Nivolumab Delivers Remarkable Remission in Late Liver Metastasis Recurrence of Advanced Malignant Melanoma

A 58-year-old man arrived at Jichi Medical University Hospital in Tochigi, Japan, with fever and anorexia, and a CT scan revealed multiple liver lesions that had been absent just five months earlier. Eleven years before, he had undergone wide excision of a primary malignant melanoma on the left parietal scalp with cervical lymph node dissection, staged as T3bN2aM0 — stage IIIB under the AJCC 7th edition and stage IIIC under the 8th. He had received three years of adjuvant intralesional interferon-β therapy and had been monitored with computed tomography, showing no distant metastasis five months before presentation. The sudden appearance of hepatic lesions after more than a decade of disease-free survival set the stage for a diagnostic and therapeutic challenge that dermatologists Shoka Fukuizumi, Soichiro Kado, and colleagues describe in the Journal of Cutaneous Immunology and Allergy.

On admission, the patient exhibited fever of 38.3 °C, leukocytosis at 16,200/μL, elevated lactate dehydrogenase at 701 IU/L, and a markedly elevated C-reactive protein level of 27.07 mg/dL. Metastatic liver tumors and infection were suspected, prompting hospitalization for antibiotic treatment. However, blood cultures obtained before treatment initiation were negative, and antibiotic therapy failed to improve either the fever or the CRP elevation. His condition deteriorated rapidly, with persistent fever, worsening ascites, and a decline in performance status from 0 to 3. Planned liver biopsy and endoscopic procedures were canceled due to his declining condition, and ascitic cytology showed no malignancy. Despite the lack of histological confirmation, magnetic resonance imaging showed T1 hyperintense liver lesions, and 5-S-cysteinyldopa was elevated at 124 nmol/L, indicating metastatic melanoma.

Nivolumab treatment was initiated, resulting in rapid improvement. The fever resolved within days, and CRP promptly decreased to below 5 mg/dL by day 10, indicating a tumor-related inflammatory response rather than infection. After treatment initiation, BRAF testing revealed a V600E mutation, but nivolumab was continued given the clear clinical response. Three months post-treatment, the hepatic lesions became indistinct, and the patient’s performance status returned to 0. He has shown sustained response to nivolumab for over two years, monitored with non-contrast CT due to mild chronic kidney disease.

Malignant melanoma is a skin cancer with a high risk of recurrence and metastasis. The interval between initial treatment and subsequent recurrence or metastasis typically shortens with disease progression. In a large Duke University cohort of 7,104 patients, only 168 patients — 2.4 percent — developed their first recurrence after a 10-year disease-free interval. The majority of these patients had early-stage disease, with 92.9 percent at stage I and 6.5 percent at stage II, whereas only one patient, 0.6 percent, initially presented with stage III disease. These findings indicate that late first relapse more than 10 years after initial treatment is uncommon, and that such relapse is particularly rare in patients who initially present with stage III melanoma. Nevertheless, this patient developed hepatic metastases 11 years after surgery despite initially having stage III disease, highlighting that metastatic melanoma should remain in the differential diagnosis when evaluating new hepatic lesions even after a prolonged disease-free interval, including in patients with initially advanced-stage disease.

The mechanisms underlying late recurrence of melanoma remain incompletely understood, but long-term tumor dormancy followed by disruption of immune control or tumor immune escape has been proposed. Reschke and colleagues suggested that melanoma cells may detach from the primary tumor and disseminate via lymphatic or hematogenous routes several decades before distant metastases become clinically apparent. They discussed tumor dormancy as a multifactorial process involving immune-mediated growth control, cell-cycle arrest with reduced metabolic activity, and angiogenic regulation. They also proposed that individual immune surveillance may control residual melanoma cells for more than a decade, whereas advanced age and increasing comorbidities may disturb the immunological balance and contribute to overt recurrence.

Tissue-resident memory T cells may be one component of this immune-mediated dormancy. Plunkett and colleagues reviewed evidence that TRM can maintain melanoma in a state of immune-mediated equilibrium, preventing progression to macroscopic disease. In preclinical models, TRM surveilled skin regions containing melanoma cells and mediated protection in a TNF-α-dependent manner. However, the mechanisms by which occult melanoma subsequently becomes clinically overt remain unclear. Plunkett and colleagues described a possible immune-escape mechanism involving CD8-positive T cells and the PD-1/PD-L1 axis. In this model, engagement of PD-1 on CD8-positive T cells by tumor-expressed PD-L1 attenuates T-cell receptor signaling, proliferation, and cytotoxicity, thereby suppressing anti-tumor immune responses. This PD-1/PD-L1-mediated impairment of CD8-positive T-cell activity may represent one mechanism by which dormant melanoma cells escape long-term immune surveillance and eventually progress to clinically apparent recurrence.

In the present case, the three-year course of adjuvant intralesional interferon-β therapy may have been one of several factors contributing to prolonged immune-mediated tumor control, although its role cannot be determined. Conversely, age-related alterations in immune surveillance may have disrupted this equilibrium and contributed to the abrupt clinical manifestation of recurrence. The interplay between long-standing immune control and eventual immune escape remains a central question in understanding why some melanomas reappear after a decade or more of dormancy while others never do.

In this case, MRI played a pivotal role in diagnosing liver metastasis. Malignant melanoma often exhibits hyperintense signals in T1-weighted MRI images, a critical characteristic finding under challenging histological confirmation. MRI can be especially useful in such cases, where biopsy or other tissue-based diagnostic methods are not feasible. The combination of T1 hyperintense lesions and elevated 5-S-cysteinyldopa provided sufficient diagnostic confidence to initiate treatment without histological confirmation, a decision that proved decisive given the patient’s rapidly declining condition.

Despite liver metastases — a factor associated with diminished clinical benefit from immune checkpoint blockade — this patient showed a rapid and sustained response to nivolumab. If late relapse in this case reflected immune escape through mechanisms such as those discussed by Plunkett and colleagues, restoring antitumor immunity via PD-1 blockade could be biologically plausible and may have contributed to the marked response observed. However, whether late first relapse is associated with enhanced sensitivity to immune checkpoint inhibitors remains uncertain. The efficacy of immune checkpoint inhibitors for late recurrence in ICI-naïve patients has not been well characterized; in this regard, further case accumulation is required to better define benefit predictors.

This case underscores several important clinical lessons. First, metastatic melanoma should remain in the differential diagnosis for new hepatic lesions even after a prolonged disease-free interval, including in patients with initially advanced-stage disease. Second, MRI characteristics of melanoma metastases can be diagnostically decisive when tissue confirmation is not feasible. Third, the remarkable and sustained response to nivolumab in this patient — despite liver metastases typically being associated with diminished immunotherapy benefit — suggests that the biology of late recurrence may differ fundamentally from that of early metastatic disease, potentially reflecting a tumor that has been held in check by immune surveillance for over a decade before escaping through PD-1/PD-L1-mediated mechanisms that nivolumab can reverse.

Subject of Research: Late liver metastasis recurrence of malignant melanoma and its treatment with the PD-1 inhibitor nivolumab

Article Title: Remarkable effect of nivolumab on late liver metastasis recurrence in advanced malignant melanoma

Article References: Fukuizumi, S., Kado, S., Ando, T., Sato, A., Kamiya, K., Maekawa, T., Ohtsuki, M., & Komine, M. (2026). Remarkable effect of nivolumab on late liver metastasis recurrence in advanced malignant melanoma. Journal of Cutaneous Immunology and Allergy, 9, Article 16775. https://doi.org/10.3389/jcia.2026.16775

Image Credits: AI Generated

DOI: 10.3389/jcia.2026.16775

Keywords: melanoma, nivolumab, liver metastasis, late recurrence, immune checkpoint inhibitor, PD-1, tumor dormancy, tissue-resident memory T cells, MRI, interferon-beta, immunotherapy, case report