Osteogenic Sarcoma in a Patient Injected with Thorotrast by zqw77719


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Osteogenic Sarcoma in a Patient Injected with Thorotrast
J Bone Joint Surg Am. 1972;54:670-675.

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Publisher Information         The Journal of Bone and Joint Surgery
                              20 Pickering Street, Needham, MA 02492-3157
                                 Osteogenic                                                     Sarcoma                                          in           a          Patient
                                                       Injected                                       with                         Thorotrast*
             BY       PETER                C.        ALTNER,                      M.D.t,          CHICAGO,                      ILLINOIS,                DAVID             J.       SIMMONS,                   PH.D.1,
                  HENRY               F.        LUCAS,              JR.,             M.S3,             AND            HELEN                CUMMINSt,                      ARGONNE,                      ILLINOIS

        From            the     Department                         of Orthopaedic                        Surgery,                  University illinois
                                                                                                                                            of                          College            of     Medicine,
         Chicago,              and         the         Radiological                        Physics               Division,               Argonne             National                Laboratory,

             Osteosarcoma                               in a long                      bone           of a patient                            in the         fifth        decade                  is unusual                   and       is
particularly                    interesting                    and            significant                   if       the        patient                had         received                 Thorotrast,                        be-
cause          there then                   is a suspicion                             that           the         tumor     may
                                                                                                                              have                     been     induced      radiation.
             Thorotrast                      is the trade                            name             for         a radioactive                        contrast       medium      which                                   was        em-
ployed               extensively                        in     this ountry
                                                                  c                           between I 930    and 1945,                                         and       consists             of a 25             per
cent         colloidal                 thorium                     dioxide                  suspension.     In the body                                          it is distributed                            by the lymph
and          vascular                 channels                      to        the           reticuloendothelial                       system.              Since              its     concentration                            in
any one tissue          depends on the abundance                of reticuloendothelial       cells,   it deposits
heavily     in the liver        and spleen.Of the 90 per cent of the parent                   isotope     232thorium
(an alpha      emitter)      retained   the reticuloendothelial
                                         in                                 system     throughout        the patient’s
lifetime  6, perhaps       0.5 per cent      is translocated        and retained           in boneSome       of the                                                                   ‘.

radioactive                     decay                 products                      generated                     are        alpha,             beta,         and        gamma                  emitters.                 Of        these,
228radium                     and          224radium                         are          known             to be boneseekers                                     and         they         will         accumulate                     in
the      skeleton      as well                              as
                                                             the         translocated                            232thorium.
          Autoradiographic                                    evidence                       suggests                   that         the       cells         in        bone          (fixed          macrophages)
which             sequester                         Thorotrast                       immediately                             after         parenteral                   administration                              are        concen-
trated            along              bone             surfaces           “    .      In      sufficiently                  high          concentrations,                               radiation
                                                                                                                                                                                     the                            dose
to the             osteogenic                         population                           of    cells             from              these         deposits                might                produce               clinically
significant                changes.  Extremely                                              large           doses    of Thorotrast         administered      to                                                           experi-
mental               animals    have  produced                                             skeletal           tumors    where      thorium     was concentrated                                                                  lo-
cally        13, 15           Yet,          establishing                              a      causal                relationship                         between                  radioactivity                 bone
cancer               in       human                   patients                     who          have              been             injected              with           Thorotrast                       is    not         satisfying
from            a statistical                       point          of         view.             The              minimum                      number               of      patients                injected                 in the
United               States            alone is perhaps                                4300      ‘,      and            from             an estimated                     worldwide                      population
of       1 00,000                cases          2     receiving                     Thorotrast                        injections,                       two
                                                                                                                                                      only          cases           of bone                   sarcoma
have           been            reported.                     Within                   this       context                     and         as     the      first          recorded                  case         in     the        United
States          of        bone             sarcoma                  associated                        with            Thorotrast,                       the case                to be presented                             in this
paper             is significant.
                                                                                                Case               Report
          E.    a sixteen-year-old
                  B.,                        girl,   sustained     minor       trauma     to the left medial         malleolus        and was
admitted      to the hospital         on January            27, 1947,       because     a skin    ulcer    had developed             over      the
malleolus       and a diagnosis          of congenital         hemolytic        anemia     of undetermined          etiology      was made.
With     rest and elevation,         the ulcer       healed.     In the same year, because            of a recurrence           of the ulcer,
she was readmitted         several     times.      In February         1949, the skin over both            malleoli        became       ulcer-
ated.    Treatment       consisted       of multiple         blood     transfusions,       rest, and elevation.           Because       of poor
healing     of the ulcers,       two     admissions         were    necessary        in 195 1 for split-thickness             grafting.        At
that time,       fibrous   ankylosis       of the left ankle         was noted.        The hemolytic       anemia         was treated        with

         *     Work        performed                     under               the auspices   ofthe   United                                    States       Atomic              Energy    Commission.
         t Chicago               Medical                 School                and Mt.    Sinai   Hospital,                                     15th       Street             and California,       Chicago,
Illinois      60608.
         :1:9700 South        Cass Avenue,        Radiological                                                          Physics               Division, rgonne
                                                                                                                                                      A                         National          Laboratory,
Argonne,         Illinois60439.
         Reprint      requests:   David       J. Simmons,                                                        Center            for        Human              Radiobiology,                     Argonne                National
Laboratory,          Argonne,     Illinois 60439.

670                                                                                                                     THE          JOURNAL              OF        BONE            AND         JOINT          SURGERY
                        OSTEOGENIC                            SARCOMA                    IN        PATIENT                           INJECTED             WITH            THOROTRAST                                               671

vitamin       B12 and folic   acid                                    injections.                  A          trial           of     adrenocorticotropic                 hormone                        was        unsuccessful
in controlling       the anemia.                                  A        splenectomy                                 also        proved           unsuccessful.                     Hospital                        admissions                 were
needed           in     1952            and          1953            for       persistent,                        painful.              poorly            healing               ulcers              of         both        legs.         Roentgeno-
grams           revealed             osteoporosis                    in     the      bones                at the                knee        and          ankle           with        some                 slight           periosteal              re-
action          on     the        tibia            which              was         treated                 by            elevation,               rest,        and         physical                      therapy,                and      the       appear-
ance       of    the persistent                         ulcers       improved.      The     etiology       of the congenital      megaloblastic           anemia
remained          undetermined.                         Eventually         the patient      reacted       adversely  to transfusions.         To rule out
the      possibility        of an                     accessory spleen.        a Thorotrast        study     was done     by injecting        twenty-five
cubic        centimeters                      of     the    contrast        medium    November
                                                                                         on              15, 16, and    17. The     following        day.
flat plate of              the       abdomen                     was            read,             which                  was         negative             for       an         accessory                      spleen.             Radiopacities
in the region              of     the      liver were                 noted          (Fig.             1).


                                                                                              /     .‘        .

                                                              FIG.         1                                                                                                     FIG.          2
    Fig. 1: A supine          roentgenogram    of the abdomen                                                                             showing                liver         shadows                        markedly                 outlined
by Thorotrast.
    Fig. 2: A lateral       roentgenogram    of the   proximal                                                                       part      of the             right          tibia         and              fibula           of     a Thoro-
trast patient      showing        a poorly  defined    radiolucent                                                                            (arrow).
                                                                                                                                            lesion                  The          lesion            is     surrounded                     by
increased      density,    and the cortices     are not sharply                                                                       outlined.

         Between                 1954         and             1969,         the         patient                   was          readmitted                 for       the         following:                      chronic               suppurative
otitis     media,               paronychia               of      the        great          toe,          dental                 caries,          slightjaundice,            bilateral                     leg         ulcers,          back
pain,      dysphagia,                     and       speech                 impairment                             of      unknown                etiology.                On       July            23,          1969,           the      patient          was
readmitted                 because          of       pain             in       the       left          leg,             difficulty             in    breathing,                   and          cachexia.                      On        examina-
tion,      the        right         leg            was         swollen               and            tender,                    especially                in      the       area           of            the      proximal                 part       of      the
tibia.   In addition,         the patient           had fever           and generalized                osteoporosis.          Roentgenograms              of the
proximal       part     of the     right      tibia        revealed         areas       of     increased        radiolucenciesalternating         with
patchy     radiodensity.         Cortical        destruction was         also     present     (Fig.     2).  Linear       densities        were     noted
 in the distal      part of the tibia.      The differential                diagnosis          included      osteomyelitis            and fibrosarcoma.
A biopsy      of the proximal part of the right                   tibia was performed.
       The     sections     showed        aery
                                          v          cellular,        extremely            pleomorphic           tumor            with
                                                                                                                               tissue     extensive
small and large foci of necrosis.                  The cells and the nuclei                       were unusually            large.      Some of the cells
were       markedly                  nucleated,                       showing                 overlying                        small,           hyperchromatic nucleoli.                           These               were           some-
times      of     bizarre               appearance.                        Numerous                       atypical                   mitotic             figures           were           seen.               The         cytoplasm                 was

 VOL.      54-A,       NO. 3. APRIL                       1972
672              P.    C.    ALTNER,         D.   J.   SIMMONS,            H.     F.     LUCAS,          JR.,        AND         H.     CUMMINS

                                                                    FIG.    3
      Aphotomicrograph           ofa section     prepared      from      tissue     curetted     from  the site of the lesion
the proximal        part  of the tibia     of a Thorotrast       patient      (Fig.    2). The tumor       consists   of stromal
cells    with     typical    malignant        features     and       malignant         osteoblasts    producing     osteoid
(hematoxylin       and eosin, X 140).

eosinophilic          and     the interstitial      tissue was loose                   and edematous.     The                     tumor         was vascular,              with
a perivascular              eosinophilic       zone     which radiated                    into the adjacent                      tissue.        Occasionally              small
eosinophilic          islands         were   seen      surrounded           by         tumor        cells.         Scattered             throughout             the     section,
usually     extracellular,        some     coarsely     granular      and completely                                amorphous          material    was seen
which      was dirty       brownish-gray         in color.     The   diagnosis      of                        an osteolytic        type of osteosarcoma
was made        because      of the presence        of osteoid     and malignant                              osteoblasts     (Fig.     3). It seemed   rea-
sonable that the amorphous               material was Thorotrast        on the basis                           of the history        of the diagnostic
procedure,      and on autoradiographic              and radiochemical         analyses.
       Lung metastases         developed      and death occurred         on April      3,                       1970.       An        autopsy         was    refused.

Autoradiographic                and      Radiochemical              Studies
      Paraffin-embedded       decalcified    sections of the                      tumor           and        adjacent          bone        tissue       were      auto-
radiographed       by the dipping      method of Messier                          and          Leblond        in Kodak                NTB-2       liquid
The      pieces        of cortical      bone       were     surrounded by fibrous             tissue    containing            Thorotrast-laden
macrophages             (Fig.   4). The films         showed       alpha       tracks      radiating       from       these engorged             cells well
within       range       of the bone.         Smaller      numbers         of alpha         tracks     were       present        in the tumor          tissue
adjacent      to the bone         and there      was virtually        no activity        detected      deeper        within       the tumor.
       The       radiochemical         measurements       showed       a distribution            of radioactivity           similar       to that de-
tected      autoradiographically.         In a three-gram            sample        of bone fragments              picked        out of the biopsy
material,       the 228radium        and 228thorium           concentrations            were ±40 1 and 48 ± 2 picocuries                       per
gram      wet weight.          In contrast,        in the tumor           proper,       the respective           concentrations             of 228radium
and 228thorium             were only 0.3± 0. 1 and 0.6              ±    0.2 picocurie       per gram wet           weight.     It should       be
noted      that the activities          in the sample                 may
                                                                of bone not be entirely                  representative        of the whole
skeleton,         for the observed           concentrations are ten times              the average           skeletal       values      previously
reported      for fifty-milliliter       injections      ofThorotrast .

                                                                                THE      JOURNAL              OF     BONE         AND       JOINT           SURGERY
                            OSTEOGENIC                     SARCOMA                   IN    PATIENT               INJECTED                 WITH            THOROTRAST                     673

                                                                                             FIG.      4
    An      autoradiograph          showing       accumulations                                                of Thorotrast-laden                             macrophages                adjacent              to
bone      in the     proximal   end    of the tibia.     Note       the                                        numerous alpha      tracks                      emanating           from the
intracellular        deposits of thorium    dioxide     (hematoxylin                                                  and      eosin, X    100,         original       magnification).


            Based                 on experience                       with         tumors           in soft           tissue,         a bone             sarcoma             would             probably
qualify                as a Thorotrast-induced                                tumor              if the        following                minimum                      requirements                 were
fulfilled              3    13:

            1    .     Presence                 of Thorotrast                        particles              withinhe
                                                                                                                 t          immediate                   vicinity       of   the       tumor;
            2. A sufficiently          long                                latency          period             (the         average             duration               of   I 7. 1 years                is that
given        for soft-tissue      tumors);
            3. Exposure       to sufficiently                                      high          dosages           of
            4.   Absence                   of      other         tumor-inducing                     factors.
            There     are                 perhaps              only          two        reported              cases             m
                                                                                                                            which eet           these          requirements                    with
respect                to         bone      tumors               in        human            patients             following                Thorotrast                    injections.                In       1956,
Zak         and              associates                 reported       a case of a fifty-one-year-old                                     woman                 in     whom           a fibro-
sarcoma                     of      the         ninth          thoracic                 vertebra              developed                   twenty-one                    years         after           she       had
undergone                         hepatolienography                            with         an intravenous                       injection                of seventy-five                     milliliters
of      Thorotrast.                        Her           presenting                     symptoms                 indicated                 a cord-compression syndrome.
The         fibrosarcoma                           contained                   macrophages                       laden           with           Thorotrast                  granules,                 and       the
patient               subsequently                      died          of     pulmonary                 complications.                           The        autopsy              added           the     diag-
nosis                of a primary                   carcinoma                      of     the       liver        of     a mixed                  cholangiogenic                         and        hepato-
cellular       type, and                        fibrosis      of             lymph        nodes               and       the       ovaries.                Itshould noted
                                                                                                                                                               be                         here
that     liver     tumors                         and    tissue                fibrosisare not                uncommon                     in      individuals    subjected                      to
hepatolienography                               with        Thorotrast.

VOL.        54-A,           NO.      3, APRIL           1972
674                           P.       C.      ALTNER,                   D.     J.      SIMMONS,                      H.        F.      LUCAS,            JR.,       AND           H.     CUMMINS

                 In       1963,               Tsuya              and           associates described                                    a sixty-eight-year-old         Japanese                                       nian
who               had          received                      between           fifty   and    seventy-five                                   milliliters       of
                                                                                                                                                              Thorotrast                                    intrave-
nously                  eighteen                   years              prior      death.
                                                                                  to                 The             clinical             diagnosis                  was       that           of a pelvic                    osteo-
sarcoma                     with             liver           metastasis.                     The         cause             ofdeath                 was           listed     as
                                                                                                                                                                      cachexia.                     At      autopsy,
Thorotrast                         granules                     were distributed                      ubiquitously                           throughout                      the        reticuloendothelial
system                 and         the            lymph                 nodes                proved                  particularly                       fibrotic.              Unfortunately, the                    pri-
mary                  tumor             was          not        described,                    nor         do know
                                                                                                               we                    if Thorotrast                   granules                 were              identified
in the                pelvic             bones.                The  radiation                      dose                 was not calculated.                                   However,       the pertinence
of        this         case            is open                to question                      because                  osteosarcomas       rarely                              will   metastasize      to the
liver           alone              and           not         to other   organs                         as well.
               Possibly                  a third                case  is that                         of Schajowicz                                and            associates                  who            reported                   an
extraosseous                           chondrosarcoma                                   of     a low-grade                             malignancy                    developing                       in a Thorotrast
granuloma                          which           was          presumably                          formed                  after          the          contrast             material                     was       employed
(brachial                     arteriogram)                       to      visualize                  a hemangioma                                   in     the forearm       twenty-two                                         years
previously.                       Apparently,                             a portion                  of the injection                                   deposited     paravascularly                                          and be-
came     sequestered      in the axilla.                                                           Thorium                    dioxide     granules                              were               identified                 in       fibro-
hyaline     masses in close       proximity                                                         to the                 tumor.     The    mass                           extended                  from            the           lower
edge    of the clavicle     to the     middle                                                       of         the         humerus,                     but         there           were             no         thorium                 de-
posits           within                  the           humerus nor                   were    there  any changes    notedin the                                                 bone   structure.
               In this                 report            we have                     presented     a case in which     a bone                                                   tumor    developed
fifteen            years after                         seventy-five                        milliliters                     of         Thorotrast                    was       administered                           to       the       pa-
tient.            The latent                         period     is consistent                                  with    the criteria       defining       a Thorotrast         tumor                                                           in
soft           tissue.    The                          autoradiographs                                        demonstrated          cells       containing         alpha-particle-
emitting                     aggregates                 of      the          contrast               material,                    situated                close        enough                  to     the bone                  to      put
it        at      risk.            A         fifty-milliliter                 injection                  of      Thorotrast                          be
                                                                                                                                                   may             considered                      an adequate
tumor-inducing                                 dosage                 in some                tissues 6 but                      one      cannot                   assume  that   the                             relatively
high              alpha                doses            measured                      in        the tumor                        locality       in               this case existed                                in the             entire
               The            present case              is clearly      a case of an osteosarcoma                                                                   in a patient       injected       with
Thorotrast,                     but             there    are insufficient    data   at present on                                                             which     to prove        a causal        re-
lationship.                    The              natural     incidence       of osteosarcoma     for                                                            the United        States      population
aged twenty-five        years     and older        is of the order            of one in ten                   so
                                                                                                      man-years that                                                                                  ,

one could      expect one     osteosarcoma          to occur      spontaneously              in a period       of twenty
years  for some      4300     patients      injected        with    Thorotrast.
      We suspect       that   many       more       patients have actually        received       Thorotrast        via one
route  or another        than    are actually           or
                                                       seen reported.         The widespread          use   of the    con-
trast          material                      probably             occurred             within                   the third                   and fourth                      decade             of         this century.
Since            a latency                      period                  of      fourteen                  to      thirty-one                   years been
                                                                                                                                               has                          evidenced                        t
                                                                                                                                                                                                            inhe lit-
erature                2,              increase              in bone                 tumors      related                     to Thorotrast   injection                                  can         therefore                 be
expected,                      and            physicians               should                be alerted                    to this possibility.

     1.    EVANS,             R.       D.;      KEANE,           A.     R. J.; NEAL,
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VOL.     54.A,      NO.      3.   APRIL          1972

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