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State-of-the-art Diagnosis and Treatment of Metastatic Melanoma: MDCT Protocol Optimization to Identify Metastases in Unusual Locations and Review of Innovative Therapeutic Agents

State-of-the-art Diagnosis and Treatment of Metastatic Melanoma: MDCT Protocol Optimization to Identify Metastases in Unusual Locations and Review of Innovative Therapeutic Agents

Blake C. Jones, M.D.
Evan J. Lipson, M.D.
Brandon Childers, M.D.
Karen B. Bleich, M.D.
Elliot K. Fishman, M.D.
Pamela T. Johnson, M.D

The Russell H. Morgan Department of Radiology and Radiological Science
The Johns Hopkins Medical Institutions
Baltimore, Maryland

RSNA 2015, Educational Exhibit #MS116-ED-X
Primary Category: Multisystem/Special Interest Secondary Category: Other

 

Teaching Points

  • Melanoma has a propensity to metastasize to locations not frequently involved by other malignancies. 
  • Identification of subtle recurrence in uncommon locations is critical for devising the optimal treatment plan, but hinges on high quality MDCT technique and a comprehensive search pattern. 
  • Management algorithms and outcomes have been dramatically altered in by innovative therapies. 
This exhibit reviews:
  1. MDCT appearance of melanoma metastases in uncommon locations
  2. Importance of IV contrast, multiplanar review and high contrast displays to identify subtle metastatic disease.
  3. New therapeutic approaches tailored to genetic mutations and immunotherapeutic agents
  4. Potential complications of novel therapeutics that may be identified on MDCT

 

Outline

  • Melanoma Background
  • MDCT Technique
    • IV contrast protocol (single vs dual phase acquisition, reconstruction sections)
    • High contrast display for increasing lesion conspicuity
    • MPRs facilitate lesion detection and increase diagnostic confidence
  • Case review: utility of display tools and search pattern for less common metastatic sites
    • Heart
    • Intramuscular
    • Spinal canal
    • Parotid gland
    • Thyroid gland
    • Pancreas
    • Small bowel
    • Mesenteric
    • Perinephric
    • Uterine
    • Cutaneous/Subcutaneous
    • Complications suggesting melanoma
  • Treatment
    • Therapy tailored to BRAF mutations
    • Immunotherapies
    • Complications that may be identified on body CT (pneumonitis, colitis)
  • Future Directions

 

Impact of Melanoma

  • Melanoma is the 5th most common cancer among men and 7th most common among women1
  • 65,647 cases of melanoma and 9,128 deaths in 2011 (United States)2
    • Age-adjusted incidence 19.7 per 100,000
    • Age-adjusted melanoma death rate 2.7 per 100,000
    • Melanoma incidence doubled between 1982 and 2011; stable mortality
  • Person dying of melanoma loses 20.4 years potential life on average3
  • Annual treatment costs $3.3 billion USD (United States)4
  • Worldwide incidence of 2.8 per 100,000 in 2008; death rate 0.6 per 100,0005
  • Increased from 2.3 per 100,000 in men and 2.2 per 100,000 in women in 19906

 

Common Metastatic Sites

Common Metastatic Sites

Adapted from: Patel JK, Didolkar MS, Pickren JW, Moore RH. Metastatic pattern of malignant melanoma. A study of 216 autopsy cases. Am J Surg 1978; 135: 807–10.7

 

Common Metastatic Sites

Common Metastatic Sites

Adapted from: Trout AT et al. Melanoma metastases in the abdomen and pelvis: Frequency and patterns of spread. WJR 2013 5(2): 25-32.8

 

Less Common Metastatic Sites

Less Common Metastatic Sites

Adapted from: Trout AT et al. Melanoma metastases in the abdomen and pelvis: Frequency and patterns of spread. WJR 2013 5(2): 25-32.8

 

Factors Influencing Metastatic Site

Knowing the location of the primary is key to predicting pattern of metastatic disease:

Abdominal metastases
  • Lower extremity primaries have highest rates of abdominopelvic metastases (up to 52%)8
  • Ocular/head and neck have a predilection for the liver (up to 70% and 63%, respectively)
Metastases to bowel
  • Small bowel mets: 69% jejunum, 34% ileum, 22% duodenum (n=32)9
  • CT is 66% sensitive for small bowel metastases compared to autopsy

 

Factors Influencing Metastatic Site

Knowing the location of the primary is key to predicting pattern of metastatic disease:

Atypical locations
  • Atypical metastases present in 39% of patients with metastatic disease8
    • Represent only metastatic site in 12%
  • Lower extremity, back, and head and neck primaries have highest rates of atypical metastases
    • Often to subcutaneous locations and spleen
Soft tissue metastases
  • 2/3 patients with soft tissue metastases at autopsy
  • Metastasis to muscle most common in the lower limb, following the distribution of skeletal muscle mass10

 

CT Technique

  • Radiation modulation is important in patients who will be imaged with serial CT examinations.
  • IV contrast is critical for identifying solid organ, gastrointestinal and muscular metastases
  • Relating to CT technique, note that liver metastases are the most common site of abdominopelvic metastasis8 and are most often low attenuation
  • A single venous phase acquisition is sufficiently sensitive, with data showing no significant improvement in lesion detection by use of arterial and venous phase acquisitions11.
  • Thin sections (5 mm or less) are important for lesion detection, particularly in the liver12

 

CT Interpretation: Display

  • A high contrast window is important for identification of intramuscular and cardiac metastases.
  • Multiplanar reconstructions aid in lesion detection in certain anatomic locations
    • Mesentery
    • Subcutaneous tissues
    • Muscle
    • Spinal canal
  • MPRs also increase diagnostic confidence by confirming presence of subtle metastases

 

Cardiac Metastasis

62-year-old man with melanoma metastatic to the right ventricle. Axial IV contrast enhanced CT with soft tissue (A) and high contrast (B) windows. Tumor conspicuity is enhanced by use of high contrast window (B).

Cardiac Metastasis

 

Intramuscular Metastases

55-year-old female with melanoma. Intramuscular metastasis (A) better visualized with high contrast window (B) in axial plane. Second muscular metastasis in the same patient on standard axial soft tissue window (C) and coronal MPR with contrast window (D).

Intramuscular Metastases

 

Spinal Canal

76-year-old male with melanoma; soft tissue infiltration in the sacral spinal canal (A) is better appreciated on the sagittal MPR with a soft tissue window (B), which also reveals cortical erosion of the posterior sacrum (C).

Spinal Canal

 

CT Interpretation: Search Pattern

The radiologists’ search pattern must include unusual sites of metastatic disease using these display tools to aid in lesion detection
  • Heart and pericardium
  • Solid organs other than liver (parotid, thyroid, pancreas, spleen, uterus)
  • Gastrointestinal tract
  • Gallbladder
  • Mesentery and peritoneal surfaces
  • Perinephric space
  • Chest, abdomen and pelvic wall musculature subcutaneous tissues and skin

 

Parotid Metastasis

48-year old woman with melanoma and enhancing mass in the left parotid on axial (A) and coronal (B) IV contrast-enhanced CT. Metastases to solid organs are best visualized with high contrast windows (B). Confirmation with coronal MPR increases diagnostic confidence.

Parotid Metastasis

 

Thyroid Metastasis

55-year-old female with melanoma and thyroid metastasis seen on axial (A) and coronal (B) IV contrast-enhanced CT.

Thyroid Metastasis

 

Pancreatic Metastasis

65-year-old woman with pancreatic mass due to metastatic melanoma. Axial image (A) and coronal MPR (B) from IV contrast enhanced CT show a hypovascular mass in the pancreatic body with ductal dilation in the distal body and tail. The metastasis mimics a primary pancreatic adenocarcinoma.

Pancreatic Metastasis

 

Small Bowel

56-year-old man with multifocal small bowel wall thickening due to metastatic melanoma involving both the jejunum (A) and ileum (B) on coronal IV contrast enhanced CT. Note that this appearance mimics lymphoma involving small bowel.

Small Bowel

 

Small Bowel

78-year-old man with melanoma and nodular metastatic lesions in the small bowel wall on axial (C) and coronal (D) IV contrast enhanced CT. Small bowel should be inspected on axial and coronal planes to identify small metastases.

Small Bowel

 

Mesenteric Metastasis

66-year-old man with melanoma and new mesenteric nodule on axial (A) and coronal (B) IV contrast enhanced CT. Coronal MPRs facilitate distinction of mesenteric metastases from bowel. Note intense FDG activity (C) on correlate PET image.

Mesenteric Metastasis

 

Perinephric Metastasis

55-year-old female with melanoma and small perinephric metastases on axial (A) and coronal (B) IV contrast-enhanced CT, which enlarged at 3 month follow up (C,D). (Same patient as slide 17)

Perinephric Metastasis

 

Uterine Metastasis

44-year-old female with melanoma and small uterine/periuterine nodule seen on axial IV contrast-enhanced CT (A). Intense FDG activity noted on follow-up PET/CT (B). No clear CT correlate (C) for a second focus of intense FDG activity in the uterus (D). PET/CT can identify some solid organ metastases not visualized with CT.

Uterine Metastasis

 

Cutaneous/Subcutaneous

56-year-old man with metastatic melanoma from right gluteal primary. Axial extended-field-of-view CT image demonstrates two skin metastases. Lower extremity, back, and head and neck melanoma metastasize to subcutaneous tissues.8

Cutaneous/Subcutaneous

 

Isolated Subcutaneous Metastasis

51-year old woman with melanoma and small subcutaneous nodule that increased from 4 mm (A) to 8 mm (B). Note FDG avidity on PET/CT (C). This was the only site of metastatic disease. Careful inspection of the subcutaneous tissues with comparison to prior exams is imperative; subcutaneous metastases are often small at presentation.

Isolated Subcutaneous Metastasis

 

Literature Review

Case reports of other unusual metastatic sites:
  • Solitary renal metastasis, 14 months after treatment of primary14
  • Cardiac metastasis, causing complete atrioventricular block15
  • Report/series of 24 cases of bladder metastasis16
  • Gastric fundus and jejunal metastases 13 years after primary resection17
  • Solitary splenic metastasis, with peritoneal melanosis18
  • Large solitary metastasis to ilium/acetabulum 2 years after resection of choroidal melanoma19

 

Complications of Melanoma Mets

57-year-old male with metastatic (M) to liver lesion on axial CT (A) and active hemorrhage on IV contrast enhanced MDCT arterial (B) and venous (C) phase coronal MPRS.
  • Melanoma metastases have a propensity for hemorrhage, and may present with significant GI hemorrhage10
  • Melanoma metastatic to the small bowel may result in obstruction or serve as a lead point for intussusception
Complications of Melanoma Mets

 

New Therapies for Melanoma

Immunotherapies:
  • Monoclonal antibodies targeting immune checkpoints
    • Ex: Ipilimumab - cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4)
    • Ex: Nivolumab - programmed death 1 (PD-1) receptor
  • Both shown to improve survival as monotherapy21
  • Promising in combination with each other21 and with chemotherapy22
Small molecule therapies for BRAF-mutated melanoma:
  • BRAF inhibitors include vermurafenib, dabrafenib
  • MEK inhibitor: trametinib (MEK a downstream constituent of BRAF pathway)
  • Examples of promising outcomes:
    • BRAF inhibition in BRAF-mutated melanoma after failed immunotherapy in 3 patients (durable CR up to 15 months)23
    • Combined BRAF/MEK inhibitor therapy providing overall response rate of 13-15% after resistance to monotherapy with BRAF inhibitor24

 

On the Treatment Horizon

Adoptive cell transfer:
  • Isolation, expansion, and reinfusion of tumor infiltrating lymphocytes found in sites of disease (or modification of peripherally isolated T cells to express a T cell receptor that targets melanoma)
  • Response rates from 34-72%25
Therapy for oligometastatic disease:
  • Surgical metastasectomy improves median and 5-year survival in M1a (skin, subcutaneous, distant nodes) and M1b/M1c (visceral or osseous) disease26
  • Resection of pulmonary metastases with no extrathoracic disease also improves survival, even in patients with >5 year disease free interval27
  • Resection safe during BRAF-inhibitor therapy28
  • Stereotactic radiotherapy may be an alternative to surgery; for example, for pulmonary mets29

 

Immunotherapy Complications

Radiographically-evident immune-related adverse events in 31% of 147 patients with advanced melanoma receiving ipilimumab monotherapy30
  • Colitis 19%
  • Sarcoid-like lymphadenopathy 5%
  • Pneumonitis 5%
  • Hepatitis 2%
  • Thyroiditis 1%
  • Pancreatitis <1%
Other reports with ipilimumab:
  • Hepatitis appearing as hepatic hypodensities correlating with FDG activity on PET31
  • Adrenalitis manifested as new, symmetric, smooth adrenal enlargement, also with FDG activity32
  • Thyrotoxicosis detected as thyromegaly on CT33
Colitis in 23% and pneumonitis in 11% of 94 patients treated with ipilimumab and nivolumab in combination21

 

Immunotherapy Complications

Axial (A,B), sagittal (C), and coronal (D) IV and oral contrast enhanced CT demonstrating diffuse colonic wall thickening in a 68-year-old female on ipilimumab for therapy of metastatic melanoma. Severe colitis was found on subsequent colonoscopy: pathologic changes consistent with ipilimumab-related disease.

Immunotherapy Complications

 

Immunotherapy Complications

Axial non-contrast CT of the chest in lung windows (A,B) demonstrating consolidation in the left lung, consistent with pneumonitis in a patient who had received 4 doses of ipilimumab for therapy of melanoma.

Immunotherapy Complications

 

Immunotherapy Complications

Axial (A-C) IV contrast-enhanced CT in a 68-year-old male with metastatic melanoma on ipilimumab presenting with abdominal pain and elevated lipase, with pancreatic edema and adjacent inflammatory stranding, compatible with acute pancreatitis.

Immunotherapy Complications

 

CT in Melanoma: Past to Future

  • CT alters management in melanoma by simply detecting metastases34.
  • Therapy response assessment with CT
    • Changes in lesion density on CT as evidence of treatment response (not yet proven to correlate with survival)35
    • “Halo sign” of ground-glass attenuation surrounding pulmonary metastasis after adoptive cell therapy correlates with response36
  • In combination with other modalities
    • Targeted radiotracers for both imaging and therapy37
      • Very late antigen-4 (VLA-4; integrin α4β1) promotes adhesion and migration of melanoma cells
      • A high affinity peptidomimetic ligand (LLP2A) targets VLA-4
      • Conjugate with 68Ga allows PET/CT imaging, while conjugate with 177Lu allows therapy and monitoring with SPECT/CT
    • Targeted palliative therapy for liver metastases with chemoembolization (irinotecan drug-eluting beads) 38 and radioembolization39

 

Take-Home Points

  • PET/CT may be more sensitive to identify metastatic melanoma40, but IV contrast enhanced CT is often the first line imaging modality for follow up, underscoring the importance of careful inspection for early metastases.
  • IV contrast, high contrast display windows and MPRs facilitate identification of melanoma metastases
  • Melanoma has a propensity to metastasize to sites not often involved by other malignancies and radiologists’ search patterns must include careful scrutiny of these uncommon locations, as illustrated in this case series.
  • Hemorrhage and small bowel obstruction are suspicious for metastasis in patients with history of melanoma
  • New therapies hold promise in the treatment of melanoma, but the radiologist must be aware of imaging complications such as colitis, pneumonitis, and lymphadenopathy.

 

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