Mary S. Brady

Tumour exosome integrins determine organotropic metastasis.

Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

Sentinel Lymph Node Biopsy in the Management of Patients With Primary Cutaneous Melanoma: Review of a Large Single-institutional Experience With an Emphasis on Recurrence

ObjectiveTo analyze the authors’ experience with sentinel lymph node biopsy (SLNB) and the subsequent incidence and pattern of recurrence in patients with positive and negative nodes. Summary Background DataLymphatic mapping with SLNB has become widely accepted in the management of patients with melanoma who are at risk for occult regional lymph node metastases. Because this procedure is relatively new, the pattern of recurrence after SLNB is not yet clear. MethodsAll patients with primary cutaneous melanoma who underwent SLNB from 1991 through 1998 were identified from a prospective single-institution melanoma database. ResultsThree hundred fifty-seven consecutive patients with localized primary cutaneous melanoma who underwent SLNB were identified. The sentinel node was identified in 332 patients (93%) and was positive in 56 (17%). Fourteen percent of patients had developed a recurrence at a median follow-up of 24 months. The median time to recurrence was 13 months. The 3-year relapse-free survival rates for patients with positive and negative nodes were 56% and 75%, respectively. SLN status was the most important predictor of disease recurrence. The site of first recurrence in patients with negative and positive nodes was more commonly locoregional than distant. Reexamination of the SLN in 11 patients with negative nodes with initial nodal and in-transit recurrence showed evidence of metastases in 7 (64%). ConclusionsPatients with positive sentinel nodes have a significantly increased risk for recurrence. The early pattern of first recurrence for patients with negative and positive results is characterized by a preponderance of locoregional sites, similar to that reported in previous series of elective lymph node dissection. These data underscore the need for careful pathologic analysis of the SLN as well as a careful, directed locoregional physical examination in the follow-up of these patients.

Tumor-Infiltrating Lymphocytes Predict Sentinel Lymph Node Positivity in Patients With Cutaneous Melanoma

PURPOSE Tumor-infiltrating lymphocytes (TILs) are considered a manifestation of the host immune response to tumor, but the influence of TILs on outcome remains controversial. Studies evaluating the prognostic significance of TILs were published before routine examination of draining lymph nodes by sentinel lymph node (SLN) biopsy, the most important predictor of survival in patients with melanoma. The prognostic implications of TILs were re-evaluated in a large group of patients undergoing SLN biopsy at our institution. PATIENTS AND METHODS All patients who underwent SLN mapping for primary cutaneous melanoma between January 1996 and July 2005 were evaluated. Univariate and multivariate analyses were performed to assess factors that predict SLN positivity and survival. Factors analyzed included Breslow thickness, ulceration, anatomic site, sex, Clark level, age, mitotic rate, and the presence (brisk or nonbrisk) or absence of TIL. RESULTS Eight hundred eighty-seven patients underwent SLN mapping, and a SLN was identified in 875 patients (98.8%). The SLN was positive for tumor in 156 patients (17.6%). Multivariate analysis revealed that only Breslow thickness (P < .0001), ulceration (P = .0004), male sex (P = .03), and absent TILs (P = .0003) were independently predictive of the presence of SLN metastases. In melanomas with a brisk TIL infiltrate, the probability of a positive SLN was 3.9% as compared with 26.2% for melanomas in which TILs were absent. TILs were not an independent predictive factor for survival. CONCLUSION The absence of TILs, together with increasing Breslow thickness, presence of ulceration and male sex, predicts SLN metastasis in patients undergoing SLN biopsy for primary cutaneous melanoma.

Patterns of detection in patients with cutaneous melanoma

Despite the importance of early detection in preventing mortality from melanoma, little is known regarding how patients with the disease come to diagnosis.

Sentinel lymph node biopsy in patients with diagnostically controversial spitzoid melanocytic tumors.

Melanomas can be difficult to diagnose histologically if they deviate in their growth pattern or cytology only minimally from a nevus. On occasion, even experts on melanocytic lesions may not reach a consensus on whether a lesion is a benign but unusual nevus or a malignant melanoma mimicking a nevus. This diagnostic dilemma is particularly well known for the distinction of Spitz nevus from melanoma. Diagnostic uncertainty and disagreement among consultant pathologists lead to confusion about the prognosis and clinical management of patients. In this study we present the clinical and pathologic findings of 10 patients with diagnostically controversial melanocytic tumors, who underwent sentinel lymph node biopsy. In all of these cases, the diagnostic controversy among experts was between Spitz nevus and melanoma. Seven patients were female, and three were male, ranging in age from 7 to 46 years (mean 21 years). Histologic examination of the sentinel lymph nodes revealed tumor deposits in the lymph node parenchyma in 5 of 10 patients. Among patients with positive sentinel lymph nodes, two had satellite nodules and one showed additional tumor deposits in three nonsentinel regional lymph nodes. All patients are alive and free of disease with a follow-up of 10–54 months (mean 34 months). Our study illustrates the role of a sentinel lymph node biopsy in the evaluation of patients with diagnostically controversial melanocytic tumors. Although the presence of metastatic tumor deposits in the sentinel lymph node supports the diagnosis of malignant melanoma, further studies are needed to determine the prognostic significance of the sentinel lymph node findings in such patients.

Adult urological sarcoma.

From July 1982 to December 1989, 43 of 1,583 adults (2.7%) with soft tissue sarcoma admitted to the Memorial Sloan-Kettering Cancer Center (MSKCC) had tumors arising from the urinary tract and male genital tract (urological sarcoma). The most common site of origin of the tumor was paratesticular (14 patients), followed by the prostate/seminal vesicle (12), bladder (10) and kidney (7). The most common histological type was leiomyosarcoma (19 patients), followed by rhabdomyosarcoma (14), liposarcoma (5) and 5 other histological sarcoma categories (angiosarcoma, malignant fibrous histiocytoma, mesenchymoma and 2 undifferentiated sarcomas). Most of the tumors were high grade (86%) and more than half (56%) were greater than 5 cm. in diameter. A total of 9 patients (21%) presented with metastatic disease, 8 of whom had rhabdomyosarcoma. Complete resection with negative microscopic margins was possible in 58% of the patients. Actuarial relapse-free survival for all patients at 3 and 5 years was 55% and 40%, respectively. There were no significant differences in survival based on patient age, sex or histological tumor type. Favorable prognostic variables by univariate analysis included tumor diameter less than 5 cm., low histological grade, paratesticular or bladder tumor site and complete surgical resection. Application of the MSKCC sarcoma staging system, which is based on grade, size, depth and presence or absence of metastasis, was useful to predict survival. In our experience patients with stage 3 (high grade, greater than 5 cm., 15 patients) or stage 4 (metastatic disease, 9 patients) had a combined 3-year relapse-free survival rate of only 26% and they should be considered candidates for adjuvant treatment protocols.

Prediction of nonsentinel lymph node status in melanoma.

Background: Most melanoma patients with a positive sentinel lymph node dissection (SLND) undergo a completion lymph node dissection (CLND) that does not yield additional positive nonsentinel lymph nodes (NSLN). This study was designed to determine if NSLN status can be predicted using patient, primary tumor, and sentinel lymph node (SLN) characteristics.Methods: The study population includes melanoma patients who had a positive SLND and subsequently underwent CLND retrieved from our prospective institutional melanoma database. The primary tumor and SLN pathologies were prospectively determined. An Size/Ulceration (SU) score was derived by assigning 1 point for primary tumor ulceration and 1 point for SLN tumor size >2 mm.Results: Ninety-eight patients had a positive SLND and underwent CLND. Sixteen of these patients had a positive NSLN. On univariate analysis, primary tumor characteristics (thickness, ulceration, no regression), SLN metastasis characteristics (size >2 mm, location nonsubcapsular), and SU score were all significantly associated with positive NSLN status. However, on multivariate analysis, only the SU score was a significant independent predictor of NSLN status. No patient with an SU score of 0 had a positive NSLN.Conclusions: The SU score is predictive of NSLN status in patients with a positive SLND. Patients with an SU score of 0 are very unlikely to have positive NSLNs at CLND.

Cutaneous desmoplastic melanoma: reappraisal of morphologic heterogeneity and prognostic factors.

Desmoplastic melanoma (DM) is a variant of melanoma, which may be confused with nonmelanocytic benign or malignant spindle cell proliferations. The histologic hallmark of DM is the presence of fusiform melanocytes dispersed in a prominent collagenous stroma. Phenotypic heterogeneity of DM is underrecognized. Desmoplasia may be prominent throughout the entire tumor (“pure” DM) or represent a portion of an otherwise nondesmoplastic melanoma (“combined” DM). We reviewed melanomas with desmoplasia from 92 patients seen at a single institution between 1980 and 2002. Fifty-five of the tumors were pure DM. Thirty-seven were classified as combined. Mean follow-up of patients was 46 months for those alive at the last follow-up. Univariate analysis of clinical and pathologic parameters revealed four significant variables for disease-free survival: Clark level (IV vs. V; P = 0.005), DM subtype (pure vs. combined; P = 0.01), tumor mitotic rate (<1, 1–4, >4 mitoses/mm2; P = 0.01), and tumor thickness (<1 mm, 1–4 mm, >4 mm; P = 0.02). Only histologic subtype (P = 0.02) and Clark level (P = 0.05) were independently significant by Cox regression analysis. Our results indicate that distinguishing pure from combined forms of DM is clinically relevant for prognosis (pure forms being associated with longer disease-specific survival). Failure to make this distinction may account for conflicting reports in the literature on the biologic behavior and prognosis of DM.

Childhood melanoma survival

Melanoma in childhood is uncommon. Some believe that melanoma among children is associated with a better prognosis than among adults.

Five hundred patients with Merkel cell carcinoma evaluated at a single institution.

Objective:To identify factors associated with survival in Merkel cell carcinoma (MCC). Background:Merkel cell carcinoma is a rare cutaneous neoplasm. Staging and treatment are based on studies, which incompletely characterize the disease. Methods:Review of a prospective database was performed. Overall survival (OS) was estimated by the Kaplan-Meier method. Disease-specific death (DSD) was analyzed by the competing risks method. Factors associated with OS and DSD were determined by the log-rank test and Grays test, respectively. Results:A total of 500 patients with MCC treated at our institution from 1969 to 2010 were identified. Eighty-eight patients presented older than 6 months after diagnosis and were excluded from further analysis. Of the remaining 412 patients, the median age at diagnosis was 71 years. Median follow-up was 3 years. Fifty percent of patients died during follow-up: 25% died of disease, 24% died of other causes. Five-year OS and DSD were 56% and 30%, respectively. Pathologic stage and lymphovascular invasion were independent predictors of DSD. Patients with metastatic disease (stage 4) or clinically positive lymph nodes (stage 3b) had increased DSD compared with patients with microscopically positive (stage 3a) or negative lymph nodes (stage 1 and 2). There was no difference in DSD between stage 3a or 2 compared with stage 1. Importantly, only 1 of 132 patients without lymphovascular invasion died of MCC. Conclusions:OS is a poor measure of the influence of MCC on life expectancy. The presence of lymphovascular invasion and clinically, but not microscopically, positive lymph nodes were associated with increased DSD. These factors should be incorporated into MCC staging and treatment recommendations.