After the operation, the patient was treated with interferon α2b therapy. During the first month, the interferon α2b was administered by intravenous injection at a dose of 1,800 IU/d for 5 days with a 2-day break per week. From the 2nd to the 12th month, the interferon α2b was reduced to 900 IU/d three times a week. The interferon α2b therapy continued for nearly 1 year until the occurrence of thyroid dysfunction, and then oral imatinib was given as a substitution for 3 months. The interferon therapy was then resumed and was still being continued at the time of this writing. No adverse reaction occurred. She has been clinically free of tumors for 24 months after the surgery.
Vulvar MM during pregnancy is extremely rare. An extensive literature review revealed that only 4 cases have been reported since 1946.2–6 One case involved a 27-year-old patient complaint a firm mass of 4 cm on her right labium majora for years, and a biopsy during her pregnancy revealed melanoma.2 The patient underwent local excision without lymphadenectomy, 2 years later she developed lymph node metastasis with subsequent remote metastasis, and died 3.5 years with multiple metastases. Dyduch et al.3 described a 34-year-old patient with a pigmented lesion of 0.6 cm on the left labium majora 2 months before pregnancy. The lesion recurred twice during the pregnancy and after delivery, respectively, as a result of local excision with a margin of < 0.5 cm. The Breslow thickness was < 1 cm with ulceration. Neither sentinel lymph node (SLN) biopsy nor lymph node dissection was performed, and no long-term follow-up was recorded. Berlin and Winters4 described a patient who survived for 6 years after surgery, and a 31-year-old Asian patient described in 1983 remained free of melanoma for 23 months of follow-up.5 These two patients had small lesions with a short duration and had undergone radical vulvectomy and lymph node dissection along with additional complemental therapy.
Two important points can be raised after comprehensive analysis of the above cases. First, nevi on the genitalia may have features simulating melanoma, and it has been noted that melanocytic nevi (MN) may enlarge and darken during pregnancy.6 Differentiation between vulvar melanoma in pregnancy and peculiar longstanding nevi in the vulvar region can be difficult, especially when the nevi on the vulva are large in size and have an irregular border and atypical pathology. Second, melanoma during pregnancy must be properly managed to improve the prognosis.
Prospective studies of pregnant women have shown no significant changes in MN during pregnancy except in women diagnosed with dysplastic nevus syndrome.7 One study revealed that dermoscopic changes in MN during pregnancy involved primarily expansion of anatomic locations. Driscoll and Grant-Kels7 suggested that a changing melanocytic nevus during pregnancy should therefore not be considered to be physiologic, and prompt biopsy is indicated, just as in women who are not pregnant. Rapid growth and recent evolution are useful clues when MM is suspected.
Pathologically, genital nevi may show similar features of melanoma such as an increased cellular density, a few deeply situated mitoses, and ill-defined nests with regard to the intradermal component. Efforts have been made to differentiate the two conditions. Mihic-Probst et al.8 confirmed that the absence of p16 immunostaining was associated with an increased proliferation rate and a strong argument for MM. They considered that the relevance of p16 could be an additional marker. Uguen et al.9 explored a triple p16-Ki-67-HMB45 immunohistochemistry scoring system to assist the differential diagnosis between melanomas and nevi. They found that a high Ki-67 index, low to null of p16, and absence of HMB45 gradient were more frequent in melanomas than in nevi.
Genetic analyses of melanomas have revealed several recurrent aberrations that are absent in unequivocally benign lesions and have therefore been applied to differentiate them. A four-probe FISH assay targeting 6p25 (RREB1), 6q23 (MYB), Cep6 (centromere 6), and 11q13 (CCND1) is being increasingly applied to distinguish between histologically unequivocal melanomas and nevi with high sensitivity and specificity.10 Furthermore, studies have disclosed distinct molecular alterations in melanoma arising from different anatomic sites.11-12 KIT mutation was found to be significantly associated with vulvar melanoma, leading to the expansion of diagnostic and treatment options,13–15 but the prognostic value of the KIT gene is controversial.14-15
In the present case, the patient developed a rapidly evolving pigmented lesion with an unclear duration that later presented characteristics consistent with the “ABCD” criteria of MM when it recurred. The histopathological findings after the delivery confirmed the diagnosis of MM. KIT mutation was detected. Immunohistochemical staining of CD117 revealed moderate but diffuse expression in both the original and recurrent lesions. The positive staining of CD117 supports the original consideration of MM combined with the histopathology result of HMB45 and Ki-67.
Melanomas arising in pregnancy have traditionally presented unique challenges not only because of the diagnostic dilemma, but also because they raise issues with respect to treatment and prognosis. For many years, there had been concern that the hormonal and immunological changes that occur during pregnancy may be disadvantageous in the evolution or progression of melanoma and lead to poorer outcomes. However, increasingly data have indicated that pregnancy before, during, or after a diagnosis of localized melanoma does not appear to affect the prognosis.16 The prognosis of vulvar MM is poor basically because of the biological aggressiveness of the neoplasm, occult occurrence, lack of early symptoms, thin underlying dermis, delayed diagnosis, and less radical surgical therapy. Compared with the more common subtype of MM in the Chinese (i.e., acral type MM), our patient's lesion showed more rapid progression and aggressive behavior.
No consensus regarding the most adequate staging system and treatment for neither vulvar melanoma nor melanoma in pregnancy has been reached. It is suggested that wide local excision may be safe under local anesthesia during pregnancy. For non-pregnant patients, SLN mapping and biopsy is recommended for melanomas with a Breslow thickness of ≥ 1 mm or for thinner melanomas of Clark level IV/V, mitoses, and microsatellites. For pregnant patients, SLN biopsy under local anesthesia should be postponed until the postpartum period except when the pregnancy involves enhanced lymphangiogenesis, which is associated with increased metastasis of melanoma. In such patients, timely SLN biopsy and lymph node dissection are indicated. Considering the Breslow thickness of 3 mm and stage of TIIIa, partial vulvectomy with an excision margin of 2 cm without lymph node dissection was performed in our patient followed by interferon α2b treatment for almost 24 months, and the patient was free of melanoma at the time of this writing. Under the same surgical guideline, the 34-year-old patient described by Dyduch et al.3 had a maximum Breslow depth of 0.9 mm, and a margin of 1 cm was theoretically suitable; this may explain the consecutive recurrence.
In summary, vulvar melanoma during pregnancy is very rare. The diagnosis may be a great dilemma because vulvar melanoma is difficult to differentiate from a peculiar nevus. Overdiagnosis or misdiagnosis can lead to inappropriate outcomes. Our literature review indicates that recent and rapid evolution of a pigmented lesion and cytological atypia in the deep dermis are indicative of MM. Immunohistochemical staining with high expression of Ki-67 and negative expression of p16 support the diagnosis of MM. Additionally, FISH detection of genomic expansion or activated mutations of certain genes may confirm the diagnosis. Surgical resection of vulva with 2-cm margins along with adjuvant immunotherapy leads to a relatively good prognosis.
This work was supported by the CAMS Innovation Fund for Medical Sciences (CIFMS-2017-I2M-1-017).
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