A.

Breast cancer and breast implants: can a chronic granulomatous inflammation provoked by a breast implant with rough-spongious surface produce acquired immunity against tumors?- the role of IFN-γ and TNF secreting epithelioid cells.

 I.Lyras, P. Rapti*, T. Nassif, G. Gotta- Pereira and I. Pitanquy

Department of Plastic Surgery, IPGMCC, PC University, Rio de Janeiro, Brazil and * Department of Endocrinology, “Lito” Maternity Hospital, Athens, Greece

INTRODUCTION

A great deal of recent scientific progress in the  fight against cancer has been achieved in the direction of immunoprotection and immunotherapy. Nowadays, induction of prospective immunity to tumors can actually be accomplished by active immunization procedures.

Recent experiments demonstrate that in some cases of disease, intense inflammatory infiltrates accumulate around cytokine-secreting tumors. (Eosinophils and macrophages dominate IFN-γ secreting tumors and massive lymphocyte infiltrates, surround IL-2 producing tumors). This way, depending on the type of infiltrate cells recruited around a tumor or a granuloma by different cytokines, different effector as well as accessory cell functions lead to the optimal activation of T cells. Local production of cytokines and lymphokines may augment specific T cell responses to tumor antigens.

Untill 1991, silicone gel- filled breast implants, (used since 1960 for breast augmentation and breast reconstruction) were considered safe, biocompatible medical devices. For the past 4 years their use has been  restricted because  of the great public and scientific concern related to the complications the provoke, although recent reports  demonstrate that breast cancer is rarer and of better prognosis in women that carry breast implants .

The present study is based mainly on the importance of surface morphology of the implants and how it affect the healing process on the site of the inclusion.

The results of the present study have offered  us good reasons for further investigations in collaboration with other centers. Currently, we are investigating the variations of interferon, tumor necrosis factor and other lymphokine blood levels in women with breast prostheses before and after the implantation of these devices for both aesthetic and reconstructive reasons. Another experimental study, currently underway in our laboratory examines the effects of the presence of specially designed and patented by Dr. I. Lyras, medical implants in animals suffering from provoked or diagnosed cancer.

MATERIAL AND METHODS

Fourty-eight, adult Wistar rats weighting about 270 grams at the time of implantation were used for this experimental study. One smooth, one textured and one spongious (polyurethane covered) surface silicone 2 ml mini implants, were placed subcutaneously through three lateral 2 cm long incision into the back of each animal.

All animals  were obtained from the same supplier, were conditioned for a period of four weeks before use  and were maintained with a standard  laboratory chow and water ad libitum. 400 days after implantation we examined the tissue reaction –implant complex.

Light, polarization and electron microscopy was performed on the material (caplules and liver) harvested from the animals.  We used H-E, Gomori and Picrosirius  staining techniques and gold impregnation for scanning electron microscopy (Jeol 100 Cx electron microscope). Immunohistochemistry is underway.

RESULTS

Four hundred days after inclusion, the following situations were documented:

1.    Smooth surface implants

Completely balanced reaction. All fibroblasts had become myofibroblasts. Almost no residual inflammatory cells were observed inside the capsule which was dense, thick, compact and practically acascular. Complete insolation of the implant from the host organism through  fibrotic repair (type I collagen fibres) of the connective tissue (Synovial Metaplasia) was accomplished. Very few lymphocytes and eosinophils were present inside the capsule. No inflammatory exudate was observed.

2.    Textured surface implants

Fibroblasts formed a strange type of capsule. They hang on multiple vascular axons the way “birthday party flags” hang on cords, being always vertical to the surface of the implant in a perfect organization. Among them much exudate, some type III collagen fibrilles, some lymphocytes and eosinophils and a variable number of epitelioid cells in contact with the silicone were observed. Angiogenesis was moderate.

3. Polyurethane foam covered implants

The entire foam was filled with adipocytes, occupying the place of the present initially but totally absent in the phase fibroblasts. Multinucleated giant cells were covering completely the particles of polyurethane, and a great number of epitelioid cells were found in contact with internal membrane of the implants. Some lymphocytes and eosinophils were actively present inside a discrete quantity of inflammatory exudate. Angiogenesis was very intense. No collagen was observed.

4. Infection

Three cases of tissue necrosis with infection occurs 30 days after implantation. The causative pathogen was enterbacter. The implants involved were carrying a rough surface (two foams and one textured). 

5. Liver

No pathology related to the presence of polyurethane or silicone was observed in the liver. Some macrophages and lymphocytes were observed inside small vassels of the liver parenchyma.

6. Carcinogenesis

No carcinogenesis was observed to any of the animals.

7. Degradation of biomaterials

Some degradation of the rough surfaces was observed without altering the characteristics of the implants.

DISCUSSION

The qualitative nature of the inflammatory response to a surgical procedure may vary with the kind of injury produced and the presence of foreign at the site of the injury. In most noncontaminated surgical wounds, the acute inflammatory reaction subsides and recognizable repair commences in three to five days.

When the wound contains foreign material this reaction becomes chronic. As a general principle the body reacts to any insoluble foreign material either by extruding it if it can be moved or by walling it off by a granulomatous-type reaction. The intensity and the extent  of the reaction vary widely, depending on both the physical and chemical nature of the foreign body. Repair of the reacting tissue is accomplished both by regeneration of parenchymal cells and replacement by connective tissue which in time produces fibrosis and scaring when the foreign body has a smooth surface. There are four components  to this process:

Migration of fibroblasts and their subsequent proliferation are mediated by growth factors such as PDGF, PGF, EGF, FGF, VPF, VEGF, somatomedins and TGF-β. TGF- β is particularly critical in favouring fibrous tissue deposition. It induces fibroblast migration and proliferation as well as increased collagen synthesis and decreased collagen degradation of excess cellular matrix biometalloproteinases. TGF- β is thus thought to play an important role in chronic inflammatory fibrosis.

Formation of a fibrous capsule around an implant is markedly aided if very fine lines are etched on the surface of this implant. On absolutely smooth surfaces, fibroblasts move bidirectionally and when they come in contact they soon acquire active contractive properties, with the formation of a fibrous capsule.

The reaction of the host organism against foreign bodies with rough surface is dramatically different to the one against foreign bodies with smooth surface, practically leading to a chronic granulomatous inflammation. This type of reaction is characterized by granulomas- small collections of modified macrophages.

Macrophages are central figures in chronic inflammation because of the great number of biologically active products they can secrete. They are derived from peripheral blood monocytes that have been induced to emigrate actross the endothelium by chemotactic agents. The latter include C5a, fibrinopeptides, cytokines (MCP-1), platelet-devired growth factor (PDGF), and collagen and fibronectin fragments. Macrophages can be activated to secrete numerous factors, including neutral proteases, chemotactic factors, arachidonic acid metabolites, reactive oxygen species, complement components, coagulation factors, growth factors, cytokines (such as IL-1 and TNF), and other factors (e.g. PAF and  a-interferon). Macrophage activation in inflammation is triggered by lymphokines (γ-interferon) produced by immune activated T cells, or by nomimmune factors  (e.g. endotoxin). The secretory products of macrophages induce the changes characteristic of chronic inflammation, tissue destruction (proteases and oxygen –devired free radicals), neocascularization, fibroblast proliferation (growth factors), connective tissue accumulation (cytokines and growth factors), and remodeling (collagenases). Macrophages when modified acquire abundant pink cytoplasm and are called epithelioid cells. Epithelioid cells may coalese to form multinucleate giant cells. Lymphocytes, plasma cells, neutrophils, and central necrosis may also be present in a granuloma.

 There are two types of granulomas:

 Granulomas are characteristic of certain diseases caused by particular infectious agents (e.g., tuberculosis), mineral dusts (e.g. silicosis), or other unknown conditions (e.g. sarcoidosis).

Formation of granulomas around foreign bodies is also influenced by:

Some authors have recently noticed a slight degrease of the expected icidence rates of primary or second primary breast cancer in women that have undergone breast augmentation and breast reconstruction with breast implants. These observations are somehow important and one could suggest that there must be a biological reason involved in this situation.

The fact that around implants, specially the ones with rough-slongious type of surface (as in polyurethane foams), phagocygosis will not subside even after one year, makes chronic inflammation continues and acquire the characteristics of a granulomas disease like tubercusis or sarcoidosis.

One could observe a strange similarity in this type of cellular and hymoral disorder of the cell-mediated immune response to different antigens. Tuberculosis is a good example of a disease in which protective cell-mediated immunity after some time will lead to antigenic stimulation and T cell and macrophage activation with formation of granulomas. Reaction to sarcoidosis is also very  much alike in most cases.

On the other side, this type of immune reaction could also lead to a delayed type of hypersensitivity which could cause tissue injury, or under certain conditions, (preexisting undiagnosed tumors)  to immune or genetic accidents of tumor growth stimulation or tumors escape, evasion or “genetic instability” instead of a much desired tumor suppression, repression and regression. Tolerogens are believed to play an important role in preventing these accidents.  The fact that medical implants are sterile devices, certainly is important because this way the antigenic stimulus is not recognised by the host organism, neither as an extra or intracellular bacteria, nor as a virus or a parasite. This leads to a situation where an implant behaves as a nonspecific, (polyclonal) antigen, leading to a general increase of both the humoral and the cellular types of immune response.  The regulation of this immune reaction to the foreign body (breast implant) seems to be self-limited since no clinical sign of disease was noticed to any of the animals examined. Reports on patients are still inconclusive. Further large scale research on the subject is required.

In any way, it has already been accepted that although immunization against tumors would likely be used in patients with already established tumors, general “vaccinations” against tumor antigens could conceivably be performed profilactically in populations at high risc for certain cancers.

CONCLUSION

A different model of active immunization against tumors is presented. By a specially designed high quality biocompatible medical implant (with rough-spongious surface morphology) placed somewhere inside the body, we can provoke a permanent low grade granulomatous chronic inflammation and this way a nonspecific stimulation of the immune system of patients. The mechanism of this stimulation involves a markedly increased humoral response, lymphocyte memory enhancement and continuous antigenic activity and is based on the rationale than an implant containing granuloma behaves and should be considered as a cytokine and lymphokine-secreting tumor. Interferon-γ (IFN-γ), tumor necrosis factor (TNF) and interleukin (il)-secreting lymphocytes and epithelioid cells are key factors of this process. We propose that this method of preventive nonspecific stimulation of the immune system should be seriously considered as a useful approach for achieving acquired immune defence against cancer.

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