Melanoma in Hepato-Pancreato-Biliary (HPB) Diseases
Introduction
Melanoma is a malignant tumor of melanocytes, known for its aggressive behavior and potential to metastasize to various organs.
Gastrointestinal metastases of malignant melanoma are common; however, isolated disease of the pancreas is rare, with surgical experience limited to small case series.
Melanoma Metastases to the Pancreas
Incidence and Clinical Features
Pancreatic metastases from melanoma are uncommon but have been reported, often originating disproportionately from primary ocular melanoma.
In up to 13% of cases, the primary site may not be identified, suggesting a possibility of misdiagnosis as a primary pancreatic malignancy.
Surgical Management
Surgical resection for pancreatic metastases from melanoma should be considered a palliative treatment.
Indications for resection:
Patients with long disease-free intervals after treatment of the primary tumor.
Small series suggest a 5-year survival of 50% for patients with R0 resected isolated melanoma metastases.
In comparison, a 9% 5-year survival for patients treated with non-operative management.
Due to retrospective and highly selective data, a clear benefit of resection cannot be firmly established.
Imaging Findings
Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) play crucial roles in detecting pancreatic metastases.
Hypervascular neoplasms like melanoma are generally evaluated using a multiphasic protocol that includes:
Precontrast imaging
Late arterial phase
Portal venous phase
FDG-PET scans may be useful, especially if the patient has a history of colonic, renal, or melanoma primary tumors.
Familial Atypical Multiple Mole and Melanoma (FAMMM) Syndrome
Genetic Basis
FAMMM syndrome is associated with p16 germline mutations, a tumor suppressor gene that may be mutated or have altered expression due to post-transcriptional methylation.
Clinical Features
Predisposes individuals to:
Melanomas
Multiple nevi
Atypical nevi
Pancreatic cancer (PC)
Patients with FAMMM have:
An approximately 80% lifetime risk of melanoma.
A 20% to 34-fold increased risk of pancreatic adenocarcinoma (PDA) over their lifetime.
Melanoma Metastases to the Liver
Incidence and Clinical Features
Metastatic melanoma to the liver can occur, sometimes with an unknown primary site.
Melanoma metastases can form polypoid lesions and mimic primary tumors, especially when the history of melanoma is not apparent.
Imaging Findings
CT Imaging:
Melanoma liver metastases are hypervascular lesions.
Multiphasic imaging is advantageous for detecting hypervascular liver metastases.
Approximately 14% of melanoma metastases are not seen on portal venous phase images alone.
MRI Imaging:
Metastases may be hyperintense on T1-weighted images due to melanin content.
On T2-weighted images, they are usually moderately brighter than the liver.
Diffusion-weighted imaging (DWI) can provide additional signal characteristics.
Subtraction imaging can demonstrate the "doughnut sign", indicating peripheral rim enhancement and central hypoenhancement due to necrosis.
Surgical Management
Some propose that patients with isolated hepatic melanoma metastases may benefit from surgery when complete resection is possible.
Outcomes after resection:
Reports suggest improved survival rates in selected patients.
Resection for non-colorectal, non-neuroendocrine (NCNN) liver metastases shows varying survival benefits based on the primary tumor site.
Melanoma liver metastases showed promising survival outcomes in some studies.
Melanoma Involving the Biliary Tree
Metastases Mimicking Primary Tumors
The biliary tree can be involved by metastases from various carcinomas, including melanoma, which may form polypoid luminal lesions.
Metastatic melanoma can mimic primary biliary tumors, often without an apparent history of melanoma.
Imaging and Pathology
Gross appearance:
Metastatic melanoma in the pancreas or biliary tree may appear black if intensely pigmented.
Microscopic examination:
Melanoma cells are not arranged in a particular pattern and display diffuse, noncohesive infiltration.
Immunohistochemistry:
Positive for melanocytic markers (S100, SOX10, Melan-A, HMB45).
Negative for cytokeratin, helping to confirm the diagnosis.
Molecular Aspects
Mutational burden in HPB malignancies is not exceptionally high compared to other cancers.
Melanomas fall at the upper end of the spectrum with higher mutational loads.
Tumor Mutation Burden (TMB):
Positively correlated with increased likelihood of neoantigen production.
Potentially results in a beneficial response to checkpoint inhibitor therapies.
Treatment
Role of Type I Interferons
Type I Interferons (IFNs), including Interferon-α (IFN-α) and Interferon-β (IFN-β), are crucial in the immune response to viral infections.
Clinical use:
IFN-α has been used in the treatment of viral hepatitis and as an adjuvant therapy for melanoma.
Mechanism of action:
Direct antiviral action by triggering infected cells to produce enzymes that interfere with viral replication.
Increase expression of MHC class I molecules, enhancing recognition by CD8+ T cells.
Inhibit cellular proliferation.
Chemotherapy and Immunotherapy
The efficacy of surgical treatment compared with evolving forms of chemotherapy and immunotherapy is not well-established due to insufficient data.
Checkpoint inhibitors and other immunotherapies may be considered, especially given the higher TMB in melanoma.
Conclusion
Melanoma metastases to the pancreas, liver, and biliary tree are rare but clinically significant.
Surgical resection may offer survival benefits in selected patients with isolated metastases and long disease-free intervals.
FAMMM syndrome significantly increases the risk of melanoma and pancreatic cancer, necessitating careful monitoring.
Imaging techniques like CT, MRI, and FDG-PET are essential for detection and management planning.
Molecular profiling and understanding of TMB are important for guiding immunotherapy options.
A multidisciplinary approach is crucial in managing melanoma in HPB diseases to optimize patient outcomes.
Melanoma in Hepato-Pancreato-Biliary (HPB) Diseases
Introduction
Melanoma is a malignant tumor of melanocytes known for its aggressive behavior and potential to metastasize to various organs.
In 2020, melanoma was estimated to account for approximately 7% of new cancer cases in men and 5% in women in the United States.
Most cases (90%) involve melanoma of cutaneous origin, whereas a small subset is derived from the uvea (5%) or other body sites.
The pattern of metastatic spread depends on the site of the primary melanoma.
Cutaneous Melanoma
Incidence and Patterns of Metastasis
Cutaneous melanomas disseminate to the liver in 15% to 20% of patients with metastatic disease.
They are often associated with simultaneous extrahepatic disease.
Cutaneous melanoma recurs after potentially curative resection in approximately one-third of patients, with almost every organ being at risk.
Hepatic metastases are diagnosed in approximately 10% to 20% of patients with stage IV melanoma, even though it is well documented that most patients have liver metastases on postmortem examination.
Surgical Management
Before the introduction of targeted therapy (BRAF and MEK inhibitors) and checkpoint inhibitors, most patients were considered to have unresectable melanoma due to extrahepatic disease or disseminated hepatic metastases.
Study from John Wayne Cancer Institute and Sydney Melanoma Unit (1971-1999):
26,204 patients with melanoma were reviewed.
1,750 patients (6.7%) had liver metastases.
Only 34 patients underwent surgical exploration for attempted liver resection.
Hepatectomy was performed in 24 patients.
Of these, 12 had synchronous extrahepatic disease, and 18 could be rendered disease-free surgically.
10 patients who underwent exploration only had a median survival of 4 months.
The overall survival of all patients with liver metastases treated nonoperatively was 6 months.
Patients who underwent complete resection had an overall survival of 28 months, with a median disease-free survival (DFS) of 12 months.
One patient achieved 10-year survival, and the 5-year overall survival was 29%.
Complete gross resection and histologically negative margins were associated with improved DFS.
Complete gross resection showed a trend for improved overall survival (P = .06).
Conclusions:
Extrahepatic disease per se is not a contraindication for resection, provided that all disease is resectable.
Patient selection is crucial.
Only 1.4% of patients with liver metastases underwent hepatic resection.
These patients had a median disease-free interval of 58 months before presenting with hepatic metastases.
Other small series report median survival times of 10 to 51 months after liver resection for metastatic melanoma.
Repeat hepatic resection might be beneficial for some patients who can be rendered disease-free surgically.
Impact of Targeted Therapies
In the last decade, there has been a paradigm shift in the treatment of metastatic melanoma with the introduction of targeted therapy using BRAF or MEK inhibitors and immune checkpoint inhibitors.
Current studies have shown that the median survival in selected patients with metastatic melanoma and a BRAF V600 mutation can be extended to more than 21 months.
Combination therapy with dabrafenib and trametinib resulted in an objective tumor response rate of 64%.
This effective systemic therapy has a powerful impact on patients undergoing resection in metastasized melanoma.
Recent studies have shown that patients undergoing hepatectomy for liver metastases of melanoma can experience:
1-year survival of 51%.
2-year survival of 38%.
These data are encouraging in that targeted therapy might render more patients eligible for a curative surgical approach when they present with liver metastases.
Uveal Melanoma
Incidence and Patterns of Metastasis
Uveal melanoma is a distinct entity with different tumor biology and commonly spreads to the liver.
Approximately 50% to 80% of patients with uveal melanoma who develop distant metastases have liver involvement.
In 40% of patients with liver metastases from uveal melanoma, the liver is the only organ of secondary disease without additional extrahepatic disease.
Therefore, the number of liver metastases resected from uveal melanoma is nearly equivalent to that of cutaneous melanoma.
Surgical Management
Mariani et al. investigated the management of liver metastases from uveal melanoma in 798 patients.
255 patients received surgical treatment.
The median overall survival after hepatic surgery was 14 months compared with 8 months in those who had no surgery.
Survival analysis based on resection status showed:
R0 resection: median overall survival of 27 months.
R1 resection: median overall survival of 17 months.
R2 resection: median overall survival of 11 months.
Prognostic classifiers identified were:
Time to liver metastases ≤24 months.
Number of liver metastases resected ≤4 lesions.
Absence of miliary disease.
Hsueh et al. reported on 112 patients with metastatic uveal melanoma.
78 patients had liver metastases.
24 patients underwent surgical resection for metastatic disease, 5 with liver metastases.
Multivariate analysis showed that resection, but not the site of metastasis, was a significant predictor of survival.
The median survival for patients undergoing resection was 38 months, with a 5-year survival of 39%.
Pawlik et al. reported on 16 patients with liver metastases from ocular melanoma who underwent resection.
The median time to recurrence was 8.8 months.
Compared with patients undergoing liver resection for metastatic cutaneous melanoma:
More patients with ocular melanoma experienced recurrent disease in the liver (53% vs. 17%).
However, the 5-year survival was significantly better for metastatic ocular melanoma (21% vs. 0%; P = .015).
Despite these data, most patients with liver metastases from uveal melanoma are not candidates for complete resection.
Imaging and Patient Selection
For optimal selection of patients eligible for liver resection in uveal melanoma, diligent staging is mandatory.
Magnetic Resonance Imaging (MRI) might be superior to Fluorodeoxyglucose Positron-Emission Tomography (FDG-PET), as reported in a preliminary study.
Melanoma Metastases to the Pancreas
Gastrointestinal metastases of malignant melanoma are common, but isolated disease of the pancreas is rare.
Reports indicate that metastases to the pancreas have been described to originate disproportionately from primary ocular melanoma.
Surgical experience is limited to small case series.
Surgical resection for pancreatic metastases from melanoma is considered a palliative treatment.
Generally performed in patients with:
Long disease-free intervals.
A negative extent-of-disease workup.
After a multidisciplinary discussion.
Prognosis after resection:
Small series suggest a 5-year survival of 50% for R0 resected isolated melanoma metastases.
Compared with 9% for patients treated with non-operative management.
Data are retrospective and highly selective; thus, a clear benefit of resection cannot be assessed.
Melanoma Metastases to the Liver
Metastatic melanoma to the liver can occur, sometimes with an unknown primary site.
Melanoma metastases can form polypoid lesions and mimic primary tumors, especially when the history of melanoma is not apparent.
On gross appearance, metastatic melanoma in the pancreas or biliary tree may be black if intensely pigmented.
Microscopic examination:
Tumor cells are not arranged in a particular pattern but display diffuse and noncohesive infiltration.
Immunohistochemistry:
Positive for melanocytic markers (S100, SOX10, Melan-A, HMB45).
Negative labeling for cytokeratin confirms the diagnosis.
Imaging Findings
Computed Tomography (CT):
Melanoma liver metastases are hypervascular lesions.
Multiphasic imaging is advantageous for detecting hypervascular liver metastases.
Approximately 14% of melanoma metastases are not seen on portal venous phase images when the arterial phase is not provided.
Magnetic Resonance Imaging (MRI):
Metastases may be hyperintense on T1-weighted images due to melanin content.
On T2-weighted images, they are usually moderately brighter than the liver.
Diffusion-weighted imaging (DWI) provides additional signal characteristics.
Subtraction imaging can demonstrate a "doughnut sign", indicating peripheral rim enhancement and central hypoenhancement due to necrosis.
Surgical Management
Some propose that patients with isolated hepatic melanoma may benefit from surgery when complete resection is possible.
Outcomes after resection:
Reports suggest improved survival rates in selected patients.
Patients with unknown primary melanoma appear to have equivalent or better outcomes than patients with known primaries of a similar stage.
Imaging in Melanoma
Computed Tomography (CT)
State-of-the-art CT evaluation may include:
Precontrast images.
Contrast-enhanced early arterial phase.
Late arterial phase.
Portal venous phase.
Delayed phase.
Routine CT is usually performed in the portal venous phase, but hypervascular neoplasms like melanoma require a multiphasic protocol.
Magnetic Resonance Imaging (MRI)
MRI has superior contrast resolution, enhancing its sensitivity for liver metastases.
Metastatic tumors like melanoma maintain the histologic features seen in their primary location.
Melanin demonstrates high signal on T1-weighted images.
MRI diffusion sequences may help in distinguishing cystic metastases from other cystic lesions.
Role of FDG-PET
FDG-PET scans may be useful, particularly if the patient has a history of colonic, renal, or melanoma primary tumors.
MRI might be superior to FDG-PET in staging patients for liver resection in uveal melanoma.
Molecular Aspects
Melanomas fall at the upper end of the spectrum in terms of mutational burden.
Tumor Mutation Burden (TMB) is positively correlated with increased likelihood of neoantigen production.
This potentially results in a beneficial response to checkpoint inhibitor therapies.
Treatment
Role of Targeted Therapy and Immunotherapy
Targeted therapy using BRAF or MEK inhibitors and immune checkpoint inhibitors has led to a paradigm shift in the treatment of metastatic melanoma.
Median survival in selected patients with metastatic melanoma and a BRAF V600 mutation can be extended to more than 21 months.
Combination therapy with dabrafenib and trametinib resulted in an objective tumor response rate of 64%.
Systemic therapies have a powerful impact on patients undergoing resection in metastasized melanoma.
Effective systemic therapy might render more patients eligible for a curative surgical approach when they present with liver metastases.
Type I Interferons
Type I Interferons, including Interferon-α (IFN-α) and Interferon-β (IFN-β), are crucial in the immune response.
IFN-α has been used clinically as an adjuvant therapy for melanoma.
They inhibit cellular proliferation and enhance immune responses against tumor cells.
Conclusion
Melanoma metastases to the pancreas, liver, and biliary tree are rare but clinically significant.
Surgical resection may offer survival benefits in selected patients with isolated metastases and long disease-free intervals.
Patient selection is crucial, requiring diligent staging and multidisciplinary discussions.
Targeted therapies and immunotherapies have improved survival and may increase eligibility for surgical intervention.
A multidisciplinary approach is essential for optimizing patient outcomes in melanoma involving HPB diseases.