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Background and Methods
Skipped nodal metastasis (SNM) is a recognized phenomenon of visceral cancers when metastases bypass the regional basin and skip to a distant nodal basin without evidence of distant metastases. Its occurrence is undocumented in cutaneous melanoma patients but of potential prognostic significance. We therefore assessed the frequency of SNM in a large series of patients with limb melanomas.
Patients and Methods
We studied melanoma patients attending a tertiary oncology hospital in northwest England using two approaches. First, we systematically searched medical records of an unselected patient sample treated 2002-2015, and second, we studied lymphoscintigrams of all patients with limb melanoma who underwent sentinel node biopsy 2008-2019.
Of 672 melanoma patients whose clinical records were examined, 16 had regional nodal metastases without apparent visceral spread and one appeared to have SNM but further scans were uncovered that showed concurrent pulmonary metastases. Of 667 limb melanoma patients with lymphoscintigrams, 7 showed dual lymphatic drainage patterns to distal as well as regional nodal basins, but none had micro-metastases solely in the distant basin.
Occurrence of SNM in cutaneous melanoma is highly unlikely.
Lymph node metastasis (LNM) is a standard mechanism of cancer progression in esophageal squamous cell carcinoma (ESCC). We aimed to clarify the anatomical mechanism of skip nodal metastasis to mediastinal zones by analyzing the relationship between LNM to sentinel zones and lymphatic vessel counts in the muscle layer adjacent to the outer esophagus.
We examined the surgical records of 287 patients with ESCC who underwent potentially curative surgery (three-field lymphadenectomy) and whole esophagi, including pharynges and stomachs from 10 cadavers, to determine the number of lymphatic vessels in the intra-outer longitudinal muscle layer adjacent to the outer esophagus of the cervical (Ce), upper thoracic, middle thoracic (Mt), lower thoracic (Lt), and abdominal esophagi (Ae).
The frequency of LNM to the middle mediastinal and supraclavicular zones, including the Mt and Ce, respectively, was lower than to the upper and lower mediastinal and abdominal zone in patients with superficial and advanced thoracic ESCC. In cadavers, the lymphatic vessel counts of the intra-outer longitudinal muscle layer in the Mt and Ce were significantly lower than those of the Lt and Ae, suggesting that lymphatic flow toward the outside of the Mt and Ce was not more abundant than to other sites.
Our anatomical data suggested that the absence of intra-muscle lymphatic vessels in the middle mediastinal and supraclavicular zones causes skip LNM in patients with thoracic ESCC. Thus, standard esophagectomy with lymph node dissection, including distant zones, may be appropriate for treating patients with superficial thoracic ESCC.
This study aimed to investigate the incidence of nodal skip metastasis (NSM) to identify the risk factors that influence NSM and to assess the prognostic value of NSM in patients with thoracic esophageal squamous cell carcinoma (ESCC).
Patients and methods
Between January 2009 and December 2013, 285 patients with ESCC with positive lymph nodes who underwent complete resection were enrolled.
For the entire group, NSM occurred in 32.3% (92/285) of patients. The median survival time and 5-year survival rate in the NSM group were 28 months and 12.0%, respectively, compared with 36.3 months and 25.0%, respectively, in the non-NSM group (P=0.008). Both N stage (P=0.001) and T stage (P=0.014) were associated with the incidence of NSM. NSM (P=0.008), T stage (P=0.000), and N stage (P=0.000) were independent prognostic factors for survival. In the NSM group, T stage (P=0.014) and N stage (P=0.000) were independent prognostic factors for survival.
It was concluded that NSM is common in ESCC and is associated with poor survival.
Nodal skip metastasis is a prognostic factor in some sites of malignancies, but its role in esophageal cancer is still unclear. The present study aimed to investigate occurrence and effect of nodal skip metastases in thoracic esophageal squamous cell carcinoma. Methods
All 578 patients undergoing esophagectomy for thoracic esophageal squamous cell carcinoma at the Center for Esophageal Diseases located in Padova between January 1992 and December 2010 were retrospectively evaluated. Selection criteria were R0 resection, pathological M0 stage and pathological lymph node involvement. Patients receiving neoadjuvant therapy were excluded. ResultsThe selection identified 88 patients with lymph node involvement confirmed by pathological evaluation. Sixteen patients (18.2%) had nodal skip metastasis. Adjusting for the number of lymph node metastases, patient with nodal skip metastasis had similar 5-year overall survival (14% vs. 13%, p = 0.93) and 5-year disease free survival (14% vs. 9%, p = 0.48) compared to patients with both peritumoral and distant lymph node metastases. The risk difference of nodal skip metastasis was: −24.1% (95% C.I. -43.1% to −5.2%) in patients with more than one lymph node metastasis compared to those with one lymph node metastasis; −2.3% (95% C.I. -29.8% to 25.2%) in middle thoracic esophagus and −23.0% (95% C.I. -47.8% to 1.8%) in lower thoracic esophagus compared to upper thoracic esophagus; 18.1% (95% C.I. 3.2% to 33.0%) in clinical N0 stage vs. clinical N+ stage. Conclusions
Nodal skip metastasis is a common pattern of metastatic lymph involvement in thoracic esophageal squamous cell carcinoma. However, neither overall survival nor disease free survival are associated with nodal skip metastasis occurrence.
The objective of this study is to evaluate the lymph drainage from the primary focus to the regional lymph nodes in patients with melanomas of the upper extremity and upper trunk region.
The study is a retrospective study of 20 patients with upper extremity melanomas and 14 patients with upper trunk melanomas treated with axillary lymph node dissection (ALND) or sentinel lymph node biopsy at the hospital. ALND was performed in 14 cases. In these cases, 12 were curative dissections and 2 were elective dissections. The dominant lymph drainage patterns from the primary regions were analyzed.
Among the upper extremity and upper trunk region melanomas, lymph drainage to Level I was determined in all cases. In these two regions there were no cases of lymph drainage to Level II not passing through Level I. Furthermore, there were no cases where sentinel lymph node or metastasis of the lymph nodes was clearly determined in Level III. Among the upper extremity melanomas, lymph drainages to the cubital (10 %) and mid-arm nodes (5 %) were established. Among the scapular region melanomas, lymph drainages to the supraclavicular nodes (25 %) were determined.
There was a dominant lymph drainage pattern of melanomas of the upper extremity and upper trunk region to Level I. No lymph node dissection of Level III in patients with melanomas of the upper extremity and upper trunk region is necessary unless preoperative examination determines a high possibility of metastasis-positive lymph nodes in level III.
To determine the incidence and pattern of cervical lymphatic drainage in patients with melanomas located on the upper limb or trunk, and to evaluate our current neck dissection protocol for those patients with a N+ neck.
Of 1192 melanoma patients who underwent sentinel node biopsy, 631 were selected with a primary tumor on the upper limb or trunk. All lymphoscintigrams, SPECT/CT images and operative reports were reviewed to determine the exact locations of sentinel nodes visualized preoperatively and dissected during operation.
Thirty-nine (6.2 %) of 631 patients with a melanoma on the upper limb or trunk showing cervical lymph node drainage were identified. In 34 (87 %) of 39 patients, sentinel nodes were excised from level IV or Vb, and in 30 of those 39 patients simultaneous from the axilla. In the remaining five patients (13 %), sentinel nodes were collected from level IIb, level III or the suboccipital region. All collected sentinel nodes were located in the intended dissection area for N+ patients. Thirteen patients (33 %) had a total of 22 tumor-positive sentinel nodes in either the axilla (n = 10), level IV (n = 2), Vb (n = 9) or suboccipital (n = 1).
Only a minority of the patients with upper limb or trunk melanomas demonstrated lymphatic drainage to cervical lymph node basins, with preferential drainage to levels IV and Vb. Our current dissection protocol of levels II-V, with or without extension to the suboccipital region, in those patients with involved cervical sentinel nodes seems sufficient.
We evaluated the contribution of sentinel-node biopsy to outcomes in patients with newly diagnosed melanoma.
Patients with a primary cutaneous melanoma were randomly assigned to wide excision and postoperative observation of regional lymph nodes with lymphadenectomy if nodal relapse occurred, or to wide excision and sentinel-node biopsy with immediate lymphadenectomy if nodal micrometastases were detected on biopsy.
Among 1269 patients with an intermediate-thickness primary melanoma, the mean (+/-SE) estimated 5-year disease-free survival rate for the population was 78.3+/-1.6% in the biopsy group and 73.1+/-2.1% in the observation group (hazard ratio for recurrence[corrected], 0.74; 95% confidence interval [CI], 0.59 to 0.93; P=0.009). Five-year melanoma-specific survival rates were similar in the two groups (87.1+/-1.3% and 86.6+/-1.6%, respectively). In the biopsy group, the presence of metastases in the sentinel node was the most important prognostic factor; the 5-year survival rate was 72.3+/-4.6% among patients with tumor-positive sentinel nodes and 90.2+/-1.3% among those with tumor-negative sentinel nodes (hazard ratio for death, 2.48; 95% CI, 1.54 to 3.98; P<0.001). The incidence of sentinel-node micrometastases was 16.0% (122 of 764 patients), and the rate of nodal relapse in the observation group was 15.6% (78 of 500 patients). The corresponding mean number of tumor-involved nodes was 1.4 in the biopsy group and 3.3 in the observation group (P<0.001), indicating disease progression during observation. Among patients with nodal metastases, the 5-year survival rate was higher among those who underwent immediate lymphadenectomy than among those in whom lymphadenectomy was delayed (72.3+/-4.6% vs. 52.4+/-5.9%; hazard ratio for death, 0.51; 95% CI, 0.32 to 0.81; P=0.004).
The staging of intermediate-thickness (1.2 to 3.5 mm) primary melanomas according to the results of sentinel-node biopsy provides important prognostic information and identifies patients with nodal metastases whose survival can be prolonged by immediate lymphadenectomy. (ClinicalTrials.gov number, NCT00275496 [ClinicalTrials.gov].).
Patterns of axillary lymph node metastases were analyzed in 1228 recently performed modified, radical, and extended radical mastectomies. In these specimens the position or level of lymph nodes was designated intraoperatively by the surgeon. No lymph node metastases were found in 720 (58) of the specimens while the remainder (508 or 41%) had at least one affected lymph node. The distribution of involvement by level showed progressive spread from level I to III as the number of positive lymph nodes increased. Discontinuous or "skip" metastases not following this pattern occurred in 1.6% of all cases and 3% of those with lymph node metastases (95% confidence interval, 1-5%). Half of those with "skip" metastases had tumor limited to level II. The presence of "skip" metastases was not related to the size, location in the breast, or histologic type of the primary tumor. It is apparent that the potential risk from "skip" metastases is not great and that this should not be a major consideration in therapeutic decisions. The risk is likely to be negligible for women treated by axillary dissections that include level II.
The aim of this study was to determine the order of melanoma nodal metastases.
Most solid tumors are thought to demonstrate a random nodal metastatic pattern. The incidence of skip nodal metastases precluded the use of sampling procedures of first station nodal basins to achieve adequate pathological staging. Malignant melanoma may be different from other malignancies in that the cutaneous lymphatic flow is better defined and can be mapped accurately. The concept of an orderly progression of nodal metastases is radically different than what is thought to occur in the natural history of metastases from most other solid malignancies.
The investigators performed preoperative and intraoperative mapping of the cutaneous lymphatics from the primary melanoma in an attempt to identify the "sentinel" lymph node in the regional basin. All patients had primary melanomas with tumor thicknesses > 0.76 mm and were considered candidates for elective lymph node dissection. The sentinel lymph node was harvested and submitted separately to pathology, followed by a complete node dissection. The null hypothesis tested was whether nodal metastases from malignant melanoma occurred in equal proportions among sentinel and nonsentinel nodes.
Forty-two patients met the criteria of the protocol based on prognostic factors of their primary melanoma. Thirty-four patients had histologically negative sentinel nodes, with the rest of the nodes in the basin also being negative. Thus, there were no skip metastases documented. Eight patients had positive sentinel nodes, with seven of the eight having the sentinel node as the only site of disease. In these seven patients, the frequency of sentinel nodal metastases was 92%, whereas none of the higher nodes had documented metastatic disease. Nodal involvement was compared between the sentinel and nonsentinel nodal groups, based on the binomial distribution. Under the null hypothesis of equality in distribution of nodal metastases, the probability that all seven unpaired observations would demonstrate that involvement of the sentinel node is 0.008.
The data presented demonstrate that nodal metastases from cutaneous melanoma are not random events. The sentinel lymph nodes in the lymphatic basins can be mapped and identified individually, and they have been shown to contain the first evidence of melanoma metastases. This information can be used to revolutionize melanoma care so that only those patients with evidence of nodal metastatic disease are subjected to the morbidity and expense of a complete node dissection. Because sentinel node histology accurately reflects the histology of the remainder of the lymphatic basin, information gained from the sentinel node biopsy can be used as a prognostic factor for melanoma. These findings demonstrate effective pathologic staging, no decrease in standards of care, and a reduction of morbidity with a less aggressive, rational surgical approach.
Approximately 20 per cent of melanomas greater than 0.76 mm in thickness will metastasize to the regional lymph nodes if treated with wide local excision alone (WLE). Elective lymph node dissection (ELND) is associated with significant morbidity, which includes lymphedema, wound complications, and paresthesias of the extremity. An alternative operative approach uses selective lymphadenectomy with the identification of the sentinel node, defined as the first node in the lymphatic basin that drains the primary cutaneous site. This study consisted of 132 patients with melanomas greater than 0.76 mm. One hundred nine patients (83%) had histologic negative sentinel nodes, and 23 patients (17%) had one or more sentinel nodes positive for disease. In patients with metastatic disease, 30/35 (86%) sentinel nodes were positive, and 25/357 (7%) nonsentinel nodes were positive (P < 0.001). In 18 patients (78%) of the 23 patients with metastatic disease, the sentinel node was the only node positive, strongly suggesting that there is an orderly progression of metastases. Two patients developed metastatic nodal disease after removal of a negative sentinel node (false negative rate = 1.5). The mean follow-up was 1 year. Sentinel node histology reflects the histology of the remainder of the nodes in the lymphatic basin and "skip" metastases, defined as a negative sentinel node but positive nodes higher in the regional chain positive for metastases or an axillary recurrence after a negative sentinel node biopsy, are rare for malignant melanoma. Harvesting the sentinel node in patients with intermediate or greater thickness melanoma will, therefore, identify a subset of patients with metastatic disease who have the most to benefit from a complete node dissection. This surgical approach allows for complete pathological staging and therapeutic management of patients while significantly reducing expense and overall morbidity.
Any sentinel lymph node that receives lymph drainage directly from a primary melanoma site, regardless of its location, may contain metastatic disease. This is true even if the sentinel node does not lie in a recognized node field. Interval (in-transit) nodes that lie along the course of a lymphatic vessel between a primary melanoma site and a recognized node field are sometimes seen during lymphatic mapping for sentinel node biopsy. If drainage to such interval nodes is ignored by the surgeon during sentinel node biopsy, metastatic melanoma will be missed in some patients.
When lymph drains directly from a cutaneous melanoma site to an interval node, that sentinel node has the same chance of harboring micrometastatic disease as a sentinel node in a recognized node field.
Preoperative lymphoscintigraphy with technetiumTc 99m antimony trisulfide colloid was performed to define lymphatic drainage patterns and, since 1992, to locate the sentinel lymph nodes for surgical biopsy or for permanent skin marking of their location with point tattoos.
Melanoma unit of a university teaching hospital.
A total of 2045 patients with cutaneous melanoma were studied in 13 years.
Interval nodes were found in 148 patients (7.2%). The incidence of interval nodes varied with the site of the primary melanoma. Interval nodes were more common with melanomas on the trunk than with those on the lower limbs. Micrometastatic disease was found in 14% of interval nodes that underwent biopsy as sentinel nodes. This incidence is similar to that found in sentinel nodes located in recognized node fields, confirming the potential clinical importance of interval nodes.
Interval nodes should be removed surgically along with any additional sentinel nodes in standard node fields if the sentinel node biopsy procedure is to be complete. In some patients, an interval node will be the only lymph node that contains metastatic disease.
The aims of this study were to assess the incidence of micrometastases of lymph nodes in patients with early gastric cancer invading the submucosal layer and to investigate the correlation between nodal micrometastases and malignancy potential to determine whether micrometastases of lymph nodes have prognostic significance, by use of an anticytokeratin immunohistochemical technique.
A total of 2272 lymph nodes taken from 88 patients (25.8 per case) were assessed by immunohistochemical technique by use of monoclonal anti-human cytokeratin 8 antibodies. Clinicopathologic parameters and prognosis were compared between patients with and without micrometastases.
The incidence of nodal involvement by tumor cells in 88 patients with submucosal gastric cancer increased from 19.3% (17 patients) by hematoxylin-eosin (H&E) staining to 31.8% (28 patients) by cytokeratin immunostaining. The rate of positive node in this study increased from 1.0% (23 of 2272 nodes) by H&E staining to 2.5% (57 of 2272 nodes) by immunostaining (P = .0002). No correlation was observed between the incidence of lymph node micrometastases and various clinicopathologic parameters, including tumor site and size, histological differentiation, Lauren classification, gross tumor type, vascular and lymphatic invasion, and perineural invasion. There was no difference in disease-free survival, estimated by the Kaplan-Meier life-table method, between the micrometastasis-negative and -positive groups (95% and 92.9%, respectively). Multivariate analyses showed that tumor size and diffuse subtype by the Lauren classification were significant factors for survival time (P = .0042 and .014, respectively).
Immunohistochemical staining with an anticytokeratin antibody seems to be of little prognostic value in patients with submucosal gastric carcinoma. Thus, this immunostaining technique does not offer a significant benefit of different strategies for additional therapy or follow-up over conventional pathologic staging with H&E staining.