Association between melanocytic neoplasms and seborrheic keratosis: more than a coincidental collision?

Clinical observations and an expanding knowledge of cell-to-cell communication have led us to speculate that the finding of a melanocytic nevus in conjunction with a seborrheic keratosis is more than a coincidental collision of two lesions. Here we present five cases demonstrating dermoscopic features of both melanocytic lesions and seborrheic keratoses with corresponding histology. Four cases demonstrate dermoscopic features of a melanocytic nevus and seborrheic keratosis, and the final case a melanoma arising in association with a seborrheic keratosis.


Introduction
The presence of a seborrheic keratoses (SK) found in association with a melanocytic nevus has been observed often in our clinical practice. The utilization of dermoscopy highlights the specific features associated with both the nevus component and seborrheic keratosis found in these "colli-sion" lesions. The occurrence of this finding, which is more readily appreciated with dermoscopy, has led us to speculate whether this is a coincidental finding or phenotypic expression of underlying melanocyte cell-signaling. Here we present five cases with histology, collected retrospectively, highlighting the association between melanocytic lesions and SK.
Clinical observations and an expanding knowledge of cell-to-cell communication have led us to speculate that the finding of a melanocytic nevus in conjunction with a seborrheic keratosis is more than a coincidental collision of two lesions. Here we present five cases demonstrating dermoscopic features of both melanocytic lesions and seborrheic keratoses with corresponding histology. Four cases demonstrate dermoscopic features of a melanocytic nevus and seborrheic keratosis, and the final case a melanoma arising in association with a seborrheic keratosis.

Case 1
A 31-year-old male with history of multiple nevi presented for routine skin surveillance. On exam a lesion of the pectoral region was noted by the physician and examined with dermoscopy. Dermoscopy ( Figure 1A) revealed a macular lesion with a heavily pigmented center and peripheral reticulated network, partially occluded by a second raised component with a distinctive cerebriform appearance. A biopsy was performed. On histology ( Figure 1B

Discussion
Altered cell-cell communication between melanocytes and keratinocytes may result in the proliferation of melanocytes and/or keratinocytes [1,2]. Via dermoscopy, we have come to appreciate that it is not uncommon to encounter melanocytic nevi displaying a seborrheic keratosis (SK) like component.
Our clinical experience has led us to speculate that the association between nevi and SK may not simply be due to the coincidental collision between these two benign tumors. It is quite possible that nevi can in fact induce the formation of SK [3]. It is interesting to note that research has also revealed that keratinocyte derived factors can regulate the proliferation of melanocytes, epidermal growth factor mutations are sometimes encountered in melanocytic neoplasms, fibroblast growth factor mutations are common in SK, specifically activating FGFR3 mutation, and fibroblast growth factor can be produced by melanocytic tumors [4][5][6][7][8][9]. A mutation in the There are no dermoscopic criteria for a melanocytic lesion present. The same lesion, two years later (5B), has dermoscopic features concerning for melanoma including, annular granular, blue-gray and dark brown structures, irregular dots and milky red areas (vascular blush) at the inferior portion of the lesion, while superiorly features of a seborrheic keratosis can still be appreciated. On histology (5C), the silhouette of the lesion shows a seborrheic keratosis with mixed acanthotic and reticulated growth patterns, but a proliferation of melanocytes along the dermoepidermal junction and in the dermis is also apparent. Figure 5D shows a close-up view of the melanoma associated with a seborrheic keratosis (box in 5C). There is an atypical junctional melanocytic proliferation associated with an intradermal spindle cell melanoma. In Figure 5E PI3K pathway has been described in SK [10]. Supplementary to this, it is known that therapies targeting BRAF, which is the most common mutation among nevi, induce eruptive keratinocyte tumors [11].
Mature nevi, which are in a state of senescence, are stable lesions that do not grow. However, SK developing in association with nevi may continue to grow. It is conceivable that the enlarging SK component may eventually mask the underlying nevus. In the unfortunate scenario of the development of a nevus-associated melanoma beneath the SK, the malignancy would of course eventually become visible, as may have occurred in Case 5 presented here [12][13][14][15]. Alternative explanations include that some of these lesions may have been melanomas from their inception that were masquerading themselves as SK [16], that normally occurring melanocytes within an SK mutated into melanoma [12], or that the initial lesion was a keratotic melanocytic nevus, which on histology have hyperkeratotic epidermal rete ridges and pseudohorn cysts, and clinically can have a warty appearance [17] mistaken for a seborrheic keratosis. Melanoma may arise from this lesion giving the clinical appearance of a melanoma arising in a seborrheic keratosis or perhaps the association between melanoma and SK is purely due to the coincidental collision between these two entities [18].
Seborrheic keratoses in association with melanocytic nevi and melanoma have been reported previously. In a retrospective study published by Boyd and Rapini, 69 collision tumors were observed after assessing 40,000 cutaneous biopsies. Of those 69, 14 were nevus and seborrheic keratosis [19]. In a retrospective case series by Lim, over a 12-month period, histology of 639 SK was evaluated and 85 (9%) were found in association with other lesions. Seven melanomas (8.2%) were reported with one found to have arisen within the seborrheic keratosis and six adjacent to a seborrheic keratosis.
Thirteen melanocytic nevi (15.3%) adjacent to SK were also reported [20]. These findings may be more than coincidental and may suggest a not yet fully understood local phenomenon. This concept has been proposed previously by Brownstein [21], where it was suggested that nevi may interact with the stroma to induce epithelial growths. The melanocytic nevus may alter the local milieu and induce the development of the adjacent seborrheic keratosis, accounting for our clinical observations.

Conclusion
We have presented five cases of melanocytic lesions found in association with SK. Nevus in association with seborrheic keratosis has been observed frequently in our clinical experience and is more readily appreciated with dermoscopic inspection. The frequency with which this has been noted and an ever-increasing understanding of cell-signaling has led us to postulate that this may be more than a chance occurrence. Further exploration of cell-cell signaling of melanocytes and keratinocytes is needed to truly understand this clinical observation.