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Original Article |

Skip Metastases in Thyroid Cancer Leaping the Central Lymph Node Compartment FREE

Andreas Machens, MD; Hans-Jürgen Holzhausen, MD; Henning Dralle, MD
[+] Author Affiliations

From the Departments of General, Visceral, and Vascular Surgery (Drs Machens and Dralle) and Pathology (Dr Holzhausen), Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.


Arch Surg. 2004;139(1):43-45. doi:10.1001/archsurg.139.1.43.
Text Size: A A A
Published online

Hypothesis  Discontinuous nodal metastasis, or skip metastasis, in thyroid cancer may display clinicopathologic features different from those seen in continuous nodal metastasis and thus may have a different prognosis.

Design  Retrospective analysis.

Setting  Tertiary referral center at a university hospital.

Patients  Two hundred fifteen consecutive patients who underwent systematic central lymph node dissection for papillary, follicular, or medullary thyroid cancer and who on histopathologic analysis exhibited nodal metastases in at least 1 lateral or mediastinal lymph node compartment.

Main Outcome Measures  Various clinicopathologic variables that were stratified for tumor entity and type of nodal metastasis (discontinuous vs continuous).

Results  Skip metastases (negative central and positive lateral or mediastinal compartments) were found in 13 (19.7%) of 66 papillary, 0 of 8 follicular, and 30 (21.3%) of 141 medullary thyroid cancers. After adjustment for multiple testing, skip metastasis was only associated with significantly fewer positive lymph nodes: 3.7 vs 12.9 nodes (r = −0.43, P<.001) in papillary thyroid cancer and 6.0 vs 17.1 nodes (r = −0.40, P<.001) in medullary thyroid cancer. No other significant correlation was identified with any other clinicopathologic variable.

Conclusions  Skip metastasis is an epiphenomenon of low-intensity nodal metastasis in thyroid cancer and entails a moderate risk of local recurrence. Consequently, clearing the central lymph node compartment should be considered when lateral or mediastinal lymph node compartments are involved.

Nodal metastasis is a common mechanism of extrathyroidal tumor cell dissemination in thyroid cancer.15 This phenomenon is more prevalent in papillary and medullary thyroid cancer than in follicular thyroid cancer.5 Recent clinicopathologic investigations have revealed that dissemination of tumor cells through the lymphatic system evolves in a stepwise sequential fashion: Spreading from the thyroid gland, the central and lateral lymph node compartments on the side of the thyroid tumor represent the first echelons of lymphatic drainage. The opposite lateral and the mediastinal lymph node compartments then follow suit.5

Despite the recognized sequence of lymphatic dissemination, discontinuous lymphatic spread, or skip metastasis, is not uncommon in node-positive papillary thyroid cancer.68 The significance of this finding is unknown. Depending on the lymph node levels under comparison, the frequency of skip metastasis (of which the pattern of spread is unpredictable7) varies between 11.1% and 37.5% in node-positive papillary thyroid cancer.6,7 As of this writing, no data on skip metastases have been published for follicular or medullary thyroid cancer.

Notwithstanding these recent advances in our understanding of lymphatic spread, the clinical significance of discontinuous, as opposed to continuous, lymphatic dissemination in thyroid cancer remains to be elucidated. The present institutional cohort study was set up to clarify the significance of skip metastases in thyroid cancer.

PATIENT SELECTION

Between November 1, 1994, and November 30, 2002, 215 of 772 consecutive patients who were operated on at this institution for papillary (66 of 320 patients), follicular (8 of 144 patients), or medullary (141 of 308 patients) thyroid cancer had nodal metastases in at least 1 lateral or mediastinal lymph node compartment. These 215 patients formed the study population. There were 73 primary (34.0%) and 142 reoperative (66.0%) patients. Reoperations were all carried out with therapeutic intent when nodal macrometastases in the neck were suspected clinically or on ultrasonography or had been confirmed through fine-needle aspiration cytology or tissue biopsy, or when calcitonin levels failed to normalize after surgery for medullary thyroid cancer. All 215 patients underwent systematic dissection of the central lymph node compartment, which extends vertically from the hyoid bone to the thoracic inlet and horizontally between the carotid sheaths.5 The lateral lymph node compartments were dissected in 95.3% (ipsilateral) and 73.5% (contralateral) and the mediastinal lymph node compartment was dissected in 37.2%. Before surgery, informed consent was obtained for each of the procedures. All specimens were subjected to pathological examination. A diagnosis of skip metastasis was only made on histopathologic confirmation of nodal metastases in the lateral or mediastinal compartment, with simultaneous freedom of nodal metastases in the central compartment on primary and reoperative surgery.

HISTOPATHOLOGIC EXAMINATION AND TUMOR STAGING

After gross evaluation by the pathologist, the entire thyroid gland was divided vertically to separate the left and right lobes. The thyroid halves were then sectioned horizontally from the superior to the inferior pole, as described previously.9 After fixation in formalin, the whole thyroid gland was embedded in paraffin. Soft tissue and lymph nodes were processed separately. Conventional staining (hematoxylin-eosin) and, where appropriate, thyroglobulin or calcitonin immunohistochemistry were performed on every surgical specimen, using the standard avidin-biotin complex peroxidase approach. The diagnosis of papillary, follicular, or medullary thyroid carcinoma was based on the World Health Organization histological classification of tumors.10 Staging was performed according to the American Joint Committee on Cancer11 and International Union Against Cancer tumor-node-metastasis12 classifications. While a diagnosis of nodal metastasis always required histopathologic confirmation, this need was waived for distant metastasis when there was unequivocal evidence on ultrasonography (liver), computed tomography, magnetic resonance imaging, positron emission tomography, scintiscan, or a combination thereof.

STATISTICAL ANALYSIS

Categorical and continuous data were tested on univariate analysis using the 2-tailed Fisher exact test and 2-tailed exact Mann-Whitney (Wilcoxon) rank sum test, respectively. Multiple testing was adjusted by using the Bonferroni method. Spearman rank correlation coefficient (ρ) was calculated to assess correlations between categorical and metric variables. The level of significance was set at P = .05.

Skip metastases were encountered in 13 (19.7%) of 66 papillary, 0 of 8 follicular, and 30 (21.3%) of 141 medullary thyroid cancers. Therefore, subsequent analyses were limited to papillary and medullary thyroid cancer.

Table 1 stratifies various pathological and demographic variables for skip metastasis and tumor entity. After adjustment for multiple testing, the only significant difference between discontinuous (skip metastases) and continuous nodal metastases concerned the number of positive lymph nodes in papillary and medullary thyroid cancer. Skip metastasis consistently was associated with significantly fewer positive lymph nodes: 3.7 vs 12.9 nodes (r = −0.43, P<.001) in papillary thyroid cancer and 6.0 vs 17.1 nodes (r = −0.40, P<.001) in medullary thyroid cancer. There was no significant correlation with any demographic variable. Neither reoperation nor previous lymph node dissection produced differential rates of skip metastases in either thyroid cancer. This finding indicates that skip metastases are genuine phenomena in thyroid cancer and not simply artifacts caused by differential dissection of the central compartment and differential histopathologic analysis (detection bias) owing to intensive scarring after primary operation.

Table Graphic Jump LocationPathological and Demographic Variables in Patients With Thyroid Cancer Grouped by Presence or Absence of Skip Metastasis*

To our knowledge, this cohort study provides the most comprehensive analysis of skip metastasis in thyroid cancer to date. There was a significant inverse correlation between the presence of skip metastasis and the total number of involved lymph nodes. The frequency of skip metastasis was 19.7% (n = 66) in papillary thyroid cancer and 21.3% (n = 141) in medullary thyroid cancer. These data agree well with the rates of 11.1% (n = 36) to 37.5% (n = 51) published in the literature for papillary thyroid cancer.6,7 Similar rates of 13% and 15.8% have been reported for skip metastasis in T3-T4 cancer of the alveolobuccal complex13 and squamous carcinoma of the oral tongue,14 respectively.

THE NATURE OF SKIP METASTASIS

The phenomenon of skip metastases has been attributed to limited lymph node sampling, leading to false-negative histopathologic staging.15 This explanation does not account for skip metastasis in thyroid cancer, as evidenced in this series by similar rates of reoperations and previous lymph node dissections in discontinuous and continuous nodal metastasis. Clearing entire lymph node compartments, the compartment-oriented lymph node dissection enables an unbiased assessment of nodal metastasis in thyroid cancer.5 With the introduction of intraoperative lymphatic mapping using technetium-labeled sulfur or tin colloid particles, the rates of axillary skip metastases in breast cancer have plummeted from the range of 10% to 15.5%1618 to 0% to 0.2%.19,20 This dramatic decline with the advent of more sophisticated detection technology supports the concept of stepwise lymphatic dissemination through successive echelons of lymph nodes. The use of routine thyroglobulin and calcitonin immunohistochemistry on every surgical specimen and pathological slide, respectively, might further lower the rates of skip metastases owing to improved capture of occult nodal metastases. As in this series of patients with papillary thyroid cancer, skip metastasis is also more frequent in breast cancer when fewer than 4 nodes are positive.16

CLINICAL IMPLICATIONS

The present clinicopathologic study demonstrates that skip metastasis with its erratic mode of lymphatic spread is an epiphenomenon of low-intensity nodal dissemination in thyroid cancer. Because of the recognized association between nodal metastasis and local recurrence,5 skip metastasis in thyroid cancer is likely to entail a moderate risk of local recurrence, at least in the seemingly skipped central and the involved lateral or mediastinal lymph node compartments. Leaving positive lymph nodes in the tracheoesophageal groove unattended for a prolonged period may expose the patient to the risk of tracheoesophageal invasion.21 Therefore, systematic lymph node dissection should follow the recognized sequence of lymph node drainage.15 When lateral or mediastinal lymph node compartments are involved on histopathologic examination, clearing the central lymph node compartment should be considered, rather than waiting for nodal recurrence to emerge. Balancing patients' moderate risk of local recurrence against the risk of surgical morbidity, these patients should be referred for lymph node dissection to a specialist center where the requisite surgical skills and expertise are available.

Corresponding author: Andreas Machens, MD, Department of General, Visceral, and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06097 Halle (Saale), Germany (e-mail: gensurg@medizin.uni-halle.de).

Accepted for publication June 29, 2003.

Moley  JFDeBenedetti  MK Patterns of nodal metastases in palpable medullary thyroid carcinoma: recommendations for extent of node dissection. Ann Surg. 1999;229880- 888
PubMed Link to Article
Beenken  SRoye  DWeiss  H  et al.  Extent of surgery for intermediate-risk well-differentiated thyroid cancer. Am J Surg. 2000;17951- 56
PubMed Link to Article
Kebebew  EKikuchi  SDuh  QYClark  OH Long-term results of reoperation and localizing studies in patients with persistent or recurrent medullary thyroid carcinoma. Arch Surg. 2000;135895- 901
PubMed Link to Article
Sivanandan  RSoo  KC Pattern of cervical lymph node metastases from papillary carcinoma of the thyroid. Br J Surg. 2001;881241- 1244
PubMed Link to Article
Machens  AHinze  RThomusch  ODralle  H Pattern of nodal metastasis for primary and reoperative thyroid cancer. World J Surg. 2002;2622- 28
PubMed Link to Article
Ducci  MAppetecchia  MMarzetti  M Neck dissection for surgical treatment of lymph node metastasis in papillary thyroid carcinoma. J Exp Clin Cancer Res. 1997;16333- 335
PubMed
Coatesworth  APMacLennan  K Cervical metastasis in papillary carcinoma of the thyroid: a histopathological study. Int J Clin Pract. 2002;56241- 242
PubMed
Pingpank Jr  JFSasson  ARHanlon  ALFriedman  CDRidge  JA Tumor above the spinal accessory nerve in papillary thyroid cancer that involves lateral neck nodes: a common occurrence. Arch Otolaryngol Head Neck Surg. 2002;1281275- 1278
PubMed Link to Article
Hinze  RHolzhausen  HJGimm  O  et al.  Primary hereditary medullary thyroid carcinoma: C-cell morphology and correlation with preoperative calcitonin levels. Virchows Arch. 1998;433203- 208
PubMed Link to Article
World Health Organization, International Histological Classification of Tumours. 2nd ed. Berlin, Germany Springer-Verlag1988;
Fleming  ICooper  JSHenson  DE  et al.  AJCC Cancer Staging Manual.  Philadelphia, Pa American Joint Committee on Cancer1997;
Sobin  LHWittekind  C TNM Classification of Malignant Tumors. 5th ed. New York, NY Wiley-Liss1997;
Rao  RSDeshmane  VHParikh  HKParikh  DMSukthankar  PS Extent of lymph node dissection in T3/T4 cancer of the alveolo-buccal complex. Head Neck. 1995;17199- 203
PubMed Link to Article
Byers  RMWeber  RSAndrews  TMcGill  DKare  RWolf  P Frequency and therapeutic implications of "skip metastases" in the neck from squamous carcinoma of the oral tongue. Head Neck. 1997;1914- 19
PubMed Link to Article
Hosch  SBStoecklein  NHPichlmeier  U  et al.  Esophageal cancer: the mode of lymphatic tumor cell spread and its prognostic significance. J Clin Oncol. 2001;191970- 1975
PubMed
Gaglia  PBussone  RCaldarola  BLai  MJayme  ACaldarola  L The correlation between the spread of metastases by level in the axillary nodes and disease-free survival in breast cancer: a multifactorial analysis. Eur J Cancer Clin Oncol. 1987;23849- 854
PubMed Link to Article
Toma  SLeonessa  FRomanini  A  et al.  Predictive value of some clinical and pathological parameters on upper level axillary lymph node involvement in breast cancer. Anticancer Res. 1991;111439- 1443
PubMed
Canavese  GCatturich  AVecchio  C  et al.  Prognostic role of lymph-node level involvement in patients undergoing axillary dissection for breast cancer. Eur J Surg Oncol. 1998;24104- 109
PubMed Link to Article
Cox  CEPendas  SCox  JM  et al.  Guidelines for sentinel node biopsy and lymphatic mapping of patients with breast cancer. Ann Surg. 1998;227645- 651
PubMed Link to Article
Sato  KHiraide  HUematsu  M  et al.  Efficacy and significance of sentinel lymph node identification with technetium-99m-labeled tin colloids for breast cancer. Breast Cancer. 1998;25389- 393
PubMed Link to Article
Machens  AHinze  RLautenschläger  CThomusch  ODralle  H Thyroid carcinoma invading the cervicovisceral axis: routes of invasion and clinical implications. Surgery. 2001;12923- 28
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationPathological and Demographic Variables in Patients With Thyroid Cancer Grouped by Presence or Absence of Skip Metastasis*

References

Moley  JFDeBenedetti  MK Patterns of nodal metastases in palpable medullary thyroid carcinoma: recommendations for extent of node dissection. Ann Surg. 1999;229880- 888
PubMed Link to Article
Beenken  SRoye  DWeiss  H  et al.  Extent of surgery for intermediate-risk well-differentiated thyroid cancer. Am J Surg. 2000;17951- 56
PubMed Link to Article
Kebebew  EKikuchi  SDuh  QYClark  OH Long-term results of reoperation and localizing studies in patients with persistent or recurrent medullary thyroid carcinoma. Arch Surg. 2000;135895- 901
PubMed Link to Article
Sivanandan  RSoo  KC Pattern of cervical lymph node metastases from papillary carcinoma of the thyroid. Br J Surg. 2001;881241- 1244
PubMed Link to Article
Machens  AHinze  RThomusch  ODralle  H Pattern of nodal metastasis for primary and reoperative thyroid cancer. World J Surg. 2002;2622- 28
PubMed Link to Article
Ducci  MAppetecchia  MMarzetti  M Neck dissection for surgical treatment of lymph node metastasis in papillary thyroid carcinoma. J Exp Clin Cancer Res. 1997;16333- 335
PubMed
Coatesworth  APMacLennan  K Cervical metastasis in papillary carcinoma of the thyroid: a histopathological study. Int J Clin Pract. 2002;56241- 242
PubMed
Pingpank Jr  JFSasson  ARHanlon  ALFriedman  CDRidge  JA Tumor above the spinal accessory nerve in papillary thyroid cancer that involves lateral neck nodes: a common occurrence. Arch Otolaryngol Head Neck Surg. 2002;1281275- 1278
PubMed Link to Article
Hinze  RHolzhausen  HJGimm  O  et al.  Primary hereditary medullary thyroid carcinoma: C-cell morphology and correlation with preoperative calcitonin levels. Virchows Arch. 1998;433203- 208
PubMed Link to Article
World Health Organization, International Histological Classification of Tumours. 2nd ed. Berlin, Germany Springer-Verlag1988;
Fleming  ICooper  JSHenson  DE  et al.  AJCC Cancer Staging Manual.  Philadelphia, Pa American Joint Committee on Cancer1997;
Sobin  LHWittekind  C TNM Classification of Malignant Tumors. 5th ed. New York, NY Wiley-Liss1997;
Rao  RSDeshmane  VHParikh  HKParikh  DMSukthankar  PS Extent of lymph node dissection in T3/T4 cancer of the alveolo-buccal complex. Head Neck. 1995;17199- 203
PubMed Link to Article
Byers  RMWeber  RSAndrews  TMcGill  DKare  RWolf  P Frequency and therapeutic implications of "skip metastases" in the neck from squamous carcinoma of the oral tongue. Head Neck. 1997;1914- 19
PubMed Link to Article
Hosch  SBStoecklein  NHPichlmeier  U  et al.  Esophageal cancer: the mode of lymphatic tumor cell spread and its prognostic significance. J Clin Oncol. 2001;191970- 1975
PubMed
Gaglia  PBussone  RCaldarola  BLai  MJayme  ACaldarola  L The correlation between the spread of metastases by level in the axillary nodes and disease-free survival in breast cancer: a multifactorial analysis. Eur J Cancer Clin Oncol. 1987;23849- 854
PubMed Link to Article
Toma  SLeonessa  FRomanini  A  et al.  Predictive value of some clinical and pathological parameters on upper level axillary lymph node involvement in breast cancer. Anticancer Res. 1991;111439- 1443
PubMed
Canavese  GCatturich  AVecchio  C  et al.  Prognostic role of lymph-node level involvement in patients undergoing axillary dissection for breast cancer. Eur J Surg Oncol. 1998;24104- 109
PubMed Link to Article
Cox  CEPendas  SCox  JM  et al.  Guidelines for sentinel node biopsy and lymphatic mapping of patients with breast cancer. Ann Surg. 1998;227645- 651
PubMed Link to Article
Sato  KHiraide  HUematsu  M  et al.  Efficacy and significance of sentinel lymph node identification with technetium-99m-labeled tin colloids for breast cancer. Breast Cancer. 1998;25389- 393
PubMed Link to Article
Machens  AHinze  RLautenschläger  CThomusch  ODralle  H Thyroid carcinoma invading the cervicovisceral axis: routes of invasion and clinical implications. Surgery. 2001;12923- 28
PubMed Link to Article

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