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
P. Rapti*, T. Nassif, G. Gotta- Pereira and I.
Department of Plastic Surgery,
IPGMCC, PC University, Rio de Janeiro, Brazil and * Department of Endocrinology, “Lito”
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
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.
Four hundred days after inclusion,
the following situations were documented:
1. Smooth surface
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
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
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.
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
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.
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.
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:
- Formation of new blood vessels
- Migration and proliferation of fibroblasts
- Deposition of extracellular matrix
- Maturation and reorganization of the
fibrous tissue, also known as remodeling.
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:
- Foreign body granulomas, incited by
relatively inert foreign bodies as in the case of our textured surface
- Immune granulomas, formed by immune T
cell-mediated reactions to poorly degradable antigens. Lymphokines,
principally γ-interferon from activated T
cells, cause transformation of macrophages to epithelioid cells and
multinucleate giant cells as in the case of our polyurethane foam covered
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:
- Lymphocytes modilized by antibody and
cell-mediated immune reactions. Lymphocytes have a unique reciprocal
relationship to macrophages in chronic inflammation. They can be activated
by contact with the implant. Activated lymphocytes produce lymphokines,
and these (particularly γ-interferon) are major stimulators of monocytes and macrophages.
- Plasma cells. They produce antibodies
dierected against foreign antigen.
- Eosinophils. Their granules contain
(toxic) major basic protein (MBP).
- Intracellular adhesion molecule (ICAM) and
major histocompatibility complex (MCH). Very important defence mecanisms
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
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.
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.
Abbas, A.K. Lichtman,
A.H, Rober, J.S. (1994) Immunity to tumors. In: cellular and molecular
Immunology, W.B. Saunders (Edit), Second Edition : 357-375.
Dreapen, D.M, Brody,
G.S. (1992) Augmentation Mammoplasty and Breast Cancer: A 5-year update of the Los Angeles study. Plast.
Reconstr. Surg. 89:660.
Petit, J,Y., Le, M.G.,
Mouriesse, H., Rietjens M., Gill, P. Contesso, G. Lehmann, A. (1994). Can breast
reconstruction with Gel-Filled Silicone Implants Increase the risk of death and
second Primary Cancer in Patients treated by mastectomy for Breast cancer.
Plast. Reconstr. Surg. 94. 1-115-125.
Birdsell, D.C., Jenkins, H. Berkel, h. (1993). Breast
Canser Diagnosis and Survival in women with and without Breast implants. Plast.
Reconstr. Surg. 92; 5:795-800.
Raso, D.S., Crymes,
L.W., Metcalf, J.S. (1994). Histological assessement of Fifty Capsules from
smooth and textured augmentation and reconstruction mammoplasty
prostheses with emphasis on the role of Sinovial Metaplasia. Mod. Pathol.
Peacock, E.E. Jr., Van
Winkel, W. Jr. (1976). Would repair. W.B. Saunders Company, Second edition,
Fiers, W., Bouckaert,
P., Guisez, Y. et al. (1986). Recombinant interferon-gamma and its synergism
with tumor necrosis factor in the human and mouse systems. In: Schellekens, H.,
Stewart, W.E. (Eds), The Biology of the interferon System. P. 241, Elsevier
Ijermans, J.N.M., Bruin, R.W. Fetal (1987). Antitumor activity of recombinant
mouse tumor necrosis factor (TNF) on colon Cancer in rats is promoted by
recombinant rat interferon-gamma:toxicity is reduced by indomethacin. Int. J.
Hosang, M. (1988).
inhibits the mitogenic effect of platelet-derived Growth Factor at a level
distal to the Growth Factor receptor. J. Cell. Phys. 134:396-404.
10) Kindler, V. et al. (1989). The
inducing role of tumor necrosis factor in the development of Bacterial
gramulomas during BCG infection. Cell 56:731-740.