In a general sense, combined nevi may be composed of any combination of common acquired nevus, blue nevus, or Spitz nevus and may occur in both cutaneous and mucosal sites (Table 8) (Fig. 13). Variants of blue nevi such as dendritic blue nevi are frequently observed in combined nevi. The more controversial entity “deep penetrating nevus,” whether considered a variant of blue nevus, a variant of Spitz nevus, a hybrid of the latter 2 categories (so-called Blitz nevus), or a separate melanocytic neoplasm is also frequently present in combined nevi.90–92,95 Histopathologically similar tumors that have been described under a variety of other terms including inverted type A nevus,3 clonal nevus,99–101 nevus with focal atypical epithelioid component,99 and atypical dermal nodules in benign melanocytic nevus102 probably represent examples of combined nevi. None of the latter lesions have been associated with malignant behavior in any of the cases reported thus far.
There was considerable controversy among the Group regarding the entity “deep penetrating nevus” (Table 10).6,90,103 Some recognized this lesion as a distinct entity, which is commonly associated with a second discrete type of nevus, that is, forming part of a combined nevus.90,92,95 They recommended that the term “deep penetrating nevus” be applied to “monophasic” tumors (ie, those with no associated second melanocytic population) and combined nevus to those with 2 cell populations (in the latter instance, the 2 constituent nevus cell components should be described).
Some members of the Group recognized 2 variants of deep penetrating nevus, one with an epithelioid cell phenotype (which usually constitutes a variant of combined nevi and has been termed clonal nevus, inverted type A nevus, atypical dermal nodule in a benign melanocytic nevus, and melanocytic nevus with atypical epithelioid cell component).95,100,101 The second variant was described as showing a spindle cell phenotype (that has been termed inverted or plexiform pigmented spindle cell nevus).91,92 However, such plexiform nevi may also exhibit a cellular composition of both spindle and epithelioid cells.6,7,91 Deep penetrating nevi share histologic features with blue nevi (deep extension, associated stromal sclerosis, plump cells, pigmentation, and HMB45 positivity) and Spitz nevi (enlarged epithelioid and/or spindle cells, enlarged nuclei, and nuclear pseudoinclusions) but most participants were of the opinion that they are sufficiently distinctive to allow their recognition in most cases.90,103 Some participants object to the term deep penetrating nevus altogether and prefer plexiform spindle (and epithelioid cell) nevus as a more accurate depiction of this entity that stands apart from both blue nevus and Spitz nevus.6,91
There was general agreement that occasional cases of “deep penetrating” nevus may involve regional lymph nodes but spread beyond the regional nodes for typical cases has been rare. Some members of the Group recommended that, in view of the latter, all deep penetrating nevi should be reported as melanomas. Others contended that as most of these tumors behave in a clinically benign manner, they should be regarded as nevi and that a note may be added to indicate that there seems to be a low, but definite risk of metastasis (estimated to be less than 2% of cases without unusual features such as increased mitotic activity, expansile growth, or excessive nuclear pleomorphism). Others indicated a preference to categorize them as being of intermediate malignant or indeterminate or uncertain biologic potential, especially if any mitotic activity is present (Fig. 14). There was a consensus of opinion that further study of these lesions correlated with long-term follow-up was necessary before definitive conclusions could be drawn regarding their malignant potential and preferred terminology.104,105
For combined nevi that include a Spitzoid component, the latter component should be assessed for atypical features as described above (in the section on Spitz tumors) and reported in concordance with these recommendations. For example, a tumor manifesting a compound or dermal nevus associated with a dermal Spitzoid component with atypical features (but without clear-cut evidence of malignancy) may be reported as a combined melanocytic tumor with atypical Spitzoid tumor and conventional nevus components.
There was also a controversy among the Group about the entity of regressing or “halo” Spitz nevus component occurring as part of a combined nevus. Some thought the latter should be regarded as being of indeterminate or uncertain malignant potential whereas others accepted that this was not an uncommon component of combined nevi. Some members maintained that in many instances, the use of the term “Spitz” nevus component in the latter context of an inflamed or halo melanocytic lesion may not be appropriate and may be a misnomer.6 In fact, the epitheloid cell “Spitzoid” component in the latter lesions may not be a true Spitz component but rather represent induced or reactive changes secondary to the lymphocytic infiltrate. Again, further study of patients with these lesions correlated with long-term follow-up and molecular analysis are needed to clarify many of these issues.
As already mentioned in the above section, there is considerable controversy as to the agreement about whether certain candidate lesions can be reproducibly classified as variants of blue nevus versus variants of Spitz nevus or placed into a third category of “combined” nevus or melanocytic nevus with phenotypic heterogeneity. In effect at present, a wastebasket or “black hole” of melanocytic lesions often with mixed cellular phenotypes, particularly those with pigmented epithelioid cells and also many suggesting Spitz nevi, blue nevi, and “combined” nevi has been created that generally lacks definition or any agreement about nomenclature. To make progress in this area, consensus sessions at the microscope and molecular characterization will be needed to hammer out some agreement about and reproducible definitions of these various melanocytic phenotypes and a nomenclature that makes sense and can be used by the general dermatopathology community.
In the last few years, several reports have highlighted the difficulties in the histopathologic diagnosis and differential diagnosis of a particular group of melanocytic lesions often characterized by a thick dermal component that suggests melanoma.2,6,7,105 In particular, these tumors may exhibit a predominance of epithelioid cells or spindle cells. Perhaps other cellular phenotypes may be present. Terminology reflects the uncertainty in classification and interpretation of these atypical melanocytic tumors, and the many terms proposed in the past (such as malignant Spitz nevus, diagnostically controversial spitzoid melanocytic tumors, atypical epithelioid melanocytic proliferations of uncertain biologic potential, atypical Spitz tumors, deep penetrating nevi, and atypical blue nevi among others) testify to the diagnostic difficulties in differentiating tumors with benign behavior from those with a malignant clinical course. Histologic criteria used routinely for the distinction of benign melanocytic nevi from melanomas are not reliable in this group of tumors, and they are often referred to as “melanocytic neoplasms with indeterminate biologic potential” or “melanocytic tumor of uncertain malignant potential—MELTUMP.” We believe that the difficulty in correctly classifying these cases as “benign” or “malignant” reflects an inherent biologic problem, namely, the fact that they probably represent a single group of low-grade melanocytic tumors with potential for lymph node involvement and rarely for distant metastases.
There currently exists considerable agreement about the nomenclature and nature of many entities in the spectrum of benign melanocytic neoplasms. Nonetheless, certain entities continue to resist standardized classification and definition as to their biologic nature and natural history. The latter problems can clearly be attributed to the lack of sufficiently focused study and application of the appropriate techniques to resolve the relevant questions at hand, among those that can be resolved.
The following are among the most pressing issues with regard to benign melanocytic neoplasms and may be the subjects for future Workshops:
1. The development of broad consensus and standardized terminology for melanocytic cellular phenotypes;
2. The development of more standardized criteria and terminology for melanocytic nevi with unusual, deviant, atypical, or “dysplastic” features versus common nevi and nevi from particular anatomic sites;
3. The development of criteria for the classification or grading of melanocytic nevi that are biologically significant in terms of risk for progression to melanoma or that serve as indicators of melanoma risk in the individual patient;
4. The development of more standardized criteria for the distinction of melanocytic nevi from melanoma and classification schemes that are more clinically and biologically relevant as in other organ systems;
5. The development of consensus and more standardized terminology for Spitzoid lesions, blue nevi, and combined nevi, or nevi with phenotypic heterogeneity.
Finally, it is common in dermatopathology practice, as has already been mentioned, to encounter melanocytic lesions that share histologic criteria of dysplastic nevi and melanoma, just as the presence of atypical “spitzoid” lesions that share features of Spitz nevi and melanoma. Gray zone, or so-called “borderline,” lesions of these types will, as a rule, defy uniformity of diagnostic interpretation among experienced observers. That fact can easily be illustrated with their independent interpretation by multiple observers; “blinded” interobserver exercises of this nature will usually evoke a distressing divergence of interpretation, which may, not uncommonly, range from “indubitably benign” at one extreme to “clearly malignant” at the other. Nevertheless, when dealing with a diagnostically difficult melanocytic tumor, it is probably prudent to seek opinion from one or more experienced colleagues.
When there is no uniformity of opinion as to diagnosis, the medicolegal standard of dermatopathologic, as well as clinical, practice is difficult to define in an unambiguous manner. One approach to this complex problem recommended by the Group is to acknowledge the diagnostic and biologic uncertainty of a lesion through the use of terminology such as melanocytic neoplasm with indeterminate biologic potential (or melanocytic tumor with uncertain malignant potential). At a minimum, complete resection of the primary lesion to achieve histologically clear margins is an obvious management choice in the interest of patient safety, given the uncertainty of diagnosis; whether the arbitrarily wide margins that have come to be customary for melanomas of classical histologic phenotypes should be applied to them is a matter of differing perspective, with no uniformity of opinion. Nonetheless, there is no reason to presume, in the instances of diagnostically indeterminate lesions that ultimately prove by their natural histories to be malignant, that patients' chances for survival have been compromised by the application of narrower surgical margins than are customary for melanomas of the common varieties, provided that local recurrences at the treatment sites have not occurred before more distant metastases.
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