Histopathology review

Pathology Review Group
Professor J.P. Sloane, University of Liverpool
Dr. A. J. Darby, Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry
Professor A. J. Freemont, University of Manchester
Professor F. D. Lee, University of Glasgow

1. Review material
Fifty two 35mm colour transparencies and accompanying legends submitted by Professor Radford Shanklin, University of Tennessee. The transparencies were photomicrographs of histological sections prepared from tissue removed from women who had been implanted with breast prostheses. Most were of tissue in the immediate vicinity of the implant but some were from distant sites.

2. Review process
Three copies of all the transparencies and Professor Shanklin's interpretations of them were prepared by the University of Liverpool and sent to Dr. Darby and Professors Freemont and Lee. A meeting was held on Wednesday 5th November 1997 in the University of Manchester Medical School at which each transparency was projected onto a screen and discussed in detail. A table was drawn up in which the reviewers' consensus opinion on each transparency was recorded alongside that of Professor Shanklin (see Table 1).

2.    A second meeting was held on Wednesday 10th December 1997 in the University of Manchester Medical School at which the interpretation of the transparencies was discussed with Professor Shanklin. This meeting was attended by Dr. Darby, Professors Freemont and Sloane, Professor Sturrock (Chairman of the Independent Review Group). Dr. Susanne Ludgate and Mr. Jeremy Tinkler of the Medical Devices Agency (Secretariat of the Independent Review Group) were also present. This meeting was recorded and a transcript was prepared.

Professor Lee could not attend either meeting but submitted a summary of his opinion of the transparencies.

3. Main findings
1.    The photographs show materials with different optical characteristics around implants. These materials appear as white light on dark ground illumination and using crossed polarisers. They are associated with macrophage responses and different patterns of macrophage differentiation. Some of the macrophages contain globular material presumed to be silicone. In some of the illustrations the material is associated with fibrosis and infiltration of lymphocytes and plasma cells. Elsewhere, however, the foreign material is not associated with inflammatory changes and sometimes inflammatory changes occur apparently in the absence of foreign material.

2.    A synovial-like membrane may develop between the implant and the host.

3.    Foreign material, identified by its optical characteristics, may be present in regional lymph nodes or rarely at more distant sites. The material is often within macrophages.

4.    The precise nature of the foreign material cannot be determined with confidence from the submitted photographs. Much of it is likely to be silicone in view of its optical appearance and the composition of the implant. More sophisticated physical and chemical analyses, however, are needed to determine the precise nature of the material and in particular, if other compounds, such as silica, are present in detectable or significant amounts.

5.    The review group did not agree with Professor Shanklin that there was evidence in the submitted photomicrographs of an immune response to the foreign material. At the meeting on 10th December, it became clear that the reason for this fundamental disagreement was due to a difference in diagnostic criteria. Professor Shanklin was prepared to conclude that simply because lymphocytes were present in the tissues that an immune response was taking place and that it was not even necessary to demonstrate that these cells exhibited molecular evidence of activation. The review group could not support this contention.

6.    More specifically there was disagreement on the criteria for diagnosing vasculitis said by Professor Shanklin to be present in several of the photographs. The review group, in line with standard practice, insisted that in order to diagnose vasculitis, there should be evidence of inflammation of the blood vessel walls themselves as manifested by one or more of the following changes:

   a) evidence of damage to endothelial cells
   b) the presence of intravascular thrombus
   c) perivascular oedema and/or erythrocyte extravasation
   d) fibrinoid change of the vessel wall

Professor Shanklin on the other hand, accepted as evidence of vascuiltis, the mere presence of inflammatory cells around blood vessels.

4. Conclusions
The review group agreed with Professor Shanklin that silicone breast implants are associated with macrophage responses to the foreign material, presumed to be silicone, and that other inflammatory cells, particularly lymphocytes and plasma cells, may be present. The review group also agreed that implants may be associated with local fibrosis and the formation of a synovial-like membrane between the implant and the host. The foreign material may occasionally be seen in sites other than the breast, particularly regional lymph nodes. The review group did not agree, however, that Professor Shanklin had provided evidence that any of the illustrated changes constituted an immune response and in particular that there was any evidence of vasculitis.

Table 1: Review of 35mm photographs and accompanying legends submitted by Professor Shanklin

Sequence	Accession	Prof Shanklin's comment	Reviewer's comment
1	SI-0699	Folded papillary interface between capsules and device.	We agree. A synovial-like appearance is commonly produced at moving interfaces between connective tissue ad other substances. This is an unremarkable change.
2	SI-0699	Plasmacytic infiltration in field of silicone within a capsule.	We agree. There are also lymphocytes and foam cells in addition to plasma cells. The foam cells could contain silicone. The appearances are consistent with an unremarkable inflammatory reaction to foreign material. Once cannot draw the conclusion that this represents an immune response.
3	SI-0342	Vascular change in skin near implant: nodular lymphocytosis, involuting vascular injury (near lymphocytes) and hemosiderin (opposite the lymphocytes).	See below.
4	SI-0342	Are moved to take in detail at the other end. Near the vertical end: near the vertical edge of the lymphoid zone is a small focus of macrophages.	See below.
5	SI-0342	Photo #4 by polarised light: the small focus contains 1+ crystalline silica.	3, 4 and 5: We agree on the presence of hemosiderin and lymphocytes. There is a focus of lymphocytic infiltration next to a probable blood vessel but this needs to be confirmed by elastin stains. There is also dense collagenous fibrosis. These appearances are non-specific and could have resulted from surgical trauma. We agree on the presence of birefringent material but we feel there is insufficient evidence to conclude that this is silica. Chemical analysis of this tissue would help to resolve this point.
6	SI-0342	Same case, earlier biopsy. Intense but loose infiltrate of plasma cells with one eosinophil.	We agree. There also appears to be some fine granular material of uncertain significance. Again these appearances are consistent with a local inflammatory response to some agent.
7	O-5194-92	Fibrous nodule from wrist in woman with a ruptured ipsilateral implant. By dark field illumination: characteristic white light of silicone.	We agree that there is something emitting white light when using dark field illumination. We cannot determine the chemical composition of this material without further analysis.
8	S81-6256	Dense fibrous capsule by dark field illumination: the characteristic white light of silicone is evident.	We agree except that further analysis is necessary to establish the chemical composition of the material emitting the white light.
9	SI-0485	Shards of polyurethane silicone elastomer in hypocellular scar at device: capsule interface.	We agree that there are shards of material in macrophages in a cellular infiltrate surrounded by fibrosis. We cannot, however, be certain about the nature of this material without further analysis.
10	SI-0485	Aggregated lymphocytes at the capsule: pericapsular tissue boundary.	We agree.
11	SI-0485	Thoracic periperal nerve near capsule.	We agree that the illustration shows a peripheral nerve surrounded by connective tissue.
12	SI-0485	#11 but by polarized light: silica at the nerve bundle.	There is birefringent material near the nerve but we cannot be certain of its chemical composition. Further analysis is needed. There is no inflammatory response to this material.
13	SI-0485	Axillary lymph node with silicone granuloma and other silicone foci.	There are droplets of phagocytosed material within giant cells in a lymph node. We cannot conclude what the nature of the material is from this section but its appearances are entirely consistent with silicone.
14	86-2415	Lymph node with silicone in peripheral sinuses.	The photograph shows a lymph node in which the peripheral sinus contains droplets of material consistent with silicone. The underlying lymph node shows several non-necrotising ganulomata. These contain little silicone-like material.
15	86-2415	Detail: granulomas in node by dark field with condenser all the way down (this eliminates the phase effect).	This photograph shows droplets of foreign material but there are no granulomas.
16	86-2415	Photo #15 by dark field with condenser up to show the white light of silicone.	There is white light indicating foreign material but we cannot be certain of its chemical composition without further analysis.
17	A2-657-94	Epithelioid granuloma	We agree that there is an epithelioid granulomatous response to foreign material.
18	PA20657-94	#17 by dark field to show the silicone.	We agree that the foreign material shows a white light in this illustration. White light is also emitted from another small area nearby where there is no inflammatory response.
19	PA20657-94	Massive lymphocytosis at the capsule: tissue boundary, adjacent to fibrous granulomas.	We agree.
20	PA20657-94	Plasmacytic vasculitis deep inside capsule.	The illustration shows capillary blood vessels partially surrounded by small numbers of plasma cells and some droplets of foreign material ? silicone. We do not agree, however, that this illustration shows evidence of vasculitis for the following reasons: 1) the endothelial cells appear normal, 2) there is no thrombosis, 3) there is no red cell extravasation, 4) there is no fibrinoid change.
21	SI-0373	Lymph node with silicone.	See below.
22	SI-0373	#21 polarized to show the intensity of silica conversion of migratory silicone.	21 & 22.  There is an infiltrate of lymphocytes, plasma cells and macrophages containing numerous clear droplets. Under polarised light there is white birefringent material but we cannot be certain of the nature of this material without further analysis.
23	94M4131	Woman with nodular scar in explantation site: after removal she had a severe anamnestic T cell reaction; this is partially polarised to show outline of granuloma.	See below.
24	94M4131	#23 fully polarised to show the intensity of silicosis.	23&24. There is a granulomatous response around white material under polarised light. We cannot be certain of the nature of this material without further analysis.
25	S90-5153L	Low power, full thickness: has device surface, tissue boundary, for orientation.	There is a linear focus of lymphocytic infiltration adjacent to a zone of dense fibrosis.
26	S90-5153L	Pockets of silicone. The condenser is down, the silicone is refractile.	There are globules of foreign material within the dense fibrous tissue. The appearances are consistent with silicone. There is, however, no inflammatory reaction to this material.
27	S90-5153L	Detail of capsule: tissue boundary; linear collection of T lymphocytes (not the same collection seen in #25).	We agree there is a linear aggregate of lymphocytes. Although it is likely they are T cells, we cannot be certain of this without immunostaining.
28	S90-5153L	Focal vasculitis within the capsule.	See below.
29	S90-5153L	Similar, smaller focus.	28&29. There are small capillaries with a few perivascular lymphocytes and plasma cells. We cannot conclude that this represents vasculitis for the same reasons given in slide 20.
30	SI-0533	Intense mixture of plasma cells and granular, pigmented macrophages; the pigment was not identified. It is not hemosiderin.	We agree. We are also uncertain of the nature of the brown pigment.
31	S90-5155	Another example of linear lymphocytosis, capsule: tissue boundary.	We agree that there is a linear aggregate of lymphocytes but their significance is uncertain.
32	S91-1129	Intense lymphocytosis in capsule.	There is a focus of dense lymphocytic infiltration surrounded by dense fibrous tissue consistent with a capsule.
33	S91-1129	Mixture of polyurethane foam and silicone, small granulomas and lymphocytes.	There is a reaction to two types of foreign material but their chemical composition cannot be determined without further analysis.
34	S91-1129	Plasmacytic infiltrate near small vessels in capsule.	There is an infiltrate of plasma cells and lymphocytes.
35	S91-1129	Cleft with polyurethane and silicone in exuberant chronic inflammatory tissue.	See below.
36	S91-1129	Detail of #35 by dark field to show silicone component.	35&36. There is chronic inflammation and fibrosis around foreign material but we cannot be certain of its chemical composition without further analysis.
37	SI-0699	Same case as photos #1 and #2: hypocellular device interface with thin line of fibrinoid change.	There is zone of dense fibrosis covered by a small amount of fibrin underlying which there are a few inflammatory cells. The appearances are not interpreted as fibrinoid change.
38	SI-0699	Mixed granulomatous and plasmacytic vasculitis in capsule.	There are giant cells containing droplets of foreign material. There is an infiltrate of chronic inflammatory cells, mostly lymphocytes but with some plasma cells. We do not feel there is evidence of vasculitis for the same reasons given in slide 20.
39	SI-0199	Condenser low, intense granulomatosis.	See below.
40	SI-0199	Same field, #39 by dark field to show silicone in granulomas.	39 & 40. Granulomatous response to globular droplets of foreign material, the nature of which is uncertain without further analysis.
41	SI-0199	More granulomas with open spaces for silicone.	See below.
42	SI-0199	Same field, #41 by dark field to show silicone.	See below.
43	SI-0199	Same field, #41 by dark field to show silicone.	See below.
44	SI-0199	#43 by dark field. This woman had massive rupture and "dump" after a so-called closed capsulotomy. Note the different dates by labels (39,40 in 1990, 41,42 in 1989; 43, 44 were also 1989).	See below.
45	SI-0199	Micronizing silicone (ever smaller droplets; some think this means a high silicone oil content to the gel.	See below.
46	SI-0199	Field polarised to show the scattered silica.	41 - 46. Granulomatous response to globular foreign material appearing white in dark field illumination. The chemical composition of this material is uncertain without further analysis.
47	S97-11450	Device: capsule interface with high cellularity.	We agree.
48	S97-11450	Nodular lymphocytosis.	There is an aggregate of lymphocytic infiltration.
49	S97-11450	Mixed lymphocyte - plasma cell vasculitis in capsule.	There is a lymphocytic infiltrate around small blood vessels. We do not feel there is evidence of vasculitis for the reasons outlined in slide 20.
50	S97-11450	Microgranuloma with silicone.	There is a multinucleate giant cell containing droplets of foreign material.
51	S97-11450	Histiocytic vasculitis near capsule: tissue boundary.	There are macrophages around blood vessels only. We do not think there is evidence of vasculitis for the reasons given in slide 20.
52	S97-11450	#51 polarised: abundant silica in the perivascular macrophages.	There is white material in the macrophages under polarised light. The nature of this material can only be determined by further analysis.