Case 2 -

Benign Melanocytic Nevi with Pregnancy-associated Changes Steven R. Tahan Harvard Medical School and Beth Israel Deaconess Medical School Boston, MA

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Clinical History: This nevus was shaved from the neck of a 35 year old woman who was 29 weeks pregnant for indication of increasing size. Case 2 - Figure 1 Low power view showing bosselated surface of nevus removed at 29 weeks of pregnancy. Case 2 - Figure 2 Higher power of superficial micronodules. Case 2 - Figure 3 Superficial micronodules showing small clusters of large epithelioid cells within expanded surface bosselation. Case 2 - Figure 4 Superficial micronodules Case 2 - Figure 5 Superficial micronodules Case 2 - Figure 6 Superficial micronodules comprised of rounded clusters of 3-20 large epithelioid melanocytes with prominent nucleoli, abundant pale eosinophilic cytoplasm, and occasional fine melanosomes. Case 2 - Figure 7 Mitoses within superficial micronodules Case 2 - Figure 8 Mitoses within superficial micronodules Case 2 - Figure 9 MIB-1 immunostain for Ki-67 shows positive cells, predominantly in superficial micronodules. Case 2 - Figure 10 HMB45 immunostain reacts with cells in superficial micronodules and mid-dermis Case 2 - Figure 11 Nevoid melanoma showing deceptively small cell size, but monotonous. Case 2 - Figure 12 Nevoid melanoma with large dermal nests. Case 2 - Figure 13 Congenital nevus with large proliferative nodule (lower portion of lesion), courtesy of Dr. Xaiwei Xu of UPenn, with permission. Introduction: Asymmetric and rapid enlargement of nevi during pregnancy can be clinically alarming, especially when coupled with histologic features normally associated with biologic transformation, such as cellular enlargement, mitotic activity, and HMB45 immunoreactivity. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: Key Histologic Features Low power view shows a cellular appearing predominantly dermal melanocytic nevus with slightly asymmetric architecture, specifically in superficial areas that show a bosselated appearance (figures 1 and 2). Absence of intraepidermal component. Higher magnification of superficial aspect reveals numerous rounded clusters of 3-20 intermediate-sized epithelioid melanocytes with prominent nucleoli, abundant pale eosinophilic cytoplasm, and occasional fine melanosomes (figure 3 to 6). These clusters are distinct from the aggregates and single smaller type B and C nevic melanocytes in deeper areas. Mitoses are ready found, predominantly superficially within the superficial micronodules, but also scattered within the mid-dermal area of the lesion (figures 7 and 8). Ki-67 highlights clusters of cells in proliferative phase (figure 9). HMB45 immunostain strongly reacts with cells of the superficial micronodules, but also marks scattered melanocytic cells in the mid-dermis (figure 10). Differential Diagnoses: The principle differential diagnosis is nevoid melanoma, which can similarly show mitotic activity,HMB45 positivity, and intemediate-size epithelioid cytomorphology. Some congenital nevi develop "proliferative" nodules, but these are usually much larger than the superficial micronodules of this lesion, and positioned in the mid- dermis. Final Diagnosis: The features of a predominantly dermal nevus with superficial micronodules of medium-sized epithelioid cells, mitotic activity, HMB45 positivity predominantly superficially, maturation in deeper areas, and lack of intraepidermal component are consistent with a benign melanocytic nevi with pregnancy-associated changes. Observing changes of this type in histologic evaluation of a changing nevus should trigger inquiry regarding the pregnancy status of the patient. Case Discussion: We recently studied the histologic features and Ki-67 proliferation index in 16 dermal nevi excised from pregnant women (n = 16) compared with nevi from location- and aged-matched control patients (n = 15) [1]. Mean gestational age at the time of excision was 23.9 ± 11.5 weeks in the pregnant group. Both groups included similar numbers of nevi excised from the trunk, head and neck, and genitalia (vulva/labia). Among the nevi of pregnancy, the most common indication (8 cases) for removal was "changing" or "enlarging mole". Other indications included "atypical nevus" (4 cases), "irritated nevus" (3 cases), and "new mole" (1 case). Ten of the 16 (62%) of the pregnancy nevi had dermal mitoses at a rate of 1.4 per mm2 compared with 2 of the 14 (13%) controls (P= 0.028) at a rate of 0.2 per mm2 (P=0.0027). The Ki-67 proliferative rate was 3.0% in pregnancy nevi compared to 1.0% in controls (P=0.07). Superficial micronodules, defined as rounded clusters of 3– 20 large epithelioid melanocytes with prominent nucleoli, abundant pale eosinophilic cytoplasm and occasional fine melanosomes, were present in 13 (81%) pregnancy nevi compared with 4 (27%) control nevi (P= 0.04). Given the predilection for these to be a feature of pregnancy nevi, we designated these "superficial micronodules of pregnancy (SMOPs). In nevi with SMOPs, nearly all cells of the SMOPs were positive for HMB45 in all cases tested (12/12 pregnancy nevi and 4/4 controls). In addition, in half of (6/12) pregnancy cases and one control, scattered cells in the mid-deep aspect of the nevi were also positive for HMB45. Two other studies have examined the histologic features of benign nevi during pregnancy. Sanchez et al. examined 22 banal melanocytic nevi(predominantly intradermal) from pregnant women and compared them to age-matched controls [2]. These nevi were examined for the presence of melanocytic hyperplasia, elongation of rete ridges, papillary dermal fibroplasia, inflammatory cell infiltrate, melanocytic maturation with depth, vascular dilation, symmetry, circumscription, and melanocytic atypia (defined by pleomorphism, hyperchromatic nuclei, prominent nucleoli, increased nuclear:cytoplasmic ratio, and mitoses). In contrast to our findings, their study showed no significant differences between the nevi of pregnancy and the controls. Such discrepancy may in part be due to the differences in the parameters being evaluated. Many of the parameters used in their study are not included in our study because all of our cases showed maturation with depth, overall symmetry, and circumscription. In their study, 'mitoses' was grouped with other factors as criteria for atypia,whereas in our study, the number of mitoses is evaluated independently. Furthermore, using our criteria, 'prominent nucleoli' are included in the definition of 'SMOPs' rather than 'melanocytic atypia'. In another study, Foucar et al. assessed the degree of atypia in 128 melanocytic nevi excised from pregnant women [3]. Each nevus was given an 'atypia score' based on the following features: cohesion of melanocytic nests, intraepidermal migration of proliferation, mitotic activity, degree of pigment dispersion, prominent nucleoli, presence of small nevus cells in the lower dermis, demarcation of melanocytes at the lateral margins, and nuclear size. Again, no statistically significant difference was observed between the nevi of pregnancy and the age matched controls; however, there was a trend toward higher 'atypia score' in the former (p = 0.056). In an attempt to explain the discrepancy between our studies, we suggest that the features which may have contributed to the 'higher atypia score' may include increased mitotic activity, prominent nucleoli, and enlarged nuclear size, as observed in our study. An important differential diagnosis of a mitotically active nevus is nevoid melanoma (figure 11). Nevoid melanomas are known to be a diagnostic pitfall due to their deceptively banal histologic appearance including overall symmetry, circumscription, pseudomaturation, and nevoid morphology of the melanocytes [4] (figure 12). Indeed, both nevi of pregnancy and nevoid melanoma can exhibit dermal mitoses, however pregnancy nevi lack cytologic atypia in the deeper aspects, namely prominent nucleoli, hyperchromatism, and nuclear membrane irregularity [5]. Furthermore, unlike nevoid melanomas which may have crowded back-to-back nests or sheets of melanocytes, the cellularity of the nevi in our study in areas away from the superficial micronodules was not increased compared to typical nevi [6]. Taken together, these nevi can in most cases be distinguished from nevoid melanomas despite their mitotic activity. Nevi can spontaneously develop proliferative nodules in their core, usually in congenital nevi in young children, but sometimes in older children and even adults (figure 13). Unlike SMOPs, these nodules are usually solitary, relatively large, and arise in the midst of the nevi [7]. These have not been associated with pregnancy and should not pose significant confusion with SMOPs or other features characteristic of pregnancy induced changes in nevi. Conclusion(s): Observing changes of the type illustrated by this nevus should trigger inquiry regarding the pregnancy status of the patient. Even in the setting of pregnancy, any concerning features, such as a spreading intraepidermal component or lack of maturation, should be carefully evaluated. References: Chan MP, Chan MM, Tahan SR. Melanocytic nevi in pregnancy: histologic features and Ki-67 proliferation index. J Cutan Pathol 2009: Dec 14. [Epub ahead of print]. Sanchez JL, Figueroa LD, Rodriguez E. Behavior of melanocytic nevi during pregnancy. Am J Dermatopathol 1984; 6:89–91. Foucar E, Bentley TJ, Laube DW, Rosai J. A histopathologicevaluation of nevocellular nevi during pregnancy. Arch Dermatol 1985; 121: 350. Schmoeckel C, Castro CE, Braun-Falco O. Nevoid malignant melanoma. Arch Dermatol Res 1985; 277: 362. Magro CM, Crowson AN, Mihm MC Jr. Unusual variants of malignant melanoma. Mod Pathol 2006; 19: 41–70. McNutt NS, Urmacher C, Hakimian J, Hoss DM, Lugo J. Nevoid malignant melanoma: morphologic patterns and immunohistochemical reactivity. J Cutan Pathol 1995; 22: 502–517. Massi G. Melanocytic nevi simulant of melanoma with medicolegal relevance. Virchows Arch (2007) 451:623–647.