Is the Sentinel Lymph Node Concept Practicable and Acceptable
in the Diagnosis and Treatment of Thyroid Cancer?
In thyroid cancer, extensive neck dissection has long been discontinued; rather so-called berry picking of nodes for intraoperative examination by imprint cytology or in frozen sections and paraffin embedding of the residual material with consecu- tive serial sectioning is practiced.
Sentinel nodes cannot be defined accurately in relation to the intrathyroidal localization of a pri- mary. This is understandable:
·
Because the intrathyroidal network of lymph- atics can be severely altered by regressive changes in goiters.
·
Because no ªspecific basinsº can be definitely related to particular parts of the thyroid gland.
The lymph nodes primarily involved in regional metastatic processes are mainly localized in the cervical chain of paratracheal nodes along the course of the large cervical blood vessels and the upper mediastinal nodes (see Figs. 25, 26).
In addition, the involvement of the nodes de- pends to some degree on the intra- and, in rare cases, extrathyroidal localization of the primary tumor.
For instance, Kelemen and his colleagues (1998) injected 0.1±0.8 ml of 1% isosulfan blue dye direct- ly into suspicious thyroid masses and found that the blue dye passed along the lymphatics to the sentinel node within seconds. All sentinel nodes located in the paratracheal area were stained blue, while in two cases the jugular nodes were also stained. The authors suggested on the basis of their preliminary results that sentinel node biopsy could be helpful in further decision making. Papil- lary thyroid cancer often presents with enlarged extrathyroidal lymph nodes. The primary ascer-
tainment of this tumor type (papillary structure and psammoma bodies) is confirmed in surgical biopsy specimens of the excised node by histologi- cal examination. Because more than 90% of papil- lary carcinomas express sodium iodine symporter, positive nodes, but not micrometastases, can also be detected by iodine-131 scintigraphy.
Before the labeling of regional lymph nodes by blue stain and/or
99mTc application the question arises as to whether FDG-PET can helpby yielding more information:
·
On the nature and extension of the primary, and perhaps also on multifocality and/or bi- laterality
·
On regional lymph node involvement
These question are discussed in the next section by Avril et al.
Is FDG-PET Helpful in T- and N-staging of Thyroid Cancer?
N. Avril, W. Weber, M. Schwaiger
No systematic single-center or multicenter studies are available in which the results of searching spe- cifically for sentinel lymph nodes (SLNs) that were already tumor-infiltrated with FDG-PET search have been compared with those yielded by differ- ent preoperative N-staging methods.
A limiting factor for more extensive study pro- grams that must be taken account of is the exis- tence of different cancer subtypes and a scale of different degrees of differentiation. All this means that a large number of cases are required for com- parison, as is intensive cooperation between endo- crinologists, surgeons, nuclear medicine special- ists, and pathologists.
Generally, the experience reported from the published investigations has led to the conclusion that thyroid cancers with persisting functional dif-
Thyroid Cancer 22
ferentiation for hormone synthesis and iodine up- take appear to have low glucose metabolism, whereas undifferentiated tumors are often charac- terized by high glucose utilization (Feine et al.
1996).
Recently a multicenter study has been con- ducted to evaluate the clinical value of FDG-PET in differentiated thyroid carcinoma and to compare the results with those of both
131I whole-body scintigraphy and
99mtechnetium 2-methoxyiso- butylisonitrile (MIBI) or thallium-201 scintigraphy (Grçnwald et al. 1999). In each case clinical evalu- ation included histology, cytology, thyroglobulin level, ultrasonography, computed tomography and subsequent clinical progression. FDG-PET was per- formed in 222 patients: 134 with papillary tumors, 80 with follicular tumors, and 8 with mixed-cell type tumors.
The sensitivity was 75% for the whole patient groupand 85% for the 166 patients with negative
131
I whole-body scintigraphy. Specificity was 90%
in the whole patient group. The sensitivity and specificity of
131I whole-body scintigraphy were 50% and 99%, respectively. When FDG-PET and
131
I whole-body scintigraphy were combined, tu- mor tissue was missed in only 7% of patients. The sensitivity and specificity of MIBI/Tl were 53%
and 92%, respectively.
The conclusion that can be drawn from these results is that FDG-PET indirectly helps to provide support for the SLN concept, because preoperative- ly confirmed regional lymph node involvement makes the search for SLN(s) unnecessary and all further operative and adjuvant regimens can be planned on the basis of the N-positive stage.
In contrast to the lack of studies on the detec- tion of cancer-infiltrated SLNs, investigations de- signed to detect recurrences with node metastasis have been quite successful.
Alnafisi et al. (2000) studied 11 asymptomatic patients with a history of papillary thyroid cancer who had undergone total thyroidectomy, therapy with
131I, and negative findings on
131I whole-body scintigraphy but persisting elevations of thyro- globulin. All these patients had FDG uptake in the neck region or upper mediastinum.
Sonographically guided biopsy confirmed malig- nancy in 6 patients, was nondiagnostic in 2 pa- tients, and gave normal findings in 1 patient. In 2 patients, the sonographic results were normal and no biopsy was attempted. FDG imaging redirected the treatment of 7 patients, resulting in surgery
and/or external-beam radiotherapy. Surgical histo- pathology confirmed thyroid tumor in all 4 surgi- cally treated patients.
Properties of Primaries in the Thyroid Gland and Staging by Surgeons and Histo-
and Cytopathologists Working Together A. Schauer
Because thyroid cancer, in contrast to many other tumor types, is increasing slightly in frequency and the survival rates have not yet been optimized, this tumor needs continuous special attention.
Therefore, in thyroid cancer too, early detection, regional node staging, and exact surgical treatment with the aim of R0 resection are all of great impor- tance.
The scintigraphically ªcoldº node is the indica- tor for further investigations in order to confirm or to rule out thyroid cancer disease.
The rate of such nodes in which malignancy is ascertained by pathologists ranges from approxi- mately 2% to 20%.
FNAC, the Most Frequently Used
Initial Diagnostic Method for Ascertainment of Cancer Diagnosis in the Primary
As in the strategies applied in breast cancer diag- nosis before sentinel node evaluation, a morpho- logically based diagnosis is also highly valuable for decisions on thyroid cancer treatment in cases raising the suspicion of thyroid cancer.
In Germany some university hospital depart-
ments of surgery have a main emphasis on thyroid
cancer diagnosis and treatment as well as abdom-
inal surgery. One of these departments is that in
the charge of Ræher and his colleagues. Even in
the 1980s he compared the detection rates of thy-
roid cancers before and after introduction of cyto-
diagnosis for diagnostic clearance of thyroid le-
sions. Together with Wahl, he compared the cancer
detection rates among his patients in the time-
span 1966±1971, before cytodiagnosis was used, in
the early phases of cytodiagnosis (1974±1976), and
after systematic technical and cytodiagnostic train-
ing had started. Their results allow the conclusion
that when the doctors concerned were more ex-
perienced the cancer detection rate was twice as
high as before routine use of cytodiagnosis in FNACs. The results of these evaluations are listed in Table 1.
Whereas in different sites the fine-needle aspira- tion cytology (FNAC) is partly substituted by other methods (operation according to CT and MRT, core biopsy, vacuum biopsy, etc.), FNAC has re- tained the diagnostic ªdomainº in undiagnosed le- sions of the thyroid.
In view of excellent experience in recent de- cades, the prominence of FNAC for diagnosis can easily be understood, because in many cases surgi- cal intervention can be avoided. Additional crite- ria, which can at least help in making decisions on whether FNAC should be applied and possibly, in special cases, also whether an operation is indi- cated are listed in Table 2. It is necessary that all relevant criteria are assessed in an integrative way and not as single points, to avoid unnecessary sur- gical interventions. As is well known, the radioio- dine scintigraphy criteria can support diagnostic
evaluations using FNAC and help in making deci- sions on surgery-based evaluations together with histopathologists.
Syringe Quality and Handling of the FNAC Puncture For minimally invasive, diagnostic investigations the Cameco device with changeable syringe (Fig.
1) has an important role and is frequently used.
As already mentioned in Chapter 17, this meth- od allows fan-shaped guidance of the fine needle and thus collection of cell material from a circum- scribed area.
These procedures are demonstrated and sche- matically described in Fig. 2.
In diagnostic programs with FNAC as the initial diagnostic instrument, it must be borne in mind that suspicious cold nodes may be located in- trathyroidally. In this case these nodes may not be detected by scintigraphic investigations (see Fig. 3). In such cases the result of palpation is at odds with the scintigraphic picture.
Table 1.Thyroid cancer detection rates before and after use of cytodiagnosis for the evaluation of suspicious thyroid le- sions. (From Ræher and Wahl 1981)
No. of surgical
treated cases Rate of malig- nant tumors Before use of
cytodiagnosis 1966±1971
837 5.1%
After introduc- tion of cytodiag- nosis 1974±1976
280 6.4%
1977±1979 177 11.3%
Fig. 1.Cameco syringe:one-way syringe within a pistol-like casing, mostly used for fine-needle aspiration cytology (FNAC)
Table 2. Relevant factors which can in combination signal increased risk for thyroid cancer development
Increased risk
(geographical factor) In endemic-areas
Sex <>, (relative frequency)
Age <20 years
>60 years
Number of nodes Solitary node > multiple nodes
Recurrent goiter 2±4 times Previous radiation of the
neck region 30±40%
In addition, if there is a cold node within the thyroid near to the palpable, partly or totally ex- trathyroidal, node, the last-mentioned node (posi- tion c in Fig. 3) may give the impression that it is a sentinel node, justifying the suspicion of cancer infiltration.
pT Classification (Fig. 4)
The postoperative histopathological pT classifica- tion (Fig. 4) must include the following subpoints:
pT1: Solitary tumor nodule with 1 cm or less maximal extension, without perforation of the thyroid gland capsule
± With tumor capsule
± Without tumor capsule or with invasion or perforation of the tumor capsule
± Without invasion of blood vessels and/or lymph vessels
± With invasion into blood vessels and/or lymph vessels
pT2: Solitary tumor with more than 1 cm diame- ter without invasion of the thyroid-gland capsule
± With tumor capsule
± Without tumor capsule or with tumor cap- sule invasion or perforation
± Without invasion in blood vessels and/or lymph vessels
± With invasion into blood vessels and/or lymph vessels
Fig. 2. Schematic illustrating performance of FNAC in five steps. I Puncture of the node or the suspicious area. II As- piration, with development of pressure lower than atmo-
spheric pressure. III Guidance of needle through a fan shape in the course of aspiration. IV Development of pressure equilibrium. V Retraction of the needle
Fig. 3.There are cold nodes in three positions.aIntrathyr- oidal suspicious cold node. b Mainly extrathyroidal cold node, not detectable in anterior-posterior scintigraphy; in view from side seen as subcapsular small defect. c Extra- thyroidal cold node not detectable in anterior-posterior and side views. On palpation arouses suspicion as sentinel lymph node (SLN)
pT3: Multiple tumors (uni- or bilateral) and/or isthmic tumor without transgression of the thyroid gland capsule
± With tumor capsule
± Without tumor capsule or with invasion or perforation of the tumor capsule
± Without invasion into blood vessels and/or lymph vessels
± With invasion into blood vessels and/or lymph vessels
pT4: Tumor with extension through the capsule of the gland
In cases with massive tumor growth (pT4), the SLN concept does not have an important role, be- cause during operation tumor-free margins and re- gional lymph nodes removed by local en bloc re- section must be histologically controlled intraoper- atively with the aim of widening the operation field if this is indicated by the histological results.
As in many other tumor types, with increasing tumor mass (pT1<1 cm diameter, pT2>1 cm di- ameter or multifocality) the risk of metastatic spread also increases.
Fig. 4.Comparison of clinical classification (TNM) with postoperative classification according to the pTNM system. The scheme is in accordance with drawings that appear in the TNM Atlas (Spiessl and Scheibe 1982)
Pitfalls of Atypically Located Nodes Nonetheless Connected with the Organ
In physical and nuclear medical evaluation, it is well known that superficially located benign or malignant lesions can break out of the organ. The different node positions and the pitfalls in diagno- sis are summarized in Fig. 3.
Regional lymphatic spread of thyroid cancers depends on two main factors:
a) Tumor type
b) Local extension of the primary (pT)
In relation to these statements it is obvious that the involvement of the regional SLN(s) must pre- ferentially also be seen under these aspects.
With reference to point a, it should be remarked that, whereas follicular thyroid cancer mostly de- velops hematogenous spread into the lungs and bone marrow even in cases with a highly differen- tiated follicular pattern, papillary cancer, at least initially, mostly spreads into regional lymph nodes, at least in the early stages of the metastatic pro- cess.
Cases in which papillary thyroid cancer is found primarily in regional (sentinel) lymph nodes are not rare, and they are important evidence for early and preferential lymphatic spread.
The relatively low percentage of undifferentiated thyroid cancers (polymorphous or small cell ana- plastic) shows initial local fast growth and early breakthrough so that they pass through the cap- sule, with subsequent regional tumor infiltration and lymph node involvement.
Difficulties in and Limitations of Preoperative Thyroid Cancer Diagnosis Before the Search for SLN(s)
·
Confirmation of thyroid cancers without caus- ing bleeding and harm to the organ before the search for sentinel node(s) starts is only possi- ble by means of FNAC.
·
In addition, sentinel node labeling is only of in- terest in cases with differentiated cancers, which means not in cancer cases with diffuse extra- thyroidal invasive growth (anaplastic cancer subtypes). In such cases preoperatively initiated sentinel node search programs would have no value. The main subtypes of nondifferentiated thyroid cancers are summarized in Fig. 5a±c.
Figure 6 (a and b) demonstrates a polymorphous cellular type of thyroid cancer (histology) and Fig. 7 (a±c), the small-cell anaplastic carcinoma subtype. (Fig. 7a shows the cytology after Giemsa staining; Fig. 7b, the histological evidence of vi- mentin expression; and Fig. 7c, an anaplastic can- cer with angiomatoid pattern and fibrosis.)
Papillary thyroid cancers can mostly be diag- nosed with certainty (papillary growth pattern, psammoma bodies), because real papillary prolif- erations are practically always malignant, only in the course of thyrostatic therapy real papillary proliferations can develop focally.
Besides the clear-cut papillary proliferations which can also be verified in cytological smears, psammoma bodies are highly characteristic for this tumor subtype (Fig. 8).
According to Hedinger and Sobin (1974), differ- ent subtypes of papillary thyroid cancers, some with favorable (Fig. 9a±c) and some with more unfavor- able prognosis (Fig, 10a±d), can be distinguished.
Fig. 5a±c.Main types of low-differentiation thyroid cancers and their differential diagnosis by histo- and cytopathology.
aSpindle-cell-shaped cancer (pseudosarcoma) with epithe- lial character confirmed by use of cytokeratin antibodies.
bPolymorphous nuclear cancer.cSmall-cell anaplastic can-
cer. Conditions that must be checked for in the differential di- agnosis of each of these subentities areafibrosarcoma and malignant fibrous histiocytoma;bmalignant polymorphous cellular histiocytoma and endocrine metastasis of a polymor- phous cellular lung cancer;cnon-Hodgkin lymphomas
These subtypes have been schematically demon- strated by Schauer (1984) (Fig. 9a±c and 10a±d).
It is well known that papillary thyroid cancers can developeven in childhood or youth. In all age groups, cervical lymph node metastases can be the first substrate detected, and the primary cannot be precisely localized until after this.
Figure 11a shows a cervical lymph node metas- tasis from a papillary thyroid cancer, which was not diagnosed until this metastasis was found. Fig.
11b demonstrates papillary oncocytic cancer, 11c Lindsay-tumor (see also Fig. 9c).
In aspiration cytology follicular cancers often cannot be diagnosed with certainty, because it is fre- quently impossible to differentiate between follicular adenomas and cancers. In such cases, the only diag- nosis possible is ªfollicular proliferation.º Even after
pathohistological examination of highly differen- tiated follicular cancers showing strong thyroglobu- lin synthesis (Fig. 12a±c), a diagnosis of highly dif- ferentiated follicular cancer can only be safely made after detection of vascular invasions (Fig. 13a±d) or cancer-related perforation of the capsule of the sus- picious node (Fig. 13e). In moderately differentiated cancers with clear-cut invasive cancer growth, ex- pression of thyroglobulin (Fig. 14) and higher pro- liferative activity (Fig. 15), histopathological verifi- cation of malignancy is not problematic. In conclu- sion, how useful sentinel node labeling is cannot be evaluated until after the histological diagnosis has been made in material from the nodal lesion, and in difficult cases in serial sections.
All these facts lead to the conclusion that in cases in which a more precise cytological diagno-
Fig. 6. aPolymorphous nuclear anaplas- tic thyroid cancer; note the high degree of nuclear polymorphism. SLN labeling is possible only in very early stages.bPolymorphous cellular thyroid cancer.
Note the large, in some cases multinu- cleated, cancer cells. Differential diagno- sis: metastasis from polymorphous nu- clear lung cancer. SLN search is useful only in early stages; when capsular breakthrough has already occurred it is of no value
Fig. 7. aSmall-cell anaplastic thyroid cancer with cell picture reminiscent of lymphoma cells. Caveat: This is a diag- nostic pitfall! Rule out lymphoma by using common leukocyte antigen anti- bodies (CLA): for B-cell lymphomas use 4KB5, and for T-cell lymphomas use CD43, UCHL1. Confirm epithelial origin by using pan-cytokeratin antibodies.
bSmall cell anaplastic thyroid cancer with double-expression of cytokeratins and vimentin. Staining with antibodies directed to vimentin in the figure. SLN labeling only possible in very early stages.cSmall cell anaplastic thyroid cancer with angiomatoid pattern and in- terstitial fibrosis
sis than ªfollicular proliferationº is not possible, the SLN labeling procedures would be carried out in an unclear situation as far as the diagnosis of the lesion under scrutiny is concerned.
A similarly critical situation pertains with the diagnosis of oncocytomas or oncocytic carcinomas (Hçrthle cell adenoma or carcinoma) by FNAC. In this connection it must be added that oncocytes in fine-needle aspirates are not always the substrate of an oncocytic tumor, because oncocytic transfor- mations also occur in regressively altered thyroid tissue. In our own series, in follow-upstudies of 33 patients with oncocytic tumors, 2 had a malig- nant course culminating in death.
In a separate case, intraoperatively we found a follicular, highly differentiated lesion not definitely
meeting the criteria of malignancy and in addition a metastasis in a contralateral node. Lastly, in the thyroidectomy preparation a small nodule of a on- cocytic cancer, which had not been primarily de- tected during the preoperative scintigraphic inves- tigations, was found.
This case demands meticulous care in view of the frequent multifocality of thyroid cancers and the frequent simultaneous occurrence of different subtypes. In Fig. 16 a typically reddish brown col- ored oncocytic cancer nodule is shown, while Fig. 17a,b shows highly to moderately differen- tiated oncocytic cancer.
Figure 18 demonstrates lymph vessel invasion by a malignant oncocytoma and Fig. 19, regional lymph node metastases.
Fig. 8. Typical picture of a papillary thyroid cancer with typical psammoma bodies.a Typical papillary growth pat- tern, three calified psammoma bodies at the top.
b Papillary thyroid cancer with follicular growth pattern and ground glass nuclei. Note multiple psammoma bodies, partyl with tree stemlike layering
Fig. 9a±c.Subtypes of papillary thyroid cancers with differ- ent prognosis. Highly differentiated cancer subtypes with favorable prognosis.aSubtype with typical papillary growth pattern and ground-glass nuclei of the cancer cells, there can be psammoma bodies in the interstitium.bHighly dif-
ferentiated papillary thyroid cancer with normal chromatin distribution of the cancer cell nuclei; no ground-glass nuclei can be seen.cHighly differentiated follicular structured thy- roid cancer (Lindsay tumor) with typical ground-glass nu- clei
a b
Direct perforation of the vascular wall, endothe- lial adhesion, and cancer cell necrosis are impor- tant criteria of vascular invasion and, with that, of malignancy of the lesion.
Johnson et al. (1999) investigated 11 patients with Hçrthle cell neoplasms, using isosulfan blue dye for sentinel node marking. One of the cases was considered malignant. No positive sentinels were found in any of these cases. The authors con- cluded that the addition of sentinel node sampling to the operative strategies might yield further valu- able prognostic information.
It is easier to diagnose a medullary thyroid can- cer (MTC), because neuroendocrine granules can be suspected even in Giemsa stainings of the smears and be confirmed in immunohistochemical stainings using antibodies directed to chromogra- nin A or calcitonin.
In Fig. 20a,b a medullary cancer with a positive reaction for calcitonin is illustrated. Figure 20a de- monstrates the typical perifollicular growth pattern and Fig. 20b, multifocal development from the parafollicular cell populations. In Fig 20c the char- acteristic chromogranin staining is shown and in
Fig. 20d, the characteristic calcitonin staining. In Fig. 20e blood vessel invasion can be seen, indicat- ing possible hematogenous metastasis. Figure 21 demonstrates interposed neuroendocrine amyloid masses in addition to a positive calcitonin reac- tion. In Fig. 22 a spindle-cell differentiated medul- lary cancer is shown. This growth pattern makes it necessary to exclude cancers with similar cellular- ity (e.g., metastasis of lung cancer or melanoma).
In conclusion, with a view to the main types of neoplastic thyroid lesions subtyping is possible by FNAC and/or histopathology in most cases; how- ever confirmation of malignancy is only possible when clear-cut cytological criteria of malignancy are found, whereas the discrimination of premalig- nant or low-grade malignant lesions from benign lesions is difficult or even impossible on FNAC, and sometimes even on histopathological examina- tion involving for vascular invasions and/or per- foration of the capsule by invasive cell formations in serial sections. None of this really restricts deci- sions for pre- and intraoperative sentinel node la- beling.
Fig. 10a±d.Subtypes of papillary thyroid cancers with dif- ferent prognosis. Low-differentiation papillary cancers, some with a worse prognosis.aPapillary and solid growth pattern with sclerosis, higher degree of polymorphism, hy- perchromasia and mitotic activity; b papillary and solid
growth pattern without sclerosis;csome areas with ground- glass nuclei, squamous cell metaplasia (:), and vascular in- vasions ( )) (arrows);dsome follicles with ground glass nu- clei (:), marked atypia, squamous cell metaplasia, and high rate of vascular invasions ( )) (arrows)
Fig. 11. aPapillary thyroid cancer: only a few ground glass nuclei are seen (ar- rows).bPapillary thyroid cancer, onco- cytic type. Note moderate polymorphism of the cancer cell nuclei. SLN-labeling helps to detect lymphatic spread.cPapil- lary thyroid cancer, follicular type. Typi- cal ground glass nuclei, especially on the left side of the figure (Lindsay tumor).
SLN-labeling helps in detection of local lymphatic spread (compare with Fig. 9c)
Fig. 12 aHighly differentiated thyroid cancer. Note isomorphism of cancer cell nuclei. It is not rare for hematogenous metastasis to precede regional lymphatic spread.bHighly differentiated follicular thyroid cancer; far-reaching nuclear iso- morphism. Hardly any mitotic activity is detectable. Development of99mTc-nano- colloid labeling can be helpful in region- al SLN detection and regional surgical cancer clearance.cFollicular type of thy- roid cancer: immunohistochemical reac- tion with antibodies directed to thyro- globulin. Note the strong staining of the cancer cells (red)
Fig. 13. aHighly differentiated follicular thyroid can- cer. Lymph vessels are seen in the upper part and a small vein with cancer cell invasion in the lower part of the figure. Perforation of the capsule by the highly differentiated follicular cancer is seen at the upper right.bLow-differentiation follicular thyroid cancer.
Note cancer cell invasion into a small vein in the upper part of the picture and lymph vessel invasion in the lower right. Capsule has been perforated by a solid cancer cell group.cBlood vessel (capillary) in- vasion by a moderately differentiated thyroid cancer.
Note endothelial proliferation with growth over the cancer cell cluster (arrows).dInvasive, moderately differentiated thyroid cancer of follicular type with clear cell differentiation and cancer growth within a larger vein (left).eModerately differentiated thyroid cancer with capsular perforation (arrows) and cancer growth in the regional soft tissue. Parts of the pri- mary are seen (left). Cancer infiltration into the re- gional soft tissue (right)
Fig. 14.Moderately differentiated follicu- lar thyroid cancer with solid growth pat- tern. Expression of thyroglobulin docu- mented by immunohistochemical reac- tion. Hematogenous spread is prevalent, with locoregional spread in some cases.
However, SLN labeling is helpful in re- gional cancer clearance
Fig. 15.Invasive moderately differentiated follicular thyroid cancer. Immunohisto- chemical staining for Ki67 (with the antibody MIB I). Approximately 50% of the cancer cells are in the proliferative compartment
Fig. 16.Typical sharply delineated red- dish brown node in the presence of an oncocytic tumor
Fig. 17. aOncocytic thyroid cancer (Hçrthle cell carcinoma), in parts with follicular differentiation. Hematogenous and lymphatic spread are possible.bOn- cocytic (Hçrthle) cell cancer, with mod- erate differentiation. Note the strongly eosinophilic, abundant granular cyto- plasm
Fig. 18.Oncocytic thyroid cancer: lymph vessel invasion
Fig. 19.Lymph node metastasis from an invasive oncocytic thyroid cancer, with a moderate degree of nuclear polymorph- ism and eosinophilic granular cytoplasm.
Hematogenous and lymphatic spread are possible, SLN labeling can be helpful in locoregional cancer clearance
Fig. 20. aMedullary thyroid cancer:
growth around the pre-existent follicular structures of the thyroid gland. Immu- nohistochemical staining for calcitonin.
bMedullary thyroid cancer: multifocal cancer development, perifollicular to thy- roid follicular structures, filled with thyroglobulin. Immunohistochemical staining for calcitonin.cInvasive medul- lary thyroid cancer: immunohistochem- ical staining for chromogranin.dSame invasive medullary thyroid cancer: im- munohistochemical staining for calcito- nin. Local lymphatic and also hemato- genous spread are possible.eInvasive medullary thyroid cancer with blood vessel invasion: immunohistochemical staining for chromogranin. Note intrava- sal erythrocytes besides cancer cell pop- ulations at bottom right
Fig. 20c±e
Choice of the Most Efficient Labeling Strategy
Peritumoral injection in thyroid gland must be seen as an absolutely different entity than at other tumor sites. Whereas in breast cancers and mela- nomas the labeling solutions are injected into soft tissue structures from where they can be resorbed by the highly developed lymphatic network, in the thyroid gland the solution has to be injected into a highly capillarized endocrine parenchyma. This means that lymphatic resorption is low relative to the fast vascular resorption (endocrine organ).
This can easily be understood, because resorption here follows principles similar to those of hormone
resorption, so that the labeling solutions pass di- rectly into the blood stream.
Therefore, some special points must be taken in account:
·
The volume of the injected solution should be as small as humanly possible.
·
Direct intraoperative labeling using blue dye so- lution has benefits over preoperative labeling procedures.
·
If
99mTc-colloid solutions are used the dosage should be as low as possible because of the high hematogenous uptake.
Fig. 21.Medullary thyroid cancer: immu- nohistochemical staining for calcitonin.
Note the interstitial homogeneous, brownish masses corresponding to neu- roendocrine amyloid
Fig. 22.Undifferentiated, spindle-cellular medullary thyroid cancer. Spindle cell sarcoma and malignant fibrous histiocy- toma must both be excluded.
Main Basins of Lymphatic Drainage from Thyroid Cancers
Most papillary cancers show early lymphatic spread. The most important basins (Fig. 23) are:
·
The paratracheal node group
·
The cervical groups both sides
·
The upper mediastinal nodes
These nodes can also be subgrouped according to their localizations at different levels. A comparison between the various specifically named node groups that can be involved (Fig. 23) and their co- ordination to the different levels is demonstrated in Fig. 24a,b and Table 3. Figure 25 reflects the surgical operation site, from which as a rule early lymphatic spread (N1a and N1b positions can be reached (see also Fig. 26).
New Approaches to the Search for Sentinel Node(s) in Thyroid Cancer
Catarci et al. (2001) compared the three different strategies used in sentinel node detection. They as- certained the following identification rates:
·
Preoperative lymphoscintigraphy: 66%
·
Vital dye (Blue Patent V, 2.5%): 50%
·
Probe scanning (optimal dosage 22 MBq): 83%
The identification rate increased to 100% when all three methods were used. On the basis of the data obtained the groupis now recommending a con- trolled trial.
The results of preliminary studies based on lim- ited numbers of patients are listed in Tables (Ta- bles 4±7). Some of the groups taking part pre- ferred intraoperative labeling, using blue dye solu- tion, while others used labeling with
99mTc-nano- colloid.
99m
Tc-nanocolloid labeling may achieve increas- ing clinical significance
Fig. 23.Lymph node groups that can be the SLNs in thyroid cancer. Group A:
paratracheal nodes; group B: paravasal nodes; group C: nodes of the upper me- diastinum
·
Because radioiodine scintigraphy does not allow detection of regional lymph node metastasis owing to by the high uptake of radioiodine by the pre-existing thyroid parenchyma.
·
Because iodine-131 can only mark lymph node metastasis after total thyroidectomy (see Fig. 27).
·
Because radioiodine labeling can only detect lymph nodes that are already metastatic, and not cancer-free SLNs.
Fig. 24a,b.Comparison ofacervical lymph node groups 1±8 (Hermanek et al. 1993) withblevel-related grouping (I±VI) (Robbins et al. 1991)
Table 3.Lymph node groups 1±8 with corresponding levels and names according to Robbins et al. (1991) and the TNM At- las
Level (Robbins et al. 1991) Lymph node group
number TNM Atlas (1992)a Robbins et al. (1991)
I 1 Submental nodes Submental group
2 Submandibular nodes Submandibular group
II 3 Cranial jugular nodes Upper jugular group
III 4 Medial jugular nodes Middle jugular group
IV 5 Caudal jugular nodes Lower jugular group
V 6 Dorsal cervical nodes along
the accessory nerve Posterior triangle group
7 Supraclavicular nodes
VI 8 Prelaryngeal and paratra-
cheal nodes Anterior compartment
group
aTNM Supplement (1993)
It might be, therefore, that labeling of sentinel nodes with
99mTc-nanocolloid allows a most selec- tive lymphadenectomy intraoperatively, with a higher degree of certainty of locoregional cancer clearance.
Rettenbacher et al. (2000) recently published impressive preliminary results obtained with
99m
Tc. His strategy can be briefly summarized as follows:
·
Injection of 0.5 ml containing 37 MBq
99mTc- nanocolloid divided into four aliquots into the primary.
·
Dynamic images (high-resolution collimator, 1 frame per 15 s, 64´64 matrix, GE Elscint, mod- el SP6) obtained upto 10 min after tracer ad- ministration, followed by static anterior and lat- eral oblique images (256´256 matrix upto 1 h after tracer administration.
·
Identification of the SLN with the handheld gamma probe (c-Trak, Care Wise, Morgan Hill, Calif., USA).
·
Marking of SLN detected on the skin with water-resistant colored pen.
·
After total or subtotal thyroidectomy, removal of the SLNs, supported and controlled with the gamma probe.
The results obtained by the Salzburg groupare summarized in Table 6. I am grateful to Dr. Re- ttenbacher for the well-documented case reported in his original publication (Fig. 28).
Work on finding optimal strategies is apparently still in progress, but practically all groups are al-
Fig. 25.Middle field, in which the majority of SLNs corre-sponding to thyroid cancer are located, as delineated by Robbins et al. (1991). The field is fully consistent with the nominated lymph node group subsumed at N1a and N1b in the classification system published by the German Society of Otolaryngology (Bootz 2000). The published N-classifica- tion of thyroid cancers is illustrated in Fig. 26
Fig. 26.N-Classification of thyroid can- cer. N1a Metastases in ipsilateral cervical nodes; N1b metastases in bilaterally, medially, contralaterally or mediastinally located nodes
ready in favor of applying the sentinel node con- cept in thyroid cancer too. It seems that this con- cept can take the place of more or less uncon-
trolled lymphadenectomy (berry picking) prac- ticed in many clinics up to now.
Tables 4±7 show new approaches in sentinel node labeling using blue dye or
99mTc-nanocolloid solutions.
Pelizzo et al. (2001) investigated 29 cases with papillary thyroid cancers in an attempt at screen- ing. For SLN marking the authors injected patent blue V dye solution into the thyroid nodule. Thyr- oidectomy and lymph node removal at levels III, IV, VI, and VII (see Fig. 24a) followed.
The thyroid nodule and sentinel and nonsenti- nel nodes were investigated in frozen sections and the remaining specimens, in paraffin sections. The results obtained in these investigations are given below (Table 8).
In investigations carried out by Haigh and Giu- liano (2000) the identification rate in a papillary thyroid cancer series was high. In 15 of 16 cases SLNs could be detected and exactly localized. In 9
Fig. 27.Follicular thyroid cancer: pT3N1M0. Status after to-tal thyroidectomy and central neck dissection. Postoperative radioiodine ablative therapy. In a later iodine-131 control scintigraphy a supraclavicular lymph node metastasis was detected. (These pictures were kindly put at our disposal by Priv. Doz. Dr Meller, Department of Nuclear Medicine, Uni- versity Hospital, Gættingen)
Table 4.Results of sentinel node labeling in thyroid lesions by Kelemen et al. (1998) Pharma-
ceutical used
No. of
patients Size of
nodules Malig- nantlesion(s)
Benign
lesion(s) Cases in which SLN de- tected (n)
Cases in which SLN not detected (n)
SLNpositive in ma- lignant cases (n=%)
Location of SLN
Isosulfan blue dye meanvol.
0.5 ml
17 0.4±
4.0 cm 12 5 15/17 2/17 5/12
=42% 13 2
Para- Jugular tracheal
Fig. 28.Lymphoscintigraphy of a 35-year-old patient with an invasive papillary thyroid cancer 1.8 cm in diameter.99mTc- nanocolloid, 30 MBq, was injected into the primary, the in- jection area being covered by a lead shield. Two SLN are lo- calized in the medial jugular compartment (thick arrow), and one SLN can be seen in the lower jugular region (thin arrow). (Lymph scintigrams have been kindly donated by Dr. L. Rettenbacher and Prof. Dr. G. Galvan, Department of Nuclear Medicine and Endocrinology, State Hospital, Salz- burg, Austria)
Table 5.Results of sentinel node labeling by Dixon et al. (2000) No. of
patients Pharma- ceutical used
Drainage
verified (n) SLN detection rate
Drainage through:
central lateral to mediastinal nodes
Central
SLN Truly
positive SLN in papillary cancers
Negative SLN in papillary cancers
40 Isosulfan
blue dye 31 26 11 6 4/12 2/12
SLN detected in benign lesions: 14/18
Table 6.Results of sentinel node labeling in thyroid lesions by Rettenbacher et al. 2000 Pharma-
ceutical used
No. of
patients Site and timing of injec- tion
Imaging
strategy Malig-
nancies Benign
lesions Identifi- cation of SLNs
SLNfailure Nos. of
SLN False
nega- tives
99mTc- Nanocol- loid, 37 MBq
9 Intratu-
moral 1 h be- fore op- eration
Dynamic up to 10' planar andoblique up to 1 h
6 1 Onco-
cytoma All 4 papillary cancers
Both (2) follicular cancers
5 ´1 0
4 Papil-
lary 2 other 1´3
2 Folli-
cular 1 ´4
Table 7.Strategies of investigationa(Sahin et al. 2001) No. of
patients Pharmaceu-
tical used Palpable solitary node
Diagnosis
by Injection
modality Volume 1st hour 90±120 min
after injection
13 99mTc nano-
colloid 13 pat FNAC 3 Days
before operation 15 MBq (0.4 mCi)
99mTc
0.2 ml Dynamic
images 60 frames´
1 min
Static ante- rior and lateral images
aResults
No. of pa-
tients Early
frames Lymph
node detec- tion
Dynamic
acquisition Malignant
lesions Positive nodes
13 Intratumor-
al accumu- lation
10/15 7/10 5/13 1
cases metastasis was found in the SLNs. The num- ber of follicular cancers in their series was too small to allow firm conclusions (Table 9).
Value of the SLN Concept in Thyroid Cancer Treatment In the course of the last three decades there has been significant progress in locoregional clearance of thyroid cancers:
·
It was very important to leave the uni- or bilat- eral neck dissection strategy behind and to look for a less injurious method, especially in view of the subsequent local neural lesions.
·
This had been attempted with the so-called ber- ry-picking strategy, meaning removal of palp- able enlarged lymph nodes; this method has only low-grade specificity and is also inadequate in terms of topographical-anatomical continuity between the lymphatic network and the in- trathyroid primary. Therefore, this method could only be seen as a strategy that might be
successful, and then only more or less by chance.
·
After experience of these unsatisfactory surgical strategies, followed by the incalculable local cancer clearance, the introduction of the senti- nel node concept seemed to be helpful and to offer hope of developing significant advances:
± by providing better surgical guidance with respect to local cancer clearance.
± by including lymph node basins not reliably detected by the berry picking strategy.
In contrast to earlier methods, extirpation of re- gional labeled lymph node(s) corresponding to the direct lymphatic basin of the primary after peritu- moral injection with patent blue stain or isosulfan blue dye-solution and/or
99mTc nanocolloid solu- tion, gives rise to the hope that more selective lymphatic tumor clearance can be achieved. This procedure, with or without the use of
99mTc as a labeling substance, could be adopted as the classic method in place of iodine labeling, which is still the most frequently used but can only be evaluated in cases in which regional lymphatic spread has al- ready occurred.
It must be pointed out that not only the follicular thyroid cancers show a positive reaction on
131/125I- scintigraphy, but also the papillary cancers, which synthesize thyroglobulin in more than 90% of cases.
Whereas this method is suitable for detection of metastases,
99mTc-labeled nanocolloids are the best markers to detect the regional tumor-free SLNs for excision and histopathological and immunohisto- chemical investigation.
That both methods, iodine-131 scintigraphy and the dye method (using blue stains), combined with the labeled nanocolloid method are appropriate for the improvement of local surgical tumor clearance results from the fact that in the case of positive scintigraphic results using iodine as marker N- positivity must be stated a priori and the operative strategy must be adapted to this. However, it must be emphasized that micrometastases and metasta- ses from cancers that have already lost the biologi- cal capability of using iodine for thyroglobulin
Table 8.Significance of sentinel node labeling in papillary thyroid cancer casesRate of SLNs detected
intraoperatively SLNs with neoplastic
involvement Non-sentinel nodes
infiltrated by cancer SLN not involved and other nodes also free
22/29=75% 4/22=18.2% 2 cases 18/18
Table 9.Results of SLN search during thyroidectomy (Haigh and Giuliano 2000)
Pathology N SN
identified SN metastases
Benign 21 17/21
(81%) ±
Follicular adenoma 7 6 ±
Hçrthle cell
adenoma 3 2 ±
Colloid nodule/
multinodular goiter
7 5 ±
Hashimoto
thyroiditis 4 4 ±
Malignant 17 16/17
(94%) 9/16
(56%)
Papillary 16 15 9
Follicular 1 1 0
synthesis cannot be detected. In addition, it is also not possible to localize the sentinel nodes for in- tensive investigations using serial-section and im- munohistochemical techniques to exclude very early development of micrometastasis.
In spite of the intensively developed network of the cervical lymphatics and their node stations, which is also responsible also for contralateral me- tastases, three main fields of lymph node localiza- tion can be defined.
These are mentioned above with more detail:
·
The paratracheal (retrothyroidal) lymph nodes above and below the isthmus of the thyroid gland
·
The cervical lymph nodes along the carotid ar- teries and the jugular veins at both sides
·
The upper mediastinal nodes
These three fields of node localization must all be borne in mind both in scintigraphic evaluations and in any investigations in all steps of the intrao- perative search for the nodes (Figs. 23, 26).
Dependence of Therapy Regimens on (Sentinel) Lymph Node Status in Thyroid Cancer Subtypes In cases with papillary or follicular thyroid cancer classed as pT1aN0M0 no further adjuvant treat- ment is given, whereas in thyroid cancer classed as pT1a and higher pTsN1M0 and M+ a radioiodine treatment regimen is applied in institutes of nucle- ar medicine (see also Chapter 33).
In papillary cancers with the highest rate of re- gional lymphatic spread, the adjuvant therapy problem is looked at in a different way. A large proportion of papillary thyroid cancers are seen clinically by reactions to radioiodine and, in addi- tion, in reactions to antibodies directed to thyro- globulin, which are positive in more than 90% of cases. Therefore, radioiodine therapy is performed in more highly differentiated cases with cancer-in- filtrated regional (sentinel) lymph nodes.
In undifferentiated invasive thyroid cancers the sentinel node concept does not play any significant part, because of the diffuse regional cancer inva- sion.
With reference to regional lymph node involve- ment in oncocytoma, the metastatic process can be seen as similar to that in follicular cancers.
However, because oncocytomas do not incorporate
radioactive iodine at any significant rate, adjuvant radioiodine therapy cannot be considered. In both node-negative and node-positive cases a ªwait and seeº strategy is emerging more and more as the method of choice.
It must be made clear that in approximately 5±
10% of cases cancer of the thyroid develops as a multifocal cancer. Accordingly, it can happen that a lymphogenous metastasis develops not from the main nodule but from a small focus that has not been detected preoperatively. This also applies to metastases to nodes on the opposite side to the main nodule.
In very rare cases follicular or papillary thyroid cancers can developtogether with a metastasizing malignant oncocytoma (Hçrthle cell cancer).
References
Alnafisi NS, Driedger AA, Coates G, Moote DJ, Raphael SJ (2000) FDG PET of recurrent or metastatic131I-negative papillary thyroid carcinoma. J Nucl Med 41:1010±1015 Bootz F (ed) (2000) Oncology of head and neck region
(German Society of Otolaryngology consensus report by order of the Presidium), HNO 48:104±118
Catarci M, Zaraca F, Angeloni R, Mancini B, Fillippo MG de, Massa R, Carboni M, Pasquini G (2001) Preoperative lymphoscintigraphy and sentinel lymph node biopsy in papillary thyroid cancer. A pilot study. J Surg Oncol 77(1):21±24
Dixon E, McKinnon JG, Pasieka JL (2000) Feasibility of sen- tinel lymph node biopsy and lymphatic mapping in nod- ular thyroid neoplasms. World J Surg 24(11):1396±1401 Feine U, Lietzenmayer R, Hanke JP, Held J, Wæhrle H, Mçl-
ler-Schauenberg W (1996) Fluorine-18-FDG and iodine- 131-iodide uptake in thyroid cancer. J Nucl Med 37:1468±1472
Grçnwald F, Kalicke T, Feine U, Lietzenmayer R, Scheid- hauer K, Dietlein M, Schober O, Lerch H, Brandt-Mainz K, Burchert W, Hiltermann G (1999) Fluorine-18 fluoro- deoxyglucose positron emission tomography in thyroid cancer: results of a multicentre study. Eur J Nucl Med 26:1547±1552
Haigh PI, Giuliano AE (2000) Sentinel lymph node dissec- tion for thyroid malignany. Recent Results Cancer Res 157:201±205
Hedinger C, Sobin L (1974) Histological typing of thyroid tumours. (International histological classification of tu- mours, 4, no 11) World Health Organization, Geneva Johnson LW, Sehon J, Li BD (1999) Potential utility of senti-
nel node biopsy in the original surgical assessment of Hçrthle cell tumors of the thyroid: 23-year institutional review of Hçrthle cell neoplasms. J Surg Oncol 70(2):100±102
Kelemen PR, Herle AJ van, Giuliano AE (1998) Sentinel lymphadenectomy in thyroid malignant neoplasms. Arch Surg 133:288±292
Pelizzo MR, Boschin IM, Toniato A, Bernante P, Piotto A, Rinaldo A, Ferlito A (2001) The sentinel node procedure with Patent Blue V dye in the surgical treatment of pa- pillary thyroid carcinoma. Acta Otolaryngol 121(3):421±
Rettenbacher L, Sungler P, Gmeiner D, Kassmann H, Galvan424 G (2000) Detecting the sentinel lymph node in patients with differentiated thyroid carcinoma. Eur J Nucl Med 27(9):1399±1401
Robbins KT, Medina JE, Wolfe GT, Levine PA, Sessions RB, Pruet CW (1991) Standardizing neck dissection termi- nology official report of the Academy's Committee for Head and Neck Surgery and Oncology. Arch Otolaryngol Head Neck Surg 117:601±605
Ræher HD, Wahl R (1981) Der kalte Schilddrçsenknoten, eine Stellungnahme aus der Sicht des Chirurgen. Dtsch Med Wochenschr 106:657±662
Sahin M, Yapici O, Dervisoglu A, Basoglu T, Canbaz F, Al- bayrak S, Citak A (2001) Evaluation of lymphatic drai- nage of cold thyroid nodules with intratumoral injection of Tc-99m nanocolloid. Clin Nucl Med 26(7):602±605 Schauer A (1984) Pathologie der Schilddrçsentumoren. In:
Becker HD, Heinze HG (eds) Maligne Schilddrçsentumo- ren. Springer, Berlin Heidelberg New York, pp 2±61 Spiessl B, Scheibe O, Wagner G (eds) (1982) TNM atlas.
Springer, Berlin Heidelberg New York
TNM Supplement (1993) In: Hermanek P, Henson DE, Hçt- ter RVP, Sobin LH (eds) A commentary on uniform use.
Springer, Berlin Heidelberg New York
