Axillary Node Metastases of Medullary Thyroid Cancer: A Hallmark of Terminal Disease

Abstract

Little is known about axillary node metastasis of medullary thyroid cancer (MTC). To address this, a comparative study of patients with and without axillary node metastases of MTC was conducted. Among 1215 consecutive patients with MTC, 482 patients had node-negative MTC and 733 patients node-positive MTC. Among the 733 patients with node-positive MTC, 4 patients (0.5%) had axillary node metastases, all of which were ipsilateral. Patients with axillary node metastases had 5.7–6.9-fold more node metastases removed, both at the authors’ institution (medians of 34.5 vs. 5 metastases; p=0.011) and in total (medians of 57 vs. 10 metastases; p=0.013), developed more frequently distant metastases (3 of 4 vs. 178 of 729 patients, or 75 vs. 24%; p=0.049), specifically to bone (2 of 4 vs. 67 of 729 patients, or 50 vs. 9%; p=0.046) and brain (1 of 4 vs. 4 of 729 patients, or 25 vs. 0.5%; p=0.027), and more often succumbed to cancer-specific death (3 of 4 vs. 52 of 729 patients, or 75 vs. 14%; p=0.005). Altogether, patients with axillary node metastases revealed 4–8-fold more node metastases in the ipsilateral lateral neck (medians of 11 vs. 3 metastases; p=0.021) and in the ipsilateral central neck (medians of 8 vs. 1 metastases; p=0.079) patients without axillary node metastases. Cancer-specific survival of patients with vs. patients without axillary node metastases of MTC was significantly shorter (means of 41 vs. 224 months; plog-rank<0.001). These findings show that patients with axillary node metastases of MTC have massive metastatic dissemination with poor survival.

Key words

medullary thyroid carcinoma - distant metastasis - neck node metastases - mediastinal node metastases - axillary node metastases

Introduction

Medullary thyroid cancer (MTC), also referred to as C cell carcinoma, is a rare thyroid malignancy arising from the parafollicular C cells, which are dispersed through the dorsolateral thyroid lobes. This neuroendocrine tumor is characterized by early lymphatic spread to central and lateral neck nodes on the side of the primary thyroid tumor, also referred to as ‘locoregional’ nodes [1]. Recent data suggest that the midline may represent a watershed between surgically curable and incurable solitary node-positive MTC. This is why lateral and mediastinal nodes on the side opposite to the primary thyroid tumor represent ‘distant’ node metastases indicative of systemic disease [1]. The higher the number of node metastases in the ipsilateral and contralateral central nodes, the more likely the involvement of the adjacent lateral neck compartments [2]. Mediastinal node metastases and involvement of more than 10 and 20 nodes frequently coincide with increasing frequency of distant metastases [3] [4] and decreasing biochemical cure [5].

Less clear in this concept is the role of axillary node metastases. These clinical events are exceptional and associated [6], or not associated [7] [8] with distant metastasis and poor clinical outcome. The 2015 Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma do not provide guidance as to the treatment of axillary node metastases [9]. Based on rare anecdotal evidence, axillary node metastases of MTC invariably involve the axilla on the side of the primary thyroid tumor [6] [7] [8].

None of these few case reports, focusing exclusively on axillary node dissection in the absence of a control group, provided detailed information about the number of concomitant ipsilateral and contralateral metastases in the central and lateral neck and the mediastinum. This lack of data hampers our understanding how MTC cells find their way from the thyroid gland to the arm pit. The present study, drawing on a large number of consecutive patients with node-positive MTC, was undertaken to close this evidence gap.

Patients and Methods

Study population

Considered for retrospective evaluation were all patients operated on between November 1994 and April 2023 for node-positive MTC at the authors’ institution using optical magnification and bipolar coagulation. Informed consent was obtained from each patient in accordance with the amended Declaration of Helsinki and respective national and local regulations (institutional review board approval reference 2020–237).

Systematic central node dissection, extending vertically from the hyoid bone to the thoracic inlet and horizontally between the carotid sheaths [American Joint Committee on Cancer (AJCC) level I and VI nodes], was prompted by clinical findings on high-resolution ultrasound, usually evidence of enlarged nodes in conjunction with raised serum calcitonin levels, confirmation of nodal disease on clinical work-up, or on intraoperative frozen section analysis. When nodes in the respective node compartment were suspicious on imaging, systematic lateral neck dissection, proceeding laterally from the carotid sheath to the trapezoid muscle and inferiorly from the subclavian vein to the hypoglossal nerve superiorly (AJCC level II–V nodes), mediastinal (AJCC level VII nodes) and/or axillary node dissection were informed by preoperative serum calcitonin levels [10].

Distant metastasis was diagnosed when there was unequivocal evidence on ultrasonography, computed tomography, magnetic resonance imaging, 18-fluorodeoxyglucose and/or 18-fluorodopamine positron emission tomography.

Histopathological examination

Surgical specimens of thyroid and node compartments were sent for histopathological examination and analyzed separately (thyroid vs. extrathyroid tissue). Paraffin embedded thyroid specimens were stained with hematoxylin and eosin (HE) and immunostained for calcitonin. Microscopic venous invasion was diagnosed when tumor cells resided inside the lumen of one or more venous vessels.

A diagnosis of MTC was based on histopathologic criteria proposed by the World Health Organization [11]. Primary tumor size was measured directly on the thyroid surgical specimens. Node metastases of MTC were diagnosed upon histopathological confirmation. Extrathyroid extension (tumor invasion of the neck by continuity) was defined as tumor extension beyond the thyroid capsule disregarding the extent of invasion, whereas extranodal growth (tumor invasion from within neck nodes) was diagnosed when residual lymphatic tissue surrounded these nodes [12].

Genomic RET screening

Before undergoing genetic testing before or after the operation, all patients or their parents had given informed consent after genetic counseling. For identification of RET sequence variants listed in the Web-based ARUP MEN 2 database [13] (http://www.arup.utah.edu/database/MEN2/MEN2_display.php), genomic DNA was purified from peripheral blood leukocytes using standard techniques.

Biochemical cure

Between September 1995 and May 2004, serum calcitonin levels were measured routinely with an ELSA-hCT solid two-site immunoradiometric calcitonin assay (CIS Bio International, Gif-sur-Yvette, France) (upper normal limit below 10 pg/ml). From June 2004 to July 2015, an Immulite 2000 automated calcitonin assay (Diagnostic Products, Los Angeles, California, USA), allowing determination of calcitonin levels immediately before surgery, replaced the ELSA-hCT assay; with the Immulite 2000 assay, the upper normal limit is less than 5 pg/ml for women and below 8.4 pg/ml for men. In August 2015, the calcitonin electrochemiluminescence assay Elecsys (Roche Diagnostics International, Rotkreuz, Switzerland), with an upper normal limit of 6.40 pg/ml for women and 9.52 pg/ml for men, replaced the Immulite 2000 assay.

Calcitonin levels were routinely measured preoperatively and postoperatively with the Immulite 2000 automated calcitonin assay (Diagnostic Products Corporation, Los Angeles, USA, normal upper calcitonin range <5 pg/ml for women and <8.4 pg/ml for men).

Normalization of serum calcitonin after thyroid surgery, also referred to as biochemical cure, was assumed when the upper normal limit of the assay was not exceeded.

Statistical analysis

For statistical analysis, the software package SPSS version 25 (IBM, Armonk, New York, USA) was used. Data were stratified by presence vs. absence of axillary node metastases of MTC. Missing data were not replaced, and the number of individuals analyzed was specified for each variable examined. Categorical data are presented as absolute and relative frequencies and were tested with the two-tailed Fisher’s exact test. Continuous data are presented as medians with interquartile ranges and compared with the two-tailed Mann–Whitney–Wilcoxon test. The Kaplan–Meier method [14] with the long rank test [15] was used to determine differences in cancer-specific survival. The level of statistical significance (all values were two-tailed) was set at p <0.05.

Results

A total of 1215 patients with MTC were operated on at the authors’ institution during the study period: 482 patients with node-negative MTC, and 733 patients with node-positive MTC. Four (0.5%) of the 733 patients with node-positive MTC had axillary node metastases, all of which were ipsilateral.

Study population according to axillary node metastases of medullary thyroid cancer

[Table 1] provides a breakdown of all 733 patients with node-positive MTC by presence vs. absence of axillary node metastases of MTC.

Table 1 Study population according to axillary node metastases of medullary thyroid cancer.

			Axillary node metastases of MTC		p
			Present	Absent
Category	No. of patients with node-positive MTC		4	729
Demographics	Age at thyroidectomy, y, median [IQR]		44.5 [18.3; 56.5]	48 [36; 60]	0.526
	Sex, no. (%) of male patients		1 (25)	376 (52)	0.360
	No. of carriers of pathogenic RET germline mutation†		1‡ (25)	173 (31)	>0.999
	Initial thyroidectomy at authors’ institution		2 (50)	285 (39)	0.647
	Preoperative basal calcitonin level, pg/ml, median [IQR]		3723 [700; – ]	653 [169; 2683]	0.125
Thyroid histopathology	Largest primary tumor diameter, mm, median [IQR]		20 [16.3; 50.8]	20 [13; 32] (n=644)	0.694
	No. (%) of patients with	microscopic venous invasion	2 (100) (n=2)	165 (30) (n=542)	0.094
		extrathyroid extension	1 (25)	229 (32) (n=705)	>0.999
Nodal histopathology	No. (%) of patients with	extranodal growth	2 (50)	250 (35) (n=713)	0.617
		mediastinal node metastases	1 (25)	112 (15) (n=726)	0.490
	No. of node metastases removed, median [IQR]	at the authors’ institution	34.5 [11.3; 59.3]	5 [2; 14] (n=710)	0.011
		at any time (in total)	57 [18; – ] (n=3)	10 [4; 22] (n=693)	0.013
Distant metastases	No. (%) of patients with	lung metastases	2 (50)	104 (14)	0.102
		liver metastases	1 (25)	93 (13)	0.423
		bone metastases	2 (50)	67 (9)	0.046
		brain metastases	1 (25)	4 (0.5)	0.027
		distant metastases	3 (75)	178 (24)	0.049
Outcomes	No. (%) of patients with biochemical cure¶		0	136 (21) (n=663)	0.587
	No (%) of patients dead of disease		3 (75)	52 (14)	0.005
	Duration of follow-up, mo, median [IQR]		27 [12; – ] (n=3)	30 [9; 72] (n=376)	0.916

Numbers in parentheses denote column percentages. IQR: Interquartile range; MTC: Medullary thyroid cancer; RET: REarranged during Transfection. ^† Heterogeneous germline mutations in codon 609, 611, 618, 620, 630, 634, 768, 790, 804, 891 or 918. ^‡ MEN2B patient carrying a heterozygous RET c.2753T>C (p.Met918Thr) germline mutation.^¶ Postoperative calcitonin serum levels below the upper normal assay limit.

Patients with axillary node metastases had 5.7–6.9-fold more node metastases removed, both at the authors’ institution (medians of 34.5 vs. 5 metastases; p=0.011) and in total (medians of 57 vs. 10 metastases; p=0.013), developed more frequently distant metastases (3 of 4 vs. 178 of 729 patients, or 75 vs. 24%; p=0.049), specifically to bone (2 of 4 vs. 67 of 729 patients, or 50 vs. 9%; p=0.046) and brain (1 of 4 vs. 4 of 729 patients, or 25 vs. 0.5%; p=0.027), and more often succumbed to cancer-specific death (3 of 4 vs. 52 of 729 patients, or 75 vs. 14%; p=0.005). All other variables did not reach statistical significance.

Node metastases and nodes per compartment according to axillary node metastases of medullary thyroid cancer

[Table 2] provides a breakdown of node metastases and nodes per compartment in patients with vs. patients without axillary node metastases of MTC. Patients with axillary node metastases revealed 4–8-fold more node metastases in the ipsilateral lateral neck (medians of 11 vs. 3 metastases; p=0.021) and in the ipsilateral central neck (medians of 8 vs. 1 metastases; p=0.079) patients without that condition.

Table 2 Number of node metastases and nodes per compartment according to axillary node metastases of medullary thyroid cancer.

			Axillary node metastases of MTC		p
			Present	Absent
Category	No. of patients with node-positive MTC		4	729
No. of node metastases removed, median [IQR]	Ipsilateral	central neck	8 [1; – ] (n=3)	1 [0; 4] (n=633)	0.079
		lateral neck	11 [6; – ] (n=3)	3 [1; 7] (n=604)	0.021
		axilla	11.5 [4; 21.3]	–	–
	upper anterior mediastinum		7.5 [0; – ] (n=2)	2 [0; 6] (n=141)	0.868
	Contralateral	central neck	2 [0; – ] (n=3)	0 [0; 1] (n=576)	0.110
		lateral neck	0 (n=2)	0 [0; 2] (n=494)	0.540
		axilla	–	–	–
No. of nodes removed, median [IQR]	Ipsilateral	central neck	9 [3; – ] (n=3)	5 [2; 9] (n=633)	0.243
		lateral neck	37 [10; – ] (n=3)	21 [13; 30] (n=604)	0.344
		axilla	17 [6.3; 24.8]	–	–
	upper anterior mediastinum		13 [2; – ] (n=2)	9 [4; 15] (n=141)	0.968
	Contralateral	central neck	2 [1; – ] (n=3)	4 [2; 7] (n=576)	0.519
		lateral neck	17.5 [11; –] (n=2)	21 [14; 30] (n=494)	0.554
		axilla	–	–	–

Numbers are based on dissected node compartments at the authors’ institution (first operation). IQR: Interquartile range; MTC: Medullary thyroid cancer.

Intriguingly, the number of node metastases in the ipsilateral lateral neck and ipsilateral axilla (medians of 11 vs. 11.5 metastases) were similar, as were those in the ipsilateral central neck and upper anterior mediastinum, although at a lower level (medians of 8 vs. 7.5 metastases). The metastatic lateral-to-central neck ratio was 3 (median of 11 ipsilateral lateral neck metastases) to 2 (median of 8 ipsilateral central neck metastases). Of note, the contralateral axillary nodes were clinically inapparent and thus remained undissected. By way of contrast, the numbers of nodes resected per compartment were comparable between both subgroups of patients ([Table 2]).

[Fig. 1], marrying the median numbers of nodes standardized to left-sided primary thyroid tumors ([Table 2]) with clinical outcome ([Table 1]), schematically illustrates underlying patterns of node metastases for patients with ([Fig. 1a]) versus patients without axillary node metastases ([Fig. 1b]).

Fig. 1 Patterns of node metastases and clinical outcome in medullary thyroid cancer. Numbers are medians standardized to left-sided primary thyroid tumors.

Cancer-specific survival with and without axillary node metastases of medullary thyroid cancer

Follow-up data were available for 359 patients with node-positive MTC. As depicted in [Fig. 2], cancer-specific survival patients with versus patients without axillary node metastases of MTC was significantly shorter (means of 41 vs. 224 months; p _log-rank <0.001).

Fig. 2 Cancer-specific survival with and without axillary node metastases of medullary thyroid cancer.

Discussion

The present investigation is the first systematic research on axillary node metastases of MTC. It found that axillary node metastases, which are always ipsilateral, are associated with 5.7–6.9-fold more node metastases, specifically in the ipsilateral neck (4–8-fold), more frequent distant metastases, and lower cancer-specific survival. No contralateral axillary node metastases were seen among the 733 consecutive patients with node-positive MTC. These findings, arguing against hematogenous dissemination of tumor cells from the thyroid gland to the arm pit, hint at a predominantly lymphatic origin of axillary node metastasis in MTC.

Taken together, the present data revealed a massive lymphatic tumor load in patients with axillary node metastases of MTC, with tumor cells progressing through the ipsilateral lymphatic system of the neck (medians of 11 lateral and 8 central node metastases) to the venous angle, and then to the upper anterior mediastinum (median of 7.5 node metastases) and the ipsilateral axilla (median of 11.5 node metastases). Retrograde tumor cell dissemination may be due to clogging of the venous angle by tumor cells traveling with the lymph draining the ipsilateral neck, reversing the centripetal lymphatic flow of the mediastinal lymph by gravity, and of the ipsilateral axillary lymph. Because there was no statistical significant association between mediastinal and axillary node metastases in this study ([Table 1]), mediastinal node metastasis, affecting 113 (15%) of 733 patients ([Table 1]), and axillary node metastasis, affecting 4 (0.5%) of 733 patients ([Table 1]), obviously are independent metastatic processes.

The present data provide evidence to suggest that lymphatic tumor cells may reach the ipsilateral axilla via the ipsilateral lateral and central neck at a ratio of three to two. This finding reflects the preferential clustering of parafollicular C cells and C cell carcinoma (MTC) in the dorsolateral thyroid lobe, which is drained more by the ipsilateral lateral than by the ipsilateral central neck nodes. It is reasonable to assume that primary thyroid tumors engage increasingly more central neck nodes, the closer these tumors lodge to the midline and the larger they are.

The more invasive-phase cells are in a primary tumor, the more likely it is that one of them can successfully make the journey to another organ and grow into a clinically important lesion [16]. Tumor cells penetrating blood vessels induce the development of platelet-tumor aggregates, shielding embedded tumor cells from an unfavorable environment [17]. Seeding of distant organs is thought to occur early, giving rise to the concept metastatic dormancy [18].

These oncologic concepts explain why patients with axillary node involvement who had 5.7–6.9-fold more node metastases than patients without axillary node involvement more often

• developed distant metastasis and died more often of disease

• harbored microscopic vascular invasion in the primary thyroid tumor, without attaining statistical significance (2 of 2 vs. 165 of 729, or 100 vs. 30%; p=0.094; [Table 1]).

The magnitude of effect, consistency with established dose (number of node metastases) – response (distant metastasis and cancer-specific mortality) relationships [4] [19] [20], and the biologic plausibility of the observed associations between ipsilateral central and lateral node metastases and ipsilateral axillary node metastases all attest to the validity of the presented study results.

The retrospective design of the present study enabled collection of a small group of patients who exceptionally developed axillary node metastases of MTC in parallel to a control group of patients with MTC who did not. In the course of the study period spanning almost three decades, a large number of care facilities other than the authors’ institution rendered patient care. Axillary node metastases were not systematically searched for in patients with node-positive MTC, so that the present 0.5% percentage for axillary node metastases (4 of 733 patients), the one and only in the international literature so far, could be an underestimate. To mitigate potential effects of time, the diagnosis of lymph node metastasis, unlike the diagnosis of distant metastases, required histopathological confirmation. Most follow-up investigations were carried out at other institutions and followed institutional policies. Multiple neck reoperations for recurrent nodal disease at multiple institutions resulted in missing data, diminishing the ability to detect differences between the two subgroups of patients. Because many oncologic variables in MTC are interrelated [19], some researchers may consider correction for multiple testing as a little bit conservative.

Conclusions

Medical progress, setting in over time, works to increase the percentage of sporadic MTC ≤10 mm and biochemical cure while decreasing the proportion of node-positive sporadic MTC, mediastinal lymph node metastases, and distant metastases, as described elsewhere [21] [22]. Going forward, these positive developments make it more and more difficult to study patients with axillary node metastases of MTC who have massive metastatic dissemination with poor cancer-specific survival.

This comprehensive research into a rare condition provides new oncological information, offering a unique glimpse into metastatic patterns of an infrequent tumor entity.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 17 August 2023

Accepted after revision: 09 September 2023

Accepted Manuscript online:
09 September 2023

Article published online:
09 October 2023