Cervical lymph node metastases from occult squamous cell carcinoma: cut down a tree to get an apple?

PURPOSE: To review the value of extended diagnostic work-up procedures and to compare the results of comprehensive or volume-restricted radiotherapy in patients presenting with cervical lymph node metastases from clinically undetectable squamous cell carcinoma. METHODS AND MATERIALS: A systematic review was undertaken of published papers up to May 2000. RESULTS: Positron emission tomography (PET) has an overall staging accuracy of 69%, with a positive predictive value of 56% and negative predictive value of 86%. With negative routine clinical examination and computerized tomography (CT) or magnetic resonance imaging (MRI), PET detected primary tumors in 5-25% of patients, whereas ipsilateral tonsillectomy discovered carcinoma in about 25% of patients. Laser-induced fluorescence imaging with panendoscopy and directed biopsies showed some encouraging preliminary results and warrants further study. All together, the reported mucosal carcinoma emergence rates were 2-13% (median, 9.5%) after comprehensive radiotherapy and 5-44% (median, 8%) after unilateral neck irradiation. The corresponding nodal relapse rates were 8-45% (median, 19%) and 31-63% (median, 51.5%), and 5-year survival rates were 34-63% (median, 50%) and 22-41% (median, 36.5%), respectively. Retrospective single-institution comparisons between comprehensive and unilateral neck radiotherapy did not show apparent differences in outcome. Prognostic determinants for survival are the N stage, number of nodes, extracapsular extension, and histologic grade. No data were found to support the benefit of chemotherapy in this disease. CONCLUSION: Physical examination, CT or MRI, and panendoscopy with biopsies remain the standard work-up for these patients. Routine use of PET or laser-induced fluorescence imaging cannot be firmly advocated based on presently available data. Although combination of nodal dissection with comprehensive radiotherapy yielded most favorable results, its impact on the quality of life should be recognized, and the confounding effects of patient selection for various treatment modalities on therapeutic outcome cannot be ruled out. A randomized trial comparing the therapeutic value of comprehensive vs. volume-limited radiotherapy is being considered.     

When is a completion axillary lymph node dissection necessary in the presence of a positive sentinel lymph node?

BackgroundThe management of the axilla in the presence of positive sentinel lymph node (SLN) remains controversial. Many centres forgo completion axillary lymph node dissection (cALND) in the presence of micrometastatic disease. The American College of Surgeons Oncology Group (ACOSOG) Z0011 trialists argue for extending this to macrometastasis. The aim of this study was to correlate tumour burden in SLNs with that in the residual lymph node basin to determine the likelihood of residual disease in patients with micro- and macrometastasis in the SLN.MethodsPatients who underwent cALND following a positive SLN were analysed for histopathological features of the primary tumour and burden of axillary disease.ResultsOf 155 patients, 115 (74%) had macrometastases and 40 (26%) micrometastases in the SLNs. Residual axillary disease was detected in 55/155 (35%) patients with macrometastases and 4/40 (10%) with micrometastases. Generally, with increasing size of metastasis in the SLN there was an increasing risk of further disease in residual lymph nodes. Logistic regression analysis showed increased odds ratios for further disease for all groups when compared with the <2 mm (micrometastasis) SLN group.ConclusionPatients may be advised to forgo cALND where the SLN contains isolated tumour cells or micrometastasis. Recommendations for proceeding to cALND can be based on the size of metastasis in the SLN, which relates to the risk of further disease in the residual axillary lymph nodes and subsequent regional recurrence.     

Diagnosis and treatment of ALT tumors: is Trabectedin a new therapeutic option?

Telomeres are specialized nucleoprotein structures responsible for protecting chromosome ends in order to prevent the loss of genomic information. Telomere maintenance is required for achieving immortality by neoplastic cells. While most cancer cells rely on telomerase re-activation for linear chromosome maintenance and sustained proliferation, a significant population of cancers (10–15%) employs telomerase-independent strategies, collectively referred to as Alternative Lengthening of Telomeres (ALT). ALT mechanisms involve different types of homology-directed telomere recombination and synthesis. These processes are facilitated by loss of the ATRX or DAXX chromatin-remodeling factors and by abnormalities of the telomere nucleoprotein architecture. Although the functional consequences of telomerase and ALT up-regulation are similar in that they both prevent overall telomere shortening in tumors, these telomere maintenance mechanisms (TMMs) differ in several aspects which may account for their differential prognostic significance and response to therapy in various tumor types. Therefore, reliable methods for detecting telomerase activity and ALT are likely to become an important pre-requisite for the use of treatments targeting one or other of these mechanisms. However, the question whether ALT presence can confer sensitivity to rationally designed anti-cancer therapies is still open. Here we review the latest discoveries in terms of mechanisms of ALT activation and maintenance in human tumors, methods for ALT identification in cell lines and human tissues and biomarkers validation. Then, original results on sensitivity to rational based pre-clinical and clinical anti-tumor drugs in ALT vs hTERT positive cells will be presented.     

Analysis of paraaortic lymph node involvement in pancreatic carcinoma: a significant indication for surgery?

BACKGROUND: Lymph node status is a key prognostic factor for pancreatic carcinoma. The paraaortic lymph nodes are the highest level of lymph nodes that can be resected safely in the abdomen for pancreatic and other gastrointestinal tumors. The pattern of paraaortic lymph node involvement and its relation with other lymph node groups were analyzed and the significance of this information relative to surgical therapy examined. METHODS: Between 1974-1996, 99 patients with invasive ductal carcinoma of the pancreas underwent pancreatectomy at the study institution. The pattern of lymph node involvement, particularly paraaortic, was evaluated by careful pathologic review of extended lymphadenectomy specimens. RESULTS. Fifty-eight of 76 patients (76%) with carcinoma in the pancreatic head (Ph) and 19 of 23 patients (83%) with carcinoma of the pancreatic body and tail (Pbt) had lymph node involvement. Fourteen patients with Ph disease (18%) and 4 with Pbt disease (17%) had paraaortic lymph node involvement. Tumor size did not correlate with paraaortic lymph node involvement. A correlation was found between Group 13 (posterior pancreaticoduodenal lymph nodes), Group 14 (lymph nodes surrounding the superior mesenteric artery), and the paraaortic lymph nodes for Ph disease. All paraaortic lymph node metastases were located in the 16M region (the region between the celiac trunk and the inferior mesenteric artery). For patients with Pbt disease, the distribution of paraaortic lymph node metastases was the same as for those with Ph disease. Only 33% of cases of paraaortic lymph node metastases were suspected preoperatively or perioperatively. The longest survival for a patient with paraaortic lymph node metastases was 36 months and 17 months, respectively, for patients with Ph and Pbt disease. CONCLUSIONS: The paraaortic lymph nodes are frequent sites of metastasis from pancreatic carcinoma, and are difficult to evaluate preoperatively or perioperatively. This situation mandates paraaortic lymph node dissection, at least in the 16M region.     

α-Parvin,a pseudopodial constituent,promotes cell motility and is associated with lymph node metastasis of lobular breast carcinoma

Invasive lobular carcinoma (ILC) is more frequently lymph node positive than is invasive ductal carcinoma (IDC), and ILC cell infiltration shows distinctive histological characteristics, suggesting the action of ILC-specific invasion molecules. To identify such a molecule, we used a proteomic approach in the pseudopodia of MDA-MB-231 breast cancer cells. A pseudopodial constituent was identified using excimer laser ablation, two-dimensional difference gel electrophoresis, mass spectroscopy, and immunocytofluorescence. MDA-MB-231 cells were modified to express various levels of this constituent by transient transfection and were examined for pseudopodia formation and migratory abilities using wound healing and two-chamber assays. Immunohistochemical positivity of human breast cancer cells (56 ILCs and 21 IDCs) was compared with clinicopathological variables. An actin-binding adaptor protein, α-parvin, was found to localize to pseudopodia and to form focal adhesions in cells not induced to extend pseudopodia. Pseudopodial length and density and migratory abilities correlated with α-parvin expression. Twenty-one (37.5 %) ILCs stained positive for α-parvin, whereas the results were negative for all 21 IDCs (P < 0.001). α-Parvin positivity in ILC was significantly associated with lymphatic invasion (P = 0.038) and lymph node metastasis (P = 0.003) in univariate analyses and to lymph node metastasis (P = 0.020) in multivariate analyses. α-Parvin, a pseudopodial constituent, was found to promote migration of breast cancer cells and to be expressed exclusively by ILC, suggesting that α-parvin is an ILC-specific invasion molecule that may have clinical utility as a biomarker for aggressive subsets of ILC.     

Vulvar melanoma: is there a role for sentinel lymph node biopsy?

BACKGROUND: The objective of this study was to evaluate the author's recent, preliminary experience with the sentinel lymph node procedure in patients with vulvar melanoma and to compare this experience with treatment and follow-up of patients with vulvar melanomas who were treated previously at their institution. METHODS: From 1997, sentinel lymph node procedure with the combined technique (99mTechnetium-labeled nanocolloid and Patente Blue-V) was performed as a standard staging procedure for patients with vulvar melanoma with a thickness > 1 mm and no clinically suspicious inguinofemoral lymph nodes. For the current study, clinicopathologic data from all 33 patients with vulvar melanoma who were treated between 1978 and 2000 at the University Hospital Groningen were reviewed and analyzed. RESULTS: From January 1997 until December 2000, identification of sentinel lymph nodes was successful in all nine patients who were referred for treatment of vulvar melanoma. Three patients underwent subsequent complete inguinofemoral lymphadenectomy because of metastatic sentinel lymph nodes. In follow-up, groin recurrences (in-transit metastases) occurred in two of nine patients, both 12 months after primary treatment. Both patients had melanomas with a thickness > 4 mm and previously had negative sentinel lymph nodes. There was a trend toward more frequent groin recurrences in patients after undergoing the sentinel lymph node procedure (2 of 9 patients) compared with 24 historic control patients (0 of 24 patients; P = 0.06). Five of 33 patients developed local recurrences: Two patients had groin recurrences, and 11 patients developed distant metastases. Twelve patients died of vulvar melanoma. Seventeen patients with a median follow-up of 66 months (range, 9-123 months) are currently alive (overall survival rate, 52%). CONCLUSIONS: Although the numbers were small, this study showed that the sentinel lymph node procedure is capable of identifying patients who have occult lymph node metastases and who may benefit from lymphadenectomy for locoregional control and prevention of distant metastases. However, the data also suggest that the sentinel lymph node procedure may increase the risk of locoregional recurrences (in-transit metastases), especially in patients with thick melanomas. The potential role of the sentinel lymph node procedure as an alternative method of lymph node staging in patients with vulvar melanoma needs further investigation only within the protection of clinical trials and probably should be restricted to patients with melanomas with intermediate thickness (1-4 mm).     

Scalene lymph node dissection in locally advanced cervical carcinoma: is it reasonable or unnecessary?

AIMS AND BACKGROUND: The aim of this study was to evaluate the routine use of scalene lymph node dissection to determine the degree of disease spread in women with stage IIB-IVA cervical cancer treated at our hospital. METHODS AND STUDY DESIGN: Patients with locally advanced cervical carcinoma underwent para-aortic lymph node dissection via the extraperitoneal approach. Patients with clinical evidence of scalene or supraclavicular node metastasis were excluded. If their para-aortic nodes were tumor-positive, patients underwent scalene lymph node dissection. RESULTS: Twenty-eight scalene lymph node samplings were performed. Three patients had microscopically positive scalene lymph nodes (10.7%). In one patient the thoracic duct was injured. CONCLUSION: Patients with cervical carcinoma whose only extrapelvic site of metastases is the para-aortic lymph nodes may be eligible for scalene lymph node dissection as part of their pretreatment assessment, especially if extended field radiation is considered.     

Development or existence of non-metastatic lymph nodes in the previously operated neck: a good prognostic sign for oromaxillary squamous cell carcinoma?

The aim of this study is to clarify the clinicopathological features of patients having non-metastatic lymph nodes in the previously operated neck for oromaxillary squamous cell carcinoma (OSCC). The clinicopathological factors of 9 such patients were comparatively analyzed with those of 78 other patients who underwent neck dissection (ND). The following observations were elicited from the data: (1) These 9 patients were alive and without OSCC for periods ranging from 1 year to 15 years and 9 months since their initial cancer treatments. (2) The interval between ND and clinical and/or imaging recognition of newly developed lymph nodes with suspicion of recurrence was significantly longer in these 9 patients. (3) The initially removed lymph nodes tended to be in a less advanced stage of disease. (4) Retrospectively, discrimination of non-metastatic lymph nodes from metastatic nodes was difficult in only one patient. (5) Each of the extirpated lymph nodes from 7 of the 9 patients showed a varying grade of reactive lymphadenitis on histopathology. In conclusion, the occurrence of benign hyperplastic lymph nodes in the previously operated neck region suggested favorable prognosis, though the immunological mechanism is not understood.     

Is lymph node dissection for neuroendocrine carcinoma of the stomach effective as it is for adenocarcinoma?

BackgroundWe evaluated the significance of lymph node dissection for gastric neuroendocrine carcinoma (NEC) by calculating the therapeutic value index for each station.MethodsThis study included 2164 advanced gastric cancer patients (common-type [Common-GC], n = 2125; and gastric NEC [NEC-GC], n = 39). Clinicopathological data were collected, and survival, type of recurrence, and the index for each type of gastrectomy were determined.ResultsNEC-GC was characterized by an older population (P = 0.009), upper tumor location (P = 0.021), frequent venous invasion (P < 0.001), and less neural invasion (P = 0.043). NEC-GC tended to be more frequent in men (P = 0.152), and to be associated with total gastrectomy (P = 0.177) and M1 cases (P = 0.167).The five-year overall survival rates of the Common-GC and NEC-GC groups were 73.8% (95% confidence interval: 71.8–75.6) and 54.7% (37.5–68.9), respectively (P = 0.016).Both groups showed similar index values in each station. Regarding the index of the peri-gastric nodal station (D1 station)/stations away from the stomach (D2 station), although the index of the D1 station was similar in the two groups (41.3 and 43.1), the index of the D2 station in the NEC-GC group was approximately half that of the Common-GC group (10.0 and 5.3).The total recurrence rates of the two groups were similar (P = 0.871). However, the rates of hematogenous and lymphatic recurrence tended to be higher in the NEC-GC group (P = 0.132 and P = 0.152).ConclusionsThe therapeutic efficacy of the D1 station was similar in Common-GC and NEC-GC but that of the D2 station was worse in NEC-GC. Gastrectomy with D2 dissection would be less effective for NEC-GC.     

Is there a role of sentinel lymph node biopsy in ductal carcinoma in situ?: analysis of 587 cases

SummaryBackground The role of sentinel lymph node biopsy (SLNB) in patients with a core needle-biopsy diagnosis of ductal carcinoma in situ (DCIS) has been intensely debated. Core needle-biopsy has an inherent sampling error leading to histologic underestimation of invasive disease. If SLNB is not performed at the time of the definitive operative procedure, patients found to have an invasive cancer, will require a second operative procedure. The study was designed to determine when the risk of finding invasive disease on final pathology in patients with an initial diagnosis of DCIS was sufficiently high to justify the use of SLNB.Methods We identified 587 women with an initial core needle-biopsy diagnosis of DCIS in the prospective Breast Test Wales (BTW) database from 1995 through 2005. A variety of clinical, mammographic and histologic features were identified and correlated with the presence of invasion at excision using univariate and multivariate analyses.Results Median age of patients at the time of diagnosis was 58 years (range 41 to 83 years). 201 patients (36%) were treated by mastectomy and 354 (64%) by breast conservation surgery. 220 of 587 patients (38%) were found to have invasive disease on final pathology. On univariate analysis, the rate of upstaging was related to the presence of a clinically palpable mass and size of the mass (both p<0.0001, Mann–Whitney test); mammographic presence of a mass and size of the mass (both p<0.0001, Mann–Whitney test). Multivariate logistic regression analysis revealed 2 independent predictors of invasive cancer on final pathology: mass on clinical examination (odds ratio [OR], 5.09; p<0.0001) and mammographic mass (OR, 7.37; p<0.0001). Age, grade of DCIS, microinvasion and presence of comedonecrosis did not help in distinguishing between patients with DCIS and those upstaged to invasive carcinoma at definitive surgery. Axillary nodal staging (four node sampling or clearance) was done at the time of surgery in 269 patients. Axillary nodal metastases were found in 35 of 269 patients (13%). All 35 patients had invasive carcinoma on final pathology.Conclusion The indiscriminate use of SLNB in patients with DCIS seems excessive. Our study suggests that patients with a mass on clinical examination or mammogram have an increased risk of invasive disease at the time of definitive operative procedure and should undergo SLNB at the initial procedure. In addition, SLNB should be performed in patients undergoing mastectomy because mastectomy precludes SLNB if invasive disease is subsequently discovered.Presented at the 28^th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, December 8–11, 2005     

Elective supraomohyoid neck dissection for oral cavity squamous cell carcinoma: is dissection of sublevel IIB necessary?

Spinal accessory nerve (SAN) dysfunction and related shoulder disability are common consequences of supraomohyoid neck dissection (SOHND). Nerve dysfunction is usually attributed to excessive nerve traction or devascularization during clearance of the lymph nodes posterior and superior to the SAN (sublevel IIB). The need for routine dissection of this sublevel with elective neck dissection has recently been questioned. This review article discusses whether preserving sublevel IIB lymph nodes is justified in elective SOHND for patients with squamous cell carcinoma (SCC) of the oral cavity. A review of the literature was conducted on studies of sublevel IIB dissection in elective SOHND for SCC of the oral cavity. Only two studies have prospectively investigated the incidence of lymph node metastasis in patients with clinically N0 SCC of the oral cavity. Data from these two prospective pathologic and molecular analyses of neck dissection specimens, including 122 patients with N0 oral cancer, revealed 7.3% with positive neck nodes at sublevel IIB for oral cancer in general, and 12% for tongue cancer in particular. When considering the merits of preservation of sublevel IIB, the benefit of preservation of SAN function has to be weighed against potentially reduced oncologic control.     

Autocrine stimulation of cell proliferation in colonic carcinoma: a biological curiosity or a new therapeutic target?

Chemotherapy has little efficacy in the treatment of advanced colorectal carcinoma. Biological investigation has made evident several autocrine stimulation loops; the best documented one involves epidermal growth factor (EGF): this growth factor stimulates cell proliferation and cell secretion of proteolytic enzymes. Suramin and somatostatin are able to disrupt these loops of stimulation. Clinical studies performed with octreotide, a somatostatin analogue, and suramin have been unsuccessful until now.     

Radiation therapy for squamous cell carcinoma of the tonsillar region: a preferred alternative to surgery?

PURPOSE: There are no definitive randomized studies that compare radiotherapy (RT) with surgery for tonsillar cancer. The purpose of this study was to evaluate the results of RT alone and RT combined with a planned neck dissection for carcinoma of the tonsillar area and to compare these data with the results of treatment with primary surgery. PATIENTS AND METHODS: Four hundred patients were treated between October 1964 and December 1997 and observed for at least 2 years. One hundred forty-one patients underwent planned neck dissection, and 18 patients received induction (17 patients) or concomitant (one patient) chemotherapy. RESULTS: Five-year local control rates, by tumor stage, were as follows: T1, 83%; T2, 81%; T3, 74%; and T4, 60%. Multivariate analysis revealed that local control was significantly influenced by tumor stage (P =.0001), fractionation schedule (P =.0038), and external beam dose (P =.0227). Local control after RT for early-stage cancers was higher for tonsillar fossa/posterior pillar cancers than for those arising from the anterior tonsillar pillar. Five-year cause-specific survival rates, by disease stage, were as follows: I, 100%; II, 86%; III, 82%; IVa, 63%; and IVb, 22%. Multivariate analysis revealed that cause-specific survival was significantly influenced by overall stage (P =.0001), planned neck dissection (P =.0074), and histologic differentiation (P =.0307). The incidence of severe late complications after treatment was 5%. CONCLUSION: RT alone or combined with a planned neck dissection provides cure rates that are as good as those after surgery and is associated with a lower rate of severe complications.