Melanoma in situ (MIS) is a noninvasive precursor lesion of melanoma, confined to the epidermis and classified as stage 0 [1, 2]. Although MIS is generally considered to have no metastatic potential, rare instances of recurrence or metastasis have been documented during follow-up after resection of lesions initially diagnosed as MIS [3–5]. This letter describes 3 patients with MIS who experienced recurrence and/or distant metastasis during follow-up after excision.
A 63-year-old man underwent amputation in June 2015 due to melanoma of his right toenail. He was given a histopathologic diagnosis of MIS and was subsequently followed up. In July 2019, a biopsy performed because of enlarged groin lymph nodes revealed metastasis. One of 13 nodes was involved after lymph node dissection. The patient had BRAF wild-type disease and received radiotherapy, followed by temozolomide for 6 months. In January 2020, brain magnetic resonance imaging was performed due to developing neurological complaints and revealed multiple masses with signs of leptomeningeal involvement. Despite nivolumab combined with craniospinal radiotherapy, his performance status and consciousness deteriorated, and he died 1 month later.
In the second case, a 46-year-old man underwent excision in December 2012 for melanoma arising on the right cruris. After a histopathologic diagnosis of MIS, wide local excision was performed, and no residual tumor was detected. He was followed up, and metastasis was diagnosed in September 2018 on biopsy performed because of enlarged inguinal nodes. He underwent lymph node dissection, and involvement was detected in 2 out of 12 nodes in the groin and 3 out of 14 nodes in the pelvic region. The patient was subsequently lost to follow-up after radiotherapy but was relapse-free in February 2025.
The third patient was a 67-year-old man who had undergone excision of a lesion on the sole of the right foot in November 2011. Histopathologic examination detected MIS, and the excision was extended. During follow-up, a recurrent plantar mass was excised in July 2019. Following the detection of node enlargement in the inguinal ultrasonography performed in August 2019, metastases were detected in 2 out of 5 nodes after the dissection. The patient, who was lost to follow-up after radiotherapy and temozolomide, was disease-free in February 2025.
MIS, which accounts for a substantial proportion of melanoma diagnoses, has shown a marked increase in incidence over recent decades [1]. A US Surveillance, Epidemiology, and End Results (US SEER) analysis of 137,872 patients with MIS reported a 15-year melanoma-specific survival rate of 98.4%, with overall survival exceeding that of the general population [1]. Similarly, a Swedish population-based matched cohort study of 7,772 patients with MIS found lower overall mortality than in the general population, despite an increased risk of subsequent melanoma [2].
Although the prognosis is very favorable in MIS patients, melanoma-specific survival does not reach 100%. Rare recurrence, metastasis, and melanoma-related death have been reported. The literature includes rare case reports and series on this subject [3–5]. An unusual course was observed in 9 (2.01%) of 448 MIS patients, including 5 with local recurrence, 3 with regional metastasis, and 1 with distant metastasis [5]. The mean disease-free survival was 48 months (range: 6–121 months); it was 46 months for patients with local relapse and 51 months for those with metastatic disease. Metastasis to usu lymph node and subsequently to the brain has also been described in a 73-year-old man after apparently adequate excision of MIS with negative surgical margins [4]. In-transit metastases were reported 14 months after excision in a 57-year-old woman with MIS localized on her leg [3].
Because MIS without invasion is not expected to recur after proper surgery, recurrence or metastasis should prompt consideration of alternative explanations rather than being attribute to the natural behavior of true in situ disease. The most likely possibility is that an occult invasive primary melanoma was missed during histopathological examination [1, 4]. Occult invasion was found in 11 out of 33 patients initially diagnosed with MIS when histopathological blocks were re-examined [6]. In another study, occult invasion was identified in 16 of 32 patients [7]. These findings support occult invasion as a plausible explanation for subsequent recurrence or metastasis [3]. Another assumption is that the disease is incorrectly staged, defined as stage 0 instead of a higher stage. Up to 29% of MIS patients were in the higher stages [8]. Regression of a pre-existing invasive melanoma, leaving residual epidermal disease interpreted as MIS, is also a noteworthy possibility [1, 3–5]. However, in one series, regression was found in only 1 of 9 patients with recurrence or metastasis [5]. Finally, recurrence/metastasis may represent melanoma originating from extracutaneous, mucosal, or unknown primary sites rather than from the original MIS lesion [4].
In conclusion, although MIS has an excellent prognosis, progression can rarely occur after excision. Such rare events do not justify routine escalation to more extensive excision or intensified follow-up in all patients. Rather, they highlight the importance of careful histopathologic assessment, appropriate clinicopathologic correlation, and patient education regarding the small but clinically relevant possibility of relapse and the need for regular follow-up.
