Lentiginous melanoma: a histologic pattern of melanoma to be distinguished from lentiginous nevus.

Atypical lentiginous melanocytic proliferations in elderly patients continue to pose a diagnostic dilemma with lesions variably categorized as dysplastic nevus, atypical junctional nevus, melanoma in situ (early or evolving) and premalignant melanosis. We present pigmented lesions from 16 patients (seven male and nine female) and with the exception of one case, all were older than 50 years of age. The anatomical sites included trunk (7), head and neck (6) and upper extremity (3). The clinical diagnosis was variable and included lentigo maligna, atypical nevus, pigmented basal cell carcinoma, seborrheic keratosis and lentigo. The initial biopsies mimicked lentiginous nevus or dysplastic nevus and were characterized by a lentiginous proliferation of melanocytes at the dermoepidermal junction both as single cells and as small nests with areas of confluent growth, extending to the edges of the biopsy. The retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in hematoxylin- and eosin- stained sections. Dermal fibrosis was variably present and the melanocytic proliferation demonstrated cytological atypia. The subsequent re-excisions demonstrated similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites. The diagnosis of melanoma was more easily recognized in the complete excision specimens. Immunohistochemical stains for Mitf and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes. Familiarity with this pattern of early melanoma should facilitate proper classification of lentiginous melanocytic proliferations in biopsies from older adults.     

Sentinel lymph node biopsy for patients with diagnostically controversial Spitzoid melanocytic tumors?

The distinction of a Spitz nevus from melanoma can be very difficult. Pathologists may disagree on whether a Spitzoid melanocytic proliferation is benign or malignant, or acknowledge uncertainty about the diagnosis. As long as melanoma is suspected or strongly considered, a clinical management plan is often adopted as if the patient had melanoma, which may include sentinel lymph node (SLN) biopsy for staging. The findings of the sentinel node may resolve the diagnostic controversy about the primary tumor, but there is also the risk for more diagnostic confusion, uncertainty, and errors. We review the arguments in favor and against SLN biopsy for patients with diagnostically controversial Spitzoid melanocytic tumors, summarize current experience, and illustrate diagnostic pitfalls. Although SLN biopsy provides prognostic information helpful for clinical trials, we caution against performing the procedure as a diagnostic adjunct.     

Extensive pigmented villonodular synovitis with markedly pigmented lymphadenopathy and its implication for differential diagnosis with malignant melanoma

A 51-year-old male presented with a 5 cm left knee mass. Fine needle aspiration revealed large epithelioid cells with prominent nucleoli and abundant cytoplasmic pigment, consistent with malignant melanoma. Left inguinal lymphadenopathy was present, which was suspicious for metastatic disease by ultrasound examination. A dark perianal skin lesion was also identified, therefore raising the possibility of a primary melanoma. The knee and perianal lesions were resected and inguinal sentinel node biopsy was performed. In the specimen from the knee, there were clusters and fascicles of spindle and epithelioid cells with prominent nucleoli. Many of the cells displayed abundant, granular, brown, cytoplasmic pigment. The lymph node showed clusters of similar cells located in the subcapsular sinus. Immunohistochemical study showed that the cells expressed CD68, but failed to express S-100, MART-1, and gp100. The cytoplasmic pigment was positive for iron staining. The final diagnosis was pigmented villonodular synovitis. This case illustrates that pigmented villonodular synovitis may present with lymphadenopathy, mimicking a malignant process, including melanoma. Immunohistochemical studies may be essential for establishing the correct diagnosis.     

Histologically ambiguous ("borderline") primary cutaneous melanocytic tumors: approaches to patient management including the roles of molecular testing and sentinel lymph node biopsy

It is well recognized that the pathologic diagnosis of melanocytic tumors can sometimes be difficult. For some atypical melanocytic tumors that do not display clear-cut features of malignancy, it may be difficult or impossible to exclude a diagnosis of melanoma; this includes those showing some resemblance to Spitz nevi, blue nevi, deep penetrating nevi, and possible nevoid melanomas. When there is uncertainty about whether a primary melanocytic tumor is a nevus or a melanoma, we recommend that a second opinion be sought from one or more experienced colleagues. If diagnostic uncertainty persists, the evidence for or against the various differential diagnostic considerations should be presented in the pathology report and a "most likely" or "favored" diagnosis given. Molecular testing of the primary tumor by using techniques such as comparative genomic hybridization or fluorescence in situ hybridization may assist in establishing a diagnosis of melanoma if multiple chromosomal aberrations are identified. However, these tests require further independent validation and are not widely available at present. Complete excision of the lesion is probably mandatory, but plans for further management should be formulated on a case-by-case basis. While the safest course of action will usually be to manage the tumor as if it were a melanoma (taking into account the tumor's thickness and other prognostic variables), this may not always be appropriate, particularly if it is located in a cosmetically sensitive site such as the face. In some cases, it may be appropriate for the surgical oncologist to convey the diagnostic uncertainty to patients and to present them with management choices so that they can decide whether they wish to be managed aggressively (as for a melanoma) or conservatively. While a sentinel lymph node biopsy may be recommended on the basis of the primary tumor characteristics, the clinical significance of lymph node involvement for these tumors is not yet clear, and it may not have the same prognostic implications as nodal involvement from an unequivocal "conventional" melanoma.     

Sentinel lymph node biopsy in patients with "atypical Spitz tumors." A report on 12 cases

The distinction between Spitz nevus and melanoma is currently possible, applying a set of definite histological criteria. However, in certain lesions deviating from the stereotypical morphology of classic Spitz nevi ("atypical Spitz tumors"), the differentiation between benign and malignant cases appears problematic because objective criteria for a reliable diagnosis are lacking. We report the clinicopathologic findings of 12 patients with atypical Spitz tumors, who underwent sentinel node biopsy. All the tumors, composed of spindle and/or epithelioid cells, histologically showed features referable to Spitz nevi mixed to features generally found in malignant melanomas. Nine patients were females and three males, ranging in age from 2 to 48 years (mean, 23.2 years). The size of lesions ranged from 5 to 9 mm, the thickness from 1.12 to 5.70 mm. Nodal micrometastases were found in 4 (33.3%) patients. Among the patients with positive sentinel node, two showed minimal nodal involvements; one patient showed additional tumor deposits in one nonsentinel regional node. All patients are alive and free of disease with a follow-up of 2 to 90 months (mean, 26.3 months). Metastasizing and nonmetastasizing cases appeared clinically and histologically indistinguishable. The statistical analysis showed no significant difference between the two groups. Results suggested that all the reported cases may constitute a relatively homogeneous morphological group of lesions with a relevant metastatic potential that may be underdiagnosed.     

Punch ‘scoring’: a technique that facilitates melanoma diagnosis of clinically suspicious pigmented lesions

Aims

Early recognition and accurate diagnosis underpins melanoma survival. Identifying early melanomas arising in association with pre‐existing lesions is often challenging. Clinically suspicious foci, however small, must be identified and examined histologically. This study assessed the accuracy of punch biopsy ‘scoring’ of suspicious foci in excised atypical pigmented skin lesions to identify early melanomas.

Methods and results

Forty‐one excised pigmented skin lesions with a clinically/dermoscopically focal area of concern for melanoma, with the suspicious focus marked prior to excision with a punch biopsy ‘score’ (a partial incision into the skin surface), were analysed. Melanoma was diagnosed in nine of 41 cases (22%). In eight of nine cases (89%) the melanoma was associated with a naevus, and in seven of nine (88%) cases the melanoma was identified preferentially by the scored focus. In six of nine cases (67%), the melanoma was entirely encompassed by the scored focus. In one case of melanoma in situ, the diagnostic material was identified only on further levelling through the scored focus. In 28 of 32 of non‐melanoma cases (88%), the scored focus identified either diagnostic features of a particular lesion or pathological features that correlated with the clinical impression of change/atypia including altered architecture or distribution of pigmentation, features of irritation or regression.

Conclusions

The ‘punch scoring technique’ allows direct clinicopathological correlation and facilitates early melanoma diagnosis by focusing attention on clinically suspicious areas. Furthermore, it does not require special expertise in ex‐vivo clinical techniques for implementation. Nevertheless, in some cases examination of the lesion beyond the scored focus is also necessary to make a diagnosis of melanoma.     

Prediction of metastatic melanoma in nonsentinel nodes and clinical outcome based on the primary melanoma and the sentinel node.

Lymphatic mapping and sentinel node biopsy are well-established techniques for staging and managing patients with melanoma, breast cancer and other malignancies that spread initially to the regional lymph nodes. Identification of tumor in the sentinel node is the most precise staging technique currently available. The sentinel node is the site of metastatic melanoma in approximately 20% of melanoma patients and if tumor is present in the sentinel node it is customary to perform a complete dissection of the lymph nodes of the affected nodal basin. This may be overtreatment for some patients as tumor is identified in the nonsentinel nodes of only one-third of sentinel node-positive melanoma patients treated by completion lymphadenectomy. If it were possible accurately to identify the minority of patients with tumor in the nonsentinel nodes, the patients most likely to benefit from lymphadenectomy, the remaining patients could be spared a potentially morbid operation that is unlikely to confer clinical advantage. In 90 patients with a melanoma-positive sentinel node, who subsequently had a completion lymphadenectomy, we evaluated and compared the capacity of characteristics of the primary melanoma and of the sentinel node to predict individuals likely to have tumor in nonsentinel nodes. We assessed the Breslow thickness of the primary, the amount of tumor in the sentinel node (relative tumor area) and, as an index of immune modulation of the sentinel node, the density of dendritic leukocytes in the nodal paracortex. The relative area of tumor in the sentinel node and Breslow thickness of the primary melanoma most accurately predicted the presence of tumor in the nonsentinel nodes (P=0.0001 in both cases-Wilcoxon rank sums). The presence of melanoma in the nonsentinel nodes was also predicted by the density of dendritic leukocytes in the paracortex (P=0.008-Wilcoxon rank sums). These three observations assessed alone and in combination predict the presence of tumor in the nonsentinel nodes with high accuracy. The same characteristics also significantly correlated with tumor recurrence (tumor burden, P=0.0001, Breslow, P=0.0001 and dendritic cell density, P=0.0007) and death from melanoma (tumor burden, P=0.0001, Breslow, P=0.0001 and dendritic cell density, P=0.0026).     

Handling sentinel lymph node biopsy specimens.A work in progress.

This article reviews the "state of practice" with regard to sentinel lymph node biopsy, a new and evolving technique currently used most commonly for staging of malignant melanoma and adenocarcinoma of the breast. Sentinel lymph node biopsy has the potential to both increase the accuracy of lymph node sampling as a prognostic tool and to decrease the need for unnecessary and morbid extensive lymph node dissection in such patients. The need for close cooperation and planning involving the surgeon and pathologist is stressed, and gross room tissue handling, radiation safety, microscopic examination, and the use of ancillary diagnostic techniques are discussed.     

Progression to invasive melanoma from malignant melanoma in situ, lentigo maligna type

We have previously hypothesized that lesions that have been termed lentigo maligna can be divided into 2 categories: 1 represents a pigmented lesion that is a precursor to melanoma, and the other melanoma in situ. We and others have hypothesized that there is a progressive acquisition of attributes in pigmented lesions that results in malignant melanoma. Based on these 2 hypotheses, we have predicted that the intraepidermal component of invasive malignant melanomas, lentigo maligna type, should be similar to those lesions that we have termed malignant melanoma in situ, lentigo maligna type rather than lentigo maligna. The intraepidermal component of 42 consecutive cases of invasive malignant melanoma, lentigo maligna type was evaluated by all of the authors. Malignant melanoma in situ, lentigo maligna type is characterized by pagetoid spread, confluence, and nesting of atypical melanocytes. All of the cases evaluated showed features diagnostic of malignant melanoma in situ, lentigo maligna type, in the epidermis overlying the invasive dermal component. We conclude that invasive lentigo maligna melanoma arises in association with those lesions that we have termed malignant melanoma in situ, lentigo maligna type, which may represent a step in the progression between atypical melanocytic hyperplasia (lentigo maligna) and invasive melanoma. This finding supports the distinction of these entities and may have therapeutic implications.     

Problematic pigmented lesions: approach to diagnosis

A number of pigmented lesions are difficult to classify and raise the possibility of a melanoma diagnosis. Care should be exercised to exclude non-melanocytic lesions, and benign melanocytic entities, both of which can mimic melanoma histologically. In addition, the possibility of the lesion being a melanoma variant or epidermotropic metastasis should be considered. There will still be some cases that are difficult to resolve. These usually fall into one of three categories: atypical junctional melanocytic lesion versus early melanoma; naevus versus naevoid melanoma; and atypical Spitz, cellular blue, and deep penetrating naevi versus thick melanoma. These will pose problems even for experts. The atypical Spitz lesions are perhaps the most important category because they tend to be from younger individuals, the differential diagnosis is thick melanoma, and there is no single discriminating histological feature.     

Anatomo-pathologic study of sentinel lymph nodes in melanoma. Analysis of 200 cases

Pathologic evaluation of sentinel lymph node represents a new technique for managing high-risk primary melanoma. We examined the sentinel lymph node biopsies of 200 patients affected by primary melanomas of trunk, limbs, head and neck, who had been operated at "M. Bufalini" Hospital between April 1996 and July 1998. The lymphatic mapping has been performed through the preoperative intradermal injection of vital blue dye and technetium-labelled albumin. 319 sentinel lymph nodes were harvested and the 11.3% (15% of patients) were positive for melanoma metastases. No metastases were found in melanomas < or = 1 mm. The percentage of positive sentinel lymph nodes in patients with melanomas > 1 mm in thickness was 16.3% (22% of patients). In 5 cases (2.5%) nodal nevi were found, 1 of which was associated with micrometastasis. All 30 patients with positive sentinel lymph nodes underwent regional lymph node dissection and 555 lymph nodes were harvested. Melanoma metastases were found in only 7 patients, in 31 lymph nodes. The procedure of SLN detection and biopsy is a feasible surgical approach to melanoma patients. It is extremely useful in finding early metastases and in effective pathologic staging. As a consequence of the very low incidence of metastases in the sentinel lymph nodes of patients with thin melanomas, we suggest the sentinel lymph node mapping should be offered to patients with primary melanomas at least 1 mm in depth.     

Pediatric pigmented dermatofibrosarcoma protuberans (Bednár tumor): case report and review of the literature with emphasis on the differential diagnosis

Dermatofibrosarcoma protuberans (DFSP) is a fibrous tumor of intermediate malignant potential that usually affects the trunk of young to middle-aged adults. On histological examination, it is characterized by a monomorphous population of spindle cells arranged in a storiform or cartwheel pattern. Bednár tumor (BT), formerly known as storiform pigmented neurofibroma, is currently considered the pigmented variant of DFSP due to the histological and cytogenetic similarities between these two lesions. There are very few reports on BT affecting pediatric patients. We describe a case of BT affecting the dorsal aspect of the left forearm of a 6-year-old-male patient and emphasize the diagnostic clues to distinguish this unusual cutaneous neoplasm from other pigmented lesions, including pigmented (melanotic) neurofibroma (PMN), psammomatous melanotic schwannoma (PMS), neurocristic cutaneous hamartoma (NCH), and desmoplastic malignant melanoma (DMM). We would like to stress that surgical pathologists and dermatopathologists need to be aware of the prototypical histological appearance of BT as there is the risk of misdiagnosing it either as pigmented tumors associated with neurocutaneous syndromes, such as PMN and PMS, or as a highly malignant melanocytic neoplasm (DMM).     

Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes.

Cutaneous melanoma is a common melanocytic neoplasm that can quickly metastasize to regional lymph nodes. Currently, prognosis is determined by measuring tumor thickness but more reliable markers for metastatic spread are urgently needed. We investigated whether the extent of tumor lymphangiogenesis can predict melanoma metastasis to sentinel lymph nodes. We quantified the extent of tumor lymphangiogenesis, as well as other factors, in excised primary tumors and in sentinel lymph node biopsy samples from 45 patients with primary cutaneous melanoma. The results were correlated with histological and clinical outcome. Primary melanomas from patients whose tumors had metastasized to the sentinel lymph nodes contained prominent 'hot spots' of increased lymphatic vessel density, compared to nonmetastatic tumors. Multivariate risk analysis revealed that the lymphatic vascular area of primary melanomas, an index of tumor lymphangiogenesis, was the most sensitive prognostic marker for sentinel lymph node metastasis, and was even able to more accurately predict which tumors were metastatic to sentinel lymph nodes than the currently used method of measuring tumor thickness. Highly lymphangiogenic melanomas maintained their lymphangiogenic activity after metastasis to the sentinel lymph node. The extent of tumor lymphangiogenesis is a highly sensitive (83%) and specific (89%) prognostic marker of lymph node metastasis. Assessment of lymphangiogenesis in primary melanomas may be a more effective approach than the currently used technique of measuring tumor thickness in selecting patients with early metastatic disease for aggressive therapy.     

The correlation of the standard 5 probe FISH assay with melanocytic tumors of uncertain malignant potential

BackgroundFISH has recently emerged as a technique to better assess the malignant potential of histologically ambiguous melanocytic lesions. However, the usefulness of FISH has not been conclusively established. The purpose of this study was to further explore the diagnostic value of FISH in distinguishing the borderline melanocytic tumor (BMT) from melanoma.Method73 cases with BMT were analyzed retrospectively from a dermatopathology database between 2010–2015. FISH studies were conducted in each case using probes targeting 5 loci including CCND1 on 11q13, RREB1 on 6p25, MYB on 6q23, CDKN2A on 9p21, and CEP 6 control probe for chromosome 6.ResultsThe study was composed of 50 females and 23 males with an age range of 1–73 and a mean age of 35 years. Of the 6 cases in the superficial atypical Spitz tumor (AST) category, 2 had indeterminate results due to polyploidy. In the conventional atypical Spitz tumor cases, FISH was positive in 3 of 15 cases. Of the 27 cases in the borderline nevoid tumor (BNM) category, 3 showed positive FISH and 3 were equivocal due to the possibility of polyploidy. 3 of 13 cases of the borderline tumor of deep penetrating nevus variant (B-DPN) were positive for FISH. Neither of the 2 pigmented epithelioid melanocytoma (PEM) cases had positive FISH result. Of the 4 cases in the superficial atypical dermoepidermal nevomelanocytic proliferation group, only 1 met the FISH diagnostic criteria for melanoma. None of the 6 borderline tumors with overlapping features met FISH criteria diagnostic of melanoma. Clinical follow up was available on 55 patients. None of the patients had recurrence nor died of the disease. Lymph node biopsy was performed on five patients without evidence of metastasis.ConclusionDespite the benefits of FISH, it is limited by the fact that melanomas are not genetically identical whereby certain genetic abnormalities are only seen in specific subtypes. Additionally, FISH only targets specific chromosomes resulting in limitations in sensitivity and specificity. Although FISH has proven to be highly sensitive and specific in distinguishing unequivocally benign from malignant lesions, in cases of histopathological ambiguity, these parameters cannot be assessed with great confidence because the histopathological diagnosis (gold standard) is not without uncertainty. The 4-probe set (excluding 9p21) consistently showed chromosomal aberrations throughout all groups, but only 10 of the 73 total cases (13%) met the diagnostic criteria for melanoma. Moreover, it would be wise to establish new cytogenetic reference values that incorporate these borderline lesions in an effort to better assess the possibility of malignant behavior and or define a cytogenetic profile supportive of its categorization as an indeterminate proliferation. Polyploidy is another inherent limitation, which leads to false positives due to the absolute signal counts incorrectly reflecting relative imbalances in the tumor genome.     

Biopsy of sentinel lymph node in melanoma is not yet the standard treatment

The trend to implement sentinel node biopsy as standard of care in patients with clinically localized melanoma is encouraged by the following three factors: the technique of lymphatic mapping has matured to the point that consensus was reached on how the procedure should be carried out, surgeons showed that they can find the node in nearly 100% of patients, and tumor-status was shown to be the most powerful prognostic factor. However, recent studies revealed unfavorable new information that questions the wisdom of this trend. Three studies published in 2001 with a combined total of 1,851 patients show false-negative rates of 16-25%. Another unnerving finding is the 13-19% incidence of in-transit metastases in patients with a tumor-positive sentinel node, reported by three groups. The ultimate purpose of lymphatic mapping is to provide sentinel node positive patients with early therapeutic measures, such as regional node dissection and adjuvant systemic treatment. However, there is currently no evidence that this approach results in improved regional control and survival. Sentinel node biopsy can only become part of routine patient management if the tumor-status of the sentinel node carries clear implications of proven benefit for the manner in wich patients are managed and if regional control is not jeopardized.     

A case of amelanotic spindle-cell melanoma presenting as metastases to breast and axillary lymph node: diagnosis by FNA cytology

Metastatic neoplasms to the breast are relatively rare. Spindle-cell lesions of the breast are also uncommon. Here we present a case of fine-needle aspiration (FNA) of an amelanotic, spindle-cell melanoma metastatic to the breast and axillary lymph node. The patient was a 47-yr-old female who presented with a right breast mass, left axillary adenopathy, and a pigmented skin lesion on the back. FNA of the right breast and left axilla showed malignant, nonpigmented spindle cells that were weakly positive for HMB-45 on immunocytochemistry. The skin biopsy showed a pigmented malignant melanoma with epithelioid features, and also weak positivity for HMB-45. Although malignant melanoma is one of the more common tumors to metastasize to the breast, this is the first known case that showed exclusive spindle-cell morphology. History and physical examination were crucial in making the correct FNA diagnosis. The cytologic differential diagnosis of spindle-cell tumors of breast and the discordant morphology between the primary and metastatic melanotic lesions observed in this case are discussed.