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Year : 2015  |  Volume : 52  |  Issue : 3  |  Page : 417--424

Lymph node metastasis: A bearing on prognosis in squamous cell carcinoma

C Kapoor1, S Vaidya2, V Wadhwan3, S Malik4,  
1 Department of Oral Pathology and Microbiology, Bhojia Dental College, Budd, Baddi, Solan, Himachal Pradesh, India
2 Department of Prosthodontics and Implantology, Subharti Dental College, Meerut, Uttar Pradesh, India
3 Department of Oral and Maxillofacial Pathology and Microbiology, Subharti Dental College, Meerut, Uttar Pradesh, India
4 Department of Oral Medicine and Radiology, Subharti Dental College, Meerut, Uttar Pradesh, India

Correspondence Address:
C Kapoor
Department of Oral Pathology and Microbiology, Bhojia Dental College, Budd, Baddi, Solan, Himachal Pradesh


Nodal status is a significant predictor for survival of patients with oral squamous cell carcinoma (SCC), sentinel lymph node (SLN) biopsy, step sectioning of SLNs, and immunohistochemistry have changed the detection of tumor deposits in lymph nodes (LNs). The extent of LN metastasis is a major determinant for the staging and the prognosis of most human malignancies and often guides therapeutic decisions. Metastasis to regional lymph node (RLN) is a complex process. It is often associated with several clinical and pathological characteristics. The involvement of RLN is often, a harbinger for increased risk of metastasis. New knowledge in this area can enable the clinicians and pathologists to study and treat tumors in a more directed fashion. A molecular approach to factors that predicts the likelihood of RLN metastasis could eliminate the reoccurrence of the tumor in the form of “micrometastasis” and “skip” metastasis. The aim of this review is to discuss different modes of spread of metastasis in SCC.

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Kapoor C, Vaidya S, Wadhwan V, Malik S. Lymph node metastasis: A bearing on prognosis in squamous cell carcinoma.Indian J Cancer 2015;52:417-424

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Kapoor C, Vaidya S, Wadhwan V, Malik S. Lymph node metastasis: A bearing on prognosis in squamous cell carcinoma. Indian J Cancer [serial online] 2015 [cited 2022 May 19 ];52:417-424
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The term oral cancer encompasses all malignancies that originate in the oral tissue.[1] In the scientific literature, the phrase “oral cancer”is used to describe a multitude of combinations of tumors, benign and malignant, including, those of the lip, salivary glands, and pharynx, in addition to those of the oral cavity.[2] Mouth and pharynx account for 363,000 new cases world-wide and almost 200,000 deaths. Squamous cell carcinoma (SCC) is the most common of all the neoplasm and comprises approximately 80% of cancers of oral cavity.[3] Annually, there are approximately 500,000 new cases of head and neck cancer world-wide.[4]

Metastasis, the spread of a tumor cells from its primary lymph node (LN) to distant organs, is the most fearsome aspect of cancer. Patients presenting with metastatic disease or those developing metastases after successful management of primary tumor carry a universally grave prognosis.[5] In fact, metastases is the cause of 90% of cancer deaths as stated by Hanahan et al., (2000).[6] Tumor cell invade either the blood or the lymphatic vessels to access the general circulation and then establish in other (visceral) tissues. Hence, nodal status is a significant predictor for survival of patients with malignant tumors.[6]

The concept of spread of tumor by the sentinel lymph nodes (SLNs) [Figure 1] and [Figure 2] is based on the premise that metastasis from the primary tumor follows an orderly progression and will first involve the most proximal draining (sentinel) LN before spreading to other LNs. Accordingly if the SLN is free of tumor, it is assumed that the remaining cervical LNs are free as well (cancer).[7]{Figure 1}{Figure 2}

Head and neck squamous cell carcinoma (HNSCC) also carries a high-rate of occult nodal metastasis (ONM). It is important to detect LN development in its early stage for improving the prognosis.[8] The mechanisms by which malignant tumors, invade lymphatics, and metastasize to regional lymph nodes (RLNs) are complex and inter-related, the exact mechanisms have only recently been the subject of intense interest and sophisticated experimentation.[9] Thus, metastasis to RLN is a complex process.[9] It is often associated with several clinical and pathological characteristics. The involvement of RLN is often, a harbinger for increased risk of metastasis.[10] New knowledge in this area can enable the clinicians and pathologists to study and treat tumors in a more directed fashion. A molecular approach to factors that predicts the likelihood of RLN metastasis could eliminate the reoccurrence of the tumor in the form of “micrometastasis” and “skip” metastasis.[9] The aim of this review is to discuss different modes of spread of metastasis [Figure 1] and [Figure 2].

 Back to History

The involvement of carcinoma of the oral cavity has the propensity to metastasize to the cervical LNs even in the early stages. The presence of LN metastasis is the most significant independent variable in determining survival of patients with cancer of the head and neck[Table 1] [Figure 1] and [Figure 2].[11]{Table 1}

 Definitions of Some Important Terminologies Used in LN Metastasis

[Table 2]

Structure of LN [11],[12],[13],[14],[15]

LNs are small, oval or reniform bodies, 0.1-2.5 cm long, lying in the course of the lymphatic vessels.{Table 2}

Microscopic structure of LNs [Figure 3]

A LN [18] is essentially a continuous framework consisting of the capsule, trabeculae and the reticulum, with cells enmeshed in it.{Figure 3}

Capsule and trabeculae: Is composed mainly of collagen fibers, a few fibroblasts and elastin fibers, the latter being more numerous in the deeper layers Reticulum: This network of fine reticulin fibers and associated cells permeates the spaces enclosed in the capsule and trabeculae and supports the cell masses within them.

Cells in the LNs [Figure 3]

Cells of LN are arranged in regions of different packing densities and of distinct cell types. Nopajaroonsri et al., (1971)[18] have suggested the division of the cortex into three zones, indicating the packed density of its cells:

Zone I: Is a region of loosely packed cells, predominantly small lymphocytes, macropahges and occasional plasma cells around the extreme periphery of follicles and extending centrally into medullary cords Zone II: Is a dense region internal to zone I, limited to cortical and paracortical areas and composed mainly of small lymphocytes and macrophages Zone III: Comprises the germinal centers (GCs) of follicles, which are particularly prominent in antigenically stimulated LNs; its cells include large lymphoblasts, some in mitosis, dendritic cells and macrophages.

These zones may form a maturation sequence, lymphocytes arising by the division in GCs (zone III), passing to the dense zone II, becoming smaller and finally migrating to zone I, from which they may transverse the endothelium into the sinuses. The distribution of B and T lymphocytes within the nodes can be mapped by their immunohistological reaction to monoclonal antibodies.

Lymphatic drainage pattern

In order to establish a consistent and easily reproducible, user friendly method for description of RLNs, which establishes a common language between the clinician and the pathologist, the Head and Neck Service at Memorial Sloan Kettering Cancer Center has described a leveling system of cervical LNs. This system divides the LNs in the lateral aspect of the neck into five nodal groups or levels. In addition, LNs in the central compartment of the neck are assigned levels VI and VII (The central compartment of the neck includes the delphian LN overlying the thyroid cartilage in the midline draining the larynx and parathyroid LNs adjacent to the thyroid gland)[11] [Figure 4].{Figure 4}

Levels of LNs

Level J includes two LNs: Submental and submandibular LNs [19]

Submental group Submandibular group Level II: Upper jugular group Level III: Mid-jugular group Level IV: Lower-jugular group Level V: Posterior triangle group Level VI: Central compartment group Level VII: Superior mediastinal group.

 Various Forms of Metastasis

Occult metastasis

Occult metastasis and its relation to various clinic-pathological factor

The presence of occult LN metastasis is considered as one of the most important prognostic factor, which leads to a reduction in the probability of disease control and shortens the survival of patients. The incidence of occult metastasis in neck LNs in patients with oral malignant tumors ranges from 23.7% to 42%, but the rate is found to be higher in tongue and floor of the mouth tumors. It was also found that out of the demographic, clinical and pathological factors analyzed, with the exception of muscular invasion, none were predictive of occult metastasis in neck LNs.[20],[21] On the other hand, thickness was a direct measurement by the pathologist of the vertical bulk of tumor regardless of the histologic structure of the ulcerative or exophytic form of tumor growth. Al-Rajhi et al.,[8] demonstrated that the risk of occult LN disease is minimal in cases of tumor thickness <10 mm and in these cases the author did not recommended any elective neck dissection (END). Woolgar [21] did not find neck metastasis in tumors <5 mm thickness. Kurokawa et al.,[22],[23] described that depth ≥4 mm was a predictive factor for LN metastasis. Rasgon et al., found high rates of neck metastasis in tumors thicker than 5 mm, although they did not define what methodology was used for making this measurement.[23]

 Sentinel Lymph Nodes Biopsy

Between the routine use of END in all N0 neck and a “wait and see” policy, sentinel node biopsy (SNB) in HNSCC has been suggested as a method to improve the accuracy of staging and tailor treatments. Although, in melanoma and breast cancer the SN procedure is widely employed, for SCC of the head and neck the most active proponents state that it is “safe and accurate with … the potential to become the new standard of care.”[24] The SLN is defined as the first node in the lymphatic basin into which the primary tumor drains. The primary afferent lymphatic first drains into the SLN of the respective basin. Therefore, the status of the SLN(s) accurately reflects the entire basin. If the SLN is not involved with metastatic disease, the remainder of the LNs should also be negative. Likewise, if the SLN is positive, the risk exists that higher order nodes may also be involved with metastatic disease.[25] The validity of the concept is based on the fact that if the sentinel node is free of metastasis, then other more distal nodes are also disease free. Following the first application of SNB in epidermoid carcinoma of the head and neck, Pitman using vital dyes on 16 patients did not identify any sentinel node. Koch reported 60% success in identification of the sentinel node using lymphoscintigraphy and intra-operative probes. Shoaib carried out the sentinel node procedure with lymphoscintigraphy, intra-operative probes and vital dye, obtaining a high sensitivity. Other authors established results in head and neck cancer, although in series of small samples; it being Shoaib who presented results with a high sensitivity in a sample of 40 cases of head and neck cancer. Kowalski in a review of 513 patients found that in high-risk patients the possibility of presenting contralateral metastasis is greater than 20%. Byersin a review of lingual tumors at stage T1 to T2 found 16% of cases with an unpredictable or disordered drainage and were defined as “skip metastases” and which we have named jump metastases. Other authors such as Woolgar found a 10% incidence in 154 patients. SNB should be considered a highly sensitive diagnostic procedure, thus it is a valid alternative to elective stage dissection. It reduces both time spent in surgery and postoperative morbidity. The technique should be carried out using lymphoscintigraphy, vital dye and an intra-operative gamma probe. SNB is technically feasible, and after the initial acquisition of experience by a multidisciplinary team can be safely used. Nevertheless, the role of SNB in HNSCC is still undecided. Surgeons should be aware that these patients have a N0 neck and good prognosis, and that elective Sentinel node dissection (SND) has proven reliability and world-wide acceptance. The SN concept defines the surgical approach to a N0 neck, tailoring the dissection on the lymphatic drainage pattern to the specific patient.

Skip metastasis

Discontinuous metastases defined as the metastatic spread of a cancer cells in which contiguous regions are skipped, while distant foci of the cancer cells are present, a finding with a poor prognosis.

A topic of ongoing debate in the recent literature concerns the concept of skip metastasis, in particular when the primary site of the tumor is the oral cavity and especially the tongue.[27] There are normal anatomical lymphatic channels that bypass or skip an orderly progression of nodal metastasis. Although, clinical observation suggested that the metastatic involvement of the various LN regions usually progresses from superior to inferior in the neck, LN groups may bypass even on normal lymphography. The possibility of tumor cells escaping the usual draining LNs and metastasizing to other LNs (skip metastasis) has been well documented in subsets of patients with head and neck and non-head and neck cancers.[28] This phenomenon of skip metastases in cancer of the tongue and the mouth is supported by the anatomic findings described by Rouvière.[27],[28] Metastasis to inferior cervical nodes at levels III or IV in the absence of demonstrable involvement of levels I and II have been reported in cancers of the oral cavity. In 1997, Byers et al.,[29] published an interesting paper reporting 277 previously untreated patients with SCC of the oral tongue. Of all patients, 15.8% had either level IV metastasis as the only manifestation in the neck or level III nodes were the only metastatic LNs without disease in levels I and II. In 1997, Woolgar [30] also reported a 10% incidence of skip metastasis at levels II and III in a series of neck dissections from 154 previously untreated patients with SCC of the oral mucosa. “Peppering” of nodes at multiple levels without any macroscopic focus was seen in 5% of cases. Hence, “fast-tracts” or long-range pathways accounted for the distribution of metastatic carcinoma in 15% of positive necks.[31],[32],[33] Therefore, an orderly progressive (”over or”) involvement of anatomic levels was seen in 85% of positive necks. Skipping of anatomical levels and “peppering” were seen only in association with tongue tumors, apart from the single case of a tumor of the anterior midline of the mouth.[31] In 1999, Woolgar concluded that neck dissection should include level IV when the primary tumor involves the tongue, considering the “erratic” (unpredictable) pattern of metastasis of this cancer.[34] Kerawala and Martin (1998)[32] reported two patients with cancer of the floor of the mouth with the presence of skip metastasis. In 2000, Hamakawa et al.,[16] reported a skip metastasis in a patient with tongue cancer.[31]

Risk of distant metastases and prognostic significance of extra-capsular spread

Carter et al., found that macroscopic extra-capsular spread was seen most frequently in association with large nodal masses >3 cm in diameter, but also occurred in some specimens with smaller LNs <3 cm in diameter. Macroscopic extra-capsular infiltration was associated with a high incidence of recurrent tumor in the ipsilateral neck, particularly within 12 months of surgery.[22] Microscopic extra-capsular growth was associated with a lower incidence of recurrent tumor in the ipsilateral neck but the difference did not reach statistical significance (Myers and Alvi).[33] Myers et al., retrospectively studied 266 patients with SCC of the oral tongue treated with surgical resection of the primary tumor and neck dissection, and found that extra-capsular spread was the most significant predictor of both regional recurrence and development of distant metastasis resulting in a decreased survival. Further evaluation of this cohort of patients by Greenberg et al., that the number of LNs involved with extra-capsular spread was a highly significant predictor of disease-specific and overall survival.[11]

Features related to regional metastases

The extent of cervical metastatic growth, reflected by the N stage, predicts survival. The cure rates drop roughly to half when macroscopic cervical metastasis is present at the time of diagnosis (Alvi and Johnson, 1996). The higher the N stage, the larger is the proportion of the patients presenting with DM and the worse is the survival (Alvi and Johnson, 1997). The 5 year survival rates for HNSCC patients staged N0, N1, N2, and N3 has been reported to be 63%, 32%, 26%, and 11%, respectively (Baatenburg de Jong et al., 2001). The incidence of DM in the follow up has been reported to range from 2.5% in patients with N0 neck to 29.5% in patients diagnosed as having N3 neck disease (Garavello et al., 2006). Tumor extension outside the LN capsule, i.e., extra-capsular spread, has been shown to be a powerful predictor of regional recurrence.[33],[34]

 Metastasis in Squamous Cell Carcinoma

The probability of having metastatic disease at presentation highly depends on the site of the primary tumor. Surprisingly, there are not many studies reporting on the incidence of distant metastasis at presentation in patients diagnosed with HNSCC. According to Dennington et al., the incidence of DM at the time of diagnosis in patients with HNSCC is 7% (Dennington, Carter and Meyers, 1980). Distant metastatic spread occurs relatively late in the course of the disease and it is thought to be hematogenic (Calhoun et al., 1994; Leemans et al., 1993; Leon et al., 2000). Patients with SCC of buccal mucosa, lip usually present with only local disease, while the majority of tongue cancer patients present with advanced stage disease with regional and/or distant metastasis (Dickman et al., 1999). In oral cavity tumors, metastatic LNs are most often present in levels III. Bilateral metastases are frequently encountered in tumors of the base of tongue (Lindberg)[34] (Shintani et al., 1997) investigated the relationship between the shape of invasion, depth of primary tumors, and cervical metastasis in tongue carcinomas, suggesting that the macroscopic shape of invasion was a feature that could provide important information about the prognosis of the primary tumor especially in relation to cervical LN involvement. Hiratsuka, Miyakawa et al., (1997) evaluated the clinical and histological tumor risk factors in predicting the prospect of ONM. Regauer, Mannweiler et al., (1998) analyzed the frequency of cystic LN metastases in neck dissection in specimens of 123 patients with primary SCC. They showed that SCC of weldayers ring origin had a high incidence of occult cystic LN metastasis but only a small percentage of clinically evident cystic LN metastasis. Ferlito et al., (2001) correlated the prognostic significance of LN micrometastasis and elucidated that the detection of micrometastasis can lead to a better prognosis and decreased re-occurrence of carcinomas of head and neck. Ferlito et al., (2002) reviewed the presence or absence of cervical node metastases in patients with HNSCC as a powerful prognostic indicator. Fertilo, Byers et al., (2002) analyzed the concept of skip metastasis, in particularly with respect to the oral cavity. Metastasis to cervical nodes at levels III or IV in the absence of demonstrable involvement of levels I and II have been reported in cancers of oral cavity; specifically carcinomas of tongue and floor of mouth, where the phenomenon of “skip metastasis” is supported by the anatomic findings as described by Rouvière. Barrera, et al., (2003) examined the incidence of ONM with HNSCC and the clinical significance of nodal micrometastasis by cytokeratin immunohistochemical (IHC) analysis. It was concluded that the use of serial sectioning with H/E and cytokeratin IHC analyses increases the detection of micrometastasis, which were elusive by routine process in HNSCC, and emphasized on the fact that improved methods of detecting micrometastasis can provide a useful aid for treatment planning. Amarala, Kowalski et al., (2003) predicted the incidence of occult neck metastasis in early stage tumors of the tongue and floor of the mouth to lie between 20% and 30%, and the survival rates in 5 years from 73% to 97%. In order to substansize their study they analyzed the rates of occult metastasis and prognostic factors for clinical stages I and II SCC of the tongue and floor of the mouth. Tumors of the tongue and floor of the mouth in the initial stages, which had muscular infiltration showed a higher probability of occult metastasis and lower disease-free survival; T2 tumors showed a worse survival as did patients of the male gender Simental, Myers et al., (2004) retrospectively evaluated the incidence of cervical LN metastases from SCCs of the maxillary alveolus and hard palate. A total of 26 patients were studied. Cervical metastases was found to be significant A lower incidence rate has also been reported, e.g., in an analysis of 3033 patients with mucosal head and neck cancer. The incidence of DM increases with increasing stage of the disease (Garavello et al., 2006). In 1997, Byers found the lymphatic drainage patterns of the chance tongue being responsible for higher chances of skip metastasis. It was found that the chances of skip metastasis presented a high rate of reoccurrence of tumor with decreased survival.[28],[34],[35],[36],[37],[38],[39],[40]

Montes et al., (2011) reviewed the cases of SCC after ablative surgery, those individuals who presented with clinically negative necks had a 21.4% rate of regional node metastasis. Ultimately, 50% of patients with SCCs of the palate, maxillary gingiva, buccal mucosa and maxillary alveolus developed regional or metastatic distant disease; 42.9% of the patients manifested disease to the cervical LNs alone.[41],[42]

Another cause for concern BMSCC (buccal mucosa –squamous cell carcinoma) is a rare clinical entity, accounting for approximately 10% of all oral cancers. BMSCC accounts for 26.5-37.4% of all intraoral cancers in Taiwan and buccal mucosa seems to be the site at greatest risk of contracting malignancy in betel quid chewers. BMSCC is aggressive and associated with a poor prognosis of the high incidence of locoregional recurrence rate of 26-80% reported in the literature.[2],[4],[5],[17],[18],[19],[20],[21],[22] Available data suggest that recurrent disease is most often locoregional, with distant metastases affecting a relatively small percentage of 0-23% of patients. Lin et al., (2006) demonstrated that SCC of the buccal mucosa is an aggressive cancer with a high locoregional failure rate even in patients with T1-2N0 disease. Possible reasons include inadequate treatment and an intrinsically aggressive nature. Post-operative radiotherapy has resulted in a better locoregional control rate for patients with T3-4 or N+ disease and should also be considered for patients with T1-2N0 disease for whom adjuvant therapy after radical surgery currently is not recommended by most guidelines. In conclusion, the strong influence of disease stage on prognosis emphasizes the importance of early diagnosis of BMSCC and aggressive treatment for patients with poorly/moderately differentiated cancer.[41],[42]

Extra-capsular spread is encountered even in patients with clinically N0 disease, as demonstrated in a study consisting of 109 patients undergoing END for clinically N0 disease (Alvi and Johnson, 1996). Of the patients, 34% had occult metastases and in half of them, extra-capsular spread was detected. Also in that study, extra-capsular spread was a strong indicator of recurrent disease and poor prognosis. In addition, the number of metastatic LNs (Leemans et al., 1993) and anatomical level of node involvement (Kowalski et al., 2000) have been reported to predict outcome of patients with HNSCC; the risk being higher for patients with multiple metastatic nodes, involved nodes at levels IV and V, and/or contralateral or bilateral metastatic nodes.


The structural organization and function of normal tissue is to a great extent determined by interactions between cells and the extracellular matrix (ECM). Tissues are organized into compartments separated from each other by two types of ECM: That is basement membrane and interstitial connective tissue. Although organized differently, each of these components of ECM is made up of collagens, glycoproteins, and proteoglycans. Tumor cells must interact with the ECM at several stages in the metastatic cascade. A carcinoma must first breach the underlying basement membrane, then transverse the interstitial connective tissue and ultimately gain access to the circulation by penetrating the vascular basement membrane [14],[43],[44] [Figure 5] and [Figure 6].{Figure 5}{Figure 6}

Many lymphatic and lymphatico-venous shunts bypass RLNs and these shunts allow both lymphatic and hematogenous dissemination of malignant cells. Chemokine mediated mechanisms lead to tumor cell invasion into LN. RLNs is considered to have their primary function merely not in anatomical barriers to the systemic dissemination of tumor cells but also in immunological surveillance. A large majority of lymphocytes in the LNs are static. When the LN elicits the immune response, the node enlarges in size (reactive hyperplasia). The immune response can be assessed histologically. The morphological changes indicate a cell-mediated immune response (CMR) which results in paracortical hyperplasia and sinus histiocytosis. The morphological changes indicating a humoral immune response is the follicular hyperplasia (GC formation).[44],[48],[49] of the two mechanisms the suppression of CMR, in particular T-cell, is correlated to LN metastasis.[3]

The presence or absence of LN metastasis is one of the major prognostic factors for survival in patients with clinically negative cervical LNs. Clinical and histologic factors relating to regional metastasis have been clarified. Menderhall et al., defined three risk groups for cervical LN metastasis [Figure 7]. Moore et al., determined the degree of correlation between the greatest surface measurement of the primary tumor and the pathologic LN spread: Found out that the size of the surface greatest dimension of an oral carcinoma when >2 cm, is an unreliable predictor of tumor behavior. The histological assessments of tumor depth or thickness are also reported to be of possible use in predicting the cervical LN metastasis.[49],[50],[51],[52],[53],[54]{Figure 7}

A variety of studied (as done by [Catlin et al.,]) have also indicated that the biological behavior of the cancer represented by the temporal sequence of the cancer growth in the RLNs was more important by far than the anatomic fact of the presence of the LN metastases. The timing of the LN metastases was considered as key to understanding the biological aggressiveness. It is apparent from a number of studies that cancer cells disseminate relatively early in both lymphatic and blood vessels in a large proportion of cancers, and can be detected cytologically, yet their presence is not necessarily correlated with a poor outcome.[55],[56],[57],[58],[59],[60] The experimental work of Folkmann indicates that local angiogenesis is necessary to overcome the limitations of diffusion as a sole nutrient source of metaststic cells before progressive growth of disseminated cancer cells occur and produce clinical metastases. Work by Fidler, demonstrated another aspect of the biology of the metastatic process. He has emphasized on the “biologic homing of the metaststic cells. In all, the lymphatic vasculature, the process of neoangiogenesis, the VEGFs (vascular endothelial growth factors) role in combination represents the most important pathway for tumor cell dissemination, and tumor cell metastasis [61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73] [Figure 8].{Figure 8}


Thus, to conclude the biology of the cancer is paramount. The role of LN (lymph node) metastasis is passive, not active, and helps identify the biology of tumor-host interaction. No clear evidence in any clinical study, either prospective or retrospective, indicates that such regional nodal metastasis are controlling or governing factors in prognosis. Weiss emphasized this absence of control of prognosis by LN metastasis strongly, and concluded,” local therapy aimed at LN themselves will no more effectively control (distant) metastasis than removal of the speedometer from a car will reduce its speed.


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