Andrew J. Spillane

Synovial Sarcoma: A Clinicopathologic, Staging, and Prognostic Assessment

PURPOSE Synovial sarcoma (SS) is a common soft tissue sarcoma (STS) with a propensity for young adults and notable sensitivity to chemotherapy (CT). This study provides a current clinicopathologic, staging, and prognostic assessment for SS. The problems with the current American Joint Committee for Cancer (AJCC) Staging System in relation to SS are discussed. METHODS Review of a prospective database supplemented by retrospective data. RESULTS One hundred fifty patients were assessed; median age was 30 years and median follow-up was 52 months. Overall actuarial 5-year survival rate was 57%. Size trend, but not a cutoff of less than 5 cm versus > or = 5 cm, was a prognostic indicator (P <.001). The current AJCC/International Union Against Cancer Staging System differentiated prognosis less well than the recently proposed Royal Marsden Hospital Staging System. Age greater than 20 years at diagnosis implied worse prognosis. A local recurrence event was associated with a worse survival (P <.001). Therapeutic CT was administered to 55 patients. Eleven of 19 patients had an objective response to a combination of ifosfamide and doxorubicin. Four cases had complete response after CT. Twenty-one patients had pulmonary metastasectomy, with an actuarial 5-year survival rate of 23%. CONCLUSION SS tends to affect young people. In this subtype of STS, size trend is the most significant influence on stage and hence survival; however, smaller SSs have an unexpectedly poor prognosis. Adequate local control may affect survival. SS is often chemosensitive, and given its poor prognosis, multicenter trials of adjuvant therapy are warranted.

Accuracy of biopsy techniques for limb and limb girdle soft tissue tumors

Background: The biopsy method of choice for soft tissue sarcomas (STS) of the limb and limb girdle is controversial. There have been no randomized controlled trials that compare incision biopsy with Tru-cut biopsy. We present a large series, which includes an analysis of the effectiveness of Tru-cut core biopsy both in a tertiary referral center as well as from many referring hospitals. This is compared with the other methods of biopsy of all soft tissue tumors (STT) referred to this institution.Methods: A retrospective review of all patients who were referred to Royal Marsden Hospital NHS Trust (RMH) from 1989 to 1998.Results: There were 570 patients (576 lesions) identified. Overall Tru-cut biopsy differentiated benign from malignant tumors with a sensitivity of 99.4%, specificity 98.7%, positive predictive value 99.4%, and negative predictive value 98.7% with similar results for RMH and referral hospitals. Tru-cut identified both tumor subtype and grade in approximately 80% of STS. Incision biopsy had similar sensitivity and specificity for differentiating benign from malignant STT as well as subtype of STS but was less accurate for grade assessment. Tumors from patients who were referred after enucleation had a median maximum tumor diameter (MTD) of 4.9 cm, whereas median MTD of tumors diagnosed at referring hospitals by Tru-cut biopsy was 10.6 cm. (P < 0.001).Conclusion: Tru-cut biopsy is highly sensitive and specific in the diagnosis of STT as well as subtyping and grading of STS. It is equally effective as incision biopsy in all these parameters and has a lesser morbidity. The failure to use Tru-cut biopsy is most likely because of the possibility that STS is not suspected in patients with small tumors even when they are deep to the investing fascia.

Whole-genome landscapes of major melanoma subtypes

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.

Survivorship care plans in cancer: a systematic review of care plan outcomes

Background:Eight years after the Institute of Medicine recommended survivorship care plans (SCPs) for all cancer survivors, this study systematically reviewed the evidence for their use.Methods:Studies evaluating outcomes after implementation of SCPs for cancer survivors were identified by searching databases (MEDLINE, EMBASE and Cochrane). Data were extracted and summarised.Results:Ten prospective studies (2286 survivors) met inclusion criteria (5 randomised controlled trials (RCTs)). Study populations included survivors of breast, gynaecological, colorectal and childhood cancer. Several models of SCP were evaluated (paper based/on-line, oncologist/nurse/primary-care physician-delivered and different templates). No significant effect of SCPs was found on survivor distress, satisfaction with care, cancer-care coordination or oncological outcomes in RCTs. Breast cancer survivors with SCPs were better able to correctly identify the clinician responsible for their follow-up care. One study suggested a positive impact on reducing unmet needs. Levels of survivor satisfaction with, and self-reported understanding of, their SCP were very high. Feasibility was raised by health professionals as a significant barrier, as SCPs took 1–4 h of their time to develop.Conclusions:Emerging evidence shows very few measurable benefits of SCPs. Survivors reported high levels of satisfaction with SCPs. Resource issues were identified as a significant barrier to implementation.

Sentinel lymph node biopsy in patients with thin primary cutaneous melanoma.

ObjectivesTo determine the rate and clinicopathologic factors predictive of sentinel lymph node (SLN) positivity, regional lymph node recurrence, and survival in a large series of patients with thin primary cutaneous melanoma who underwent SLN biopsy (SLNB). Methods:Patients with thin (⩽1 mm) melanomas who underwent SLNB between 1992 and 2009 at Melanoma Institute Australia were identified from the Melanoma Institute Australia database. The association of clinicopathologic features with SLN status, lymph node recurrence, and survival was analyzed. Results:In 432 patients [226 men, 206 women; median age 49.5 years (range: 14.4–85.0 years)], SLNB was positive for metastatic melanoma in 29 (6.7%) patients. No SLN positivity was detected in 37 patients with primary tumor thickness 0.50 mm or less. Breslow thickness (P = 0.012) and presence of lymphovascular invasion (P = 0.018) were the only factors significantly associated with SLN positivity. Regional lymph node recurrence was significantly more common in tumors located in the head/neck region (4/33, 12%) than in extremities (3/245, 1.2%) and trunk (2/154, 1.3%) (P < 0.001). Primary tumor mitotic rate was a significant predictor of melanoma-specific survival (Hazard Ratio [HR] = 1.2, 95% confidence interval: 1.09–1.35, P < 0.001). Conclusions:There is a low but significant rate of SLN positivity in patients with primary melanomas 0.51 to 1.0 mm in thickness. Given its prognostic importance, SLNB should be considered in such patients, particularly if there is lymphatic permeation by melanoma at the primary tumor site. More frequent regional node field recurrences in patients with head/neck primary tumors may be a consequence of complex lymphatic drainage patterns in this region.

Breast cancer-associated fibroblasts induce epithelial-to-mesenchymal transition in breast cancer cells

Cancer-associated fibroblasts (CAFs) play a role in tumour initiation and progression, possibly by inducing epithelial-to-mesenchymal transition (EMT), a series of cellular changes that is known to underlie the process of metastasis. The aim of this study was to determine whether CAFs and surrounding normal breast fibroblasts (NBFs) are able to induce EMT markers and functional changes in breast epithelial cancer cells. Matched pairs of CAFs and NBFs were established from fresh human breast cancer specimens and characterised by assessment of CXCL12 levels, α-smooth muscle actin (α-SMA) levels and response to doxorubicin. The fibroblasts were then co-cultured with MCF7 cells. Vimentin and E-cadherin expressions were determined in co-cultured MCF7 cells by immunofluorescence and confocal microscopy as well as by western blotting and quantitative PCR. Co-cultured MCF7 cells were also assessed functionally by invasion assay. CAFs secreted higher levels of CXCL12 and expressed higher levels of α-SMA compared with NBFs. CAFs were also less sensitive to doxorubicin as evidenced by less H2AX phosphorylation and reduced apoptosis on flow cytometric analysis of Annexin V compared with NBFs. When co-cultured with MCF7 cells, there was greater vimentin and less E-cadherin expression as well as greater invasiveness in MCF7 cells co-cultured with CAFs compared with those co-cultured with NBFs. CAFs have the ability to induce a greater degree of EMT in MCF7 cell lines, indicating that CAFs contribute to a more malignant breast cancer phenotype and their role in influencing therapy resistance should therefore be considered when treating breast cancer.

Effects of Mastectomy on Shoulder and Spinal Kinematics During Bilateral Upper-Limb Movement

Background Shoulder movement impairment is a commonly reported consequence of surgery for breast cancer. Objective The aim of this study was to determine whether shoulder girdle kinematics, including those of the scapula, spine, and upper limb, in women who have undergone a unilateral mastectomy for breast cancer are different from those demonstrated by an age-matched control group. Design An observational study using 3-dimensional kinematic analysis was performed. Methods Women who had a unilateral mastectomy on their dominant-arm side (n=29, mean [±SD] age=62.4±8.9 years) or nondominant-arm side (n=24, mean [±SD] age=59.8±9.9 years), as well as a control group of age-matched women without upper-limb, shoulder, or spinal problems (n=22, mean [±SD] age=58.1±11.5 years), were measured while performing bilateral arm movements in the sagittal, scapular, and coronal planes. All of the women were free of shoulder pain at the time of testing. Data were collected from the glenohumeral joint, the scapulothoracic articulation, and the spine (upper and lower thoracic and lumbar regions) using an electromagnetic tracking system. Results Women following mastectomy displayed altered patterns of scapular rotation compared with controls in all planes of movement. In particular, the scapula on the mastectomy side rotated upward to a markedly greater extent than that on the nonmastectomy side, and women following mastectomy displayed greater scapular excursion than controls. Conclusions The findings suggest that altered motor patterns of the scapula are associated with mastectomy on the same side. Whether these changes are harmful or not is unclear. Investigation of interventions designed to restore normal scapulohumeral relationships on the affected side following unilateral mastectomy for breast cancer is warranted.

High Notch1 protein expression is an early event in breast cancer development and is associated with the HER‐2 molecular subtype

Zardawi S J, Zardawi I, McNeil C M, Millar E K A, McLeod D, Morey A L, Crea P, Murphy N C, Pinese M, Lopez‐Knowles E, Oakes S R, Ormandy C J, Qiu M R, Hamilton A, Spillane A, Soon Lee C, Sutherland R L, Musgrove E A & O’Toole S A
(2010) Histopathology56, 286–296

Proposed Quality Standards for Regional Lymph Node Dissections in Patients With Melanoma

Objective:The experience of the Sydney Melanoma Unit (SMU) is documented to offer quality assurance (QA) standards and an acceptable range for lymph node yield for regional lymph node dissection (RLND) in melanoma patients. Summary Background Data:Surgery is the most effective treatment for melanoma involving lymph nodes (LN). QA for RLND procedures, including adequacy of surgery and histopathology, is not well developed. The number of LN removed is one auditable measurement, known as a reliable predictor of surgical quality in other tumors. Methods:Data were retrieved from the SMU prospective database for patients treated from 1993 to 2006. There were 2039 RLND by SMU surgeons and 324 by non-SMU surgeons. The axilla, groin, cervical dissections of ≤3 levels (CD ≤3) and cervical dissections ≥4 levels (CD ≥4) were assessed. Results:At axillary dissection the mean number of LN resected by SMU surgeons was 21.9 (median 21; range 1–83; 90% of cases ≥10 LN), groin dissection mean 14.5 LN (median 13; range 1–54; 90% of cases ≥7 LN), CD ≤3 dissection mean 19.5 LN (median 18.5; range 1–52; 90% of cases ≥6 LN) and CD ≥4 dissection mean 38.9 LN (median 36; range 5–103; 90% of cases ≥20 LN). SMU surgeons retrieved significantly more LN than non-SMU surgeons for axillary and groin dissections (P < 0.0005). Conclusions:These data benchmark performance for melanoma RLND. Cases with a low node count (below the 90th percentile) should be assessed critically. Standard RLND operations should have a reproducible mean and predictable distribution of LN retrieved.

Defining Lower Limb Lymphedema After Inguinal or Ilio-inguinal Dissection in Patients With Melanoma Using Classification and Regression Tree Analysis

Objective:This study aims to objectively define the criteria for assessing the presence of lymphedema and to report the prevalence of lymphedema after inguinal and ilio-inguinal (inguinal and pelvic) lymph node dissection for metastatic melanoma. Summary Background Data:Lymphedema of the lower limb is a common problem after inguinal and ilio-inguinal dissection for melanoma. The problem is variably perceived by both patients and clinicians. Adding to the confusion is a lack of a clear definition or criteria that allow a diagnosis of lymphedema to be made using the various subjective and objective diagnostic techniques available. Methods:Lymphedema was assessed in 66 patients who had undergone inguinal or ilio-inguinal dissection. Nine patients received postoperative radiotherapy. Assessment was performed by limb circumference measurements at standardized intervals, volume displacement measurements, and volumetric assessment calculated using an infrared optoelectronic perometer technique. Comparisons were made with the contralateral untreated limb. Patient assessment of the severity of lymphedema was compared with objective measures of volume discrepancy. Classification and regression tree analysis was used to determine a threshold fractional leg volume or circumference increase above which patients could self-detect volume changes that they reliably considered to indicate lymphedema. Results:Based on classification and regression tree analysis, both the whole limb perometer volume percentage change ≥15% and the sum of circumferences (of 6 defined sites along the limb) percentage change ≥7% performed well overall in predicting moderate or severe perceived swelling (defined as “lymphedema”). Both definitions predicted lymphedema in approximately the same fraction of patients with misclassification rates of 16% and 15%, sensitivity 56% and 50%, specificity 95% and 100%, respectively. Using ≥15% of whole perometer volume percentage change, 12% of patients with inguinal dissection had lymphedema compared with 23% of patients with ilio-inguinal dissection. Combining both groups, 18% of patients had lymphedema, positive and negative predictive values 82% and 84%. Using the definition ≥7% of the sum of circumferences percent change, 7% of patients with inguinal dissection had lymphedema compared with 19% of patients with ilio-inguinal dissection (overall 14% had lymphedema, positive and negative predictive values 100% and 82%, respectively). Of the variables assessed, only radiotherapy was significantly associated with predicted lymphedema (OR 12.6; 95% CI 1.7 to >100; P = 0.001 using whole perometer change ≥15%; and OR 13.0; 95%CI 1.4 to >100; P = 0.021 using sum circumference change ≥7%). Conclusions:A whole limb perometer volume percentage change of ≥15% and increase in the sum of circumferences of the defined points along the limb ≥7% provide robust definitions of lower limb lymphedema.