We used the lesional steps in tumor progression and multivariable logistic regression to develop a prognostic model for primary, clinical stage I cutaneous melanoma. This model is 89% accurate in predicting survival. Using histologic criteria, we assigned melanomas to tumor progression steps by ascertaining their particular growth phase. These phases were the in situ and invasive radial growth phase and the vertical growth phase (the focal formation of a dermal tumor nodule or dermal tumor plaque within the radial growth phase or such dermal growth without an evident radial growth phase). After a minimum follow-up of 100.6 months and a median follow-up of 150.2 months, 122 invasive radial-growth-phase tumors were found to be without metastases. Eight-year survival among the 264 patients whose tumors had entered the vertical growth phase was 71.2%. Survival prediction in these patients was enhanced by the use of a multivariable logistic regression model. Twenty-three attributes were tested for entry into this model. Six had independently predictive prognostic information: (a) mitotic rate per square millimeter, (b) tumor-infiltrating lymphocytes, (c) tumor thickness, (d) anatomic site of primary melanoma, (e) sex of the patient, and (f) histologic regression. When mitotic rate per square millimeter, tumor-infiltrating lymphocytes, primary site, sex, and histologic regression are added to a logistic regression model containing tumor thickness alone, they are independent predictors of 8-year survival (P less than .0005).

Model Predicting Survival in Stage I Melanoma Based on Tumor Progression

BACKGROUND
Primary cutaneous melanoma is often infiltrated by lymphocytes that provide the opportunity to study what may be the local immunologic reaction to the tumor and to correlate the presence of these lymphocytes with overall survival. In an attempt to delineate the histologic diagnostic criteria, to classify different categories of lymphocytic infiltrates, previously described by Elder et al. as brisk, nonbrisk, and absent, and to verify their prognostic significance, we reviewed 285 consecutive cases of primary cutaneous melanomas (American Joint Committee on Cancer Stage I and II).

METHODS
In addition to clinical variables (age, sex, and location of tumor) and the presence of tumor infiltrating lymphocytes in the vertical growth phase, the histopathologic attributes reviewed included mitotic rate, thickness, and regression. The results were derived from independent histopathologic review by two pathologists (C.G.C., M.C.M., Jr.) on separate occasions. A multivariate analysis of survival was performed with the Cox's regression model.

RESULTS
The 5- and 10-year survival rates for melanoma with a vertical growth phase and a brisk infiltrate were 77% and 55%, respectively. For tumors with a nonbrisk infiltrate, the 5- and 10-year survival rates were 53% and 45%, respectively, and for tumors with absent tumor infiltrating lymphocytes, the 5- and 10-year survival rates were 37% and 27%, respectively. Mitotic index, thickness, and tumor infiltrating lymphocytes were statistically (univariate analysis) significant prognostic factors (P = 0.003, 0.000001, 0.0003, respectively), whereas the presence or absence of regression is not. In the univariate statistical analysis, the sex of patients and site of melanoma also were statistically significant (P = 0.00001 and 0.002 respectively), whereas age (P = 0.98) was not statistically significant. The multivariate analysis of thickness, mitotic rate, and tumor infiltrating lymphocytes showed that thickness and presence of tumor infiltrating lymphocytes were significant and independent histologic prognostic factors. With regard to the clinical factors, sex retained its independent prognostic significance. The histologic characteristics of melanoma with vertical growth phase (brisk, nonbrisk, and absent) are exemplified.

CONCLUSIONS
We demonstrated that when categories of tumor infiltrating lymphocytes are strictly defined, they indeed have very strong predictive value for primary cutaneous melanomas with a vertical growth phase. This work confirms the work of Clark et al. and fully illustrates the brisk, nonbrisk, and absent categories of infiltration. Finally, a multivariate analysis comparing thickness, mitotic rate and presence of tumor infiltrating lymphocytes showed that only thickness and presence of tumor infiltrating lymphocytes are significant and independent positive histologic prognostic factors. Cancer 1996;77:1303-10.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/%28SICI%291097-0142%2819960401%2977%3A7%3C1303%3A%3AAID-CNCR12%3E3.0.CO%3B2-5

Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma.

Purpose To determine whether density and distribution of tumor-infiltrating lymphocytes (TILs; TIL grade) is an independent predictor of sentinel lymph node (SLN) status and survival in patients with clinically localized primary cutaneous melanoma. Methods From the Melanoma Institute Australia database, 1,865 patients with a single primary melanoma ≥ 0.75 mm in thickness were identified. The associations of clinical and pathologic factors with SLN status, recurrence-free survival (RFS), and melanoma-specific survival (MSS) were analyzed. Results The majority of patients had either no (TIL grade 0; 35.4%) or few (TIL grade 1; 45.1%) TILs, with a minority showing moderate (TIL grade 2; 16.3%) or marked (TIL grade 3; 3.2%) TILs. Tumor thickness, mitotic rate, and Clark level were inversely correlated with TIL grade (each P < .001). SLN biopsy was performed in 1,138 patients (61.0%) and was positive in 252 (22.1%). There was a significant inverse association between SLN status and TIL grade (SLN positivity ra...

Tumor-Infiltrating Lymphocyte Grade Is an Independent Predictor of Sentinel Lymph Node Status and Survival in Patients With Cutaneous Melanoma

Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecologic system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

/pdf/assessing-tumor-infiltrating-lymphocytes-in-solid-tumors-a-3kvwv8nohn.pdf

Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group Part 2 TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non–Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors

The risk of hereditary cutaneous malignant melanoma was evaluated in 401 members of 14 families with an autosomal dominant form of melanoma. We documented 127 primary melanomas in 69 famil...

High Risk of Malignant Melanoma in Melanoma-Prone Families with Dysplastic Nevi

The specificities of monoclonal antibodies against melanoma cells were analyzed using radioimmunoassay, mixed-hemadsorption assay, and quantitative absorption on a variety of malignant and nonmalignant cells. Three of the six hybridomasecreted antibodies bound to the majority of melanoma cell lines, melanoma tumors, and astrocytoma cell lines as well as to all normal and Epstein-Barr virus-transformed lymphocytes tested. The binding pattern coincides with the presence or absence of the DR antigen on human cells. Conversely, two other antibodies, 19-19 and Nu4B, detected two different antigens common to melanoma and astrocytoma cells only. Cloning of melanoma cells resulted in establishment of DR-positive and Dr-negative clones, with the binding of Nu4B antibody retained in all.

Specific Immunoreactivity of Hybridoma-secreted Monoclonal Anti-Melanoma Antibodies to Cultured Cells and Freshly Derived Human Cells

Precursor naevi in cutaneous malignant melanoma: a proposed nomenclature

The survival times of patients who had an elective regional lymph node dissection was compared with that of those who did not undergo the procedure in a database of 72 patients with clinical Stage I melanoma of intermediate thickness (1.51-3.99 mm). All of the patients had been followed for 5 years or longer or until death. No significant differences were found in other reported prognostic factors, suggesting that the two groups were comparable. By multivariate analysis, a low mitotic rate, intermediate patient age, and the presence of an infiltrative lymphocytic response were found to be associated with favorable survival. There did not appear to be any association of elective regional lymph node dissection with survival; and it was concluded that such therapy should not be regarded as "standard" for clinical Stage I melanoma of intermediate thickness.

The role of lymph node dissection for clinical stage I malignant melanoma of intermediate thickness (1.51-3.99 mm)

Intraoperative Assessment of Parathyroid Gland Pathology: A Common View From the Surgeon and the Pathologist

Of 66 specimens from benign melanocytic nevi, including common acquired and congenital nevi, Spitz tumors (epithelioid cell nevi), and melanocytic nevi with dysplasia, 57 could be grown in tissue culture. The cultured cells were identified as melanocytes by the presence of premelanosomes and melanosomes. Cells from 28 of 32 nevus cultures grew in an anchorage-independent way in soft agar with a colony-forming efficiency between 0.001 and 1%. Clones derived from single cells and soft agar-selected colonies showed marked phenotypic heterogeneity, but all had a limited life span and did not undergo transformation in culture. These cells were nontumorigenic in nude mice. Cultured nevus cells expressed antigens present on melanoma but absent on normal fibroblasts and/or melanocytes as tested with monoclonal anti-melanoma antibodies. The antimelanoma antibodies bound equally well to dysplastic, congenital, and common acquired nevi. Antigens are released by nevus cells similar to melanoma cells.

https://cancerres.aacrjournals.org/content/canres/43/11/5502.full.pdf

Phenotypic Characteristics of Cells Derived from Precursors of Human Melanoma

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