Patterns of Care for Patients with Primary Differentiated Carcinoma

192
COMMUNICATION
The Institute of Medical
Informatics, JustusLiebig-University of
Giessen, Germany
Supported by the German Federal Ministry of
Health.
The United States Thyroid Cancer Study Group:
Active members: Scott A. Hundahl, M.D. (Chair);
Blake Cady, M.D.; Myles P. Cunningham, M.D.;
Ernest Mazzaferri, M.D.; Rosemary F. McKee, CTR;
Juan Rosai, M.D.; Jatin P. Shah, M.D.; and Andrew
Stewart, M.A. Reitred members: William H. Beierwaltes, M.D. and Amy Fremgen, Ph.D. The German
Thyroid Cancer Study Group: CA Professor Dr. G.
Müller (Aachen); Univ. Prof. Dr. med. U.Büll, Dr.
Elisabeth Ostwald, Dr. Sabri (Aachen); Dipl.-Med.
R. Eibisch (Adorf); OA Dr. Schimpke (Aschaffenburg); Prof. Dr. P. Heidenreich, OA Dr. R. Dorn
(Augsburg); Prof. Dr. Heidenreich, OA Dr. Dorn
(Augsburg); CA Dr. G. Fröhlich, OA Dr. Kußmaul
(Bad Friedrichshall); CA Prof. Dr. med. Grehn (Bad
Mergentheim); Dr. M. Schmidt, leit. MTA Frau Eikens (Bamberg); CÄ Dr. sc. med. M.-L. Weiß, Dr.
Klaus-Peter Schmidt (Berlin); Priv.-Doz. Dr. med.
Guenter Kubo, Dr. med. Joerg Sauer (Berlin); Dr. J.
Markwardt, Dr. M. Richter (Berlin); Dr. Ellen Kluge
(Berlin); Dr. med. Dietmar Geipel (Berlin); CA Dr.
med. E. Bährlehner, OA Dr. med. J. Brandt, Dr.
Schmidt (Berlin); Dr. R. Finke, Dr. Wudel (Berlin);
Dr. Hagemann, Dr. Hohberg (Berlin); Dr. Rühl, Dr.
Schicker (Berlin); Prof. Dr. Munz, PD Dr. D. Sandrock (Berlin); Prof. Dr. Herrmann (Bielefeld); Prof.
Dr. med. Friedrich Ziegler (Böblingen); Prof. Dr.
K.-U. Tiedjen, OA Dr. Horst Luckhaupt (Bochum);
Dr. W. Scheef, Dr. H. Emde (Bonn); Prof. Dr. Biersack, Dr. Otte/Dr. Hamad Khaled (Bonn); Prof. Dr.
med. H. W. Keller, Dr. Quandel (Bonn); Prof. Dr.
med. Istvan Klempa, Dr. med. Barthel Kratsch
(Bremen); Dr. Winterstein, Fachärztin f. Radiologie
A. Vetter-Brahner (Buchholz); Dr. med. Theophylaktos Emmaounilidis (Bünde); Prof. Dr. med. H.
Vinz, Dr. med. U. Stradmann (Burg); CA Dr. med.
Hans-Martin Höhne, Dr. A. Huber (Burglengenfeld);
Dr. med. E. Bell, Dr. Gosmann (Dernbach); Prof. Dr.
med. Laurenz Jostarndt, OA Dr. Erwin Stein (Dortmund); Dr. med. K. H. Hering, OÄ Dr. Dansbach
(Dortmund); Prof. Dr. W.-G. Franke, Dr. Bredow
(Dresden); Prof. Dr. H.-Br. Makoski, H. Klages (Duisburg); Prof. Dr. Schmitt (Düsseldorf); Prof. Dr.
med. Bernward Ulrich, Dr. Lienert (Düsseldorf);
Prof. Dr. Endert, Dr. Göbel (Erfurt); Dr. med. Ulbricht (Erlabrunn); Prof. Dr. Sauer, Dr. med. Stefan
Birkenhake, MDA Anna Urban (Erlangen); PD Dr.
med. H. Feistel (Erlangen); Prof. Dr. med. Friedrich
A. Franke (Erlangen); Frau Dr. Imke Roese (Essen);
Prof. Dr. Klaus Mann (Essen); Prof. Dr. Dr. A.
Bockisch, Frau Dr. C. Zander (Essen); Prof. Dr.
med. Peter-Conrad Mattes, Dr. Deuble (Esslingen);
Prof. Dr. Hör, Dr. Breidert-Backes (Frankfurt); Prof.
© 2000 American Cancer Society
Patterns of Care for Patients
with Primary Differentiated
Carcinoma of the Thyroid Gland
Treated in Germany during 1996
Simon Hölzer, M.D.1
Christian Reiners, M.D.2
Klaus Mann, M.D.3
Michael Bamberg, M.D.4
Matthias Rothmund, M.D.5
Joachim Dudeck, M.D.1
Andrew K. Stewart, M.A.6
Scott A. Hundahl, M.D.7
for the U.S. and German Thyroid Cancer Group
1
Institute of Medical Informatics, Justus-Liebig-University of Giessen, Giessen, Germany.
2
Clinic and Policlinic for Nuclear Medicine of the University of Würzburg, Würzburg, Germany.
3
Department of Medicine, University of Essen, Essen Germany.
4
Department of Radiation Oncology, Eberhard Karls University, Türbingen, Germany.
5
Department of Surgery, Philipps-University, Marburg, Germany.
6
Commission on Cancer, American College of Surgeons, Chicago, Illinois.
7
Department of Surgery, Queen’s Cancer Institute, Honolulu, Hawaii.
BACKGROUND. To determine current patterns of care and disease characteristics for
patients with thyroid carcinoma, a Patient Care Evaluation Study was initiated in
1996 in the U.S. and Germany. This project addresses ongoing concerns with
respect to the diagnostic evaluation and treatment of patients diagnosed with
thyroid carcinoma and raises questions concerning how physicians are interpreting current standards and acting on the basis of these recommendations.
METHODS. Patients with primary thyroid carcinoma were entered into a prospective multicenter observational study with free choice of treatment (no control
group) between January 1, 1996 and December 31, 1996 in Germany. This resulted
in a total of 2537 cases under observation and analysis; 1685 patients had papillary
carcinoma (66.4%), 691 had follicular carcinoma (27.2%), 70 had medullary carcinoma (2.8%), and 91 had anaplastic carcinoma (3.6%). The 2376 patients with
carcinoma of either papillary or follicular histology were included in the current
analysis.
RESULTS. The major symptoms reported for patients with papillary and follicular
thyroid carcinoma was neck mass (reported in 76% and 79%, respectively) followed
by dysphagia (reported in 25% and 27%, respectively), stridor (reported in 9% and
14%, respectively), and neck pain (reported in 7% and 8%, respectively). Greater
than 50% of the patients with papillary thyroid carcinoma were reported to have
American Joint Committee on Cancer/International Union Against Cancer Stage I
disease. Between 37–39% of the follicular carcinoma patients had Stage I and Stage
II disease. Only slight differences in the diagnostic approach to patients with papillary
A Prospective Cohort Study of Thyroid Carcinoma in Germany/Hölzer et al.
or follicular carcinoma were noted. The majority of patients underwent an ultrasound of the thyroid region (78.1%), which was suggestive of carcinoma in only 39% of the cases. A thyroid scan was
performed on 76.6% of patients, and the results were suggestive of
carcinoma in 44.8% of the individuals. In contrast, fine-needle
aspiration biopsy of the thyroid is highly recommended in the
current Clinical Practice Guidelines (CPG) but results were obtained in only 27.4% of the patients. Total thyroidectomy without
lymph node dissection was the most commonly used surgical procedure in the treatment of patients with papillary and follicular
thyroid carcinoma. Only approximately 2% of patients at low risk in
the group with Stage I disease were treated with a lobectomy. In
80% of the patients with Stage I papillary thyroid carcinoma and
approximately 90% of those patients diagnosed with Stage II, III,
and IV disease treating physicians chose to utilize radioiodine as
adjuvant treatment after disease-directed surgery. External beam
radiation was added to the treatment regimen for many patients
diagnosed with Stage III and IV disease (30% in patients with
papillary thyroid carcinoma and 33% in patients with follicular
thyroid carcinoma).
193
CONCLUSIONS. To the authors’ knowledge no single effective
diagnostic test for thyroid carcinoma currently is available and
in the majority of cases a combination of ultrasound, thyroid
scan, or fine-needle aspiration biopsy together with the clinical
findings (e.g., thyroid mass) led to a diagnosis of carcinoma. The
authors suspect that the high prevalence of concomitant pathologic findings such as goiter, even in the healthy population in
Germany, reduces the accuracy of all diagnostic test methods
and may account for the frequent use of imaging techniques.
The majority of patients underwent a total or near-total thyroidectomy. Total thyroidectomy with radical lymph node dissection
was used very frequently in those patients with papillary thyroid
carcinoma (22%). German physicians tend to surgically treat
early stage thyroid carcinoma somewhat more radically than
recommended in the CPG. With respect to other treatment options employed as part of the first course of treatment, radioiodine appears to play the most important role. [See commentary
on pages 1– 4, this issue and communication on pages 202–17,
this issue.] Cancer 2000;89:192–201.
© 2000 American Cancer Society.
KEYWORDS: thyroid carcinoma, papillary carcinoma, follicular carcinoma, diagnostics, surgery, iodine-131, hormonal therapy, adjuvant
treatment, complications.
T
hyroid carcinoma is an uncommon malignancy,
with approximately 3000 cases newly diagnosed
each year in the Federal Republic of Germany.1 It can
occur in any age group, but is most common after age
30 years and its aggressiveness increases significantly
in older patients. The majority of differentiated papillary or follicular histologies are highly treatable and
usually curable. Five-year and even 10-year survival
rates are high.2 Age appears to be the most important
prognostic factor.3– 6
To determine current patterns of care and disease
characteristics for patients with thyroid carcinoma
this Patient Care Evaluation (PCE) study was initiated
in 1996 as a combined effort involving the Institute of
Medical Informatics at the University in Giessen, the
German Medical Societies of Surgery, Nuclear Medicine, Endocrinology, and Radio-Oncology, and the
American College of Surgeons Commission on Cancer
(CoC) in the U.S. The current report reflects the German contribution to this project. This project addresses the ongoing concerns with respect to the treatment and diagnostic evaluation of patients diagnosed
Dr. Böttcher, Dr. Max (Frankfurt); Dr. Grosser (Frankfurt); Hanns Meier (Frankfurt (Oder)); CA Dr. St. Szepesi, Dr. S. Liebig (Frankfurt a. O.); Dr. S. Liebig (Frankfurt
a. O.); Dr. W. Koch (Freiburg); Prof. Dr. Moser, Dr. M. Reinhardt (Freiburg i.B.); Prof. Dr. Wendenburg, Dr. Vogelsang (Fürth); Dr. med. Detlev Buettner (Gehrden);
Dr. med. Wilhelm Heidemann, Dr. Gerdes (Georgsmarienhütte); Ch. A. Dr. Hans Schuster (Gera); Prof. Dr. Schäffer (Gießen); Prof. Dr. H. von Lieven (Gießen); Prof.
Dr. Bauer, Dr. Dagmar Steiner (Gießen); Prof. Dr. Kampmann (Göppingen); Prof. Dr. Emrich, Dr. med. W. Becker (Göttingen); Dr. A. Köhler, OÄ Frau Dr. R. S. Prawiro
(Gütersloh); CA Dr. R. Souchon (Hagen); Prof. Dr. Traute Mende (Halle); Prof. Dr. J. Dunst, Thomas Kuhnt (AIP) (Halle); Prof. Dr. med.Henning Dralle (Halle); PD. Dr.
Johannes Schorcht, OA Dr. Krüll (Hamburg); Priv.-Doz. Dr. med. Jochen Kussmann (Hamburg); Prof. Dr. Wegener, Frau Dr. Garn (Hamburg); Prof. Dr. med. C. Brölsch,
Frau Prof. Frilling (Hamburg); Prof. Dr. med. Andreja Frilling (Hamburg); Prof. Dr. Leisner, Herr C. Bleckmann (AiP) (Hamburg); Dr. Piotrowski, Frau Neumann (Hamm);
OA Dr. med. Scheumann Dr. med. Musholt (Hannover); Prof. Dr. Dr. h. c. H. Hundeshagen, Dr. Ehrenheim Frau Scheer (Hannover); Prof. Dr. med. Chr. Herfarth,
PD Dr. T. Hölting, Dr. Th. Weber (Heidelberg); Prof. Dr. med. Friedhelm Raue, Dr. med. Karin Frank-Raue (Heidelberg); Prof. Dr. Georgi, Dr. S. E. Haufe (Heidelberg);
Prof. Dr. Prager (Heilbronn); Priv. Doz. Dr. Dr. P. Lindner (Hildesheim); Prof. Dr. Kirsch, Dr. Alexander (Homburg); Dr. med. Franz Stoeberl (Illertissen); Prof. Dr. Lindner
(Ingolstadt); Dr. D. Picker, OA Dr. Helmut Stirner (Ingolstadt); Dr. med. J. Hesse (Jena); Prof. Dr. D. Gottschild (Jena); Dipl.-Ing. Sylvia Sänger (Jena); Prof. Dr. med.
B. Koch, Dr. Niels Huschitt (Kaiserslautern); Dr. F.-D. Maul, Dr. Jörg Peter (Karlsruhe); Dr. Spesshardt, Dr. Kirchner (Karlsruhe); CA Dr. Wulf Haase (Karlsruhe); Prof.
Dr. Fischer, Dr. Salk (Kassel); Prof. Dr. med. Manfred Neher, Dr. Jürgen Engelhardt (Kempten); Prof. Dr. Habighorst, Frau Dr. Gajek, Dr. Amberger (Koblenz); Prof.
Dr. med. R. Kirchner, Med. Dok. A. Linde (Koblenz); Prof. Dr. Hissen, PD Dr. Kersting, Petra Löw (Koblenz); Chefarzt Priv. Doz. Dr. med. J. P. Hedde (Köln); Axel
J. Müller/Prof. Siedek (Köln); Dr. med. Artur Busch (Köln); Prof. Dr. med. Hans-Friedrich Kienzle, Dr. Karim (Köln); Prof. Dr. Schicha, Dr. med. M. Dietlein (Köln);
Prof. Dr. Dr. med. H. Pichlmaier, PD Dr. Elfriede Bollschweiler (Köln); Prof. Dr. Zwicker, Dr. med. Kuhne-Velte (Konstanz); Dr. KuhneVelte (Konstanz); Dr. med. Gerhard
Endsberger (Kulmbach); Prof. Dr. Dürr, Dr. Rath, OA Dr. W. Kullak (Landshut); Prof. Dr. Knapp, Dr. Lothar Otto (Leipzig); Frau Kowalsky/Nachsorgeregister (Lemgo);
Prof. Dr. med. Peter Alexander Hild, Dr. Pascha (Lich); CA Dr. med. Haesner (Lippstadt); Prof. Dr. Bähre, Dr. Pollack (Lübeck); Prof. Dr. Klaus Anger (Lüdenscheid);
Dr. Schneider (Ludwigsburg); Prof. Dr. Kaufmann, Dr. Sattler (Ludwigshafen); Prof. Dr. Kaufmann, Dr. Kastler (Ludwigshafen); Dr. R. Sippel (Lünen); Prof. Dr. Otto,
Dr. Braune (Magdeburg); Prof. Dr. Thelen, Dr. Diefenbach (Mainz); Prof. Dr. med. M. Stahlschmidt (Mainz); Prof. Dr. Joseph, OA Dr. Welcke, Frau Sadhoff (Marburg);
Prof. Dr. med. Matthias Rothmund, Dr. Hoffmann (Marburg); Dr. R. Schaffhauser, Dr. Hoffmann (Marktredwitz); Dr. H.-M. Kühn (Mechernich); Dr. Reinbold, Dr.
194
CANCER July 1, 2000 / Volume 89 / Number 1
with thyroid carcinoma and raises questions regarding
how physicians in both countries are interpreting current standards and acting on the basis of these recommendations.3,7–16 Arguments for or against total
thyroidectomy, lymph node dissection (LND), or the
use of adjuvant radioiodine are discussed.
To our knowledge to date the transfer and application of available evidence into the clinical routine
have remained unknown. This is to say that current
recommendations in Clinical Practice Guidelines
(CPGs) are based on expert opinions. Prospective clinical trials to answer the most compelling questions are
not available currently and will not be in the foreseeable future. The rarity of thyroid carcinoma and the
excellent prognosis for patients with this malignancy
result in a prolonged nature and increase the potential
costs of such studies.
To our knowledge to date there are no data on a
large group of patients available to describe sufficiently the demographics, disease characteristics, applied diagnostic tests, or multimodality treatment
choices for thyroid carcinoma. The current study includes 2376 patients with primary differentiated carcinoma diagnosed in 1996, accounting for approximately 80% of all cases diagnosed that year in
Germany.
The objectives of this PCE study were to describe
patient characteristics and care adequately and to
evaluate the use of standards in the clinical routine. In
the past these questions have been addressed indirectly by interviewing physicians or by using data on a
highly aggregated level, rather than the level of individual physicians or institutions. Analyzing large databases using contemporary methods of informatics,
data management, and statistics provides an alternative method of approaching these issues. Useful insights regarding cancer management problems also
are provided. The three major questions to be answered in this article are: patient and disease characteristics in Germany, usage of diagnostic tests and
procedures, and practices for the treatment of patients
with differentiated thyroid carcinoma.
MATERIALS AND METHODS
In a prospective multicenter observation study with
free choice of treatment (no control group), 2537 patients with primary thyroid carcinoma (among those
2376 patients with papillary or follicular histology)
were entered free of selection between January 1,
1996, and December 31, 1996, in Germany. To our
knowledge the current study represents the largest
summary of thyroid carcinoma patients in Europe
presented to date. A detailed methodologic review of
this PCE study was described previously.17–25
A uniform questionnaire specifically designed for
thyroid carcinoma was prepared by a multidisciplinary subcommittee of the CoC’s National Cancer
Data Committee. This data form was adopted by experts of the German Medical Societies of Surgery, Nuclear Medicine, Radio-Oncology, and Endocrinology.
After successful field testing, this form was sent to the
departments of the above mentioned medical disciplines of all acute care hospitals and cancer centers
involved in the treatment of thyroid carcinoma patients. To ensure standardized data, coding schema
followed those published in the second edition of the
International Classification of Diseases for Oncology
(ICD-O-2),26 and the fourth edition of the American
Schmidt (Minden); CÄ Dr. med. Vera Schwarzhoff (Moers); Dr. Michaela Madler (Mühldorf); Prof. Dr. C. Renate Pickardt, Prof. Dr. Roland Gärtner (München); Prof.
Dr. Schwaiger, Prof. Dr. med. H. Langhammer (München); Prof. Dr. Dr. med. Fritz Spelsberg (München); Prof. Dr. Kempken, Dr. Gisela Voigt (München); OA Dr.
Löppert (München); Prof. Dr. Hahn, Prof. Hölzel, OA Dr. med. Weiss, Fr. Dr. Duesberg (München); Prof. Dr. K. Horn (München); Prof. Dr. Peter C. Scriba (München);
Prof. Dr. R. Gärtner (München); Prof. Dr. med. Dr. rer. nat. O. Schober, Dr. Lerch, Fr. Dr. Puskás (Münster); Dr. Fassmann, Dr. Herpich (Nürnberg); OA Dr. J. Kauntz,
Dr. Wondra (Nürnberg); Prof. Dr. Renner, Dr. O. Ott (Nürnberg); Priv.-Doz. Dr. med. Bernhard Arlt (Oberhausen); Dr. Schnabel, Dr. U. Melsbach, Dr. U. Melsbach
(Offenbach); Prof. Dr. med. Manfred Clemens, Frau Dr. Richter-Eckhardt (Osnabrück); Prof. Dr. med. Bernhard Stallkamp (Osnabrück); Dr. Schöneich, Dr. med.
Gabriele Holl (Potsdam); Prof. Dr. med. Karl-Walter Jauch, Dr. Ayman Agha (Regensburg); OA Dr. M. Weppler (Regensburg); Dr. med. Michael Allgäuer, Dr. Harjung
(Regensburg); OÄ Dr. Jutta Brederhoff (Rheine); PD Dr. P. Groth (Rostock); OA Dr. med. D. Hamann (Rostock); Wilhelm Kessler (Saarbrücken); Dr. Jacobs
(Saarbrücken); Dr. Schneider (Schwäbisch Hall); Prof. Dr. med. Volker Lenner, Dr. Großmann (Schwäbisch Hall); Dr. Höwner, CA Dr. med. Ch. Kerber (Schwerin);
Priv.-Doz. Dr. med. J. Jakschik, OA Dr. Franczak (Siegen); Dr. Bangard, Frau Dr. Pfeiffer-Büdenbender (Siegen); Prof. Dr. med. Hans-Joachim Meyer, Dr. med. F.
Lepique, Dr. med. Apfelstedt (Solingen); Dr. Kätlitz (Stade); Dr. Höller-Tellez, Frau Dr. Thiel (Stade); CA Dr. med. Oberschulte-Beckmann (Stolberg); Prof. Dr. med.
R. Bittner, Herr Zeller/Frau Mitschke (Stuttgart); Prof. Dr. Metzger, OA Dr. Roos (Stuttgart); CA Dr. med. F. Klein (Traunstein); Frau Dr. Gluth-Stender (Traunstein); Dr. W. Dornoff
(Trier); Dipl.-Inf. med. Birgit Trilling (Tübingen); Prof. Dr. med. R. Bares, Dr. M. H. Thelen (Tübingen); Prof. Dr. Bamberg (Tübingen); Dr. G. Heyder, Frau Dr. Troidl (Weiden);
Dr. med. Theobald Hoyer (Werdau); Dr. med. Erwin Wernet, Dr. med. Georg Gröger (Werne); Prof. Dr. med. Friedrich-Eckart Isemer (Wiesbaden); Manfred Sagner (Wuppertal);
Dr. med. José M. Garcia-Rodriguez, OA Dr. J. Sahm, Dr J. Sensfuß (Wuppertal); Prof. Dr. Berberich, Frau Dr. Stuer (Wuppertal); Prof. Dr. med. Erich Schmidt, OA Dr.
Endres-Paul (Würzburg); Prof. Dr. Chr. Reiners, Dr. Farahati (Würzburg); DM Anja Geiling (Zwickau); and Dr. John, Alexander Boicev (Zwickau).
Address for reprints: Andrew K. Stewart, M.A., Commission on Cancer, National Cancer Data Base, American College of Surgeons, 633 N. St. Clair St., Chicago,
IL 60611-3211.
Received September 14, 1999; revision received March 28, 2000; accepted April 7, 2000.
A Prospective Cohort Study of Thyroid Carcinoma in Germany/Hölzer et al.
TABLE 1
Tumor Histology and Patient Age
Age
Histology
Patient
cases
%
Median
25th percentile
75th percentile
Papillary
Follicular
Medullary
Anaplastic
Total
1685
691
70
91
2537
66.4
27.2
2.8
3.6
100.0
50.0
55.0
45.5
66.0
38.0
42.0
33.0
56.0
60.0
67.0
62.0
75.0
Joint Committee on Cancer (AJCC) Staging manual.27
Analyses of results are intended to identify general
standards of care and offer insight into the more specific issues mentioned earlier.
For inclusion in this study the tumor had to be of
papillary or follicular histology. A detailed analysis of
medullary and analplastic carcinoma is not presented
in this article due to the limited number of patients
available for review in the German data (Table 1). For
all patients data were collected in a uniform manner
and contained information regarding patient age, gender, personal history of cancer, symptoms, pathology,
diagnostic procedures, treatment, tumor status, and
life status. All standard imaging techniques as well as
the specific diagnostic workup for thyroid carcinoma
(e.g., thyroid ultrasound, thyroid scan, and fine-needle
aspiration biopsy) were included. Disease-directed
surgery was divided into local excision, lobectomy,
near-total thyroidectomy, total thyroidectomy without
lymph node dissection (LND), total thyroidectomy
with limited LND, total thyroidectomy with radical
LND, surgery of regional/distant sites, and surgery not
otherwise specified. The treatment recorded reflects
the initial treatment approach, usually within 4
months after diagnosis. The following treatment options in the scope of the primary therapy are documented: radioactive iodine therapy, external beam
radiation therapy, hormone therapy, and chemotherapy. Complications and side effects for all types of
therapy were reported. In addition to standard clinical
and pathologic stage, a combined AJCC (equal to the
International Union Against Cancer (UICC)) stage was
employed to represent pathologic stage supplemented, if necessary, by clinical stage.
Analysis of the data was performed using Microsoft ACCESS database software (Microsoft Corporation, Redmond, WA) MS Excel spreadsheet (Microsoft Corporation) and the SPSS statistics software
package.28 We performed a variety of edit checks that
included validity checks for individual data fields and
for interfield logic consistancy. Based on the methodology of data collection for this descriptive report, the
195
assumptions of inferential statistics were not met.
These data are not a probable sample of patients in
Germany, and the findings cannot be generalized statistically. Because of the large sample size, we recommend a straightforward, stratified, and conservative
assessment of the data pattern presented. Data acquisition in the scope of the follow-up of the included
patients is ongoing and will provide disease specific
survival rates in 5–10 years.
CPGs for the diagnosis and treatment of differentiated thyroid carcinoma are available in Germany.
They are a distillation of current evidence and opinion
concerning best practice. On account of the previously
mentioned lack of controlled trials, these CPGs are
based mainly on analytic, uncontrolled, or descriptive
studies or are based on the opinions of respected
authorities and expert committees.4,10,29 –36 The most
commonly used CPGs, to which we are referring, were
developed by the Society of Nuclear Medicine in Germany (DGN) and the German Cancer Society (DKG).
These guidelines have been available since early 1996
on the Internet at http://www.uni-duesseldorf.de/
WWW/AWMF/ll/nukl-002.htm (for DGN) and http://
www.uni-duesseldorf.de/WWW/AWMF/ll/cho-tmst.
htm (for DKG).
RESULTS
Completed data forms were received from ⬎ 170 medical institutions representing an estimated 80% of all
cases diagnosed in Germany in 1996. From an original
number of 2650 patients, 113 were excluded because
of multiple case entries or incomplete data. This resulted in a total of 2537 cases available for analysis
(Table 1): 1685 patients with papillary (66.4%), 691
with follicular (27.2%), 70 with medullary (2.8%), and
91 with anaplastic thyroid carcinoma (3.6%).
Patient Characteristics
The median age at the time of first diagnosis was 50
years among patients diagnosed with papillary carcinoma and 55 years among those diagnosed with follicular carcinoma. Using the German population in
1996 as a baseline, the age-adjusted case distribution
of the current study data showed a peak in the 50 –54
years age group for both men and women with papillary thyroid carcinoma. Women have the highest risk
for follicular carcinoma in the age groups 50 –54 years
and 65– 69 years, whereas men have only 1 peak in the
70 –74 years age group. Follicular carcinoma is more
common in older patients than papillary carcinoma.
The female to male ratio for carcinoma of the thyroid
gland was 3.5 to 1 for papillary carcinoma and 2.8 to 1
for follicular carcinoma.
196
CANCER July 1, 2000 / Volume 89 / Number 1
TABLE 2
Symptoms at Presentation by Tumor Type
Symptoms
Papillary
carcinoma
cases
Thyroid mass
Dysphagia
Neck pain
Hoarseness
Cervical lymph node mass
Stridor
Bone pain
Pathologic fracture
Weight loss
Other
1276
412
115
65
111
154
19
9
59
275
TABLE 4
Tumor Size (mm)
%
Follicular
carcinoma
cases
%
75.7
24.5
6.8
3.9
6.6
9.1
1.1
0.5
3.5
16.3
546
185
54
46
23
97
35
15
39
115
79.0
26.8
7.8
6.7
3.3
14.0
5.1
2.2
5.6
16.6
TABLE 3
Stage Distribution
AJCC/UICC
stage
Papillary
carcinoma cases
I
II
III
IV
Total known
Unknown
Total
891
320
235
48
1494
191
1685
%
59.6
21.4
15.7
3.2
100.0
11.3
Follicular
carcinoma cases
229
220
69
74
592
99
691
%
38.7
37.2
11.7
12.5
100.0
14.3
AJCC/UICC: American Joint Committee on Cancer/International Union Against Cancer.
Disease Characteristics
The major symptoms reported for patients with papillary and follicular thyroid carcinoma were a neck
mass in 76% and 79%, respectively; followed by dysphagia in 25% and 27%, respectively; stridor in 9% and
14%, respectively; and neck pain in 7% and 8%, respectively (Table 2).
The distribution of the combined AJCC/UICC
stage of disease revealed that ⬎ 50% of the patients
with papillary carcinoma were reported to have Stage
I disease. Between 37–39% of the patients with follicular carcinoma were found to have Stage I and II
disease (Table 3). However, 11% of the patients with
papillary and 14% of the patients with follicular carcinoma could not be staged on the basis of the reported
data.
Tumor size by histology is reported in Table 4.
Greater than 67% of the patients with papillary thyroid
carcinoma had a tumor volume ⱕ 20 mm. Tumors
with a volume ⬎ 40 mm were uncommon. Papillary
thyroid carcinoma primarily metastasizes to regional
lymph nodes. Figure 1 shows the frequency of positive
lymph nodes in relation to the pathologic tumor classification (pT). If the tumor was limited in its greatest
1–5
6–10
11–15
16–20
21–25
26–30
31–35
36–40
41–45
46–50
51–60
61–70
⬎ 70
Unknown
Cases
Papillary carcinoma (%)
Follicular carcinoma (%)
16.8
18.9
17.0
10.8
7.8
5.2
4.0
3.9
1.7
2.0
1.7
1.1
1.2
7.8
1685
3.0
8.4
7.5
10.4
9.6
8.1
5.4
8.0
6.2
6.7
6.8
4.0
5.2
10.7
691
dimension to the thyroid capsule (pT1, pT2, and pT3),
the frequency of positive regional lymph nodes ranged
from 10 –20%. In patients with pT4 tumors (tumor
extending beyond the thyroid capsule), the frequency
of positive lymph nodes increased sharply to ⬎ 50%.
Distant metastases in patients with papillary thyroid
carcinoma are rare. Less than 9% of the tumors with
extrathyroidal extension had distant metastases.
At the time of the initial diagnosis tumor sizes of
⬎ 40 mm were not rare (occurring in ⬎ 25% of patients in the current study) (Table 4). If the primary
tumor is limited to the thyroid capsule, regional lymph
nodes are expected to be positive in ⬍ 7% of cases. In
the presence of a pT4 tumor, approximately 33% of
patients in the current study had positive regional
lymph nodes, and in 25% of these distant metastases
were detectable. In both papillary and follicular thyroid carcinoma the frequency of extrathyroidal extension was 17.5%. Primary tumors were located slightly
more often in the right lobe than in the left lobe. Both
lobes were affected more often in patients with papillary thyroid carcinoma (12%) than in patients with
follicular thyroid carcinoma (7%).
Diagnostic Procedures
This section focuses on fine-needle aspiration biopsy
of the thyroid, thyroid ultrasound, and thyroid scan.
Although other diagnostic options such as X-ray, computed tomography, magnetic resonance imaging, laryngoscopy, or laboratory tests (including tumor
markers) are reported, these measures generally did
not play an important role in the primary diagnostic
workup. We noted only slight differences in the diagnostic approach toward patients with papillary or follicular thyroid carcinoma. The diagnostic tests per-
A Prospective Cohort Study of Thyroid Carcinoma in Germany/Hölzer et al.
197
FIGURE 1. Papillary thyroid carcinoma
cases according to pathologic tumor size
and regional lymph node involvement.
TABLE 5
Diagnostic Procedures for Differentiated Thyroid Carcinoma
Test results
Ultrasound
cases
Abnormal, suggestive of carcinoma
Abnormal, not suggestive of carcinoma
Normal
Subtotal: test done, results known
Test done or incomplete, results unknown
Subtotal: test done
Unknown if test done
Test not done
Total
657
995
34
1686
170
1856
416
104
2376
%
39.0
59.0
2.0
100.0
7.2
78.1
17.5
4.4
formed and the proportion that were suggestive of
carcinoma are illustrated in Table 5 for both histologies combined. It is apparent that recording the result
of diagnostic tests is not always complete. The majority of patients in the current study underwent an ultrasound of the thyroid region (78.1%), which was
suggestive of carcinoma in only 39% of these cases;
76.6% underwent a thyroid scan, which was suggestive
of carcinoma in only 44.8% of cases. Approximately
59% of the ultrasounds and 53% of the thyroid scans
performed were abnormal but not suggestive of carcinoma. One of the reasons for these findings is the
high rate of incidence of multinodular goiter in the
German population, which complicates the correct
diagnosis.37 Although fine-needle aspiration biopsy of
Thyroid
scan cases
766
904
41
1711
111
1822
415
139
2376
%
44.8
52.8
2.4
100.0
46.7
76.7
17.5
5.9
Fine-needle
biopsy cases
405
136
83
624
27
651
554
1171
2376
%
64.9
21.8
13.3
100.0
1.1
27.4
23.3
49.3
the thyroid is highly recommended in current CPGs,
results were obtained in only 27.4% of the patients.
The diagnostic utility of this test method was higher in
comparison with ultrasound or thyroid scans. Approximately 67% of the results were abnormal and suggestive of carcinoma, 21.8% were abnormal but not suggestive of carcinoma, and 13.3% of the results were
normal.
Treatment for Papillary Thyroid Carcinoma
Table 6 illustrates the frequency of applied surgical
procedures for all patients with papillary thyroid carcinoma by combined AJCC/UICC stage. Only 61 of all
reported patients underwent a local excision or lobec-
198
CANCER July 1, 2000 / Volume 89 / Number 1
TABLE 6
Surgical Treatment of Papillary Thyroid Carcinoma by AJCC/UICC Stage of Disease
Surgery
Stage I
cases
%
Stage II
cases
%
Stage III
cases
%
Stage IV
cases
%
Unknown
stage cases
%
Total
cases
%
No disease-directed surgery
Local excision
Lobectomy
Near-total thyroidectomy
Total thyroidectomy w/o LND
Total thyroidectomy w/limited LND
Total thyroidectomy w/ radical LND
Thyroidectomy, NOS
Surgery of regional/distant sites
Surgery, NOS
Total
7
16
15
220
235
154
201
26
3
14
891
0.8
1.8
1.7
24.7
26.4
17.3
22.6
2.9
0.3
1.6
100.0
1
0
4
75
99
55
63
23
0
0
320
0.3
0.0
1.3
23.4
30.9
17.2
19.7
7.2
0.0
0.0
100.0
1
1
6
35
35
61
83
7
2
4
235
0.4
0.4
2.6
14.9
14.9
26.0
35.3
3.0
0.9
1.7
100.0
1
1
0
7
15
9
13
1
1
0
48
2.1
2.1
0.0
14.6
31.3
18.8
27.1
2.1
2.1
0.0
100.0
3
8
10
43
92
8
11
11
0
5
191
1.6
4.2
5.2
22.5
48.2
4.2
5.8
5.8
0.0
2.6
100.0
13
26
35
380
476
287
371
68
6
23
1685
0.8
1.5
2.1
22.6
28.2
17.0
22.0
4.0
0.4
1.4
100.0
AJCC/UICC: American Joint Committee on Cancer/International Union Against Cancer; w/o: without; LND: lymph node dissection; w/: with; NOS: not otherwise specified.
TABLE 7
Multimodality Treatment of Papillary Thyroid Carcinoma
Treatment modality
Stage I
cases
%
Stage II
cases
%
Stage III
cases
%
Stage IV
cases
%
Unknown
stage cases
%
Total
cases
%
Surgery, radioiodine, hormones
Surgery, radioiodine, external beam radiation, hormones
Surgery, hormones
Surgery
Other
Total
661
47
114
29
40
891
74.2
5.3
12.8
3.3
4.5
100.0
288
6
11
1
14
320
90.0
1.9
3.4
0.3
4.3
100.0
143
65
9
4
14
235
60.9
27.7
3.8
1.7
6.0
100.0
34
11
0
0
3
48
70.8
22.9
0.0
0.0
6.3
100.0
132
13
28
3
15
191
69.1
6.8
14.7
1.6
7.9
100.0
1258
142
162
37
86
1685
74.7
8.4
9.6
2.2
5.1
100.0
tomy. Even among patients with Stage I disease, ⬍ 5%
were treated this way. Approximately 1% of patients
did not undergo disease-directed surgery. Surprisingly, the most frequently employed type of surgery
was a total thyroidectomy without LND, even though
a limited (central) LND is recommended for the majority of the cases, particularly those patients with
Stage II–IV disease. Approximately 23% of reported
patients underwent a near-total thyroidectomy. Approximately 50% of the patients with unknown disease
stage underwent a total thyroidectomy without LND,
and thus the status of the regional lymph nodes remained unknown. It is interesting to note that 23% of
the patients with AJCC/UICC Stage I disease underwent a radical LND and 33% of the patients with Stage
IV disease underwent a total thyroidectomy without
LND. Overall, we could not identify a clear pattern of
surgical treatment utilized with respect to stage of
disease.
Depending on the histologic type and stage of
disease, four nonsurgical treatment modalities (radioiodine, external beam radiation, hormone therapy,
and chemotherapy), alone or in combination with one
another, are utilized in the management of patients
with thyroid carcinoma. Surgery with or without hormones; surgery in combination with radioiodine and
hormones; or surgery in combination with radioiodine, external beam radiation, and hormones were
used in the treatment of the majority of patients. Two
percent of reported patients with papillary thyroid
carcinoma received treatment with surgery alone and
9.6% received treatment with surgery and hormonal
therapy to suppress thyroid-stimulating hormones.
The majority of patients with papillary thyroid carcinoma (83.1%) were treated using a combined schema
including radioiodine (Table 7). Among 8.4% of the
patients external beam radiation therapy was added
and 5.1% were treated using other combinations.
Among patients with AJCC/UICC Stage I disease,
⬍ 20% of the patients were surgically treated with or
without the administration of hormones.
Treatment for Follicular Thyroid Carcinoma
Total thyroidectomy without LND was the most commonly used surgical procedure in the treatment of
patients with follicular thyroid carcinoma (37%), followed by near-total thyroidectomy (21%), and total
thyroidectomy with limited LND (17%). Radical LND
A Prospective Cohort Study of Thyroid Carcinoma in Germany/Hölzer et al.
199
TABLE 8
Surgical Treatment of Follicular Thyroid Carcinoma by AJCC/UICC Stage of Disease
Surgery
Stage I
cases
%
Stage II
cases
%
Stage III
cases
%
Stage IV
cases
%
Unknown
stage cases
%
Total
cases
%
No disease-directed surgery
Local excision
Lobectomy
Near-total thyroidectomy
Total thyroidectomy w/o LND
Total thyroidectomy w/ limited LND
Total thyroidectomy w/ radical LND
Thyroidectomy, NOS
Surgery of regional/distant sites
Surgery, NOS
Total
1
3
4
42
88
43
34
11
0
3
229
0.4
1.3
1.7
18.3
38.4
18.8
14.8
4.8
0.0
1.3
100.0
1
1
6
52
76
39
29
14
0
2
220
0.5
0.5
2.7
23.6
34.5
17.7
13.2
6.4
0.0
0.9
100.0
1
1
1
12
13
16
24
0
0
1
69
1.4
1.4
1.4
17.4
18.8
23.2
34.8
0.0
0.0
1.4
100.0
2
0
0
12
25
15
9
6
4
1
74
2.7
0.0
0.0
16.2
33.8
20.3
12.2
8.1
5.4
1.4
100.0
2
1
5
24
53
5
3
6
0
0
99
2.0
1.0
5.1
24.2
53.5
5.1
3.0
6.1
0.0
0.0
100.0
7
6
16
142
255
118
99
37
4
7
691
1.0
0.9
2.3
20.5
36.9
17.1
14.3
5.4
0.6
1.0
100.0
AJCC/UICC: American Joint Committee on Cancer/International Union Against Cancer; w/o: without; LND: lymph node dissection; w/: with; NOS: not otherwise specified.
was utilized in 35% of patients reported as having
AJCC/UICC Stage III disease and between 12–15% of
patients with Stages I, II, and IV disease (Table 8).
Otherwise, little difference in the disease-directed surgical approach between patients with different stages
of disease was noticeable. Postoperative death within
30 days occurred in ⬍ 0.5% of all patients.
With respect to other treatment options employed
as part of the first course of treatment, radioiodine
plays the most important role. Radioiodine treatment
is recommended for all patients with follicular thyroid
carcinoma. In ⬎ 90% of the patients with follicular
thyroid carcinoma, radioiodine was administered, regardless of AJCC/UICC stage. External beam radiation
therapy played an important role (used in ⬎ 20% of
cases) in the treatment of patients with Stage III and
Stage IV disease. Among patients with papillary thyroid carcinoma, 80% of those with Stage I disease and
approximately 90% of those diagnosed with Stage II,
III, and IV disease were treated with radioiodine as
adjuvant therapy after disease-directed surgery. External beam radiation therapy was added to the treatment regimen for many patients diagnosed with Stage
III or IV disease (30% in patients with papillary thyroid
carcinoma and 33% in patients with follicular thyroid
carcinoma. The proportion of patients treated with
chemotherapy was negligible (0.3% in both histologic
groups).
Residual Tumor and Complications
Residual primary tumor after disease-directed surgery,
according to information found in surgical reports,
was noted in 4.3% of patients in the current study,
2.6% with positive microscopic (R1) results and 1.7%
with positive macroscopic (R2) results (Table 9).
Hypoparathyroidism/hypocalcemia led the list of
TABLE 9
Residual Tumor after Surgery
Classification
Cases
%
No residual tumor (R0)
Microscopic (R1)
Macroscopic (R2)
Subtotal
Unknown
Total
1482
40
27
1549
123
1672
95.7
2.6
1.7
100
7.4
postoperative complications with 15.8% of patients
affected, closely followed by recurrent nerve injury
(12.9%). Postoperative bleeding and wound infection
was reported in 2.9% and 1.4%, respectively, of patients. Strict criteria were not applied to recording
events summarizing temporary or permanent complications. Nevertheless, a high rate of temporary complications still suggests a reduced postoperative quality of life for the patient. The distinction between
temporary and permanent complications will be determined during follow-up investigations.
Pain in the neck (9.9%), nausea (5.8%), and sialadenitis (3.3%) were the most frequent complications or
side effects of radioiodine therapy among the 636 patients treated with this modality. Erythema (58%) and
mucositis (32%) were the most frequently reported
acute side effects after external beam radiation therapy.
DISCUSSION
The results of the current study indicate that the management of patients with thyroid carcinoma with similar features (age, histology, and extent of disease)
varied widely. To our knowledge there is no single
200
CANCER July 1, 2000 / Volume 89 / Number 1
effective diagnostic test available and in the majority
of cases in the current study a combination of ultrasound, thyroid scan, or fine-needle aspiration biopsy
together with the clinical findings (e.g., thyroid mass)
led to a diagnosis of carcinoma. All diagnostic tests are
altered by the high frequency of concomitant pathologic findings. We suspect that the high prevalence of
goiter, even in the normal population in Germany,37
reduces the accuracy of all diagnostic test methods
and may contribute to the frequent use of imaging
techniques. As much as 80% of the current patient
cohort underwent a thyroid scan or ultrasound,
whereas ⬍ 50% of findings were abnormal and suggestive of carcinoma. Fine-needle aspiration biopsy is
considered the most cost-effective method but was
not used frequently because of the previously mentioned pathologic circumstances.
CPGs for the treatment of thyroid carcinoma were
developed in 1994 and 1995 by the German Cancer
Society in cooperation with several medical societies
in Germany. In early 1996 these guidelines were disseminated widely, published in medical journals, and
made available on the Internet. They are based on
expert opinions developed in consensus or Delphi
conferences. The problems associated with developing evidence-based CPGs have been mentioned earlier.
The majority of patients reported in the current
study underwent a total or near-total thyroidectomy.
Total thyroidectomy with radical LND frequently was
used in patients with papillary thyroid carcinoma
(22%) and suggests that German surgeons tend to
perform somewhat more radical surgery than recommended by the CPGs. Only approximately 2% of patients at low risk with AJCC/UICC Stage I disease were
treated with a lobectomy, in contrast with 23% of
patients with papillary and 15% of patients with follicular thyroid carcinoma who underwent a radical
LND. The CPGs in Germany generally recommend a
total or near-total thyroidectomy for these patients.
For a subgroup of patients with papillary thyroid carcinoma measuring ⬍1 cm without lymph node involvement or distant metastases, a local excision or
lobectomy is recommended. However, the current
study found that only 5.8% of this subgroup underwent a lobectomy or local excision. Although concomitant diseases such as goiter can justify a more comprehensive surgical approach for select cases, in the
current study a considerable proportion of these low
risk patients (T1N0M0) were treated with radical LND
(14.9%). We believe group should be considered to be
overtreated.
The results of the current study indicate that it has
been impossible to date to reach a consensus regard-
ing a stage-adapted surgical strategy, and suggest that
an educational effort is needed to ensure the efficient
implementation of CPGs. Although several discrepancies between actual practice and current CPGs could
be identified, the appropriateness of the surgical care
delivered can be evaluated once long term outcome
data are available for this patient cohort.
PCE studies are valid and comprehensive tools of
quality assurance in oncology. They can serve as a
direct measure of the current pattern of care and assist
in the evaluation of standards with respect to diagnostic procedures, multimodality treatment, and followup. We believe the current methodology of data collection, data management, analysis, and publication
of results provides clinically relevant and up-to-date
information. With the availability of outcome data for
this patient cohort, we will be able to assess critically
the validity of the applied procedures. The methodologic structure of these studies (lack of control
groups) may never resolve dilemmas regarding treatment choices completely, but these studies can be
viewed as a tool to analyze real-world practices that
may or may not be compatible with current recommendations representing the best available evidence
in the management of cancer patients. These findings
may serve as a stimulus for further selective research.
We believe that with the realization of this parallel
international PCE study in the U.S. and Germany,
valuable insights with respect to healthcare systems,
diagnostic strategy, and treatment are available.
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