PET > PET tumor imaging > Melanoma

Melanoma:

General:

Melanoma is the most aggressive form of skin cancer. The most predictive factor for recurrence and prognosis is the tumor thickness- measured in millimeters (Breslow thickness) [4]. For localized lesions with a tumor thickness of less than 1.5 mm (stage I or II), melanoma can be cured by total resection with a 5-yr overall survival approaching 90% [22] (early-stage melanoma can be treated with surgery with a 5-year survival rate of 98.3% [25]). However, in patients who develop metastases (stage IV) the median survival rate is around 6-12 months and survival at 5 years does not exceed 5% [22]. Between 6-10% of patients have detectable metastases at the time of diagnosis [11]. Regional lymph nodes are the most frequent site for metastases [1]. The presence of lymph node metastases is also well established as a negative prognostic indicator. Surgical excision of involved nodes is the most effective treatment for either cure or local disease control [4]. Furthermore, 50-80% of patients with locoregional metastases and nearly all patients with distant metastases will experience disease recurrence after treatment [25]. Once distant metastases occur, median survival is only about 4-6 months [16,19] and therapy is always palliative [4].

Prognostic factors include Breslow thickness of the primary tumor, evidence of primary tumor ulceration, the mitotic rate of the primary tumor, the extent of local and regional lymph node involvement, and the presence of distant metastases [25]. 

FDG PET imaging is of limited use in patients with early stage melanoma (I-II) disease because of their low risk for metastatic disease [8,17]. Sentniel lymph node status is the single most important prognostic factor for disease recurrence and survival [25]. High risk for regional lymph node metastases include a Brelow thickness ≥ 1.00 mm, primary tumor ulceration, high mitotic index, vertical growth phase, male sex, young age, and high Clark level of invasion [25]. These patients presently undergo surgical resection of the lesion followed by examination of the sentinal node [1]. The sentinal node is the first draining node of the lymphatic bed draining the tumor- if the sentinal node is free of tumor, the remainder of the nodes in that basin are likely to be free of tumor. This approach obviates the need for a more radical lymph node dissection [1]. Regional lymph node mets can be categorized as micrometastases (clinically occult), macrometastases, or in-transit or satellite mets [25]. Between 5-30% of patients with AJCC stage I-II melanoma are upstaged to AJCC stage II following SLNB [25].

In patients with more advanced melanoma (thickness greater than 1-4mm, ulcerated lesions, or those with a high mitotic rate, or AJCC stages III/IV) one may reasonable consider the utility of FDG PET imaging for more effective tumor staging [16,19]. PET/CT imaging seems to be more precise than PET imaging alone [19]. In a meta-analysis, FDG-PET had a sensitivity of 83% and a specificity of 85%, at initial staging [22].

Although FDG PET imaging has shown excellent results for the evaluation of cutaneous melanoma, the exam may lack sensitivity for the detection of uveal melanoma [14].

Presently, FDG PET is reimbursed for the following indications in patients with melanoma:

1- Evaluation of extranodal metastases at initial staging or during follow-up after treatment

2- Evaluation for recurrent melanoma as an alternative to gallium scan

PET imaging is not reimbursed for the evaluation of regional lymph node metastases for primary staging.

Detection of Metastatic Disease:

Lymph node staging: For the evaluation of lymph node metastases FDG-PET has been suggested to have a sensitivity as high as 95%, a specificity of 84%, and an accuracy of 91% [2]. However, pooled data from multiple studies indicates that FDG PET has a very low sensitivity of only about 17% (0-40%) for the detection of sentinel lymph node metastases [16], particularly in patients with Stage I/II disease [25]. In general, the detection of nodal metastases is dependent upon the size of the metastasis [2,7,16]. Detection can be as high as 100% for metastases greater than 1 cm in size, a diameter of at least 6 mm is associated with a detection sensitivity of over 83%, while detection of metastases smaller than 5 mm is only 23% [2,7]. A tumor volume of greater than 78 mm³ is a associated with a sensitivity for detection of greater than 90% [7]. Because micrometastases to the sentinel node can be found in up to 38% of patients [13], FDG PET imaging should not replace sentinel node biopsy in the clinical management scheme of melanoma patients [5,16]. Overall, sentinel node biopsy is more sensitive than PET imaging for the detection of microscopic nodal metastases [8,11] with a reported sensitivity of 94%, and a specificity of 100% [4].

Distant metastatic disease: With exception of MRI for staging brain and liver metastatic disease, FDG PET/CT is superior to other imaging modalities for the detection of distant metastatic disease [25]. Pooled data indicates that FDG-PET imaging is more accurate for systemic staging, than for staging of regional lymph nodes [5]. Melanoma can spread widely and unpredictably throughout the body [16]. FDG-PET can be useful in detecting lymph node and distant metastases -- particularly in stage III or IV high-risk patients (melanoma thickness greater than 1.5 mm or Clark?s level IV) [1,3,6,17]. FDG-PET imaging has been shown to be superior to conventional imaging for the detection of melanoma metastases [3,11]. Studies have shown that peripheral skin metastases as small as 3 mm can be detected [3]. Overall, pooled data for FDG-PET imaging in the detection of melanoma metastases indicates a sensitivity of 79-83% (95% confidence interval 66%-93%) and a specificity of 85-86% (95% confidence interval 78%-95%) [5,7,19]. Dedicated evaluation of co-registered CT images has been shown to improve the exams sensitivity and accuracy [18]. In up to 13% of patients, metastases may only be depicted on the co-registered CT exam [18]. The presence of distant metastases on PET imaging also carries prognostic significance with a 5 year survival of 48% in patients with a negative PET exam, and only 17% if the exam is positive for distant metastatic disease [25].

Impact on patient management/Prognosis:

PET scan results can have a significant impact on patient management by detecting additional unsuspected sites of disease (in one prospective study PET detected unexpected metastases in 12% of patients [21]) [9]. When PET is added to CT for the initial staging of high-risk melanoma patients, management can be changed in about 33% of patients (range 12% to 90% of cases) [9,15,19,21]. In one prospective study of patients with stage III disease, PET findings resulted in a change in patient management in 15% of cases [12]. In a separate prospective study of patients with suspected recurrent melanoma, PET findings resulted in a change in therapy in 40% of the cases [16]. Unfortunately, CT is still superior to PET for the detection of lung metastases [11].

SUVmax, TLG and MTV are all predictors of disease free survival [32].

 

 

Recurrent Melanoma:

Recurrent melanoma can occur anywhere in the body and the patients initial stage determines the subsequent risk for disease recurrence. Patients with stage I and II lesion are more likely to have locoregional recurrences, while patients with stage III and IV lesions more frequently present with distant metastases [10]. Patients with AJCC stage IIB disease have a 17% rate of recurrence and patients with stage IIIA disease have a greater than 30% recurrence rate, with most recurrences happening within the first 5 years [25].

FDG PET imaging can aid in the evaluation of patients with suspected recurrent melanoma [10] and has been shown to be superior to conventional imaging [17]. The sensitivity and specificity of PET for detecting lesions on a per-patient basis are 74-92% and 86-94%, respectively, compared to 57-81% and 45-87% for conventional imaging [10,17]. PET is superior to CT in detecting skin lesions, lymph node, abdominal, liver, and bone metastases [10]. The overall accuracy of PET was 81%, compared to 52% for conventional imaging [10]. In another study, FDG PET was found to be more accurate than conventional imaging in re-staging and follow-up of melanoma with a site sensitivity of 92% versus 57.5%, and a specificity of 94% versus 45%, respectively [6]. The addition of PET to conventional re-staging aids in the identification of unsuspected sites of disease and treatment planning can be changed in 20-36% of cases [9,10]. The net effect of these changes can result in an overall cost savings (of about $4,400 per patient) due to the prevention of unnecessary surgery [9].

There is less data supporting the effectiveness and diagnostic performance of FDG PET CT in detecting recurrence in asymptomatic patients [25].

Treatment:

¹²³I-BZA2 and ¹²³I-BA52 are melanin-targeted radiotracers for the identification of melanin containing melanoma metastases [22,23]. Initial studies suggest that radioimmunotherapy with ¹³¹I-BA52 may be of benefit in patients with melanin containing melanoma metastases [23].

Immune checkpoint inhibitors have demonstrated benefit for the treatment of patients with advanced melanoma [29]. Agents include cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blocking therapy (ipilmumab), programmed cell death protein 1 (PD-1) blocking therapy (nivolumab, pembrolizumab), and programmed cell death ligand 1 (PD-L1) blocking therapy (atezolizumab, avelumab, durvalumab) [29].

Ipilimumab is a fully human monoclonal antibody (IgG1) that promotes anti-tumor immunity by activating cytotoxic T lymphocytes by blocking cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), an immune checkpoint molecule that down-regulates pathways of T-cell activation [20,24]. The agent is effective in only 10-15% of patients and is often associated with autoimmune adverse events [24,25,26]. Note that patients that experience autoimmune adverse events have been shown to be much more likely to respond to the agent [26]. However, other authors report that the response rate to combine nivolumab (PD-1) and ipilimumab (CTLA-4) treatment was 58% with a 5-year progression free survival of 36% [33]. Gastrointestinal and hepatic events typically occur after 6-7 weeks of therapy, and endocrine events occur later [24].

Programmed cell death ligand 1 (PD-L1) is part of an immune checkpoint system essential for preventing autoimmunity and cancer [28]. Tumor cells have developed the ability to co-opt these immune checkpoints to suppress anti-tumor immunity [28]. Advanced melanoma patients with over-expression of PD-L1 have been shown to have a 39% response rate to treatment with anti-PD-L1 therapy, compared to a 13% response rate in PD-L1 negative patients [28].

Autoimmune adverse events include:

- Enterocolitis (most common toxicity seen in 31-46% of patients)- usually within the first 3 months of therapy and can be segmental or diffuse
- Hypophysitis (5% of patients), hepatitis (3-9% of patients)
- Dermatitis, myopathy
- Pancreatitis
- Thyroiditis
- Nephritis
- Benign reactive lymphadenopathy in a sarcoid-like distribution (5% of patients)
- Pneumonitis (5% of patients)

Monitoring treatment response to ipilimumab using radiologic techniques is complex because lesions may initially enlarge and tumor-regression responses are not often observed until after 3 months of treatment (pseudoprogression) [25,29]. Inflammatory reactions and tumor progression often precede the treatment response [25,29]. Patients with stable anatomic disease can demonstrate modest to marked increased FDG uptake between 3-4 weeks following initiation of therapy likely related to an inflammatory response to the therapy (related to tumor infiltration by immune cells) and these patients tend to demonstrate eventual tumor regression [29,30]. New lesions can also be seen, but have been found to be associated with progressive disease in only about half (55%) of cases [30]. In patients with stable or decreasing target lesions, the appearance of new lesions may be considered indeterminate [30]. The initial expansion and recruitment of cytotoxic T lymphocytes after checkpoint inhibition occur in lymph nodes systemically or in the immediate draining nodal stations [34]. In the setting of ipilimumab for melanoma, all patients with new mediastinal or hilar nodal uptake on FDG PET/CT (sarcoid-like adenopathy) ultimately demonstrated apparent clinical benefit from treatment [34]. Short term followup in 1-2 months can be performed to assess for change over time [25]. FDG PET scans can also demonstrate mild tracer uptake in multiple lymph nodes after immune modulation therapy [25].

Pseudoprogression is more commonly observed after treatment with anti-CTLA-4 agents, as compared to anti-PD agents [34]. In two-thirds of cases, pseudoprogression is observed before week 12 (early), whereas in one-third of cases it occurred after week 12 (delayed) [34].

Ocular melanoma:

Ocular melanoma is the most common noncutaneous melanoma and the most common ocular primary in adults [27]. Ocular melanoma represents about 4% of all cases of melanoma and 73% of cases of noncutaneous melanoma [27]. Ocular melanoma has a predilection for white patients (8-10x's higher rate compared to other races) and the mean age at diagnosis is 60 years [27]. Sun exposure is contested as a risk factor [27]. The lesion is often diagnosed during routine eye exam [27]. Symptoms can include blurry vision, photopsia (perceived flashes of light), or visual field defects [27].

The choroid of the uveal tract is the most common site for ocular melanoma and approximately 25% of choroidal melanomas are amelanotic [27]. Uveal melanoma typically spreads hematogenously because of lack of lymphatics in the uveal tract- most commonly to the liver (90% of cases), lung (24% of cases), and bone (16% of cases) [27]. Approximately half of patients with choroidal melanoma will die of metastatic disease despite eradication of the primary tumor and enucleation does not appear to confer a survival benefit over occular sparing therapies [27]. The best predictor of metastatic risk is genetic tumoral analysis for the presence of monosomy 3 [27].

On CT, uveal melanoma generally appears as a non-specific soft-tissue mass that is hyperdense relative to the vitreous humor and shows mild-to-moderate enhancement with contrast [27].

REFERENCES:

(1) J Nucl Med 1999; Delbeke D. Oncological applications of FDG PET imaging: Brain tumors, colorectal cancer, lymphoma, and melanoma. 40: 591-603

(2) J Nucl Med 2000; Crippa F, et al. Which kinds of lymph node metastases can FDG PET detect? A clinical study in melanoma. 41: 1491-1494

(3) Cancer 1998; Rinne D, et al. Primary staging and follow-up of high risk melanoma patients with whole-body 18-F-fluorodeoxyglucose positron emission tomography: Results of a prospective study of 100 patients. 82: 1664-71

(4) J Cancer Res Clin Oncol 2000; Ilknur AK, et al. Positron emission tomography with 2-[18F] fluoro-2-deoxy-D-glucose in oncology: Part II: The clinical value in detecting and staging primary tumours. 126: 560-574

(5) Cancer 2001; Mijnhout GS, et al. Systematic review of the diagnostic accuracy of 18F-Fluorodeoxyglucose positron emission tomography in melanoma patients. 91: 1530-42

(6) Radiographics 2003; Kostakoglu L, et al. Clinical role of FDG PET in evaluation of cancer patients. 23: 315-340

(7) J Nucl Med 2003; Cobben DCP, et al. 3'-¹⁸F-fluoro-3'-deoxy-L-thymidine: a new tracer for staging metastatic melanoma? 44: 1927-1932

(8) J Nucl Med 2004; Schoder H, et al. PET/CT in oncology: integration into clinical management of lymphoma, melanoma, and gastrointestinal malignancies. 45 (Suppl): 72S-81S

(9) Radiology 2004; Rohren EM, et al. Clinical applications of PET in oncology. 231: 305-332

(10) J Nucl Med 2004; Fuster D, et al. Is ¹⁸F-FDG PET more accurate than standard diagnostic procedures in the detection of suspected recurrent melanoma? 45: 1323-1327

(11) Radiol Clin N Am 2005; Kumar R, et al. Fluorodeoxyglucose-PET in the management of malignant melanoma. 43: 23-33

(12) Cancer 2000; Tyler DS, et al. Positron emission tomography scanning in malignant melanoma. 89: 1019-1025

(13) J Nucl Med 2006; Rossi CR, et al. The impact of lymphoscintigraphy technique on the outcome of sentinel node biopsy in 1,313 patients with cutaneous melanoma: an Italian mutlicentric study (SOLISM-IMI). 47: 234-241

(14) J Nucl Med 2006; Kato K, et al. Low efficacy of ¹⁸F-FDG PET for detection of uveal malignant melanoma compared with ¹²³I-IMP SPECT. 47: 404-409

(15) Ann Surg Oncol 2006; Brady MS, et al. Utility of preoperative [(18)]f fluorodeoxyglucose-positron emission tomography scanning in high-risk melanoma patients. 13: 525-32

(16) J Nucl Med 2006; Belhocine TZ, et al. Role of nuclear medicine in the management of cutaneous malignant melanoma. 47: 957-967

(17) Radiology 2007; Blodgett TM, et al. PET/CT: form and function. 242: 360-38

(18) Radiology 2007; Strobel K, et al. High-risk melanoma: accuracy of FDG PET/CT with added CT morphologic information for detection of metastases. 244: 566-574

(19) Radiology 2008; Krug B, et al. Role of PET in the initial staging of cutaneous malignant melanoma: a systematic review. 249: 836-844

(20) AJR 2012; Nishino M, et al. Personalized tumor response assessment in the era of molecular medicine: cancer-specific and therapy-specific response criteria to complement pitfalls of RECIST. 198: 737-745

(21) AJR 2012; Bronstein Y, et al. PET/CT in the management of patients with stage IIIC and IV metastatic melanoma considered candidates for surgery: evaluation of the additive value after conventional imaging. 198: 902-908

(22) J Nucl Med 2014; Cachin F, et al. ¹²³I-BZA2 as a melanin-targeted radiotracer for the identification of melanoma metastases: results and perspectives of a multicenter phase III clinical trial. 55: 15-22

(23) J Nucl Med 2014; Mier W, et al. Radiopharmaceutical therapy of patients with metastasized melanoma with the melanin-binding benzamide  ¹³¹I-BA52. 55: 9-14

(24) AJR 2015; Howard SA, et al Beyond the vascular endothelial growth factor axis: update on the role of imaging in nonantiangiogenic molecular targeted therapy. 204: 919-932

(25) AJR 2015; Perng P, et al. ¹⁸F-FDG PET/CT and melanoma: staging, immune modulation and mutation-targeted therapy assessment, and prognosis. 205: 259-270

(26) AJR 2016; Holler Howard SA, et al. A new look at toxicity in the era of precision oncology: relationship with tumor response, and effect on metastasectomy. 207: 4-14

(27) AJR 2017; Wong VK, et al. Clinical and imaging features of noncutaneous melanoma. 208: 942-959

(28) J Nucl Med 2017; Nedrow JR, et al. Imaging of programmed cell death ligand 1: impact of protein concentration on distribution of anti-PD-L1 SPECT agents in an immunocompetant murine model. 58: 1560-1566

(29) J Nucl Med 2017; Cho SY, et al. Prediction of response to immune checkpoint inhibitor therapy using early-time-point ¹⁸F-FDG PET/CT imaging in patients with advanced melanoma. 58: 1421-1428

(30) J Nucl Med 2019; Ito K, et al. ¹⁸F-FDG PET/CT for monitoring of ipilimumab therapy in patients with metastatic melanoma. 60: 335-341

(31) AJR 2019; Sanli Y, et al. Tumor heterogeneity on FDG PET/CT and immunotherapy: an imaging biomarker for predicting treatment response in patients with metastatic melanoma. 212: 1318-1326

(32) Clin Nucl Med 2016; Son SH, et al. Prognostic value of volumetric parameters measured by pretreatment ¹⁸F-FDG PE/CT in patients with cutaneous melanoma. 41: e266-273

(33) J Nucl Med 2020; Niemeiher AL, et al. Imaging responses to immunotherapy with novel PET tracers. 61: 641-642

(34) J Nucl Med 2020; Iravani A, Hicks RJ. Imaging the cancer immune environment and its response to pharnacologic intervention, part 1: the role of ¹⁸F-FDG PET/CT. 61: 943-950