Microscopic Extension Research Articles

Surgical Margins and Handling of Soft-Tissue Sarcoma in Extremities: A Clinical Practice Guideline

In limb salvage surgery for extremity soft-tissue sarcoma (sts), what is an adequate surgical margin?What is the appropriate number of samples to take from the margins of a surgical resection specimen?What is the appropriate handling of surgical resection specimens? Surgery is the primary treatment for extremity sts. The combination of radiotherapy with surgery allows for limb salvage by using radiation to biologically "sterilize" microscopic extensions of tumour and to spare neurovascular and osseous structures. Adjuvant chemotherapy in sts-except for rhabdomyosarcoma and Ewing sarcoma-continues to be controversial. The medline and embase databases (1975 to June 2011) and the Cochrane Library were searched for pertinent studies. The Web sites of the main guideline organizations and the American Society of Clinical Oncology conference proceedings (2007-2010) were also searched. Thirty-three papers, including four guidelines, one protocol, and one abstract, were eligible for inclusion. The data suggest that patients with clear margins have a better prognosis, but no prospective studies have indicated how wide margins should be. In limb-salvage surgery for extremity sts, the procedure should be planned to achieve a clear margin. However, to preserve functionality, surgery may result in a very close (<1 cm) or even microscopically positive margin. In this circumstance, the use of preoperative or postoperative radiation should be considered. No studies described the optimal number of tissue sections required to assess adequacy of excision nor the appropriate handling of surgical resection specimens. The Sarcoma Disease Site Group made its recommendations based on expert opinion and consensus.

Radioactive iodine ablation does not prevent recurrences in patients with papillary thyroid microcarcinoma

Although papillary thyroid microcarcinoma (PTMC) has a favourable long-term prognosis, disease recurrence after initial treatment remains a problem and controversy exists regarding the role of radioactive iodine (RAI) ablation in PTMC. We performed this study to evaluate the effect of RAI ablation on disease recurrence in patients with PTMC. Between 1994 and 2004, 2579 patients underwent thyroid surgery for thyroid cancer at Samsung Medical Center. Among these patients, 704 patients with PTMC presumed disease-free after initial treatment were followed up for disease recurrence (median, 64 months; range, 1-185 months). Patients with PTMC with microscopic extrathyroidal extension, cervical lymph node metastases or multifocality were considered to be in the intermediate-risk group for recurrence. Disease recurrence was found in six patients at a median of 29 months (range, 10-70 months) after initial treatment; all six patients with recurrent tumours had received RAI treatment after total thyroidectomy. Disease-related mortality was not observed, even after recurrence. Based on a Cox regression model considering the standardized inverse probability of treatment weight (IPTW) within each propensity score stratum of patients with a similar likelihood of having received RAI ablation, the likelihood ratio for recurrence did not differ between the RAI ablation group and no RAI group (P = 0·17). When we performed a subgroup analysis considering only patients with PTMC at intermediate-risk for recurrence, RAI ablation again did not have a significant effect on recurrence (P = 0·79). Radioactive iodine ablation after total thyroidectomy in low- and intermediate-risk patients with PTMC did not prevent recurrent tumours. Future randomized, controlled, multicenter prospective trials involving a larger sample of patients followed-up for a longer duration are warranted to confirm our findings.

Evaluation of microscopic tumor extension in early-stage cervical cancer: quantifying subclinical uncertainties by pathological and magnetic resonance imaging findings

We performed a detailed analysis of hysterectomy specimens of uterine cervical cancer to determine the appropriate length of uterine body to include within the clinical target volume. Between 2008 and 2011, 54 patients with uterine cervical carcinoma underwent hysterectomy. Those with quality pre-operative magnetic resonance imaging (MRI) data were included for analysis. Tumor sizes measured by MRI and microscopy were compared with regard to brachytherapy-oriented parameters. Detailed descriptive analysis focusing on the extent of tumor involvement was also performed. A total of 31 specimens were analyzed. The median maximal tumor length measured by MRI was slightly shorter than microscopic length (19 vs. 24 mm, respectively), while the maximal radius was almost identical. No tumors with a maximal size <2 cm by MRI (n = 6) extended to the uterine body ≥ 1/3. The majority of maximal tumor length underestimation on MRI was within 1 cm. Precise tumor delineation can be made by MRI. For patients with tumors <2 cm on MRI, treating the entire uterine body length may not be necessary. A 1-cm margin around an MRI-based gross tumor seems to be adequate to cover the actual tumor involvement.

Comparison of microscopic (pT3a) and gross extravesical extension (pT3b) in pathological staging of bladder cancer: analysis of patient outcomes

To determine the prognostic value of pT3 bladder urothelial carcinoma substaging in patients without lymphatic involvement. Pathologic and clinical data were reviewed on patients who underwent radical cystectomy for urothelial carcinoma between 1991 and 2010. Of the 460 reviewed patients, 74 patients were diagnosed with pathologic T3No urothelial carcinoma of the bladder. The impact of pathologic substaging (pT3a vs. pT3b) was examined to determine the effect on overall and disease-specific survival. Five years disease-specific and overall survival rates were 46.9 % and 39.6 % for patients with pT3aNo tumor, whereas these ratios were 34.4 and 30.3 %, respectively, for patients with pT3bNo tumor (p > 0.05). Mean disease-specific survival time was 43.94 ± 6.50 months for pT3aNo, while it was 39.01 ± 7.19 months for pT3bNo (p = 0.539). In multivariate cox regression analysis, age (p = 0.459), gender (p = 0.710), urinary diversion type (p = 0.088), and pT3 substaging (p = 0.554) were not noticed as an independent predictive factor for survival. Macroscopic extravesical extension (pT3b) is not associated with a worse outcome than pT3a disease in lymph node-negative cases of bladder urothelial carcinoma.

Associations between body mass index and clinico‐pathological characteristics of papillary thyroid cancer

Epidemiological studies have demonstrated that excess weight increases the risk of thyroid cancer. However, the associations between excess weight and prognostic factors for thyroid cancer are uncertain. We evaluated the relationships between body mass index (BMI) and clinico-pathological features and outcomes of papillary thyroid cancer (PTC). Retrospective analysis of 2057 patients with PTC was performed. Patients were grouped according to BMI (underweight, normal weight, overweight and obesity)-based World Health Organization standardized categories. Logistic regression models were used to assess the relationships between BMI and clinico-pathological features of PTC. A Cox proportional hazards model was used to examine the association between BMI and disease recurrence. A 5-kg/m(2) increase in BMI was associated with PTC tumours larger than 1 cm [odds ratio (OR) 1.31, P < 0.001], with microscopic extrathyroidal invasion (OR 1.23, P = 0.006), and with advanced tumour-node-metastasis (TNM) stage (OR, 1.30, P = 0.003), which is independent of confounding variables such as gender, age, serum TSH, total cholesterol and fasting glucose level. The multivariate-adjusted OR [95% confidence intervals (CI)] in the overweight (25.0-29.9 kg/m(2)) and obese (BMI ≥ 30) groups for tumours larger than 1 cm were 1.41 (1.10-1.81) and 2.17 (1.23-3.82), respectively, compared to the normal weight group (BMI 18.5-24.9). The multivariate-adjusted OR (95% CI) for microscopic extrathyroidal extension in the obesity group was 1.88 (1.06-3.32), and the OR for advanced TNM stage in the overweight group was 1.35 (1.02-1.79) compared to the normal weight group. During follow-up (median, 84 month; range, 1-185), 43 patients (2.1%) experienced recurrence. There were no significant differences in recurrence of PTCs among BMI groups. Higher BMI was strongly associated with larger tumour size, extrathyroidal invasion and advanced TNM stage of PTCs. However, there was no difference in recurrence rate among BMI groups. This study suggests that excess weight is associated with aggressive features of PTCs. Further studies with long-term follow-up are needed to confirm this finding.

The prognostic value of the metastatic lymph node ratio and maximal metastatic tumor size in pathological N1a papillary thyroid carcinoma

The presence of central neck lymph node (LN) metastases (defined as pN1a according to Tumor Node Metastasis classification) in papillary thyroid cancer (PTC) is known as an independent risk factor for recurrence. Extent of LN metastasis and the completeness of removal of metastatic LN must have an impact on prognosis but they are not easy to measure. Moreover, the significance of the size of metastatic tumors in LNs has not been clarified. This study was to evaluate the impact of the extent of LN metastasis and size of metastatic tumors on the recurrence in pathological N1a PTC. This retrospective observational cohort study enrolled 292 PTC patients who underwent total thyroidectomy with central neck dissection from 1999 to 2005. LN ratio was defined as the number of metastatic LNs divided by the number of removed LNs, which was regarded as variable reflecting both extent of LN metastasis and completeness of resection, and LN size as the maximal diameter of tumor in metastatic LN. The significant risk factors for recurrence in univariate analysis were large primary tumor size (defined as larger than 2 cm), high LN ratio (defined as higher than 0.4), and presence of macrometastasis (defined as larger than 0.2 cm). Age, sex, clinical node status, and microscopic perithyroidal extension had no effect on recurrence. In multivariate analysis, high LN ratio and presence of macrometastasis were independent risk factors for recurrence. LN ratio and size of metastatic nodes had a significant prognostic value in pathological N1a PTC. We suggest that risk stratification of pathological N1a PTC according to the pattern of LN metastasis such as LN ratio and size would give valuable information to clinicians.

Extent of local invasion and safe resection in cT1–2 tonsil cancer

Although intraoral resection of small-sized tonsil cancer achieves excellent tumor control, the extent of local invasion and adequate safety margin in resection have not been studied. Thus, we aim to determine the extent of local invasion in terms of mucosal spread and deep infiltration in stage T1-2 tonsil cancer. We re-analyzed the surgical specimens from 49 cT1-2 tonsil cancers. Microscopic tumor cell extension from the tumor gross boundary of specimens was assessed in representative sections of each tumor. We also tested whether local extension correlates with human papilloma virus (HPV) status of tumors. The extent of microscopic deep invasion from the gross tumor border was 0.52 ± 0.41 mm, which was significantly less than that of mucosal spread (0.83 ± 0.61 mm, P = 0.01) in cT1-2 tonsil cancer. The microscopic deep invasion correlated with tumor size (rho = 0.703, P < 0.001). We found tumor invasion into superior constrictor muscles in 58.1%, no cases of tumor invasion into the deep fascia. In terms of HPV status (genotyping plus p16 staining), there were no differences in microscopic tumor extension. Our detailed pathologic analyses confirm that an oropharyngectomy including the superior constrictor muscle is an oncologically safe procedure for stage T1-2 tonsil cancer.

Significance of Microscopic Disease Extension in Regional Control of Lung Cancer

Significance of Microscopic Disease Extension in Regional Control of Lung Cancer

Radiologic Tumor Regression and Correlation With Pathologic Findings After Neoadjuvant Therapy for Non-small Cell Lung Cancer

Radiologic Tumor Regression and Correlation With Pathologic Findings After Neoadjuvant Therapy for Non-small Cell Lung Cancer

Radiation Therapy for Nasopharyngeal Carcinoma Using Simultaneously Integrated Boost (SIB) Protocol: A Comparison Planning Study between Intensity Modulated Arc Radiotherapy vs. Intensity Modulated Radiotherapy

The aim of this paper is to compare the dosimetric difference between intensity-modulated arc therapy (IMAT) and conventional intensity-modulated radiation therapy (IMRT) for radiotherapy of nasopharyngeal carcinoma (NPC) using simultaneously integrated boost (SIB) protocol. Ten patients with nasopharyngeal carcinoma underwent SIB protocol were retrospectively studied. The plan target volume (PTV) of NPC contained nasopharynx gross target volume and the positive neck lymph nodes, PTV1 contained the high-risk sites of microscopic extension and the whole nasopharynx and PTV2 contained the low-risk sites. The prescription dose of PTV was 66 Gy/30 fractions, and for PTV1 60 Gy/30 fractions and for PTV2 54 Gy/30 fractions. IMAT (two 358° arcs) and IMRT (7 fields) plans were designed for each patients using SIB strategies. The monitor unit (MU), treatment time (T) and dosimetric difference between IMRT and IMAT were compared. IMAT can achieve better conformal index (CI) than IMRT (P < 0.05) for all PTVs, while no significant difference were found in homogeneity index (HI) (P > 0.05). There's no significant difference found in radiation dose of brain stem, lenses and parotids, while the maximum dose of spinal cord of IMAT was higher than IMRT (P < 0.05). The monitor unit of IMRT (1308 ± 213) was more than IMAT (606 ± 96) (P < 0.05), while the treatment time of IMRT (540 ± 160S) was more than IMAT (160 ± 10S). This study shows that IMAT using SIB strategies for NPC radiotherapy can achieve similar target coverage with better conformity with less MU and delivery time comparing to IMRT.

Recommendations for CTV margins in radiotherapy planning for non melanoma skin cancer

PurposeTo provide practice guidelines for delineating clinical target volume (CTV) for radiotherapy planning of non melanoma (NMSC) skin cancers. Methods and materialsA prospective, single arm, study. Preoperatively, a radiation oncologist outlined the boundary of a gross lesion, and drew 5-mm incremental marks in four directions from the delineated border. Under local anesthesia, the lesion was excised, and resection margins were assessed microscopically by frozen section. Once resection margins were clear, the microscopic tumor extent was calculated using the presurgical incremental markings as references. A potential relationship between the distance of microscopic tumor extension and other variables was analyzed. ResultsA total of 159 lesions in 150 consecutive patients, selected for surgical excision with frozen section assisted assessment of resection margins, were accrued. The distance of microscopic tumor extension beyond a gross lesion varied from 1mm to 15mm, with a mean of 5.3mm. The microscopic tumor extent was positively correlated with the size of gross lesion, histology and number of surgical attempts required to obtain a clear margin. To provide a 95% or greater chance of covering microscopic disease we make the following recommendations for CTV margins; 10mm for BCC less than 2cm, 13mm for BCC greater than 2cm, 11mm for SCC less than 2cm, and 14mm for SCC greater than 2cm. ConclusionsTumors greater than 2cm and SCC histology required larger margins to adequately cover the microscopic extent of disease. This information is crucial in radiation planning of NMSC. Clinicians should be cautioned, as these guidelines may not offer optimum treatment for patients with extremely large or small lesions.

External Validation of a Risk Model to Predict Recurrence-Free Survival After Radical Cystectomy in Patients With Pathological Tumor Stage T3N0 Urothelial Carcinoma of the Bladder

Patients with stage pT3N0 urothelial bladder cancer vary in outcome after radical cystectomy. To improve prognosis estimation a model was recently developed that defines 3 risk groups for recurrence-free survival based on pT substaging, lymphovascular invasion and positive surgical margin. We present what is to our knowledge the first external validation of this risk model. Analogous to the risk model derivation cohort our study group comprised 472 patients with stage pT3, pN0, cM0 disease without perioperative chemotherapy and with a median followup of 42 months (IQR 20-75). The primary end point was recurrence-free survival. The effect of variables was determined by univariate and multivariate Cox regression analysis, and predictive accuracy was determined by ROC analysis. Stage pT3aN0 and pT3bN0 cases showed significantly different recurrence-free survival after 5 years (51% vs 29%, p<0.001). In the multivariate Cox model pT3 substage (HR 1.86, p<0.001), lymphovascular invasion (HR 1.48, p=0.002), positive surgical margins (HR 1.90, p=0.030) and patient age with a dichotomy at 70 years (HR 1.51, p=0.001) had an independent effect on recurrence-free survival. In the low (221 patients or 47%), intermediate (184 or 39%) and high (67 or 14%) risk groups the 5-year recurrence-free survival rate was 55%, 45% and 13%, respectively (p<0.001). The concordance index of the risk model to predict recurrence-free survival was 0.64 (95% CI 0.59-0.69). This user friendly risk model can be recommended to estimate prognosis in patients with stage pT3N0 after radical cystectomy. Patients at high risk showed clearly compromised recurrence-free survival and should be included in adjuvant therapy studies.

A universal crack extension criterion based on the equivalent stress gradient: I. theory and numerical verification

In this contribution, the microscopic fracture mechanism and extension criterion for mixed type crack in ductile material under plane mixed mode loading are investigated in details. A universal extension criterion for the mixed type crack, i.e. the crack propagates along the direction of the maximum gradient of equivalent stress, is suggested. This new criterion is used to predict the propagation direction of mixed type crack, showing a good agreement with other theories for different types of mode mixity. Moreover, the numerical verification is also carried out for the case of an edge crack with different mixed mode loadings. Finally, a potential application to three-dimensional fracture in the ductile material induced by holes is also discussed.

Subungal malignant eccrine porocarcinoma: An unusual presentation

We describe the case of a 58-year-old man who presented with a lesion consistent with paronychia on his right middle finger. Biopsies were suspicious for squamous cell carcinoma, and the patient was taken to the operating room for definitive excision. Frozen section revealed microscopic extension into the distal phalanx. The dorsal half of the phalanx was excised, which then had a negative margin. Histologic examination was consistent with a malignant eccrine poroma (porocarcinoma), an uncommon malignancy which is rarely found on the hands. Subungal and periungal porocarcinomas have historically been treated with distal finger amputations, but our patient fortunately has had no local recurrence or lymphatic involvement to date.

In SilicoModelling of Tumour Margin Diffusion and Infiltration: Review of Current Status

As a result of advanced treatment techniques, requiring precise target definitions, a need for more accurate delineation of the Clinical Target Volume (CTV) has arisen. Mathematical modelling is found to be a powerful tool to provide fairly accurate predictions for the Microscopic Extension (ME) of a tumour to be incorporated in a CTV. In general terms, biomathematical models based on a sequence of observations or development of a hypothesis assume some links between biological mechanisms involved in cancer development and progression to provide quantitative or qualitative measures of tumour behaviour as well as tumour response to treatment. Generally, two approaches are taken: deterministic and stochastic modelling. In this paper, recent mathematical models, including deterministic and stochastic methods, are reviewed and critically compared. It is concluded that stochastic models are more promising to provide a realistic description of cancer tumour behaviour due to being intrinsically probabilistic as well as discrete, which enables incorporation of patient-specific biomedical data such as tumour heterogeneity and anatomical boundaries.

Long-Term Survival after Gamma Knife Radiosurgery in a Case of Recurrent Glioblastoma Multiforme: A Case Report and Review of the Literature

The management of recurrent glioblastoma is highly challenging, and treatment outcomes remain uniformly poor. Glioblastoma is a highly infiltrative tumor, and complete surgical resection of all microscopic extensions cannot be achieved at the time of initial diagnosis, and hence local recurrence is observed in most patients. Gamma Knife radiosurgery has been used to treat these tumor recurrences for select cases and has been successful in prolonging the median survival by 8–12 months on average for select cases. We present the unique case of a 63-year-old male with multiple sequential recurrences of glioblastoma after initial standard treatment with surgery followed by concomitant external beam radiation therapy and chemotherapy (temozolomide). The patient was followed clinically as well as with surveillance MRI scans at every 2-3-month intervals. The patient underwent Gamma Knife radiosurgery three times for 3 separate tumor recurrences, and the patient survived for seven years following the initial diagnosis with this aggressive treatment. The median survival in patients with recurrent glioblastoma is usually 8–12 months after recurrence, and this unique case illustrates that aggressive local therapy can lead to long-term survivors in select situations. We advocate that each patient treatment at the time of recurrence should be tailored to each clinical situation and desire for quality of life and improved longevity.

Cancer Permeates Locally within Ontogenetic Compartments: Clinical Evidence and Implications for Cancer Surgery

The pathophysiologic process of local tumor spread is regarded as an isotropic infiltration of microscopic extensions of the malignant lesion irrespective of tissue boundaries. By contrast, the ontogenetic compartment theory states that malignant solid tumors are locally confined, for a relatively long phase during their natural course, to a permissive compartment derived from a common primordium in embryonic development. Tumor permeation is isotropic within the permissive ontogenetic compartment, but it is suppressed at the compartment borders. The validity of the ontogenetic compartment theory has been shown for cancer of the rectum and of the female lower genital tract. It is hypothesized that ontogenetic compartment resection, the translation of the theory into cancer surgery, holds a great potential to improve oncologic treatment results.

The impact of microscopic extrathyroid extension on outcome in patients with clinical T1 and T2 well-differentiated thyroid cancer

To report the impact of microscopic extrathyroid extension (ETE) on outcome in patients with cT1/cT2 well-differentiated thyroid cancer (WDTC), and to determine the effect of extent of surgery and adjuvant radioactive iodine (RAI) treatment on outcome in patients with microscopic ETE. From an institutional database, we identified 984 patients (54%) who underwent surgery for cT1/T2N0 disease. Of these, 869 patients were pT1/T2 and 115 were upstaged to pT3 based on the finding of microscopic ETE. Disease-specific survival (DSS) and recurrence-free survival (RFS) were analyzed for each group using the Kaplan-Meier method. In the pT3 group, factors predictive of outcome were analyzed by univariate and multivariate analyses. There was no difference in the 10-year DSS (99% vs 100%; P = .733) or RFS (98% vs 95%; P = .188) on comparison of the pT1/pT2 and pT3 cohorts. Extent of surgery and administration of postoperative RAI were not significant for recurrence on univariate or multivariate analysis in the pT3 cohort. Outcomes in patients with cT1T2N0 WDTC are excellent and not affected by microscopic ETE. The extent of resection and administration of postoperative RAI in patients with microscopic ETE does not impact survival or recurrence.

Inverted papilloma with associated carcinoma of the nasal cavity and paranasal sinuses: Treatment outcomes

Conclusions: Degenerated inverted papilloma is a rare, aggressive, and lethal disease. To avoid missing the target, it is absolutely necessary to consider the microscopic extension even in cases of complete exeresis and to irradiate the whole of the adjacent sinuses. A dose increase may lead to better locoregional control. Objective: To evaluate overall survival and progression-free survival of external radiotherapy in the management of nasal cavity and paranasal sinus inverted papilloma with associated carcinoma. Methods: Clinical data from 11 patients treated by surgery followed by external radiotherapy (three-dimensional conformational radiotherapy until 2007 then intensity-modulated radiation therapy) for degenerated inverted papilloma in the Léon Bérard Cancer Centre between 1985 and 2009 were retrospectively analyzed. Results: Five patients (45%) had a local recurrence and died from their recurrence. Three had a premature recurrence, just before or during radiotherapy. We could not determine the prognostic factors for overall survival and progression-free survival.

The impact of microscopic disease on the tumor control probability in non-small-cell lung cancer

PurposeTo indicate which clinical target volume (CTV) margin (if any) is needed for an adequate treatment of non-small-cell lung cancer (NSCLC) using either 3D conformal or stereotactic radiotherapy, taking the distribution of the microscopic disease extension (MDE) into account. Methods and materialsOn the basis of the linear-quadratic biological model, a Monte-Carlo simulation was used to study the impact of MDE and setup deviations on the tumor control probability (TCP) after typical 3D conformal and stereotactic irradiation techniques. Setup deviations were properly accounted for in the planning target volume (PTV) margin. Previously measured distributions of MDE outside the macroscopic tumor in NSCLC patients were used. The dependence of the TCP on the CTV margins was quantified. ResultsThe presence of MDE had a demonstratable influence on the TCP in both the 3D conformal and the stereotactic technique when no CTV margins were employed. The impact of MDE on the TCP values was greater in the 3D conformal scenario (67% TCP with MDE; 84% TCP without MDE) than for stereotactic radiotherapy (91% TCP with MDE; 100% TCP without MDE). Accordingly, an increase of the CTV margin had the greatest impact for the 3D conformal technique. Larger setup errors, with appropriate PTV margins, lead to an increase in TCP for both techniques, showing the interdependence of CTV and PTV margins. ConclusionsMDE may not always be eradicated by the beam penumbra or existing PTV margins using either 3D conformal or stereotactic radiotherapy. Nonetheless, TCP modeling indicates an overall local control rate above 90% for the stereotactic technique, while a non-zero CTV margin is recommended for better local control of MDE when using the 3D conformal technique.