/herceptin receptor status that is known to affect the risk of cancer recurrence. Chaput et al.6,7 described a different pathological pattern of local recurrence following lipofilling after mastectomy: tumour cells in bundles along the tunnels created by autologous fat grafting. Extension to the sternum was also reported and supposed to be related either with dissemination through the cannula or with metastatic progression of the tumour. This aggressive, invasive carcinoma recurrence occurred 4 months after fat injections and two years after mastectomy and axillary dissection. Unfortunately, the biological characteristics of the invasive carcinoma were not reported and the report of a single case remains anecdotal. Nevertheless, the case history suggests a discussion on the timing between transfer of fat and adult stem cells and growth of a recurrent or new tumour. Based on cancer biology, we should assume that the local relapse was already present in a subclinical onset, before fat grafting, or not investigated by imaging in the previous months. The smallest detectable size of breast cancers (in optimal conditions) is 2 mm by mammography.8 Most of them have minimal doubling time of 50-200 days. Therefore, a cluster of tumour cells may take years to become large enough to be detected.9,10 The fat tunnels could have facilitated more dissemination than multiplication of pre-existing tumour cells. On the other hand, the hypothesis of a direct carcinogenesis in such a short period of 4 months is less plausible even if angiogenic cytokines and stem cells can supply cancer proliferation in vitro and in vivo.11-15 Nevertheless, the cases of Smit et al.5 and Chaput et al.7 show common aspects, such as invasive carcinoma, recurrence after modified radical mastectomy and radiotherapy, mastectomy scar at site of either extensive fat grafting or recurrence origin, long free-disease times from primary surgery to lipofilling (5 and 2 years respectively). Based on the local relapse histology (i.e., signs of fat grafting in the tumour specimen) and timing (i.e., 7 years after primary surgery and two from the first lipofilling), the case of Smit et al.5 seems to be more suggestive for the hypothesis of a new fat-linked tumour cell growth. According to our institutional experience,16 a retrospective series of 60 breast cancer patients (55 with invasive carcinoma), with 12 years of oncological followup, showed features analogous to the cited case reports. Although there are some limitations mentioned in the inherent discussions, our study did not report higher risks than those usually expected after total mastectomy. The intervals from fat injection to recurrence (found in two patients) were nearly 2 and 6 years; they are much longer than the 10 and 4 months respectively reported by Smit and Chaput.5,7 The cumulative risk of local recurrence after lipofilling were respectively 7.25% (95% confidence interval [CI], 0-15.4%) for locoregional recurrences and 7.6% (95% CI, 0.2-15%) for distant metastases.4,16 Fat grafting was meanly performed 56.5 months after mastectomy. Overall 12-year incidence of local relapse was almost 5%: 1.6% before and 3.3% after lipofilling. It occurred only in patients with stage 2 and none with stage I. It stated a rate of local recurrence per year per 100 patients that might be oncologically safe: 0.43 compared to 0.36 of the observation period from mastectomy to lipofilling; the same rate was 1.04 when only Stage 2 cases were considered. After reading both these reports in literature, we have revised the histology of our post-mastectomy local recurrence after lipofilling in order to find any peculiar pattern. Histology only describes dermo-hypodermal localization of tumour cells without signs related to prior fat grafting. This discussion may be useful to the future researchers. We should start to debate about early and late local recurrences in the presence of adipose-derived stem cells or adipose-cell and stromal microenvironments,17-19 and also to study the behavior of different molecular patterns associated with fat injections. Ribelles et al.20 analyzed stage 1-3 breast cancer recurrences and found: i) slow risk increase in Luminal A, with peak after 3 years and then steady; ii) risk increase in the first 5 years in Luminal B; iii) a peak nearly 20 months after surgery in Her 2, with a greater risk in Ki-67=14% (a second peak can occur at 72 months); iv) low proliferation rate in triple negative tumours, except of those with Ki-67=14% that shows the peak at nearly 18 months. Nevertheless, the same authors assume that proliferation pathway can play a key role in the growth of early recurrence after surgery regardless of the intrinsic subtype involved. We should start to distinguish a fast progression of subclinical tumors in presence of vascular growth factors and stem cells from the hormonal activity of grafted fat that can conceivably induce a late carcinogenesis. Furthermore, mature adipocytes can alter the epithelial cell phenotype and produce a more motile cell type increasing

Early or Late Recurrences of Breast Carcinoma Are to Be Researched in Relation to Fat Grafting