Clinicopathologically problematic melanocytic tumors: a case-based review

Background In spite of recent advances in the histopathological and molecular diagnosis of melanocytic neoplasms, a certain proportion of these lesions remain a daunting challenge for both the clinician and the pathologist. Objectives To emphasize the importance of close collaboration between clinicians and pathologists in case of problematic melanocytic lesions. Patients We report and discuss 5 problematic scenarios of melanocytic lesions, including tumoral melanosis, nevoid melanoma, lentiginous melanoma, spitzoid melanoma and BAPoma that may pose diagnostic difficulties in our practice. Conclusions Clinico-dermoscopic-pathological correlation, with incorporation of all the available data, in problematic melanocytic skin neoplasms is of paramount importance for accurate diagnosis.


Introduction
Early detection of melanoma is of paramount importance for the patient. In recent decades, relevant scientific advances in the field of pathogenesis, epidemiology, and evolution of melanocytic lesions, in conjunction with the development of new diagnostic techniques, have enhanced our ability to diagnose melanoma early and accurately [1,2]. However, the final diagnosis still relies on the correct histopathological assessment, which is considered the cornerstone in melanoma diagnosis [3].          On the other hand, a heavily pigmented Zembowicz et al morphologically analyzed 20 nevoid melanomas and were able to confirm 2 major subtypes, referred to as verrucous and nodular variants [17]. The former variant was characterized by strikingly uniform histological findings. The prototype, identically to our case, was a quite symmetric and well-defined exophytic lesion with hyperkeratosis and papillomatosis, denoting a verrucous architecture. According to the authors, "the most reliable feature distinguishing these lesions from benign nevi is the invariable presence of multiple dermal mitoses, including those within the deeper aspects of the lesions" [17].
Taking into account that nevoid melanoma has the same prognosis as the classic one, the earliest possible diagnosis is exceedingly important. Exhaustive evaluation of any "nevus" displaying unusual morphology minimizes the possibility of misdiagnosis. Significant architectural characteristics of nevoid melanoma are the sheet-like growth pattern and/or the presence of expansile nodules. In terms of cytology, the main diagnostic features include lack of or only minimal maturation, mild nuclear pleomorphism with focal hyperchromasia, and intradermal mitoses, often in a high number [15][16][17][18].
The third case in our series deals with a melanoma arising in the background of chronically sun-damaged skin on the lower leg of an elderly woman. Clinically, melanomas involving nonfacial sun-exposed areas with photodamage can raise diagnostic difficulties because they often masquerade as solar lentigines, seborrheic keratosis, or nevi and may be camouflaged among the plethora of surrounding pigmented benign lesions [19].
An additional "trap" when we deal with pigmented lesions in the elderly is associated with the limitations of incisional biopsies. The latter diagnostic approach carries a risk of underdiagnosis, as happened in our case [20]. We decided to perform an incisional biopsy because the lesion was large and located over a body site, at which primary surgical closure could be difficult. However, histopathological assessment of a small part of the lesion was in favor of dysplastic nevus, a diagnosis that was inconsistent with the patient's age and evolution of the lesion. After collaboration of the clinician and the pathologist, as well as implementation of a clinicopathological approach, it was recommended excisional biopsy that was diagnostic of a lentiginous melanoma. based on studies reporting a higher rate of metastasis among melanomas with ≥75% regression [5,6].
Apparently, for (dermato-) pathologists, the most problematic context is the rare case of a completely regressed primary cutaneous melanoma. On certain occasions it is exceedingly difficult to establish a definite melanoma diagnosis, especially in the absence of a reliable clinical history of a rapidly changing pigmented lesion [10].
In the second case we describe a nevoid verrucous melanoma clinically and dermoscopically mimicking a benign keratinizing tumor. A seborrheic keratosis resembling a melanoma is not uncommon, while the opposite-a melanoma mimicking a seborrheic keratosis-is considered rare [11,12]. This uncommon latter scenario hides serious risks for the clinician and the patient. The lack of clear-cut melanoma criteria and the presence of "benign" features may falsely lead to the diagnosis of a seborrheic keratosis or common wart. In this context, the biopsy and the histological assessment may be skipped, resulting in a significant delay in the diagnosis of melanoma, with unpredictable consequences to the patient's health. In addition, inappropriate treatment based on the mistaken diagnosis may complicate further the already noisome scenario [11][12][13][14].
It has been shown in the literature that seborrheic keratosis-like melanomas are clinically and dermoscopically challenging. However, dermoscopy has proved to be particularly useful, since despite the presence of additional seborrheic keratosis dermoscopic features, the identification of pseudopods and/or streaks, the blue-black sign, pigment network, and/or blue-white veil facilitates the correct diagnosis of the majority of the tricky melanomas [14].
The lesion in case 2 is considerably educative also from the histopathological point of view. It turned out to be a verrucous nevoid melanoma, which is a rare variant of melanoma, characterized by deceptive morphology, reminiscent of a benign melanocytic nevus. At scanning magnification these lesions show a strong resemblance to banal dermal nevi.
They are well circumscribed, usually with an inconspicuous specific diagnosis. On the other hand, the dermoscopic pattern of this entity is scantily described in the literature and seems to differ significantly from a banal dermal nevus [24].
For example, in our patient, the in-focus arborizing vessels in dermoscopy strongly suggested a basal cell carcinoma. In the field of histopathology, depending on the grade of atypia present in a Wiesner nevus, the main differentials include Spitz nevus/spitzoid tumors and melanoma [23][24][25][26][27].
The biological classification of melanocytic lesions with BAP1 loss remains controversial. Njauw et al characterized melanocytic neoplasms with germline BAP1 mutations as "severely atypical, reminiscent of nevoid melanoma," and in many cases as "short of frank malignancy, though these lesions clearly lie within the spectrum of nevoid melanomas" [27]. However, these lesions had clinical and histopathological characteristics similar to those presented by Wiesner et al [23] as benign tumors. Better understanding of their biology will enhance our ability to distinguish them from other melanocytic neoplasms and better classify them in the future [24].
The last case is devoted to the highly complex group of spitzoid tumors. It was about 1 century ago when the first report of a peculiar, rapidly growing melanocytic lesion was reported in the literature [28]. However, it seems that there is still a long way to go until the ongoing enigma is resolved, which practically refers to our inability to predict the biological behavior of these lesions based on their clinical, dermoscopic, histopathological, and morphological characteristics. The numerous and sometimes diverse attempts to establish diagnostic protocols and classification systems for spitzoid lesions reflect our scientific "weaknesses" [29,30].
In a recently published study, Geller et al [31] used a Webbased survey to assess clinical use of second opinions and pathologists' perceptions of second opinions for melanocytic lesions. It was not surprising that in daily practice, the majority of pathologists seek second opinions for atypical spitzoid tumors and for melanocytic tumors of uncertain malignant potential. Improvement of interpretive accuracy and protection from medico-legal issues were among the main reasons for requesting a second opinion [31].  it was suggested that biallelic inactivation of BAP1 is related to a clinically and morphologically distinct type of melanocytic neoplasm [23]. The latter was further reported in subsequent publications, describing sporadic cases of BAPoma, displaying identical clinical and histopathological characteristics [24][25][26][27].
Our experience suggests that Wiesner nevus, with the ambiguous clinical and histopathological characteristics, may raise some diagnostic difficulties. Clinically, these tumors develop as slowly growing pink nodules, not suggestive of a symmetric, spitzoid lesions should be managed based on patient age. In the end, lesions histopathologically diagnosed as atypical Spitz tumors warrant wide surgical excision, but not a sentinel lymph node biopsy [33].

Conclusions
We