Desmoplastic Melanoma

Desmoplastic malignant melanoma, Neurotropic melanoma

C43.9

2C30.Y

403924008; 51757004

Desmoplastic melanoma is a rare and unusual form of skin cancer that often looks like a scar rather than a typical mole or dark spot. It accounts for less than 4% of all melanomas and tends to appear on sun-damaged skin of older adults, particularly on the head and neck.

Table of contents

• What is desmoplastic melanoma?
• Who gets desmoplastic melanoma?
• Causes and risk factors
• Signs and symptoms
• Diagnosis and testing
• Pure and mixed types
• Treatment approaches
• Outlook and survival

What is desmoplastic melanoma?

Desmoplastic melanoma is a rare form of invasive melanoma, which is a skin cancer that arises from pigment-producing cells called melanocytes^[3]. The word “desmoplastic” refers to the presence of abundant fibrous tissue surrounding the cancer cells^[2]. This unusual characteristic makes desmoplastic melanoma different from other types of melanoma.

The malignant cells (cancerous cells) within the deeper layer of skin called the dermis are surrounded by thick fibrous tissue^[3]. In many cases, desmoplastic melanoma involves nerve fibers, and when this happens it is called neurotropic melanoma^[3]. The tumors are often surrounded by thick layers of fibrous tissue and may affect nerves^[4].

Desmoplastic melanoma accounts for about 1% of melanoma in Australia and New Zealand, and less than 4% of primary skin melanomas overall^[2][3]. The overall incidence rate is 2.0 per million people, with an annual percentage increase of 4.6% per year^[2].

• Skin (dermis)
• Head and neck region
• Nerve fibers

Who gets desmoplastic melanoma?

Desmoplastic melanoma occurs more commonly in certain groups of people. It usually affects white-skinned individuals and is more common in males than females, with a male to female ratio of approximately 2:1^[2][3]. The male percentage is about 65%^[3].

This type of melanoma primarily affects older individuals. The mean age at diagnosis is 66 years^[2]. Most patients are people over the age of 60 years, with an age distribution typically between 60 and 80 years old^[5][7].

Causes and risk factors

Desmoplastic melanoma is closely related to sun exposure. The cancer occurs most often on the head and neck region, which are areas particularly susceptible to sun exposure^[4][5]. More than 50% of cases appear on sun-exposed areas of the head and neck^[3].

The disease is caused by exposure to high levels of DNA-damaging ultraviolet radiation from the sun^[4]. Desmoplastic melanoma is typically found on chronically sun-damaged skin of older individuals^[2]. Compared with other melanomas that arise on the skin, desmoplastic melanomas occur in older patients on more heavily sun-damaged areas^[4].

The main risk factors for desmoplastic melanoma include^[3]:

• Increasing age
• Previous invasive melanoma or melanoma in situ
• Fair skin that burns easily
• Sun-damaged skin

Most melanomas of the skin have a large number of genetic mutations caused by ultraviolet radiation, but desmoplastic melanomas tend to have even more mutations^[4]. In fact, the average observed tumor mutational burden in desmoplastic melanoma was 77 mutations per megabase, compared with 35 mutations per megabase identified in other nondesmoplastic melanomas^[7]. These mutations create abnormal proteins that the immune system can recognize and destroy when stimulated properly with immunotherapy^[4].

Signs and symptoms

Early diagnosis of desmoplastic melanoma can be challenging because it is often amelanotic (lacking dark color) and has a predominantly deeper skin component^[2]. Desmoplastic melanoma usually lacks the typical ABCD melanoma warning signs: Asymmetry, Border irregularity, Colour variation, and large Diameter^[3].

The growth presents as a slowly enlarging area of thickened skin, sometimes described as scar-like^[3]. Common features include patches of skin that look like scars and have variable texture, or skin lesions (abnormal areas) that appear as thickened skin^[5]. The growths are often skin-colored but may be pigmented^[3].

Specific characteristics of desmoplastic melanoma include^[3]:

• Firm scar-like consistency with a smooth or irregular surface
• Flat or raised bump, patch, or lump
• Size greater than 6 millimeters and often 1 to 2 centimeters in diameter at diagnosis
• Irregular or regular borders (more often irregular)
• Variable pigmentation – most often skin-colored or pink, but may also have areas of brown, grey, blue, or black

The growths are pink or the same tone as a person’s skin and are typically 6 millimeters or more in size^[5]. These lesions become more distinctive over time, often growing over months to years before they are recognized^[3].

Deep invasive melanoma often has additional features such as a thickened lesion, a greater number of colors (especially blue or black), ulceration or bleeding, and itching or stinging^[3]. Certain desmoplastic melanoma growths may also bleed, itch, or sting^[5].

Not uncommonly, desmoplastic melanoma can be mistaken for other benign skin growths such as moles (melanocytic naevi), dermatofibroma, hypertrophic scar, or neurofibroma^[3]. In some cases, the growths may look like benign skin growths or other types of skin cancer^[5].

Diagnosis and testing

It is essential to diagnose desmoplastic melanoma accurately. The cancer can be difficult to diagnose not only clinically but also when examined under a microscope, and can be mistaken for a variety of benign and malignant non-melanocytic spindle cell tumors^[2].

A careful clinical history is important, which includes noting previous treatments received for non-resolving lesions^[3]. Palpation (touching and feeling the area) is an important step, as a large majority of desmoplastic melanoma are firm to the touch^[3].

Clinical diagnosis is aided by dermoscopy (examination with a special magnifying device) and skin biopsy (removal of a tissue sample), usually excision biopsy^[3]. Dermoscopy can be helpful in distinguishing desmoplastic melanoma from other skin lesions. The most frequently observed features under dermoscopy are^[3]:

• Melanocytic features in about 50% (pigmented globules or network)
• Asymmetrical structure and colors
• Regression features: scar-like areas, grey dots
• Multiple colors

As desmoplastic melanoma is commonly found on the head and neck, and may occur with lentigo maligna, it is possible that if such lesions are only partially biopsied, the desmoplastic melanoma may be missed^[3]. Reflectance confocal microscopy (a special imaging technique) may be useful to help guide the site of the biopsy^[3].

Depending on the thickness and proportion of desmoplasia within the invasive melanoma, sentinel lymph node biopsy (examination of nearby lymph nodes), imaging studies, and blood tests may be advised^[3].

Pure and mixed types

Desmoplastic melanoma can manifest significant variation with respect to the extent of cell density within the tumor, fibrosis, and invasion along nerves^[2]. Some tumors present with a pure desmoplastic invasive component (more than 90%) while other tumors display mixed features of desmoplastic and non-desmoplastic melanoma^[2].

This has led to the separation of desmoplastic melanoma into two subtypes based on the degree of desmoplasia present in the tumor: pure DM (pDM) and mixed DM (mDM)^[2]. This classification plays an important role in prediction of clinical outcomes^[7].

Patients with pure desmoplastic melanoma have less frequent lymph node involvement and tend to have a less aggressive clinical course than patients with mixed desmoplastic melanoma^[2]. Pure type tends to have less potential for spreading to other parts of the body (metastasis) and as a result has a more favorable prognosis than mixed type^[7].

Treatment approaches

The clinical behavior of desmoplastic melanoma differs from other subtypes of melanoma, with a higher tendency for persistent local growth and less frequent spread to lymph nodes^[2]. Desmoplastic melanoma commonly demonstrates local invasion with poor boundaries due to its infiltrative nature, which results in a high recurrence rate^[7]. Surgery to remove these tumors can be disfiguring, resulting in large scars on the head and neck^[4].

Established treatment options include surgical excision, sentinel lymph node biopsy, systemic chemotherapy, and radiation therapy^[7]. However, recent clinical trial results have shown remarkable effectiveness with immunotherapy treatment.

People with desmoplastic melanoma are likely to benefit from treatment with a single immunotherapy drug called pembrolizumab (Keytruda)^[4]. A clinical trial called S1512 tested pembrolizumab in distinct ways: as a presurgical treatment in people with operable cancer and as an initial treatment for those who could not be treated with surgery^[4].

The results from the trial with 27 people with inoperable metastatic desmoplastic melanoma were impressive. Among this group, 24 of 27 people (89%) responded to initial treatment with pembrolizumab alone^[4][11]. Nine patients (33%) had complete responses, meaning there was no evidence of their cancers after treatment, and 15 patients (55%) had their tumors shrink^[4]. The complete response rate was 37%^[11].

The new findings establish single-agent immunotherapy as the standard treatment for people with metastatic desmoplastic melanoma^[4]. Two combinations of immunotherapy drugs have been approved for melanoma, but the new findings suggest that people with desmoplastic melanoma could receive pembrolizumab alone and be spared the unnecessary side effects of additional therapies^[4].

However, patients with advanced desmoplastic melanoma are limited by a frequency of toxicities (side effects) that is numerically higher than in other patient populations^[11]. Ten patients (37%) experienced grade 3 or 4 adverse events, and nine patients (33%) discontinued treatment because of adverse events^[11].

Outlook and survival

The overall survival for patients with desmoplastic melanoma is relatively favorable despite its depth at diagnosis. The median survival at 5 and 10 years is 84.8% and 79.2%, respectively^[7]. Desmoplastic melanoma may have a higher survival rate than other forms of melanoma^[5].

From the recent clinical trial with pembrolizumab, the estimated 3-year melanoma-specific progression-free survival was 84%, and overall survival was 96%, with only one patient having died from melanoma progression^[11].

Advanced age of the patient, higher stage of the tumor, as well as increased Breslow depth (a measure of how deep the melanoma has grown into the skin) were found to be independent positive factors associated with desmoplastic melanoma^[7].