- Email: [email protected]
Somatostatin receptor imaging in neuroendocrine tumors
409 RADIOIODINE IMAGING IN MANAGEMENT OF THYROID CANCER; ROLE OF RECOMBINANT HUMAN TSH (rhTSH). Ralph R. Cavalieri. VA Medical Center, San Francisco. CA, U.S.A.. and the rhTSH Study Group. The management of patients with differentiated thyroid cancer involves scannirrg with tadbkxtine (l-131). Cunent practtt requires witMrawal of thyroid
hormone
(TH) for several weeks to raise endogenous
TSH to levels suniiiently
high lo stimulate uptake in thymid remnanf and/or metastases. Curing the period of wttMrawal patients develop hypothyroid symptoms which may sometimes bs debitttti~. Recombinant human TSH (rhTSH. Genzyme) has been tested in tw mutticenter clinical trials. In the first trtal (Metier et al, J.Clin.Endocrtol.Metab 76: 1.36. 1994). rhTSH was injected i.m. for etttw 1, 2. or 3 days while TH (L-T3) was contirwd. Pat&b after recent thyrotdectomy (N=l9) were given l-131 24 hr after the tast doss of rhTSH and 43-hr whole-body scans were done. Then L-T3 was stopped for 2U days, and a second i-131 dose was given to obtain Whdrawat scans. so that patients sewed as their own controls. l-131 uptake by thyroid remnants (normaltzed lo body background) and scan resuHs after rhTSH were similar to those in the hypothyroid phase. This inBial trial, which included patients with uptake inside (N=19) and outslds the thyroid bad (N=3). indicated that rhTSH can be safe and effective in raising serum TSH to levels sutfitnlly high to allow both radioiodine scanning and serum thyrogbbulin (Tg) measurement withotd the need to wilMraw TH. The second trial of tiTSH. recently mmpteted. provided useful information on 127 patients, including 15 patients with local and distant metastases (Ladenson et al. manuscrtpt submttted). The protocol was similar to that of the firsI trial. Scans wsre read by a panel of lr&pandent reviewers. The quality and diagnostic yield of the scar-6 performed wtth rhTSH were usually equal or better than the mnventttnal Whdrawal’ scans. and the patients felt much better after rhTSH (while etihyroid) than during the hypothyroid phase Few ontoward effects of ihs rhTSH injections were noted: transient, usually mild nausea ~ccurrd infrequently. Serum T g levels at 4B-96 hr mae as often after ~~ITSH as after TH withdrawal. A third study is currently in progress, targeting additional pattents with local and distant metastasas, which is designed to c&km the safety and efftt of rhTSH for diagnostic scanning and T g testing. Overall the clinical experience with rhTSH todate indicates that the agent is safe and allows both l-131 scanning and serum T g measurements while patients remain on TH therapy. Future studies will be needed to assess the role of rhTSH in l-131 therapy.
THE ROLE OF lMMUNOCMOCHEMlSTRY (ICC) IN CYTOLOGICAL DIAGNOSIS OF PRIMARY AND METASTATIC THYROID TUMORS I. Mamheni. G. Scuohi. R. Romani. E. For&* tstwti di Anatomia Patolooica
e di Clinica
and G. Di Cotio
Medica II*, Univenita’
90024.
In conclusion: ICC has been helplul in cytological (FNA) diagrrxis 86.8% of primaty thymid tumors and 82% of their limphrwdes melastaus. perlaming diagtis or by confirming the suspected cytological diagnosis.
of by
OF CA
USA’
Mcdullrq cs”ccts.
csninoma of tbyroid (MCT) xcouou for 4.10% of thymid It occurs in sporadic (-75-805) or hereditary (-20.25%) Prognosis is better in the hereditary form. Hereditary form occurs as pm of multiple endocrine adcnomata 2 (MEN 2) syndrome. a MEN 7.A (MCI: parathyroid bypcrplasia and phcochromocymma). and MEN 28 (MCT. phcocbromocytom8. mucosal neuromas. intestinal gsnglioneummas. M&maid habitus) or as familial MCT (FMC). MEN 2B runs . more l8gWsiVc courssc than MEN 2A or FMC. Relative proportions of MEN 2A :FMC: MEN 2B: approximate 65:20:15. Hereditary MCT is tmnsmitted in ao maosomal dominant pittem. The gent for MEN 2 bar been mapped to cbromoaome 10 q 11.2 and has been identitied II ret proto-oneogene. R~J proto-oneogeoe codes for L putative receptor kinrsc containing I cystcine-rich extncctlulu a transmembrrnc domain and an intrtccllular tymsioc domain. kinue domain. The gene appears involved in devctopmcnt/differenti~tion of neural crest tissues. Misrcnsc gcrmlinc mutations of the ret proto-oncogcnc altering cystsinc residues in cxoa 10 or 11 are found in about 95% patients with MEN 2A and over 70% p~ticnts with FMC: mutatioi affects codon 634 in nmt cases (-57%) sod codon 609. 611. 618 or 620 in otbcrs. About 95% of MEN 2B families have mutation in exoo 16 affecting codon 918. Germline mutmion seen in MEN 2B have also been detected in ahut 2040% of patients with sporadic MCTi several other cases show form.
somatic
mutations
in
the
tumor.
The
muutod
ret alleles
are
genes
demonstmting constitutivc activation of the ret kinare. Ret mutuionr are also found in -40% of families with Hirschsprung disease. Traditionally. screening for MCT has involved m~asorements of cdcitonin before and after stimulation with pentag8strin -d/or calcium. Since elevated calcilonin may not be observed for acvcr~ years. there is often a delay in the diagnosis of MEN 2. Ruxnt studies have demonstrated that direct DNA anllyres identifies mutations of ME.N 2 or FMC in I reliable and cost cffcetivc manocr. This permits early diagnosis of MEN 2 and I markedly improved prospect of 1 sureical cure. Some have advocated oroohvlactic tbyroidectomy in inf;htr dcmonstmtiog gcnnlinc muutions ‘for* t&N 2B. - Subjects .witb germline mutrtiont of MEN 2A may also undergo prophylactic thyroidcctomy in early childhood sod thus. avoid ravages of I Tnrtmcnt of MCT subsequent invrsivc. ncurrent or mctasutic MCT. remains total tbyroidectomy with lymph node dissection. External irradiation. and chemotherapy offer little in its treatment. SOMATOSTATIN A.Chiti.
di P~sa
Use of ICC I” cyttiogi~ dlagmxis is St111 limited. For thyrdd tumors diagnosis ICC is almost exclusively used to Identify medullary cancer and neck lvmohncdes metanasis from differenliated cancer in case of scanty cellular fine &d!e aspinticn (FM?) spstimen o: poody diftersn!in:e:! !WXJ~. ICC has been performed M 105 FNA specimens destained previously stained v&h Papanicolaou’s technique: 36 thymId nodules, 61 lymphnodes, 3 suspected liver metastasis from medullary cancer.The used marken (Dako) were: lhymglobulin in 20 thyroid nodules and 50 lymphnodes; chromogranm in 35 thyroid nodules. in 26 lymphmxles and 3 liver mdules; caleittin in 13 thyroid nodules. in 4 lymphnodes and 3 lwer nodules; cylokeratins in 22 lymphnodes; vimentm in 2 lymphnodes; CD20 and CD43RO in 20 lymphnodes: parathyroid hormone (BioGenex) in 3 suspected paralhyroid nodules. ICC finding has been essential to diagnose 11 thyroid nodules, 10 lymphnodes. 3 liver metaslases and 3 parathyrcid adenomas. In 22 lhymid nedties and 40 lymphnodes ICC conf~mwd the suspected cyiological diagnosis. In 16 cases ICC ws not useful al all: 4 medtilw cancer (2 met&at@ vrhlch ware chromogmnin and calcitonin negaWe, 7 powty diWerentiated carcinoma (5 metastobc) thyrcglobulin negative, 1 aMplastic carcinoma thymglobulin and chromogmnin negative, 3 metastases fmm papillary eardnoma thyreglobvlin negative m-d 1 rabdomiosareoma rAlich did not show any thyroid, epitelial and
lvmohoid .,... r-.- mati:em .-
NEW INSIGHTS INTO THB DIAGNOSIS AND MANAGEMENT b4EDlJLLARY CARCINOMA OF THYROID hider I Chosn M.D.. UCLA Center for HeaM Sciences. Los An&es.
GSavelli.
RECEFTOT;IMMA~NG
IN NEUROENDOCRINE
S.Fanti*. BBellanova*, N.Resnik, N.Monetti. EBombardieri.
A.Romeo*,
Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano Policlinico S.Orsola-Malpighi, Bologna (Italy)
and (*)
The neuroendccrine svstem includes a erouo of cells txesentinz a common phenotype. This ph&otype is caracte&ed by the &rent ecpression of moteins and bv the production of specifx hormones. Many tumors of beuroendocrink origi’n express som&tatin receptors (SR). These are a membrane glycoprotein that can bind somastatin, a peptide which acts as a
hormone and, in the central nervous system, as a neurotransmitter. Five different types of SR have been cloned up to now. Octreotidc is an octapeptide analogue of somastatin. which binds to SR type 2 and 5. caractcrized by a longer half-life compared with somastatin (2 hours vs .3 min.). Octreotide chelated with DTPA and radiolahelled with 11 I-In, has been used in viva to study the distribution somastatin receptors. The radiocompound is called I1 1-In-pentetnotide. Several studies demonstrated high sensitivity (SN) of somastatin receptor imaging (SRI) in the study of paraganglioma (SN=97%). small cell lung cancer (SN=95%) and neuroendocrine gastroenteropancreatic (GEP) tumors (SN=86’%). SRI has been used in medullary thyroid carcinoma (SN=66%). neuroblastoma (SN=77%) and pheocromoeytoma (SN=SS%), although the clinical usefulness in these ncoplasms is controversial. We are now evaluating the effectiveness of SRI in staging and follow-up GEP tumors. Up to now we evaluated 78 patients (pts) with known (59 cases) or suspected (19 cases) GEP tumors. Images we acquired after i;v. injection of 200-250 MBq of the tracer. In all pts the diagnostic workup at least 2 other imaging procedures: computed tomography (Cr) in 65 p’s, ultrasound (US) in 63 pts and other procedures in 50 pts. SN for the primary tomor was 81% for RX 62 % for CT and 58% for US. For metastasis localization SN was 90% for SRI, 1% for CT and 74% for US. In 17/78 ots 122%) SRI showed unknown lesions Pat were later confirmed.
.4f!er S’RL‘therapy
(20%). SRI has to be considered tUrnOr managemettt.
was modified
an useful diagnostic
in 16178 pts
procedure
in GEP
hormone
(TH) for several weeks to raise endogenous
TSH to levels suniiiently
high lo stimulate uptake in thymid remnanf and/or metastases. Curing the period of wttMrawal patients develop hypothyroid symptoms which may sometimes bs debitttti~. Recombinant human TSH (rhTSH. Genzyme) has been tested in tw mutticenter clinical trials. In the first trtal (Metier et al, J.Clin.Endocrtol.Metab 76: 1.36. 1994). rhTSH was injected i.m. for etttw 1, 2. or 3 days while TH (L-T3) was contirwd. Pat&b after recent thyrotdectomy (N=l9) were given l-131 24 hr after the tast doss of rhTSH and 43-hr whole-body scans were done. Then L-T3 was stopped for 2U days, and a second i-131 dose was given to obtain Whdrawat scans. so that patients sewed as their own controls. l-131 uptake by thyroid remnants (normaltzed lo body background) and scan resuHs after rhTSH were similar to those in the hypothyroid phase. This inBial trial, which included patients with uptake inside (N=19) and outslds the thyroid bad (N=3). indicated that rhTSH can be safe and effective in raising serum TSH to levels sutfitnlly high to allow both radioiodine scanning and serum thyrogbbulin (Tg) measurement withotd the need to wilMraw TH. The second trial of tiTSH. recently mmpteted. provided useful information on 127 patients, including 15 patients with local and distant metastases (Ladenson et al. manuscrtpt submttted). The protocol was similar to that of the firsI trial. Scans wsre read by a panel of lr&pandent reviewers. The quality and diagnostic yield of the scar-6 performed wtth rhTSH were usually equal or better than the mnventttnal Whdrawal’ scans. and the patients felt much better after rhTSH (while etihyroid) than during the hypothyroid phase Few ontoward effects of ihs rhTSH injections were noted: transient, usually mild nausea ~ccurrd infrequently. Serum T g levels at 4B-96 hr mae as often after ~~ITSH as after TH withdrawal. A third study is currently in progress, targeting additional pattents with local and distant metastasas, which is designed to c&km the safety and efftt of rhTSH for diagnostic scanning and T g testing. Overall the clinical experience with rhTSH todate indicates that the agent is safe and allows both l-131 scanning and serum T g measurements while patients remain on TH therapy. Future studies will be needed to assess the role of rhTSH in l-131 therapy.
THE ROLE OF lMMUNOCMOCHEMlSTRY (ICC) IN CYTOLOGICAL DIAGNOSIS OF PRIMARY AND METASTATIC THYROID TUMORS I. Mamheni. G. Scuohi. R. Romani. E. For&* tstwti di Anatomia Patolooica
e di Clinica
and G. Di Cotio
Medica II*, Univenita’
90024.
In conclusion: ICC has been helplul in cytological (FNA) diagrrxis 86.8% of primaty thymid tumors and 82% of their limphrwdes melastaus. perlaming diagtis or by confirming the suspected cytological diagnosis.
of by
OF CA
USA’
Mcdullrq cs”ccts.
csninoma of tbyroid (MCT) xcouou for 4.10% of thymid It occurs in sporadic (-75-805) or hereditary (-20.25%) Prognosis is better in the hereditary form. Hereditary form occurs as pm of multiple endocrine adcnomata 2 (MEN 2) syndrome. a MEN 7.A (MCI: parathyroid bypcrplasia and phcochromocymma). and MEN 28 (MCT. phcocbromocytom8. mucosal neuromas. intestinal gsnglioneummas. M&maid habitus) or as familial MCT (FMC). MEN 2B runs . more l8gWsiVc courssc than MEN 2A or FMC. Relative proportions of MEN 2A :FMC: MEN 2B: approximate 65:20:15. Hereditary MCT is tmnsmitted in ao maosomal dominant pittem. The gent for MEN 2 bar been mapped to cbromoaome 10 q 11.2 and has been identitied II ret proto-oneogene. R~J proto-oneogeoe codes for L putative receptor kinrsc containing I cystcine-rich extncctlulu a transmembrrnc domain and an intrtccllular tymsioc domain. kinue domain. The gene appears involved in devctopmcnt/differenti~tion of neural crest tissues. Misrcnsc gcrmlinc mutations of the ret proto-oncogcnc altering cystsinc residues in cxoa 10 or 11 are found in about 95% patients with MEN 2A and over 70% p~ticnts with FMC: mutatioi affects codon 634 in nmt cases (-57%) sod codon 609. 611. 618 or 620 in otbcrs. About 95% of MEN 2B families have mutation in exoo 16 affecting codon 918. Germline mutmion seen in MEN 2B have also been detected in ahut 2040% of patients with sporadic MCTi several other cases show form.
somatic
mutations
in
the
tumor.
The
muutod
ret alleles
are
genes
demonstmting constitutivc activation of the ret kinare. Ret mutuionr are also found in -40% of families with Hirschsprung disease. Traditionally. screening for MCT has involved m~asorements of cdcitonin before and after stimulation with pentag8strin -d/or calcium. Since elevated calcilonin may not be observed for acvcr~ years. there is often a delay in the diagnosis of MEN 2. Ruxnt studies have demonstrated that direct DNA anllyres identifies mutations of ME.N 2 or FMC in I reliable and cost cffcetivc manocr. This permits early diagnosis of MEN 2 and I markedly improved prospect of 1 sureical cure. Some have advocated oroohvlactic tbyroidectomy in inf;htr dcmonstmtiog gcnnlinc muutions ‘for* t&N 2B. - Subjects .witb germline mutrtiont of MEN 2A may also undergo prophylactic thyroidcctomy in early childhood sod thus. avoid ravages of I Tnrtmcnt of MCT subsequent invrsivc. ncurrent or mctasutic MCT. remains total tbyroidectomy with lymph node dissection. External irradiation. and chemotherapy offer little in its treatment. SOMATOSTATIN A.Chiti.
di P~sa
Use of ICC I” cyttiogi~ dlagmxis is St111 limited. For thyrdd tumors diagnosis ICC is almost exclusively used to Identify medullary cancer and neck lvmohncdes metanasis from differenliated cancer in case of scanty cellular fine &d!e aspinticn (FM?) spstimen o: poody diftersn!in:e:! !WXJ~. ICC has been performed M 105 FNA specimens destained previously stained v&h Papanicolaou’s technique: 36 thymId nodules, 61 lymphnodes, 3 suspected liver metastasis from medullary cancer.The used marken (Dako) were: lhymglobulin in 20 thyroid nodules and 50 lymphnodes; chromogranm in 35 thyroid nodules. in 26 lymphmxles and 3 liver mdules; caleittin in 13 thyroid nodules. in 4 lymphnodes and 3 lwer nodules; cylokeratins in 22 lymphnodes; vimentm in 2 lymphnodes; CD20 and CD43RO in 20 lymphnodes: parathyroid hormone (BioGenex) in 3 suspected paralhyroid nodules. ICC finding has been essential to diagnose 11 thyroid nodules, 10 lymphnodes. 3 liver metaslases and 3 parathyrcid adenomas. In 22 lhymid nedties and 40 lymphnodes ICC conf~mwd the suspected cyiological diagnosis. In 16 cases ICC ws not useful al all: 4 medtilw cancer (2 met&at@ vrhlch ware chromogmnin and calcitonin negaWe, 7 powty diWerentiated carcinoma (5 metastobc) thyrcglobulin negative, 1 aMplastic carcinoma thymglobulin and chromogmnin negative, 3 metastases fmm papillary eardnoma thyreglobvlin negative m-d 1 rabdomiosareoma rAlich did not show any thyroid, epitelial and
lvmohoid .,... r-.- mati:em .-
NEW INSIGHTS INTO THB DIAGNOSIS AND MANAGEMENT b4EDlJLLARY CARCINOMA OF THYROID hider I Chosn M.D.. UCLA Center for HeaM Sciences. Los An&es.
GSavelli.
RECEFTOT;IMMA~NG
IN NEUROENDOCRINE
S.Fanti*. BBellanova*, N.Resnik, N.Monetti. EBombardieri.
A.Romeo*,
Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano Policlinico S.Orsola-Malpighi, Bologna (Italy)
and (*)
The neuroendccrine svstem includes a erouo of cells txesentinz a common phenotype. This ph&otype is caracte&ed by the &rent ecpression of moteins and bv the production of specifx hormones. Many tumors of beuroendocrink origi’n express som&tatin receptors (SR). These are a membrane glycoprotein that can bind somastatin, a peptide which acts as a
hormone and, in the central nervous system, as a neurotransmitter. Five different types of SR have been cloned up to now. Octreotidc is an octapeptide analogue of somastatin. which binds to SR type 2 and 5. caractcrized by a longer half-life compared with somastatin (2 hours vs .3 min.). Octreotide chelated with DTPA and radiolahelled with 11 I-In, has been used in viva to study the distribution somastatin receptors. The radiocompound is called I1 1-In-pentetnotide. Several studies demonstrated high sensitivity (SN) of somastatin receptor imaging (SRI) in the study of paraganglioma (SN=97%). small cell lung cancer (SN=95%) and neuroendocrine gastroenteropancreatic (GEP) tumors (SN=86’%). SRI has been used in medullary thyroid carcinoma (SN=66%). neuroblastoma (SN=77%) and pheocromoeytoma (SN=SS%), although the clinical usefulness in these ncoplasms is controversial. We are now evaluating the effectiveness of SRI in staging and follow-up GEP tumors. Up to now we evaluated 78 patients (pts) with known (59 cases) or suspected (19 cases) GEP tumors. Images we acquired after i;v. injection of 200-250 MBq of the tracer. In all pts the diagnostic workup at least 2 other imaging procedures: computed tomography (Cr) in 65 p’s, ultrasound (US) in 63 pts and other procedures in 50 pts. SN for the primary tomor was 81% for RX 62 % for CT and 58% for US. For metastasis localization SN was 90% for SRI, 1% for CT and 74% for US. In 17/78 ots 122%) SRI showed unknown lesions Pat were later confirmed.
.4f!er S’RL‘therapy
(20%). SRI has to be considered tUrnOr managemettt.
was modified
an useful diagnostic
in 16178 pts
procedure
in GEP