Malignant melanoma. Prognostic significance of "microscopic satellites" in the reticular dermis and subcutaneous fat.

A review of the microscope slides of the primary tumors for 596 patients with clinical Stage I melanoma revealed that primary lesions displayed two distinct patterns of invasion: 1) single cell invasion with direct extension of the main body of tumor into the reticular dermis or subcutaneous fat, and 2) invasion with "microscope satellites" (i.e. discrete tumor nests greater than 0.05 mm in diameter, that were separated from the main body of the tumor by normal reticular dermal collagen or subcutaneous fat). The five-year disease free survival rate for 95 patients with "microscopic satellites" was 36% +/- 6%. This is in contrast to a five-year disease free survival rate of 89% +/- 2% for 501 patients without these satellites (p = 4.3 x 10(-29), generalized Wilcoxon test). "Microscopic satellites" (present vs absent) was comparable to histologic ulceration in its additive prognostic effect of tumor thickness (Breslow).     

Are Locoregional Cutaneous Metastases in Melanoma Predictable?

Background: In-transit metastases and satellite lesions are manifestations of locoregional cutaneous recurrence that are characteristic of malignant melanoma. They are the result of tumor cell emboli entrapped in the dermal lymphatics between the primary tumor and the regional lymph node basin. Histopathological features of lymphatic invasion were investigated to determine the possibility of predicting locoregional cutaneous metastases in melanoma patients.Methods: In a prospective study, 258 patients with clinical stage I melanoma underwent wide local excision and sentinel node biopsy. Nodal metastases were found in 53 (21%) patients. Of 29 patients (11.2%) who had developed recurrences to date, 17 (6.6%) had locoregional cutaneous metastases. All surgical specimens were examined with particular attention to histopathological signs of lymphatic vascular invasion or microscopic satellites.Results: Unequivocal signs of lymphatic invasion were observed in 14 of 258 patients (5.4%), and 13 (93%) of these patients subsequently developed in-transit metastases, after a median interval of 10 months. The primary melanoma was located on the extremities in seven patients. The median Breslow thickness was 2.5 mm, and 5 showed ulceration. In 244 of 258 patients (94.6%), there were no signs of lymphatic invasion. To date, only four patients (1.6%) have had a locoregional cutaneous recurrence, occurring after a median interval of 29 months. All four of these patients had ulcerative melanomas on an extremity, with a median thickness of 4.0 mm. The presence of lymphatic invasion was significantly related to early locoregional cutaneous relapse (P _ .0001).Conclusions: Locoregional cutaneous recurrence appears to be highly predictable in the presence of histopathological signs of lymphatic invasion. Lymphatic invasion is an important prognostic parameter and should be included as a stratification criterion when selecting patients for adjuvant (locoregional) therapy. Presented at the 51st Annual Cancer Symposium of The Society of Surgical Oncology, San Diego, California, March 26–29, 1998.     

Preliminary results on the use of a noninvasive instrument for the evaluation of the depth of pigmented skin lesions: numerical simulations and experimental measurements

The early detection of cutaneous pigmented lesions is an important aid to the clinician in recognizing malignant melanoma. In an attempt to correlate the depth of a pigmented skin lesion with its malignant potential, phantoms able to simulate the diffuse reflectance of some lesions of different thicknesses were manufactured and tested to validate a diagnostic instrument developed in-house. Such optical skin-tissue phantoms may be useful for accelerating and optimizing the diagnosis of suspicious lesions of the skin. In fact, benign melanocytic lesions are different in terms of their diffuse reflectance from melanoma. The diffuse reflectance of pigmented skin lesions depends on the amount and distribution of the absorbing/diffusing chromophores embedded in the skin layers. The basic phantom material is a PVA hydrogel in which appropriate amounts of optical scatter are added extraneously at the time of formation to achieve tunability of the optical properties. Liquid Indian ink is used to simulate melanin and all the other chromophores. Slabs were prepared to mimic lesions of different depths. The optical properties of the tissue phantoms were determined in the visible and near-infrared spectral ranges using a noninvasive instrument made from a purpose-modified digital camera. The measured reflectance was correlated with the depth of the lesion both in a Monte Carlo simulation environment and in a laboratory experiment.     

Dermoscopy of Subcorneal Hematoma

BACKGROUND: Subcorneal hematoma is a pigmented skin lesion usually occurring on palms or soles after a trauma or sport activity. Clinically, it may exhibit overlapping features with acral melanoma or acral melanocytic nevi, leading to unnecessary excision of this otherwise harmless skin lesion. OBJECTIVE: The objective was to describe the dermoscopic features in a series of subcorneal hematomas. METHODS: Dermoscopic images of 15 subcorneal hematomas were evaluated for the presence of different colors and dermoscopic structures. RESULTS: In our series, a red-black hue was the most frequent color seen by dermoscopy (40% of the lesions) and a homogeneous pattern of pigmentation was the most frequent dermoscopic structure (53.3%). Remarkably, 40% of the lesions exhibited a parallel-ridge pattern that is usually found in early melanoma of palms and soles. In 46.7% of the lesions, red-black globules were additionally seen at the periphery as satellites disconnected from the lesion's body. Only two lesions showed either parallel-furrow or fibrillar pattern. A scratch test performed in four lesions, allowed complete or partial removal of the pigmentation. CONCLUSION: Dermoscopic features of subcorneal hematomas may be similar to those observed in acral melanocytic lesions. Nevertheless, in most cases the correct diagnosis can be facilitated by the presence of a red-black homogeneous pigmentation, often combined with satellite globules. A positive scratch test may be considered as an additional diagnostic clue.     

An overview of the epidemiology of cutaneous melanoma

Incidence of cutaneous melanoma has increased over the last several decades. Screening for melanocytic lesions is an effective approach to reducing incidence. This article presents information useful in melanoma screening, including histologic types of tumors, measurements, and anatomic sites. Causes of tumors, including ultraviolet radiation and the role of steroid hormones, are discussed. In addition, the presence of atypical and benign nevi is addressed.     

Appearance of New Vemurafenib-associated Melanocytic Nevi on Normal-appearing Skin: Case Series and a Review of Changing or New Pigmented Lesions in Patients with Metastatic Malignant Melanoma After Initiating Treatment with Vemurafenib

Background: Vemurafenib, a selective BRAF inhibitor that has antineoplastic activity in patients with unresectable or metastatic malignant melanoma whose tumor harbors a BRAF V600E mutation, has multiple drug-associated cutaneous adverse effects. Purpose: To provide a detailed and comprehensive review of reported changing or new pigmented lesions in oncology patients who have been treated with vemurafenib. Methods: The new appearance of melanocytic nevi on normal-appearing skin after initiating treatment with vemurafenib is described in two men with metastatic malignant melanoma whose tumors demonstrated a BRAF V600E mutation. Using the PubMed database, an extensive literature search was performed for the following topics: vermurafenib, nevus, nevi, melanoma, pigmented lesion, cutaneous, adverse effect, side effect. The results of the search were used to secure all reports of new or changing pigmented lesions after initiating treatment with vemurafenib. Results: Vemurafenib is associated with both changes in existing pigmented lesions (including involution, alteration of color and size, and progression to melanoma) and the onset of new melanocytic lesions—nevi (in 5 patients) and primary melanomas (in 2 patients). Visual examination, dermoscopic evaluation, and reflectance confocal microscopy have been used to document the changes in existing or new melanocytic lesions subsequent to initiating treatment with vermurafenib. Histopathology analysis has shown these lesions to usually be either dysplastic nevi or new primary melanomas. Conclusion: Vemurafenib-treated patients can develop new pigmented lesions (such as nevi) and/or morphological changes in their existing melanocytic lesions (such as involution, increase in size, or alternation of color). In addition, they can develop new primary malignant melanomas that either occur de novo on normal-appearing skin or develop in pre-existing melanocytic lesions. Therefore, total body skin examination should be considered prior to initiating treatment with vemurafenib. Regularly scheduled follow-up skin examinations are also recommended for patients while they are receiving this drug. In addition, for patients who are being treated with vemurafenib, either dermoscopic or photographic or visual modalities should be used to evaluate new or changing pigmented lesions. Also, biopsy for histopathology should be considered for vemurafenib-treated patients who develop new pigmented lesions or whose existing melanocytic lesions have morphological changes in size or color.Vemurafinib is a selective BRAF inhibitor that was approved by the United States Food and Drug Administration (FDA) on August 17, 2011, as a first-line single agent for the treatment of individuals with unresectable or metastatic malignant melanoma whose tumors demonstrated a BRAF V600E mutation as detected by an FDA-approved test.1-4 Clinical trials have demonstrated improved survival in patients with either previously untreated or treated BRAF V600E mutant metastatic malignant melanoma.5,6 The authors describe two men with metastatic malignant melanoma for which their tumor genotype demonstrated BRAF V600E mutation who experience the new onset of nevi after initiating treatment with vemurafenib and discuss changing or new pigmented lesions in patients with metastatic malignant melanoma after starting this molecularly targeted therapy.     

Transformation of a benign oral pigmentation to primary oral melanoma.

OBJECTIVE: The objective is to report the serendipitous 7-year follow-up and transformation of a melanotic palatal lesion, which was initially diagnosed histologically as a benign oral melanotic macule, into primary oral melanoma and to provide long-term follow-up of a case of oral malignant melanoma. STUDY DESIGN: Nine formalin-fixed paraffin-embedded tissue blocks from several different facilities and microscopic slides of the patient's lesions were reviewed to study the transformation of a benign, oral, pigmented lesion into melanoma. RESULTS: Review of blocks and slides of the patient's lesions suggest that the onset of melanocytic hyperplasia (increased clear cell activity) heralded the transformation of the melanotic macule into melanoma. The histology of the first biopsies was totally benign, but retrospectively, the clinical appearance was not typical and was somewhat worrisome because of the size of the lesion and feathering of the pigmentation at the periphery. This clinical presentation, however, was unknown to the pathologists. CONCLUSIONS: This study documents a case of primary oral melanoma arising from an apparent oral melanotic macule and suggests that even histologically benign-appearing oral melanotic lesions should perhaps be viewed with caution if increased numbers of melanocytes (melanocytic hyperplasia or clear cell activity) are present. Careful correlation of clinical appearance and histology is necessary to arrive at an appropriate diagnosis and prognosis for oral pigmented lesions.     

Prognostic factors for patients with clinical stage I melanoma of intermediate thickness (1.51 - 3.39 mm). A conceptual model for tumor growth and metastasis.

Fourteen variables were tested for their ability to predict visceral or bony metastases in 177 patients with clinical Stage I melanoma of intermediate thickness (1.51 - 3.39 mm). A Cox multivariate analysis yielded a combination of four variables that best predicted bony or visceral metastases for these patients: 1) mitoses greater than 6/min 2 (p = 0.0007), 2) location other than the forearm of leg) p = 0.009, 3) ulceration width greater than 3 mm (p = 0.04), 4) microscopic satellites (p = 0.05). The overall prognostic model chi square was 32.40 with 4 degrees of freedom (p less than 10 (-5). Combinations of the above variables were used to separate these patients into at least two risk groups. The high risk patients had at least a 35% or greater chance of developing visceral metastases within five years, while the low risk group had greater than an 85% chance of being disease free at five years. Criteria for the high risk group were as follows: 1) mitoses greater than 6/mm 2 in at least one area of the tumor, irrespective of primary tumor location, or 2) a melanoma located at some site other than the forearm or leg and histologic evidence in the primary tumor of either ulceration greater than 3 mm wide or microscopic satellites. The low risk group was defined as follows: 1) mitoses less than or equal to 6/mm 2 and a location on the leg or forearm, or 2) mitoses less than or equal to 6/mm 2 and the absence in histologic sections of the primary tumor of both microscopic satellites and ulceration greater then 3 mm wide. The number of patients in this series who did not undergo elective regional node dissection (N = 47) was probably too small to detect any benefit from this procedure. Based on survival rates from this and other studies, it is estimated that approximately 1500 patients with clinical Stage I melanoma of intermediate thickness in each arm of a randomized clinical trial would be needed to detect an increase in survival rates from elective regional node dissection.     

Prognostic value of the method of treatment and various modelling factors in the localized form of primary cutaneous melanoma

On the basis of studying the long-term results of treatment of 268 patients with a localized form of primary cutaneous melanoma, the prognostic value of the used methods of treatment, level of tumour invasion into the skin, sex and age of a patient, tumour localization, presence or absence of its ulceration was established.     

Comparative genomic hybridization for the diagnosis of melanoma

Despite advancements in protocols, a subset of melanocytic lesions continues to pose diagnostic challenges. This is particularly true in the pediatric population where certain congenital nevi mimic melanoma. Recently, comparative genomic hybridization (CGH) has been utilized to support diagnoses of melanocytic lesions based on DNA copy number changes. Because distinct differences in copy number changes have been shown to occur in malignant melanoma and benign nevi, CGH can be a useful adjunct when diagnosis based on histology alone is indeterminate. The authors discuss the benefits of using CGH to aid in the diagnosis of melanocytic lesions that are difficult to characterize as malignant or benign based on clinical and histologic features alone. This paper presents a brief clinical report and review of the literature. A 13-year-old Caucasian male presented to an academic tertiary care medical center after a shave biopsy unexpectedly revealed malignant melanoma with positive deep margins. Following complete excisional biopsy, the diagnosis of malignant melanoma with depth of 0.92 mm was confirmed, both by the home institution's pathologist and by consultant dermatopathologists at two separate academic tertiary medical centers. Sentinel lymph node biopsy revealed a small focus of metastatic melanoma, this lead to a left-sided modified radical neck dissection. All nodes removed were negative for disease, and surgical and postsurgical care was uncomplicated. Before proceeding with interferon therapy, CGH was performed on the tissue from the primary lesion. Other than a slight amplification of chromosome 16p, no other aberrations were detected favoring a benign lesion. Ultimately, the diagnosis was amended to compound melanocytic nevus of the nose with benign nevus cell rest in the sentinel node. While histopathologic evaluation is the current gold standard for the diagnosis of melanoma, there are many cases where it is inaccurate. The use of CGH in the evaluation of histologically equivocal lesions may allow certain patients to avoid invasive procedures and associated morbidities. The authors propose that, in these select diagnostically challenging cases, tissue analyses by CGH may be beneficial before proceeding to more invasive procedures such as sentinel node biopsy and complete lymphadenectomy.     

Dermatological perspectives of malignant melanoma

Early recognition and treatment of thin cutaneous melanoma have contributed to a decreased case-fatality rate over the past 60 years. The only known preventive measure for melanoma is sun protection in childhood, which directly affects the number of melanocytic nevi developing as an adult. Additional melanoma risk factors, clinical features, and malignant potential of precursor lesions are discussed. The four major clinicopathologic subtypes of melanoma are described, with recommendations for appropriate biopsy techniques for suspected melanoma. Nationwide skin cancer screenings by dermatologists and greater public awareness of the warning signs of melanoma have enhanced detection of early melanoma, and promoted chances for cure.     

Reexcision perineural invasion. Not a sign of malignancy

Perineural invasion has been reported to occur in both benign and malignant neoplasms. We describe two cases in which perineural invasion by epithelial cells was present in reexcision skin specimens removed because of melanocytic lesions in the original biopsy material. Because of the absence of a primary epithelial neoplasm, this phenomenon was interpreted as a reactive or reparative process, most probably resulting from regenerating traumatized sweat gland ducts. On the basis of this study alone, it may not be possible to distinguish between reexcision perineural invasion and perineural invasion from a primary epithelial neoplasm. For such cases, the following histologic features serve as provisional guidelines favoring an interpretation of reexcision perineural invasion: absence of perineural spread beyond the immediate previous biopsy site, benign appearance of the perineural epithelial cells different from the appearance of the original tumor, and absence of residual epithelial tumor in the vicinity of the involved perineurium.     

Head and neck melanoma in 534 clinical Stage I patients. A prognostic factors analysis and results of surgical treatment.

Single and multifactorial analyses were used to evaluate prognosis and results of surgical treatment in 534 clinical Stage I patients with head and neck cutaneous melanoma treated at the University of Alabama in Birmingham (U.S.A.) and the University of Sydney (Australia). This computerized data base was prospectively accumulated in over 90% of cases. Melanomas were about equally distributed between men and women. They were located on the skin of the face in 47%, neck in 27%, scalp in 13%, and the ear in 13% of patients. Both the results of the prognostic factors analyses and the surgical treatment demonstrated that lentigo maligna melanoma (LMM) was distinct from the other two growth patterns, superficial spreading melanoma and nodular melanoma (SSM and NM). In a multifactorial analysis of the 453 patients with SSM and NM, the dominant prognostic variables were tumor thickness (p less than 0.00001), anatomic subsite (p = 0.0213), and ulceration (p = 0.0289). Patients with melanomas on the scalp or neck subsites fared worse than those with tumors located on the face or ear. The results differed for LMM, where thickness was not a significant predictor of survival, and the most dominant prognostic variable was ulceration (p = 0.0042). Local recurrence rates were low, being 2.4% for tumors less than 2.5 mm in thickness, but were 12.3% for tumors greater than or equal to 4.0 mm in thickness. Patients with SSM and NM lesions located on the head and neck had a lower survival rate than those with extremity melanomas in every tumor thickness category, although only those in the 0.76 to 1.49 mm thickness subgroup were significantly different (p = 0.0007). After 5 years of follow-up, patients who underwent an elective lymph node dissection for SSM and NM with a thickness range of 1.5 to 3.99 mm had a better survival (72%) than patients with melanomas of equivalent thickness whose initial treatment was wide excision alone (45%). LMM had a less aggressive biologic behavior compared to SSM or NM and was treated more conservatively. Thus, LMM lesions had an 85% 10-year survival rate with wide excision only, and there was no significant improvement in survival with ELND. Growth patterns, tumor thickness, ulceration, and anatomic subsites should be considered when evaluating risk factors and when making treatment decisions in head and neck melanoma patients.     

Local recurrence in malignant melanoma: Long-term results of the multiinstitutional randomized surgical trial

Background: In the past, radical margins of excision were prescribed for cutaneous melanoma based on preconceived notions rather than on hard clinical evidence. Methods: In a prospective study of 742 patients with intermediate-thickness melanoma (1–4 mm), 470 patients with trunk or proximal extremity lesions were randomized into a 2-or 4-cm margin. Patients with distal extremity or head and neck lesions (n=272) received uniformly a 2-cm margin. Results: The overall rate of local recurrence was 3.8%. This rate in the randomized portion (n=470) was 2.1% for the 2-cm margin and 2.6% for the 4-cm margin (p=0.72). A progressive increase in local recurrence rates was observed with thickness: 2.3% for lesions 1.0–2.0 mm, 4.2% for those 2.01–3.0 mm, and 11.7% for those 3.01–4.0 mm thick (p=0.001). Local recurrence occurred in 1.5% of those without ulceration and in 10.6% of those with ulceration of the primary lesion (p=0.001). The local recurrence rate was not significantly affected by the margin of resection even among the thicker or ulcerated lesions. It also was not affected significantly by the method of closure of the primary site or management of the regional nodes, or the age or gender of the patients. Conclusions: A 2-cm margin is as effective as a 4-cm margin in local control and survival of intermediate-thickness melanomas. The local recurrence rate is significantly affected by the thickness of the primary lesion and the presence or not of ulceration. Presented at the 48th Annual Cancer Symposium of The Society of Surgical Oncology, Boston, Massachusetts, March 23–26, 1996.     

Malignant Melanoma Arising in a Pregnant African American Woman with a Congenital Blue Nevus

Background. The incidence of cutaneous melanoma in African-Americans is relatively low. Despite the slightly greater occurrence of congenital melanocytic nevi in black persons compared with white persons, the cumulative risk of melanoma arising in these lesions is very small. In addition, the overwhelming majority of melanomas in black persons occur on nonglaborous skin where congenital melanocytic nevi are rare.
Objective. The objective was to describe and an unusual case of melanoma arising in a congenital nevus with combined features of a blue nevus on the scalp of a pregnant African-American woman.
Results. Histologic examination revealed a polypoid malignant melanoma arising in association with a congenital blue nevus in a young African-American woman. The lesion was located on the right parietal scalp and had been enlarging over the course of her pregnancy. Pathology from parotidectomy and neck dissection confirmed metastatic melanoma involving two intraparotid lymph nodes and 3 of 26 cervical lymph nodes. Despite aggressive chemotherapy, she died in 1 year after the diagnosis.
Methods. A case is reported and the literature is reviewed.
Conclusion. Clinicians must take great care in documenting and following pigmented lesions in all patients including African-American persons. Excision is indicated for lesions that undergo significant change during pregnancy.     

Consumption of the epidermis: a diagnostic criterion for the differential diagnosis of melanoma and Spitz nevus

The distinction between melanoma and its most important simulant, Spitz nevus, is usually made on microscopically. We point out "consumption of the epidermis" (COE) as an additional diagnostic criterion. We defined COE as thinning of the epidermis with attenuation of the basal and suprabasal layers and loss of rete ridges in areas of direct contact with neoplastic melanocytes. We analyzed 102 unequivocal melanomas and 125 unequivocal Spitz nevi for the presence of COE. COE had not been used in arriving at the diagnosis of these cases because we were unaware of the criterion at the time that the cases were first evaluated. COE was found in 88 of 102 (86%) of melanomas but only 12 of 125 (9.6%) of Spitz nevi (P < 0.001). We then looked for COE in an independent set of 61 ambiguous melanocytic lesions with overlapping histopathologic features that could not be classified unequivocally as Spitz nevus or melanoma. The cases were analyzed by comparative genomic hybridization (CGH) for aberration patterns suggesting a benign or a malignant process, based on previous studies. COE was found in only 6 of 42 (14%) of the ambiguous cases in which CGH suggested a benign process and 14 of 19 (74%) of the ambiguous cases in which CGH suggested melanoma (P < 0.001). Our data suggest that COE is a useful criterion in the evaluation of melanocytic neoplasms. Because COE was frequently found at the edges of ulcers in the majority of ulcerated melanomas, the thinning of the epidermis in COE may represent an early phase of ulceration. This may prove to be important in distinguishing ulceration due to an effect of the tumor from ulceration due to trauma, which would be expected not to have the same prognostic import. Future studies are required to analyze the prognostic value of COE itself.     

Primary melanocytic neoplasms of the central nervous systems.

Primary melanocytic neoplasms of the central nervous system (CNS) consist of a spectrum ranging from well-differentiated melanocytoma to its overtly malignant counterpart, melanoma. Diagnostically difficult intermediate lesions lie between these extremes. Clinicopathologic features of 33 cases were studied to define histologic appearances, diagnostic criteria, and the clinical behavior of lesions along this spectrum. Seventeen cases were well-differentiated, solitary leptomeningeal tumors classified as melanocytomas. They contained variably pigmented melanocytic cells arranged in tight nests, sheets, or fascicles. Mitotic rates ranged from zero to one per 10 high-power fields (HPFs), with most having zero per 10 HPFs. All tumors were immunoreactive for HMB-45 and S-100 protein and negative for epithelial membrane antigen. MIB-1 staining was low (<1-2%). Nuclei were regular, often with small, eosinophilic nucleoli. These lesions arose predominantly in the spinal canal (65%) in patients ranging in age from 17 to 73 years. None recurred after surgical resection. In contrast to these benign lesions, there were 13 cases with histologic and cytologic features consistent with those of malignant melanoma. These cases contained larger, cytologically atypical, pigmented tumor cells growing in loose nests or sheets, often with CNS invasion or necrosis. Some contained bizarre, pleomorphic nuclei; others were densely cellular and mitotically active, but less pleomorphic. Mitotic rates (mean, 5.7 per 10 HPFs) and MIB-1 labeling indices (mean, 8.1%) were higher than those of melanocytomas. Melanomas occurred at spinal (38%), posterior fossa (38%), and supratentorial (23%) levels in patients ranging in age from 15 to 71 years. After resection, 8 of 13 lesions recurred, with four being fatal (mean survival, 14 months). Of five totally resected melanomas, four did not recur (mean follow-up, 26 months). Three intermediate-grade melanocytic tumors could not be classified as melanocytoma or melanoma. All showed sheetlike growth patterns, microscopic CNS invasion, and occasional mitoses. MIB-1 staining ranged from 1% to 4%. One tumor recurred after 17 months; one patient was lost to follow-up after 5 months; and the third died after surgery. Although melanocytic tumors represent a spectrum of lesions, certain histopathologic features are helpful in predicting biologic behavior.