Wednesday, June 05, 2013

Melanoma Does Not Read Textbooks I

Presented by Yoon Cohen, D.O. and David Elpern, M.D.

Abstract:  67-year-old man with a 3-month history of pigmented papules on the face and torso.

HPI: The patient is a 67-year-old man with a 3-month history of pigmented papules on the face and torso. He has past medical history of enucleation over 19 years ago for ocular melanoma. Since enucleation, he has been fairly healthy and staying active with his life. He has not noticed any recent weight loss, fatigue, and other associated constitutional symptoms.

O/E: The skin examination showed a pleasant and outgoing man with ~ 50 well defined 2-4 mm multiple scattered purple to blue-black firm papules on the face and torso. No lymphadenopathy noted. 

Clinical Pictures
Purple to blue-black firm papules on the cheek
Several scattered pigmented papules on the upper back
Dermoscopic View

Pathology: A dermal nodule of atypical, focally pigmented epithelioid cells exhibiting large nucleoli and focal tumor necrosis infiltrating the dermis and skeletal muscle consistent with metastatic malignant melanoma. No junctional component is present. Immunoperoxidase staining reveals the tumor cells to be positive for Mart-1/Melan-A, S100 and HMB45, confirming the histologic diagnosis.

Lab: CBC abd chemistries are normal. LDH is borderline high but not above normal range.

Imaging Studies
1. Abdominal Ultrasound: There are numerous heterogeneously hyperechoic masses within the liver, most compatible with metastatic disease. The largest of these is within the right hepatic lobe and measures up to 6.6 cm in greatest diameter. 
2. Chest PA/Lateral Xrays: No pulmonary nodules or pleural effusions are evident.

Diagnosis: Metastatic melanoma. Most likely ocular melanoma metastasis to the liver.

This patient poses some therapeutic question.  His melanomas do not bother him at this point and he keeps saying that he feels fine.  He's an avid golfer.  If he gets plugged into the system and loses this season; can we promise him another season in 2014?  He is a simple man; retired, no outside source of income. His melanoma, dormant for 19 years is suddenly active again. Why?

Knowing chemotherapy may significantly affect his energy level and he may experience other significant side effects, we are not sure what would be the best option for this patient at this point. We'd appreciate you sharing your similar experiences with your patients.

Follow-up: Many attempts were made to contact the patient and get him back for a follow-up discussion; but he never answered his phone or returned letters.  He died ~ 5 months later.  We hope he payed a few rounds of golf over the summer and suspect that his life was easier without futile attempts at palliation.

1. Progression of ocular melanoma metastasis to the liver: the 2012 Zimmerman lecture.
 2013 Apr;131(4):462-9. 


L. F. Montgomery Laboratory, Emory Eye Center, Atlanta, GA 30322, USA.



To the best of my knowledge, this study demonstrates for the first time small, apparently dormant micrometastasis in the liver of patients with uveal melanoma.


To evaluate the histological and immunohistochemical findings in metastatic uveal melanoma to the liver.


Samples of liver were obtained at autopsy from patients who died of metastatic uveal melanoma to the liver.


L. F. Montgomery Laboratory, Emory Eye Center, Atlanta, Georgia.


A total of 10 patients who died of metastatic uveal melanoma to the liver.


Sections of the liver were examined with hematoxylin-eosin, periodic acid-Schiff, Masson trichrome, or reticulin stains.


The tumors' morphology, growth pattern, mean vascular density, and mitotic index were determined with the aid of immunohistochemical stains for S100, HMB45, CD31, and Ki67.


Stage 1 metastases (defined as tumor clusters ≤50 μm in diameter) were identified in the sinusoidal spaces of 9 of 10 patients (90%). Stage 1 metastases were avascular and lacked mitotic activity. Stage 2 metastases (defined as tumors measuring 51-500 μm in diameter) and stage 3 metastases (defined as tumors measuring >500 μm in diameter) were found in all patients. Immunohistochemical stains were positive for S100 or HMB45 in all tumors. Overall, stage 1 metastases outnumbered stage 2 metastases (which outnumbered stage 3 metastases). The mean vascular density and mitotic index increased from stage 2 to stage 3 metastases (P < .05). The architecture of stage 2 metastases mimicked the surrounding hepatic parenchyma, whereas stage 3 metastases exhibited either lobular or portal growth patterns.


Uveal melanoma that spreads to the liver can be categorized as stage 1 (≤50 μm in diameter), stage 2 (51-500 μm in diameter), or stage 3 (>500 μm in diameter) metastases. The later stage exhibits a lobular or portal pattern of growth. During this progression, tumors become vascularized and mitotically active.
2. Domancy of Metastatic Melanoma
 2010 Feb;23(1):41-56. 


Division of Hematology and Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.


Metastatic dormancy of melanoma has not received sufficient attention, most likely because once detectable, metastasis is almost invariably fatal and, understandably, the focus has been on finding ways to prolong life of patients with overt recurrences. Nevertheless, analysis of the published clinical and experimental data on melanoma indicates that some aspect of melanoma biology imitate traits recently associated with dormancy in other solid cancers. Among them the ability of some melanomas to disseminate early during primary tumor progression and once disseminated, to remain undetected (dormant) for years. Comparison of cutaneous and uveal melanoma indicates that, in spite of being of the same origin, they differ profoundly in their clinical progression. Importantly for this discussion, between 40 and 50% of uveal melanoma remain undetected for longer than a decade, while less than 5% of cutaneous melanoma show this behavior. Both types of melanoma have activating oncogene mutations that provide autonomous pro-proliferative signals, yet the consensus is that those are not sufficient for tumor progression. If that is the case, it is possible to envision that signals from outside the tumor cell, (microenvironment) shape the fate of an individual disseminated cell, regardless of an oncogene mutation, to progress or to pause in a state of dormancy. To stimulate further debate and inquiry we describe here a few examples of potential signals that might modify the fate of disseminated cell and provide brief description of the current knowledge on dormancy in other cancers. Our hope is to convince the reader that disseminated melanoma cells do enter periods of prolonged dormancy and that finding ways to induce it, or to prolong it, might mean an extension of symptoms-free life for melanoma patients. Ultimately, understanding the biology of dormancy and the mechanisms of dormant cell survival, might allow for their specific targeting and elimination.

1 comment:

  1. From Dr. Henry Foong: This is a dilemma. To wait or not to wait. I would suggest that the patient be referred to a melanoma centre as well as an ophthalmologist with interest in eye melanoma and the final decision lies with the patient. What is worrying is chemotherapy may kill the patient or shorten his survival and give more side effects instead. From the literature review above, dormancy does occur in uveal melanoma. It is a difficult case indeed. Does treatment at this point improve survival? If not, I would wait.


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