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Armed Forces Institute of PathologyWashington, DC
MEDICAL FOREIGN BODIES: MEDICAL FOREIGN BODIES: A review of histopathologic and A review of histopathologic and
spectroscopic findingsspectroscopic findings
Michael R. LewinMichael R. Lewin--Smith, MB, BSSmith, MB, BSChief, Division of Environmental PathologyChief, Division of Environmental Pathology
Department of Environmental & Infectious Disease Sciences,Department of Environmental & Infectious Disease Sciences,Armed Forces Institute of PathologyArmed Forces Institute of Pathology
Disclaimer
The opinions or assertions contained herein are the private views of the presenter and are not to be construed as official or as reflecting the views of the US Department of the Army, the Department of Defense, or the Department of Veterans Affairs.
INTRODUCTION 1
• Medical exogenous or “foreign” materials are found in many types of anatomic pathology specimens.
• Most are incidental findings seen in histological or cytological material removed for other purposes, (e.g. dermal suture granulomas, lubricant in Pap smears).
• Some are removed because they are the cause of an undiagnosed lesion, (e.g. remote nylon suture placement), or are mimicking a pathologic condition (e.g. dental amalgam tattoo mimicking malignant melanoma).
INTRODUCTION 2
• Many medical foreign bodies are easily recognized by routine light microscopy, and do not pose a diagnostic problem for the pathologist.
• However, on occasion a fuller characterization becomes important especially to rule out other entities, such as infectious organisms, or endogenousmaterials, (e.g. melanin vs. dental amalgam), and in some instances can confirm the diagnosis, (e.g. cutaneous deposits of silver in argyria).
INTRODUCTION 3
Medical materials may be found in tissue:-1. As an expected result of the therapeutic or
diagnostic intent, (e.g. suture granuloma)2. As an unexpected result of therapeutic or
diagnostic intent, (e.g. barium sulfate aspiration)3. As a result of unintended use or misuse of the
material, (e.g. constituents of oral medication within blood vessels of IVDUs)
4. As an artifact, (e.g. transport of biopsy on gauze)
INTRODUCTION 4
• The pathologist’s task of characterizing medical foreign bodies may be hampered by:-
1. Lack of relevant clinical history2. Lack of familiarity with morphological
features, (esp. recently introduced materials)3. Lack of familiarity with, and access to
additional studies and methods for characterization
INTRODUCTION 5
• Medical uses of exogenous materials are widespread, and will likely increase.
• New medical materials and devices will continue to appear in pathology specimens.
• Infrared spectroscopy, Raman laser spectroscopy, and scanning electron microscopy with energy dispersive X-ray analysis are non-destructive techniques that can help to characterize medical “foreign bodies” in pathology specimens, even when very limited material is available.
Scanning Electron Microscopy with Energy Dispersive X-ray Analysis
(SEM/EDXA)● First introduced in the 1960s● Is a method for determining the elemental composition of a
particle that can be localized in a tissue section● Generally provides qualitative information, but methods for
quantitative SEM/EDXA are available particularly for materials for which laboratory standards of known composition are available
● Elements with atomic numbers less than 6 (carbon), are not detectable without special adaptations. (5 B, 4 Be, 3 Li, 2 He, 1 H).
SEM/EDXA Samples
● Routinely we place an unstained 5µm section on a carbon disc, and place the adjacent section from the paraffin block on a glass slide for H&E staining.
● Localize area of interest on H&E and compare to the carbon disc
● No coating necessary, but background contains carbon (C)
SEM/EDXA Samples [cont.]
• If only an original stained section is available on glass, SEM/EDXA can still be useful, (e.g. for silver in argyria) .
• Remove coverslip • Background glass examined away from the
specimen, will contain elements in glass, (usually Si, O, Ca). (Na, Mg, Al, Cl, K, variably present).
• Occasionally a stained section can be transferred to a carbon disk.
• Consider possibilities of stain artifacts, (High mag)
Electron gun
(SEM)Energy Dispersive X-Ray Spectroscopy (EDX)• Electron beam causes inner-shell electron to be ejected
• As outer electrons “fill-in”, X-rays emitted
• Energies of X-rays are characteristic
• Elemental composition
Emitted X-rays
Electron beam
specimen
Energy Diagram Spectrum
C
O
SiP
Energy (keV)
Argyria: Scanning electron microscopy
5 µm
Argyria: SEM/EDXA demonstrates presence of silver (Ag), sulfur (S) and selenium (Se).
5 µm
Argyria: SEM/EDXA mapping for sulfur (S), silver (Ag), and selenium (Se).
Infrared and Raman Laser Spectroscopy (IR) & (Raman)
• Became available in 1940s (IR), 1960s (Raman), with subsequent developments
• Gives a molecular “fingerprint” that can be compared to reference spectra
• Unstained 5µm section adjacent to H&E stained section or carbon disc section placed on aluminum coated (reflective) glass slide or semi-reflective slide (more expensive)
Vibrational Microspectroscopy:(Infrared and Raman laser)
• Advantages– Rapid– Non-destructive– High-quality spectra– Identification
• Limitations– Spatial resolution
10µm (IR), 0.5µm (Raman)
– Sample thickness– Special slide material
Infrared Spectroscopy• Absorption of infrared light
• Probes energies of molecular vibrations (and rotations)
• Molecular “fingerprint”
• Non-destructive
• 10-µm spatial resolution
Light source
Energy Level Diagram Spectrum (%T or %R)
ν1ν2ν3
ν3
ν2
ν1∆ν3 ∆ν2 ∆ν1 Absorption
Eo
Silicone infrared spectroscopy (I.R.)
Silicone infrared spectroscopy (I.R.)
∆ννο+∆ν
∆ννο-∆ν
0νο
Anti-Stokes (I)Stokes (III)
Rayleigh (II)
virtual states E1
Eο
ν1
ν2
∆ν
νο I II IIIPhoton
absorbedPhotonemitted
Energy Level Diagram
hνο
RayleighScattering
(II)hνο
Anti-Stokes
Scattering (I)
h(νο+∆νο)Stokes
Scattering (III)
h(νο-∆νο)
LASER
Raman Spectroscopy• Inelastic scattering phenomenon• Laser based technique• Probes energy of molecular
vibrations• Molecular “fingerprint”• Low light effect• 0.5-µm spatial resolution
Nylon Raman Microspectroscopy
(two excitation wavelengths)
MATERIALS
• Silicone, Cellulose, Nylon, Polypropylene• Polylactic/polyglycolic acid copolymer• Dental amalgam• Acrylic polyamide plastic embolization material• Barium sulfate• Silver (Argyria)• Polystyrene sulfonate, Crospovidone (PVP)• Talc
Silicone ((poly)dimethylsiloxane)
• Silicon: Si, element• Silica: SiO2, inorganic (mineral) form of Si• Silicone: R2SiO, an organic form of silicon• Medical silicone: poly(dimethylsiloxane)• Oil, gel, rubber/elastomer
Medical Uses of Silicone
• Implants: breast, testis, others• Coating for needles, sutures, syringes, pacemakers • Antifoams for gastric bloating/flatulence• Maxillofacial reconstruction (elastomer)• Post vitrectomy (proliferative retinopathy)• Tubing, G.I., I.V., and intra-arterial• Hydrocephalus shunts• Arthroplastic implants, hand and foot• Other
Silicone: Breast implant histopathology
• LOCAL:• Fibrous capsule, may become mineralized.• Inflammatory cells: Macrophages, T-cells,
giant cells, occasional plasma cells• “Pseudosynovium”: Ultrastructurally contains
macrophage-like and secretory cells, no basal lamina, few cell junctions
Silicone: Breast implant histopathology
• SILICONE MIGRATION:• RUPTURED IMPLANTS: Breast (silicone
granuloma), lymph nodes, lung, pleural cavity, kidney, liver, ovary, adrenals, pancreas, brain, skin & joints
• NON-RUPTURED IMPLANTS: Capsule, lymph nodes, skin, scar, synovium, alveolar macrophages, spleen, liver (Kupffer cells)
Silicone: identification in tissue
• By light microscopy, refractile, colorless, non-staining, non-birefringent (“non-polarizable”), gel-like substance
• Found within phagocyte vacuoles or extra-cellularly, especially lining partially “washed-out” spaces
• More easily seen in thicker sections, lowering condenser, (finger under the condenser), phase contrast or darkfield microscopy
• Identification by infrared (I.R.) and/or Raman spectroscopy
Breast capsule “pseudosynovium”: H&E
Refractilematerial in capsule; H&E
Perivascular silicone, near breast prosthesis, H&E
Silicone infrared spectroscopy (I.R.)
Silicone (short arrows) in giant cell with asteroid body (long arrow); H&E (lymph node)
Silicone in giant cell with asteroid bodies; (lymph node), H&E
Silicone: Axillary lymph node
Cellulose
• Present in tissue as cotton, wood splinter, food particles (aspiration), IVDU (microcrystalline cellulose from oral medications), contaminants
• Does not stain well with H&E• Birefringent under polarized light• GMS +• Unmodified cellulose is PAS +• Esters e.g. cellulose acetate may be PAS -
Cellulose (cont.)
• Generally Sirius red +, (use amyloid procedure); stains pink to red
• Other direct cotton dyes that have been suggested are Congo red & Bismarck brown.
• Identification by Infrared Spectroscopy
Cellulose, subcutaneous tissue : fibro-adipose tissue, acute inflammation (H&E)
Cellulose, birefringent under polarized light (H&E)
Sirius red (a modified cotton dye)
For connective tissue For amyloid
CellulosePAS : GMS
IR Spectroscopy: Characteristic of cellulose
Adjacent tissue
Birefringent material
Gauze (cellulose)
Wood splinter (H&E)
CELLULOSE H&E : Polarized
CELLULOSE
Sirius red GMS PAS
NYLON
• Sutures, (instruments, wound dressings)• Circular, elliptical or cylindrical structures• Colorless to brownish in H&E sections• Brightly birefringent under polarized light• Identification by infrared spectroscopy,
(Because of C-N linkage, IR spectrum is close to tissue protein, but peaks narrower; area examined needs optical localization)
Subcutaneous Nylon suture granuloma
Nylon suture granuloma, H&E, (polarized right)
Nylon infrared spectroscopy
Nylon Raman Microspectroscopy
(two excitation wavelengths)
Nylon suture granuloma H&E
Nylon
Silicone
Silicone infrared spectroscopy (I.R.)
Polypropylene
• Non-absorbable meshes for hernia repair, (Marlex®, Prolene®, Surgipro®)
• Emergency abdominal wall reconstruction• Non-absorbable sutures; Prolene®• Colorless rounded structures on H&E• Brightly birefringent under polarized light• Will stain with 72 hour Oil red O• Identification by infrared spectroscopy (IR)
Polypropylene mesh, inguinal hernia repair, (H&E)
Polypropylene mesh H&E; polarized
Polypropylene mesh H&E; polarized
Polypropylene mesh 72hr. Oil red O, polarized (right)
Polypropylene infrared spectroscopy
Polypropylene
Birefringent material
Poly-L-lactic acid and Polyglycolic acid copolymers
Poly-L-lactic acid and polyglycolic acid copolymers (PLLA/PGA) have been investigated as resorbable surgical fixation devices, (and are used in resorbable sutures).
Case example: 8 months prior to biopsy, pt. underwent mandibular surgery with reconstruction using PLLA/PGA screws & plates. By light microscopy, weakly eosinophilic to grey irregularly shaped fragments of material with variable birefringence were seen.
Mandibular biopsy, PLLA/PGA, 8 months post-op: H&E
Mandibular biopsy, PLLA/PGA, 8 months post-op ; H&E Polarized light
Infrared Spectra: (I.R.) mandibular biopsy at 8 months post-op
PLLA/PGA
PLLA/PGA screw Raman spectra
500
1000
1500
2000
2500
3000
Int
10000
20000
30000
40000
50000
60000
70000
Int
500 1000 1500 2000 2500 3000 3500 Raman shift (cm-1)
Mandible biopsy
Plastic material
Polylactic acid - Polyglycolic acid screw
Specimen X-ray: Mandibular biopsy;
25 months post-operatively
Remodelledbone in former PLLA/PGAscrew hole
Bone biopsy : 25 months
post-operatively:
H&E
Remodelledbone in former
PLLA/PGA screw hole
Dental amalgam
• Dental amalgam is a multiphasic material containing silver (Ag), tin (Sn), mercury (Hg), and lesser amounts of copper (Cu).
• Incidental tattooing of buccal mucosa may occur during dental procedures.
• Prolonged tissue implantation leads to loss of mercury, (and tin), and persistence of silver with sulfur (S) and selenium (Se) deposition.
Amalgam Tattoo
• Black/brown mucosal discoloration• May be of clinical concern (r/o melanoma)• In H&E sections, black granular material in
submucosa, (not removed by melanin bleach)• Identification by SEM/EDXA
Dental amalgam tattoo (Photograph courtesy of the Department of Oral & Maxillofacial Pathology, AFIP)
Dental amalgam tattoo, buccal biopsy, (H&E)
Dental amalgam tattoo, buccal biopsy (H&E)
Amalgam tattoo melanin bleach
Amalgam tattoo SEM/EDXA(glass slide) silver, sulfur and selenium
Amalgam tattoo SEM/EDXABackground (glass slide), carbon, oxygen,
sodium, silicon, calcium
Acrylic polyamide plastic embolization material
• Embolization microspheres have been developed for tumor embolization and treatment of vascular malformations.
• Uterine artery embolization for treatment of fibroids• Several materials have been used, (polyvinyl alcohol,
collagen, dextran, and trisacryl-co-polymer crosslinked with gelatin).
• The latter has the IR spectral characteristics of acrylic polyamide plastic.
Acrylic polyamide plastic embolization product
• Acrylic polyamide plastic embolization particles, appear as rounded often folded circular eosinophilic to weakly basophilic objects usually in an intravascular location.
• May have “Venetian blind effect”• Diameter depends on product used, and plane of
section, but in our tissue examples <700µm• Partial birefringence when stained with Sirius red,
but not in other stained sections• Oil red O, AMP, PAS negative• Mucicarmine and Sirius red positive
Intravascular acrylic polyamide plastic, (uterus), (H&E)
Acrylic polyamide plastic with “foreign body” giant cell reaction (H&E)
Intravascular acrylic polyamide plastric, uterus, (Movat)
Acrylic polyamide plastic with “Venetian blind” effect ? Pseudo-parasite (H&E)
Acrylic polyamide plastic with “Venetian blind” effect, (Trichrome)
Acrylic polyamide plastic embolization microspheres, SEM
SEM of authentic example of trisacryl-polymer-gelatin embolization product selected for IR
spectroscopy comparison
100µm
Acrylic polyamide plastic (embolization microsphere) infrared spectroscopy
Trisacryl-co-polymer with gelatin
Intravascularmaterial
Modern Pathology (2006) 19, 922-930
Barium sulfate
• Radiologic contrast medium, especially for G.I. tract imaging
• Aspiration into lung as a complication of upper G.I. studies
• Birefringent granular crystalline material may appear pale brownish/green in H&E-stained sections, often within macrophages
• (“Micropulverized BaSO4” non-birefringent)• Identification by SEM/EDXA
Barium sulfate aspiration (longstanding),canine lung, (autopsy), (H&E)
Barium sulfate aspiration, canine lung, (H&E), polarized (right)
Radiohistology as a New Diagnostic Method for Barium Granuloma
• De Mascarel A, Merlio JP, Goussot JF, Coindre JM. Arch. Pathol. Lab Med. 1988;112:634-636.
• 4 cases lower G.I. barium granulomas• Hx.s of barium enema 3 weeks to 20
months before bx.• Gastroenterologists suspected carcinoma
in 2 of 4
Barium sulfate “Radiohistology”
Barium sulfate: Scanning electron microscopy/energy dispersive X-Ray analysis (SEM/EDXA)
Barium sulfate: Infrared spectroscopy (IR)
0
5
10
15
20
25
30
35
40%
Ref
lect
ance
40
50
60
70
80
90
100
110
%R
efle
ctan
ce
10001500200025003000 3500
Wavenumbers (cm-1)
Lung tissue – foreign material
(canine)
Barium sulfate - reference
Tissue protein
Argyria
• “A permanent ashen-gray discoloration of the skin, conjunctiva, and internal organs that results from long-continued use of silver salts” Dorland’s Illustrated Medical Dictionary 28th Edition
• A rare dermatosis due to avoidance of silver-containing medicinals and decreased occupational exposure.
• New cases do still arise• Attempts at chelation Rx. generally unsuccessful• May be localized, (e.g. site of occupational injury)
Argyria (cont.)
• Most prominent clinical manifestation cosmetic• Skin pigmentation is due to silver deposits and
stimulation of melanocytes.• In H&E sections, black grains with preferential
deposition along basement membranes, elastic fibers, (and in macrophages within organs).
• Identification by SEM/EDXA • Often sulfur and selenium collocate with silver.
Argyria, skin punch biopsy, H&E
Argyria; dermo-epidermal junction (H&E)
Argyria; Eccrine gland, (H&E)
Argyria; Subcutaneous blood vessel (H&E)
Argyria; Sebaceous gland (SEM fields brown) (H&E)
Argyria; SEM on glass slide
12 µm
Argyria: SEM/EDXA glass slide
Argyria; SEM/EDXA silver granule with sulfur on glass slide
Ag
Argyria: Scanning electron microscopy carbon disc
5 microns
Argyria: SEM/EDXA demonstrates presence of silver (Ag), sulfur (S) and selenium (Se).
5 mircons
Argyria: SEM/EDXA mapping for sulfur (S), silver (Ag), and selenium (Se).
Polystyrene sulfonate
• Sodium polystyrene sulfonate (Kayexalate)• Cation-exchange resin, prepared in the sodium
phase• Sodium ions released in exchange for
potassium ions mainly in the colon• Used in the Rx. of hyperkalemia• Admin. orally (suspension) or by enema
Polystyrene sulfonate [cont.]
• In H&E sections; basophilic sheets with linear markings
• Very weakly birefringent• In a study of pediatric cases material was
present within air spaces without eliciting an inflammatory response
• Identification by infrared spectroscopy
Polystyrene sulfonate, pediatric lung, aluminized slide, (unstained)
for IR spectroscopy
Polystyrene sulfonate infrared spectra
10
20
30
40
50
60
%T
2
4
6
8
10
%T
1000 1500 2000 2500 3000 3500 4000 Wavenumbers (cm-1)
LUNG BIOPSY
POLYSTYRENE
SULFONATE
Polystyrene sulfonate Raman spectra (dispersive and FT)
Polystyrene sulfonate: Adult Lung: (H&E)
Polystyrene sulfonate within giant cell : Adult lung: H&E
CROSPOVIDONE (poly[N-vinyl-2-pyrrolidone])
• Crospovidone is a form of polyvinylpyrrolidone (PVP) formed by “pop-corn polymerization”.
• Used in oral medications as a disintegrant• Basophilic, “coral-like”, non-birefringent
particles on H&E• Not widely metabolized
CROSPOVIDONE [cont.]
• PAS negative, Mucicarmine positiveMucicarmine positive• Stains with Congo Red• Pale brown to grey with GMS• Alcian blue stains red, blue in giant cells• Movat yellow-orange, blue-green in giant cells• Identification by infrared spectroscopy =
Polyvinylpyrrolidone (PVP)
Polyvinylpyrrolidone Pathology(Non-Crospovidone)
• Subcutaneous pseudosarcomatous PVP granuloma
• Thesaurosis (hair sprayer’s lung)• Mucicarminophilic histiocytosis•• Source of errorSource of error signet ring cell gastric
adenocarcinoma
Pulmonary vessel, with “foreign-body” giant cell reaction to cellulose (A) and crospovidone (B&C) (H&E)
Infrared spectra
Crospovidone in tissue
Crospovidone in tissue
Cellulose in tissue
Cellulose, (birefringent) and crospovidone (non-birefringent) Lung, (H&E), polarized (left)
Modern Pathology 2003;16 (4): 286-292.
Crospovidone powder, H&E (x480)
Crospovidone powder: Infrared spectrum
Crospovidone powder; PASD (x100)
Crospovidone, lung, intravascular, PASD (x100)
Crospovidone powder ; Mucicarmine, (x100)
Crospovidone, lung; Mucicarmine (x50)
Crospovidone & cellulose, lung,polarized : GMS (x57)
Pulmonary pathology of I.V. administration of oral tablet suspensions
•• Pulmonary Pulmonary angiothromboticangiothrombotic granulomatosisgranulomatosiscaused by talc, cornstarch and/or microcrystalline cellulose has been widely reported.
• The development of subsequent fatal pulmonary hypertension and cor pulmonale has been emphasized.
• Ordinary illicit heroin reportedly doesn’t contain enough insoluble crystalline debris to cause extensive pulmonary angiothrombosis.
TALC (MgSiO4)
• Pleurodesis, talcosis, operative sites, inactive ingredient in medications, IVDU
• Micaceous, colorless and birefringent• Oil red O stain may be positive• Identification SEM/EDXA as containing
magnesium, silicon and oxygen• Infrared spectroscopy characteristic
Birefringent pieces of talc (MgSi04) in breast tissue of implant patient
Talc infrared spectroscopy
Talc, Pleura, (H&E)
Talc, pleura, (H&E), polarized (right)
Talc, pleura, PAS, polarized (right)
Talc, Pleura, (SEM)
Talc, (MgSiO4), pleuraSEM : EDXA
Talc energy dispersive X-ray analysis (EDXA) elemental maps
OxygenCarbon
Magnesium Silicon
Summary
• Many types of medical “foreign bodies” may be present in histopathology specimens.
• Familiarity with these materials may help pathologists avoid possible sources of diagnostic error.
• Adequate clinical history is extremely helpful.• Close collaboration with expert spectroscopists and
toxicologists, helps characterize many materials .• Accurate characterization can benefit patents,
clinicians, regulatory agencies, and other interested parties.
Acknowledgements
• VF Kalasinsky, Ph.D.• The late FB Johnson, M.D.• FG Mullick, M.D., Sc.D.• JF Tomashefski, M.D.• CS Specht M.D., LA Murakata, M.D.• Mr. A. Shirley, Mr. D. Landry• AFIP Staff, colleagues, and contributors