THE ROLE OF CONTEMPORARY IMAGING AND HYBRID METHODS IN THE DIAGNOSIS OF CUTANEOUS MALIGNANT MELANOMA(CMM) AND MERKEL CELL CARCINOMA (MCC)

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1 THE ROLE OF CONTEMPORARY IMAGING AND HYBRID METHODS IN THE DIAGNOSIS OF CUTANEOUS MALIGNANT MELANOMA(CMM) AND MERKEL CELL CARCINOMA (MCC) I.Kostadinova, Sofia, Bulgaria

2 CMM some clinical facts The incidence of cutaneous melanoma has doubled over the last two decades in the United States and around the world. Melanoma is the least common but the most deadly skin cancer, accounting for only about 5% of all cases, but the vast majority of skin cancer-related death*. 10% of all patients with melanoma have a family history. Incidence rates are higher in women than in men below the age of 50, but by age 65, rates in men double those in women, and by age 80 they are triple. ** Disease stage on initial evaluation is the most important predictor of outcome and determinant of the appropriate management and a disease free survival. *SEER (Surveillance, Epidemiology and End Results) data. seer.cancer.gov. ** American Cancer Society. Cancer Facts and Figures Atlanta: American Cancer Society; 2016.

3 * NCCN Clinical Practice Guidelines in Oncology: Melanoma. V TNM Classification for Malignant Melanoma Primary tumor (T)* TX Primary tumor cannot be assessed T0No evidence of primary Tis Melanoma in situ T1:Melanoma 1.0 mm in thickness T1a: Without ulceration and mitoses < 1/mm 2 T1b: With ulceration or mitoses 1/mm 2 T2: Melanomas mm in thickness T2a: Without ulceration T2b: With ulceration T3: Melanomas mm in thickness T3a: Without ulceration T3b: With ulceration T4: Melanomas > 4.0 mm in thickness T4a: Without ulceration T4b: With ulceration

4 TNM Classification for Malignant Melanoma-N,M NX: Patients in whom the regional nodes cannot be assessed N0: No regional metastases detected N1-3: Regional metastases based upon number of metastatic nodes and presence or absence of intralymphatic metastases (in transit or satellite metastases) N1: 1 lymph node N1a: Micrometastases N1b: Macrometastases N2: 2 or 3 lymph nodes N2a: Micrometastases N2b: Macrometastases N2c: In-transit met(s)/satellite(s) without metastatic lymph nodes N3: 4 metastatic lymph nodes, or matted lymph nodes, or in-transit met(s)/satellite(s) with metastatic lymph node(s) M0: No detectable evidence of distant metastases M1a: Metastases to skin, subcutaneous, or distant lymph nodes, normal LDH level M1b: Lung metastases, normal LDH level M1cMetastases to any site combined with an elevated serum LDH level Clinical staging Stage I ( T1 )and Stage II ( T2-4 )-no lymph node involvement Stage III nodal involvement Stage IV distant mets

5 Lymphatic and hematogeneous dissemination of CMM and location of the primary tumor Tarik Z. Belhocine et al. J Nucl Med 2006;47:957, 967

6 Choice of imaging modality for staging of CMM Imaging methods have a primary role in the staging of CMM, surgical planning and therapy approach, prognosis and long term follow-up. Basic imaging modalities such as US, CT, MRI as well as PET/CT, are used mainly for detection of local and distant metastases, but have no role in the staging of the primary process (T stage), especially in patients with disease stage I or II. Meta-analysis of 74 studies on patients show that ultrasound is superior for regional lymph nodes and PET/CT for distant metastases* CT of the abdomen, pelvis and thorax is the modality of choice for restaging of patients with stage III or IV. Patients at risk of developing cerebral or liver metastases need to have MRI examination or CT with contrast. *Xing Y. et al., J.Natl.Cancer, 2011, 103,

7 Choice of imaging modality for staging of CMM Currently, whole body MRI with diffusion weighted imaging /WB-MRI with DWI/, is established as one of the most promising modern functional imaging modalities. It is based on detection of the free movement of water molecules, which is limited when cell membrane is ruptured or in the cases of the changed tissue cellularity in the tumor*. *Schmidt G. et al.,topics in MRI, 18 /3/, 2007,

8 Choice of imaging modality for staging of CMM Additional functional information obtained from detailed anatomic WB-MRI-DWI, through the use of T1, T2 and STIR (short tau inversion recovery) sequences, gives a more detailed and accurate staging of tumours. Benefits of a whole body MRI are the absence of radiation and high sensitivity for lesions located in the bone marrow, brain and liver. Still, CT remains the modality of choice and gold standard for lesions located in the lungs, bones and thoracic cavity. Prospective studies show that WB-MRI-DWI has a lower sensitivity for detecting distant metastases, compared to PET/CT, respectively 78.8% and 86.7%, but MRI has a higher accuracy for lesions located in the bone marrow and liver*. *Pfannenberg C. et al.. Eur J Cancer 2007;43: 55764

9 Application of hybrid imaging methods SPECT/CT The most important factors determining the prognosis of CMM are: invasion depth of the tumor, presence of ulceration, number of mitosis and histologic/oncogenic status of the first lymph node responsible for drainage of the tumor (SLN). The aim of SLN visualization and histological examination in patients without palpable lymph node enlargement, is the staging of disease, since lymphatic spread in CMM is often unpredictable. Therefore, its histopathology suggests the status of the rest of the lymph nodes in the lymphatic region and gives stage and prognosis. The metastatic invasion of the SLN requires a total lymphadenectomy for therapeutic benefit.

10 Application of hybrid imaging methods SPECT/CT Because of its high sensitivity up to 100% SLNscintigraphy is the modality of choice for visualization of SLN and detection of occult metastases, especially when CMM is located in the head, neck or torso and has Clark level <4 and Breslow thickness mm* Compared to palpation, SLN scintigraphy detects more lymphatic drainage basins in 50% of the patients with CMM in the torso and in 33% of the patients with CMM located in the head and neck region **. *SNM Guidance, 2002 **Belhocine T., A.Scott, E.Sapir et al., JNM, 6 / 47/, 2006,

11 Advantages of SLN scintigraphy, combined with SPECT/CT Improved image quality, compared to a planar imaging and improved SLN detestability with up to 43%, especially when combined with intraoperative gamma probe detection.* Allows exact localization of SLN** Gives additional preoperative staging and determination of prognosis of disease* *Mar M.et al., JNM,2005,46,50 ** Kostadinova I, M.Garcheva, BCNM, Belgrade,2013

12 SPECT/CT in a patient with CMM on the back - there are SLNs in the right axilla and right scalula

13 SPECT/CT of the same patient used for staging a single lung nodule - 9mm

14 Application the hybrid imaging method PET/CT 1. Staging PET/CT has no role in the diagnosis and local tumor spread (T stage). In the early stages of disease PET/CT has a very low sensitivity of up to 17%, as micrometastases are usually missed. In this situation SLN scintigraphy, combined with surgical excision, is a choice. PET/CT examination is recommended in patients with higher risk of tumor invasion, with thickness of 2-4mm or more, where 50-70% of the patients have already invasion of lymph nodes and 10% have distant metastases* If there is no possibility for PET/CT scanning, alternatives are CT or WB- MRI-DWI** *Acland K. et al., JClin.Oncology, 19 /10/,2001, **Pfannenberg C., Radiologie Feb;55(2):

15 Staging with PET/CT

16 Application of the hybrid imaging method-pet/ct 2. Role of PET/CT in restaging of the patients In patients with disease stage III or IV, MRI of the brain and liver, CT of the abdomen and thorax as well as ultrasonography have a significant role in the visualization of recurrences and have sensitivity ranging from 57% to 81% and specificity ranging from 45% to 87%*. PET/CT has a higher sensitivity and specificity, compared to CIM for the detection of distant metastases with accuracy reaching up to 97%. In high-risk melanoma patients 18 F-FDG PET/CT is more accurate (97%) for the detection of tumor recurrence than the tumor marker S100 (65%)**. PET/CT alters the therapeutic approach in 22-29% of the patients***. *Friedman K., R.Wahl, Sem.NM, 34, 2004, **Buchbender Chr.et al.jnm,53,2012. ***Schwimmer J. et al. Q J Nucl Med. 2000;44:

17 Role of PET/CT in restaging of the patients PET/CT allows for detection of metastases up to 6 months earlier, compared to clinical investigation or CT alone*, especially in localizations, which are difficult. PET/CT influences decision making for surgical intervention in patients with disease stage III or IV. High accumulation of F18- FDG (measured by SUV) in involved lymph nodes has an important negative prognostic value for PFS. Lesions in the lung parenchyma up to 5-7mm, small lesions in the liver or in the brain can lead to false negative results on PET/CT. They require further investigation using CT or MRI**. Summarized data show that in high risk patients (disease stage III or IV) the optimal approach is to combine PET/CT with organ-specific MRI of suspicious lesions**. Very promising is the new hybrid technique PET/MRI, which is even preferred over the latter two modalities***. * Fuster D. et al., J Nucl Med. 2004;45: ** Walker R. et al., Melanoma, in Hybrid PET-CT imaging, 2010, ***Pfannenberg C, Schwenzer N. Radiologe Feb;55(2):120-6.

18 Restaging with PET/CT in a patient with CMM and multiple metastatic lesions

19 Restaging with PET/CT in a patient with CMM and multiple metastatic lesions

20 Application of the hybrid imaging method-pet/ct 3. PET/CT in the follow-up of therapy effect PET/CT may play an important role in the follow up of the therapy effect in patients with local and distant metastases, who are treated with chemo- or immunotherapy. Responders to chemotherapy identified by 18 F-FDG PET/CT have been proven to have a longer progression-free and overall survival than nonresponders * Follow-up using serial scanning PET/CT can contribute to patient-tailored therapy. PET/CT can be implemented in clinical trials involving new pharmacological substances. *Strobel K.et al., Eur J Nucl Med Mol Imaging. 2008;35:

21 PET/CT in the follow up after chemotherapy of a patient with progressive disease with CMM located in the right thigh ( thickness 3mm ) and initial metastases in the inguinal lymph nodes (not shown). PET-CT at 6 months (on the left) and at 11 months (on the right) after diagnosis of CMM.

22 Application of PET/CT in Merkel Cell Carcinoma (MCC) MCC is a rare cutaneous neoplasm, which occurs with an increasing frequency in individuals over the age of 50, grows very quickly and has a poor prognosis. It is characterized by an increased expression of somatostatine receptors, which can be utilized both for radionuclide diagnostics with 68 Ga DOTATOC/DOTATATE, reaching accuracy of up to %, as well as for specific targeted radionuclide therapy (theranostics) with radioactive labelled 90Y/177Lu - radiopharmaceuticals* According to other sources, detection rate of MCC with F18-FDG is even higher, reaching sensitivity of up to 94-97% and specificity of up to 87-96%, thus changing therapy approach in 33% of the patients ** The simultaneous visualization of the tumor using both radiopharmaceuticals is offering the possibility of individualization the of the therapy to the patient. *Beylergil V., et al.,cancers 2014, **George R. et al., Nucl.Med.Comm., 35 /3/, 2014,

23 PET/CT of a patient with MCC in the left eyelid without metastases / left /. Four months later multiple metastatic lesions were observed / right /.

24 New hybrid imaging modality - PET/MRI in the diagnostics of MCC and CMM Advantages - It is used primarily for restaging and for the detection of cerebral, subcutaneous, muscle, hepatic and bone marrow metastases. - It gives lower radiation exposure - Lesions in the soft tissues have a better contrast, compared to the CT(PET/CT) examinations, which may lead to a higher accuracy and a change in the therapeutic approach*. Disadavantages - duration of the study, high costs, contraindication due to metallic implants or cardiac devices, patients prone to claustrophobia and low sensitivity in detecting pulmonary lesions** * Buchbender Ch.et al.,jnm,53/8/, 2012, **Pace L, Clin Transl Imaging (2013) 1:31 44.

25 PET-MRI

26 PET/CT and PET/MRI-cutaneous melanoma of the right leg-t4b

27 Conclusion SLN scintigraphy, combined with surgical excision of the node is the modality of choice in stages I and II of CMM. PET/CT is the modality of choice in the primary staging and restaging of CMM in disease stage III and IV If occurrence of metastatic lesions in the brain, liver or the lungs is suspected, MRI, CT or PET/MRI play a primary role.

28 Conclusion Future role of WB/MRI and hybrid imaging modalities, such as 18F-FDG-PET/CT and PET/MRI will continue to grow and eventually replace multimodality imaging approach, due to the possibility of acquiring exact anatomical and functional data about tumor spread in a one stop shop diagnostic procedure. 18F-and 68Ga-labelled PET/CT radiopharmaceuticals can be applied simultaneously in the staging and restaging of MCC, in order to customize and individualize therapy of the patient.

29 Sofia- the host of 6-th Balkan congress of nuclear medicine