Improved Prediction of Calcitonin Normalization inMedullary Thyroid Carcinoma Patients by QuantitativeLymph Node Analysis

Andreas Machens, M.D.1

Oliver Gimm, M.D.1

Jorg Ukkat, M.D.1

Raoul Hinze, M.D.2

Ulrich Schneyer, M.D.3

Henning Dralle, M.D.1

1 Department of General Surgery, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.

2 Department of Pathology, Martin-Luther-Univer-sity Halle-Wittenberg, Halle/Saale, Germany.

3 Department of Internal Medicine, Division of En-docrinology, Martin-Luther-University Halle-Wit-tenberg, Halle/Saale, Germany.

Address for reprints: Andreas Machens, M.D., De-partment of General Surgery, Martin-Luther-Uni-versity Halle-Wittenberg, Ernst-Grube-Strasse 40D-06097, Halle/Saale, Germany.

Received May 10, 1999; revisions received August23, 1999, and December 6, 1999; accepted De-cember 6, 1999.

BACKGROUND. The aim of this study was to identify better prognostic parameters

for normalization of serum calcitonin in medullary thyroid carcinoma (MTC)

patients.

METHODS. In 73 patients who had undergone systematic lymph node dissection for

MTC between September 1995 and November 1998, preoperative (n 5 29) and

postoperative (n 5 65) basal and stimulated serum calcitonin were correlated with

the pTNM classification and the number of positive regional lymph nodes and

compartments.

RESULTS. In contrast to pT and M, there was a significant correlation between

postoperative calcitonin and the pN category. With rising numbers of positive

lymph nodes (0, 1–9, 10 –19, and $ 20), postoperative basal and stimulated calci-

tonin increased exponentially, and gross distant metastases (M1) occurred more

frequently (0%, 4%, 13%, and 50%; P 5 0.013). Conversely, serum calcitonin was

less often normalized (65%, 31%, 0%, and 0%; P 5 0.003). There was a close

correlation between the number of positive lymph nodes and the number of

affected compartments (P , 0.001; r 5 0.93). Irrespective of location, involvement

of 10 or more lymph nodes and more than 2 compartments precluded normaliza-

tion of serum calcitonin.

CONCLUSIONS. Quantitative lymph node analysis of MTC improves prediction of

calcitonin normalization. When more than two compartments are involved, nor-

malization of serum calcitonin cannot be attained. Surgery should then be less

extensive and more directed at preventing local complications. Cancer 2000;88:

1909 –15. © 2000 American Cancer Society.

KEYWORDS: basal and stimulated calcitonin, medullary thyroid carcinoma, occultmetastases, quantitative lymph node analysis.

Early lymphatic dissemination and frequent formation of occultmetastases are features of medullary thyroid carcinoma (MTC). In

a multivariate analysis,1 N and M classifications, International UnionAgainst Cancer (UICC) stage, and postoperative serum calcitoninwere found to be significant prognosticators of decreased long termsurvival. However, the individual prognosis may be vastly differentbetween patients with positive lymph node status, as not all of themharbor occult metastases and will develop local recurrences or distantmetastases.1,2

Unfortunately, microscopic cell clusters are often well below thedetection limit of all imaging modalities available thus far. Conse-quently, most localizing studies (computed tomography [CT], mag-netic resonance imaging [MRI], positron emission tomography [PET],octreotide scan, etc.) and even the most sophisticated and invasive

1909

© 2000 American Cancer Society

techniques like selective venous catheterization havefallen short of reliably identifying occult distant me-tastases.3– 8 Because of this failure, the postoperativelevel of basal and/or stimulated serum calcitonin hasbeen used as a substitute for direct evidence of occultmetastases.

The conditions under which postoperative nor-malization of hypercalcitoninemia is achievable havenot been examined in great detail. The current studywas conducted with a view to identifying indirect pa-rameters of occult metastases and to delineate prog-nostic factors associated with normalization of serumcalcitonin after extensive local resection.

PATIENTS AND METHODSPatient Demographics and Extent of SurgeryBetween September 1, 1995, and November 30, 1998,73 patients with MTC and preoperative (n 5 29) andpostoperative (n 5 65) pentagastrin stimulation wereenrolled in this study. Twenty-nine tumors were he-reditary and 44 were sporadic. The mean patient agewas 47.6 6 15.7 years. The gender ratio was almostbalanced (39 males vs. 34 females). Thirty-six percent(26 of 73) of all operations for MTC were primaryprocedures, and 64% (47 of 73) were reoperations. Inall 73 patients enrolled, total or completion thyroid-ectomy had been performed at some stage: in 38% (28of 73) at the referring institution, and at primary sur-gery or reoperation in 62% (45 of 73) at this institution.Standard systematic lymph node dissections of thecervical and mediastinal compartments had been car-ried out by the technique described previously:9 thecervicocentral compartment was excised en bloc in97% of cases (71 of 73). In the remaining 3% (2 of 73),the cervicocentral compartment was not dissected be-cause both carcinomas were incidental: 1 in a boy age5 years with proven RET proto-oncogene mutation,and another in a woman age 53 years with extensivethyroid nodular disease. The ipsilateral and contralat-eral cervicolateral compartments were removed enbloc in 74% (54 of 73) and 73% (53 of 73), respectively.The mediastinal compartment was dissected in 45%(33 of 73) of cases. Potentially, all these primary orsecondary operations were locally curative, as no vis-ible primary tumor or lymph node metastases hadbeen left in situ. The surgical specimens were sub-jected to pathologic analysis. This examination in-cluded a quantitative analysis of involved lymphnodes based on compartmental anatomy, as de-scribed previously.10 In addition, primary operatingnotes and pathology reports were obtained. All tumorswere classified according to the current pTNM classi-fication11 and the compartment classification.10

Basal and Stimulated Serum CalcitoninPerioperative evaluation for surgery in these 73 pa-tients included determination of basal and stimulatedserum calcitonin using a solid two-site immunoradio-metric assay (ELSA-hCT, CIS Bio International, Gif-sur-Yvette, France). After informed consent was ob-tained from patients, calcitonin stimulation wascarried out by intravenous bolus injection of 0.5 mg/kgBW of pentagastrin (Peptavlon, Zenica Limited,Macclesfield, UK) before surgery and on the fourth toseventh (median, sixth) postoperative day. Peripheralvenous samples were drawn prior to stimulation andafter 2 and 5 minutes following pentagastrin injection.To assess the extent of calcitonin stimulability, anincremental factor was calculated by dividing the re-spective peak calcitonin value after pentagastrin injec-tion by the respective basal value. Normalization ofserum calcitonin was assumed when neither the basalnor the stimulated serum calcitonin values exceededthe normal range of 10 pg/mL. Only complete sets ofdata (basal and stimulated serum calcitonin values)were considered for statistical analysis. Twenty-onepatients had both preoperative and postoperativestimulatory tests, 8 patients only preoperative, and 44patients only postoperative stimulatory tests. All pa-tients underwent diagnostic imaging by ultrasound,CT, or MRI to rule out gross distant metastases. Inaddition, bone scan, laparoscopy, and open lung bi-opsy were used when appropriate. Gross distant me-tastases were identified in 5 (7%) of the 73 patients:pulmonary metastases in 2 patients by pulmonarybiopsy, hepatic metastases in 1 patient by ultrasoundand CT scan, and bone metastases in 2 patients byplain X-ray and CT. Of the 65 patients with postoper-ative pentagastrin stimulation, 35% (23 of 65) accom-plished normalization of serum calcitonin. In the re-maining 65% of patients (42 of 65), whosehypercalcitoninemia failed to normalize after surgery,gross metastases were detected in only 10% (4 of 42) ofcases.

Statistical AnalysisAssociations between categoric variables were testedusing the two-tailed Fisher exact test. For analysis ofunpaired nonparametric data, the exact Mann–Whit-ney–Wilcoxon and Kruskal–Wallis rank sum tests(two-tailed) were applied as appropriate. Multiplicityof testing was corrected for by using the Bonferroniadjustment. To measure rank order associations be-tween ordinal variables, the Spearman rank correla-tion coefficient (Spearman rho) was calculated. Thelevel of significance was set at P , 0.05.

1910 CANCER April 15, 2000 / Volume 88 / Number 8

RESULTSCorrelation between Calcitonin Normalization and pTNMAs depicted in Table 1, there was no statistically sig-nificant association between basal or stimulated se-rum calcitonin and pT classification after Bonferroniadjustment for multiplicity of testing, either before orafter systematic lymph node dissection. Normaliza-tion of serum calcitonin was achieved more oftenin pT1 tumors than in pT2– 4 tumors (67% vs. 16 –25%) when N and M classifications were disre-garded. In contrast, there was a significant correla-tion (P , 0.001) between postoperative basal andstimulated serum calcitonin levels and pN classifica-tion that was maintained after adjustment for multi-plicity of testing (Table 2). Normalization of serumcalcitonin was accomplished more frequently (70% vs.20%, P , 0.001) in pN0 than in pN1 tumors. Unlikepreoperative basal calcitonin, preoperative peak calci-

tonin still reached statistical significance after multi-plicity of testing, though by a narrow margin (Table 2).The absolute levels of basal and peak calcitonin cor-related with each other, both in the preoperative (r5 0.90) and postoperative setting (r 5 0.91). Whengrouped by pN1a and pN1b classifications (23 vs. 22patients), postoperative basal and stimulated calcito-nin levels did not differ significantly: 14 pg/mL (pN1a)versus 224 pg/mL (pN1b) (P 5 0.057) and 86 pg/mL(pN1a) versus 870 pg/mL (pN1b) (P 5 0.071). In pN1apatients, serum calcitonin was normalized in 30%, asopposed to 5% in pN1b patients (P 5 0.13). There wasno significant association between basal or stimulatedcalcitonin levels and the M category, either before orafter lymph node dissection (Table 3). Rates of calci-tonin normalization did not differ significantly withinthe M category. The correlation between basal andstimulated calcitonin, normalization of serum calcito-

TABLE 1Pre- and Postoperative Serum Calcitonin in MTC Grouped by pT Classification

pT1 pT2 pT3 pT4

P valueTotal (na) 27 35 5 5

Preoperative calcitonin (n) 11 16 0 2Basal (pg/mL) 72 (9–129) 140 (7–1088) — 6552 (637–12466) 0.25Peak (pg/mL) 570 (18–5850) 1036 (174–3020) — 25371 (779–49963) 0.47

Postoperative calcitonin (na) 24 31 5 4Basal (pg/mL) 4 (2–51) 27 (5–228) 510 (13–1152) 412 (144–681) 0.053Peak (pg/mL) 7 (4–209) 94 (23–1248) 1242 (21–1214) 3529 (288–6770) 0.039b

Calcitonin normalization (%) 67 16 20 25 0.001

MTC: medullary thyroid carcinoma. All figures are given as median values, with 25% and 75% percentiles added in parentheses, or as percentages, respectively.a One reoperative patient could not be classified due to inadequate data.b Not significant after Bonferroni adjustment for multiplicity of testing.

TABLE 2Pre- and Postoperative Serum Calcitonin in MTC Grouped by pNClassification

pN0 pN1

P valueTotal (n) 25 48

Preoperative calcitonin (n) 10 19Basal (pg/mL) 11 (5–85) 518 (61–1340) 0.024Peak (pg/mL) 46 (5–1054) 1128 (290–10000) 0.014b

Incremental factora 2.7 (1.2–12.5) 8.5 (2.6–15.3) 0.22Postoperative calcitonin (n) 20 45

Basal (pg/mL) 4 (2–11) 56 (7–538) , 0.001c

Peak (pg/mL) 7 (2–17) 594 (45–1452) , 0.001c

Incremental factora 1.3 (1.0–2.1) 3.0 (1.9–7.2) , 0.001c

Calcitonin normalization (%) 70 20 , 0.001c

MTC: medullary thyroid carcinoma. All figures are given as median values, with 25% and 75% percen-

tiles added in parentheses, or as percentages, respectively.a Peak value after stimulation, divided by the respective basal value.b,c Significant on the 0.05/0.01 level after Bonferroni adjustment for multiplicity of testing.

TABLE 3Pre- and Postoperative Serum Calcitonin in MTC Grouped by MClassification

M0 M1a

P valueTotal (n) 68 5

Preoperative calcitonin (n) 27 2Basal (pg/mL) 72 (9–1001) 6552 (637–12,466) 0.12Peak (pg/mL) 981 (75–4140) 25,371 (779–49,963) 0.32

Postoperative calcitonin (n) 61 4Basal (pg/mL) 12 (2–129) 586 (439–1119) 0.008b

Peak (pg/mL) 52 (6–1030) 1193 (664–3485) 0.06Calcitonin normalization

(%) 38 0 0.29

MTC: medullary thyroid carcinoma. All figures are given as median values, with 25% and 75% percen-

tiles added in parentheses, or as percentages, respectively.a Distant metastases to lung (n 5 2), liver (n 5 1), and bone (n 5 2) confirmed by pulmonary biopsy or

CT scan.b Significant on the 0.05 level after Bonferroni adjustment for multiplicity of testing.

Prediction of Calcitonin Normalization in MTC/Machens et al. 1911

nin, and pN classification improved only slightly whenfigures were broken down by UICC stage (Table 4; r5 0.56, 0.60, and 0.56) instead of pN classification(Table 2; r 5 0.48, 0.56, and 0.48). Between the pT, pN,and M classifications, only the correlations betweenpT and pN and between pT and M were significant. InpT1, pT2, pT3, and pT4 tumors, lymph node metasta-ses were found in 44% (12 of 27), 80% (28 of 35), 60%(3 of 5), and 100% (5 of 5) of cases (P 5 0.007), andgross distant metastases in 0% (0 of 27), 6% (2 of 35),20% (1 of 5), and 40% of patients (2 of 5) (P 5 0.015).

Correlation between Calcitonin Normalization andQuantitative Lymph Node AnalysisAs shown above (Table 2), both basal and stimulatedserum calcitonin levels in patients with positive lymphnode status were significantly elevated after surgeryfor MTC. To investigate this association further, the

number of positive lymph nodes was grouped intothree categories, reflecting increasing intensity of lym-phatic seeding. As illustrated in Table 5, the morelymph nodes involved, the higher the postoperativeserum calcitonin, both basally and after pentagastrinstimulation (P , 0.001). With rising lymph node clas-sification, there was a disproportionate, almost expo-nential increase in serum calcitonin levels. This cor-relation was not significantly influenced by the overallnumber of lymph nodes removed (P 5 0.68). The morelymph nodes involved, the more frequently bilaterallymph node involvement was noted (r 5 0.35). Thecorrelation between lymph node status (pN) and post-operative basal and stimulated calcitonin (r 5 0.48and r 5 0.56) was markedly improved when lymphnode status was broken down by the number of pos-itive lymph nodes dissected (r 5 0.61 and r 5 0.69).However, there was a clear-cut correlation between

TABLE 4Pre- and Postoperative Serum Calcitonin in MTC Grouped by UICC Stage

I II III IV

P valueTotal (n) 15 10 43 5

Preoperative calcitonin (n) 7 3 17 2Basal (pg/mL) 13 (5–85) 2 (2 --) 215 (45–1257) 6552 (637 --) 0.087Peak (pg/mL) 75 (7–1054) 2 (2 --) 1128 (279–7925) 25371 (779 --) 0.092Incremental factora 5.5 (1.4–63.3) 1.1 (1 --) 8.5 (2.6–16.6) 2.6 (1.2 --) 0.028

Postoperative calcitonin (n) 12 8 41 4Basal (pg/mL) 2 (2–4) 12 (7–34) 46 (5–297) 586 (439–1119) , 0.001b

Peak (pg/mL) 5 (2–7) 27 (11–74) 280 (22–1395) 1193 (664–3485) , 0.001b

Incremental factora 1.3 (1.0–2.0) 1.5 (1.1–2.7) 3.3 (1.9–11.1) 2.3 (1.4–3.1) 0.001b

Calcitonin normalization (%) 100 25 22 0 , 0.001b

MTC: medullary thyroid carcinoma; UICC: International Union Against Cancer. All figures are given as median values, with 25% and 75% percentiles added in parentheses, or as percentages, respectively.a Peak value after stimulation, divided by the respective basal value.b Significant on the 0.01 level after Bonferroni adjustment for multiplicity of testing.

TABLE 5Postoperative Serum Calcitonin and M Classification Grouped by Quantitative Lymph Node Analysis

na

Positive lymph nodes excised

P value

0 1–9 10–19 > 20

17 26 8 4

Postoperative calcitoninBasal (pg/mL) 4 (2–12) 11 (2–71) 288 (86–1114) 843 (168–2499) , 0.001Peak (pg/mL) 6 (2–27) 86 (7–646) 1759 (1072–5769) 2548 (304–7682) , 0.001Incremental factorb 1.3 (1.0–1.8) 2.9 (1.9–10.1) 6.5 (2.4–35) 2.7 (1.4–3.2) 0.002M1 (%) 0 4 13 50 0.013Calcitonin normalization (%) 65 31 0 0 0.003

All lymph nodes excised 59 (22–69) 52 (40–72) 55 (43–74) 63 (52–81) 0.68

All figures are given as medians, with 25% and 75% percentiles added in parentheses, or as percentages, respectively.a Excluding 8 pN1 patients in whom no positive lymph nodes were found on reoperation and 2 primary patients with total thyroidectomy only.b Peak value after stimulation, divided by the respective basal value.

1912 CANCER April 15, 2000 / Volume 88 / Number 8

the rising number of lymph nodes, increasing fre-quency of gross distant metastases (P 5 0.013), anddecreasing rates of calcitonin normalization (P 50.003). It is of particular note in this regard that serumcalcitonin never normalized when 10 and more posi-tive lymph nodes were found. For a separate analysisof primary and secondary patients, numbers were in-adequate to allow for meaningful comparisons.

Correlation between Calcitonin Normalization andNumber of Affected CompartmentsTable 6 illustrates that basal and peak calcitonin alsodiffered significantly (P , 0.001) when broken downby the number of compartments that contained pos-itive lymph nodes. As before with the categories oflymph node involvement (Table 5), a similar correla-tion was noted between rising numbers of affectedcompartments and falling rates of calcitonin normal-ization (P 5 0.004). Serum calcitonin never convertedto normal when more than two compartments wereinvolved. The number of affected compartmentsclosely correlated with the quantitative lymph nodeanalysis (r 5 0.93; P , 0.001).

Correlation between Calcitonin Normalization andIndividual Affected CompartmentsWhen the cervicocentral compartment containedlymph node metastases, the ipsilateral cervicolateralcompartment was involved in 72% of cases (31 of 43).In this setting, the contralateral cervicolateral and me-diastinal compartments were affected in 28% each (12of 43 and 7 of 25). Broken down by compartmentallocation, i.e., by negative and positive individual com-partments, the following pattern was found postoper-atively: median basal and stimulated serum calcitonin

were 11 pg/mL versus 88 pg/mL (P 5 0.028) and 34pg/mL versus 594 pg/mL (P 5 0.021) when the ipsi-lateral cervicolateral compartment (25 vs. 29 patients)was involved; 13 pg/mL versus 347 pg/mL (P 5 0.021)and 81 pg/mL versus 1455 pg/mL (P 5 0.009) whensolely the contralateral cervicolateral compartment(43 vs. 10 patients) was affected; 36 pg/mL versus 461pg/mL (P 5 0.035) and 448 pg/mL versus 1455 pg/mL(P 5 0.051) when only the mediastinal compartment(20 vs. 5 patients) was involved. However, thesemarked differences in absolute calcitonin values didnot translate into significantly higher rates of calcito-nin normalization when the ipsilateral cervicolateral(17% vs. 40%, P 5 0.08), contralateral cervicolateral(10% vs. 33%, P 5 0.25), and mediastinal compartment(0% vs. 20%, P 5 0.54) was affected. It is noteworthythat the coefficients for the correlations between thepostoperative basal and stimulated serum calcitoninand the above individual compartments (r 5 0.30 andr 5 0.32; r 5 0.32 and r 5 0.36; r 5 0.32 and r 5 0.30,respectively) were smaller than those (r 5 0.38 and r5 0.42) for the correlation with the number of affectedcompartments. This suggests that the underlying sig-nificant correlation is with the number of affectedcompartments irrespective of anatomic location,rather than with an individual compartment. Signifi-cant correlations were noted between the number ofaffected compartments and involvement of the ipsi-lateral cervicolateral (r 5 0.79), contralateral cervico-lateral (r 5 0.66), and mediastinal compartment (r5 0.64) and bilateral involvement of lymph nodes(pN1b) (r 5 0.53). As opposed to contralateral cervi-colateral involvement, serum calcitonin was nevernormalized when positive mediastinal lymph nodeswere present. In this setting, more than two compart-

TABLE 6Postoperative Serum Calcitonin and M Classification Grouped by Number of Compartments Involved

na

No. of compartments involved

P value

0 1 2 > 3

17 15 13 10

Postoperative calcitoninBasal (pg/mL) 4 (2–12) 13 (2–46) 27 (4–213) 356 (237–1317) , 0.001Peak (pg/mL) 6 (2–27) 86 (7–611) 574 (14–1048) 1455 (469–2632) , 0.001Incremental factorb 1.3 (1.0–1.8) 2.9 (1.7–29.7) 5.7 (2.6–22.0) 2.3 (1.8–3.8) 0.001M1 (%) 0 0 8 30 0.011Calcitonin normalization (%) 65 33 23 0 0.004

Involved lymph nodes 0 (0–0) 2 (1–4) 6 (4–10) 16 (5–27) ,0.001All lymph nodes excised 59 (22–69) 48 (15–72) 58 (44–78) 50 (42–69) 0.68

All figures are given as medians, with 25% and 75% percentiles added in parentheses, or as percentages, respectively.a Excluding 8 pN1 patients in whom no positive lymph nodes were found on reoperation and 2 primary patients with total thyroidectomy only.b Peak value after stimulation, divided by the respective basal value.

Prediction of Calcitonin Normalization in MTC/Machens et al. 1913

ments were involved in all patients, precluding nor-malization of serum calcitonin.

DISCUSSIONBasal and Stimulated Calcitonin Levels and DistantMetastasesIn both the preoperative and postoperative setting,basal and stimulated calcitonin levels in the serumwere closely correlated with each other. Seemingly,absolute calcitonin levels primarily reflect the endog-enous tumor burden, regardless of stimulation. In thisconcept, every MTC cell would secrete calcitonin at amore or less constant basic rate, irrespective of itslocation within the body. This hypothesis is in linewith clinical observations from the literature.12,13 Tounfold their action, stimulatory agents must rely onadequate perfusion to reach occult metastatic MTCfoci. For this reason, a positive stimulatory test firstand foremost reflects the access of MTC clusters to thebloodstream. After surgical elimination of the primarytumor and of most, if not all, lymph node metastases,distant metastases should be the only source of calci-tonin production in the body. For implantation, occultdistant metastases favor parenchymal organs like theliver.14 Individual differences in the relative calcitoninincrease after pentagastrin stimulation are likely toaverage out when absolute calcitonin levels are re-garded.

After adequate local lymph node dissection, therespective calcitonin levels correlate better with thequantitative lymph node analysis than with positivelymph node status itself. This observation suggeststhat the extent of lymphatic spread parallels the de-gree of occult distant metastases and may hence beused as a substitute parameter. In the preoperativesetting, calcitonin levels are less associated withlymph node status and thus with presumptive distantmetastases. This finding indicates that inhomoge-neous perfusion of a subset of MTC cells amassed inthe primary tumor and macroscopic lymph nodesmay have resulted in decreased secretion of calcito-nin. Systematic lymph node dissection would theneliminate the largest agglomerations of MTC cells,thus improving the correlation with serum calcitoninas an indicator for occult distant metastases.

Correlation between Lymph Node Status and GrossDistant MetastasesUnlike lymph node status (pN), the quantitativelymph node analysis significantly correlated withgross distant metastases (M1). This observation sug-gests that distant metastases visible on CT or MRIrepresent the “tip of the iceberg” of occult hematog-enous dissemination. It seems plausible that occult

distant metastases evolve into gross distant metasta-ses by focal proliferation. A fraction of these subclin-ical pulmonary and hepatic metastases may be detect-able on thoracoscopy and laparoscopy,15 respectively.Gross distant metastases alone obviously are toocrude as measures of occult hematogenous dissemi-nation: In the current series, postoperative basal butnot stimulated calcitonin levels or rates of calcitoninnormalization differed significantly when brokendown by M classification (Table 3). In contrast, Tunget al.15 did not find significantly different calcitoninlevels in M0 and M1 tumors: 1.7 6 2.4 ng/mL versus6.8 6 9.2 ng/mL basally (P 5 0.06); and 21.9 6 28.1ng/mL versus 359.0 6 842.7 ng/mL after stimulation(P 5 0.18). The current data indicate that quantitativelymph node analysis is an extremely sensitive indica-tor of the extent of occult hematogenous dissemina-tion in MTC.

Lymph Node Status and Calcitonin Levels as PrognosticFactorsPostoperative hypercalcitoninemia has been associ-ated with higher recurrence rates and decreased sur-vival in MTC.1,2 When positive lymph nodes arepresent, only 45% of patients on reoperation are bio-chemically converted to normal by systematic dissec-tion of all four lymph node compartments.16 Presenceof invasive features in primary MTC, such as invasionof adjacent structures or extranodal or extracapsularspread, is significantly associated with failure to nor-malize calcitonin levels.17,18 Even extensive surgicalprocedures, such as repeat cervicomediastinal lymphnode dissection, fell short of normalizing serum calci-tonin in advanced persistent or recurrent MTC.19 Inthis series, a substantial fraction (two-fifths) of cervi-comediastinal metastases exhibited adverse patho-logic features, such as focal penetration of the lymphnode capsule or carcinomatous lymphangiosis.19 Con-sidering these findings, it is conceivable that tumorsassociated with adverse pathologic features may bemore aggressive and widespread than suggested bylymph node status alone. Higher postoperative levelsof serum calcitonin per se do not inevitably portend ableak prognosis. Despite follow-up periods of a meanof 11 years, there were no clinical recurrences in al-most one-half of Stage II and III patients.1,2 With aview to predicting prognosis on an individual basis, amathematical model has been devised based on serialcalcitonin levels, postulating a constant tumor growthrate.20 However, this model has not been evaluated ina prospective manner and has failed to gain widersupport. Distant metastases account for a substantialfraction of fatalities in MTC.2

1914 CANCER April 15, 2000 / Volume 88 / Number 8

Clinical Implications of Lymph Node Status andQuantitative Lymph Node AnalysisThe current series presents clear evidence that the riskof distant metastases (M1) is mirrored by the numberof positive lymph nodes. Involvement of 10 or morelymph nodes and of more than 2 compartments willpreclude normalization of serum calcitonin. It is in-triguing that it may occasionally be possible to dem-onstrate intraoperatively involvement of more thantwo compartments by fresh frozen section.

Surgery should then be less extensive and be di-rected at preventing local complications, as occultdistant metastases are already present. In these in-stances, selective lymph node dissection may be war-ranted in the cervicolateral and mediastinal compart-ments. Only in the cervicocentral compartment,lymph node dissection should still be performed sys-tematically to keep the tumor from encroaching onthe trachea or recurrent laryngeal nerves. Involvementof these vital structures often causes significant mor-bidity with a substantial decrease in quality of life.19

Further investigations are needed to assess the longterm risk of distant metastases by quantitative lymphnode analysis.

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Prediction of Calcitonin Normalization in MTC/Machens et al. 1915