Module 22: Nodular Melanoma

Nodular melanomas are defined as invasive melanomas without a radial growth phase. Specifically, they lack an in situ component beyond three rete ridges of the invasive vertical growth phase. Unlike SSM, which spreads laterally through the epidermis before invading vertically, NM grows directly downward into the dermis from the outset. This fundamental growth pattern explains:

• Why network, streaks, and regression structures are absent -- these features correlate with radial/pagetoid spread, which NM lacks.
• Why blue-white veil and deep pigmentation dominate -- vertical growth drives melanocytes deep into the dermis, producing blue and gray colors.
• Why shiny white structures (crystalline structures) are common -- vertical invasion causes collagen matrix alteration visible under polarized light.
• Why dermoscopic vessels are often obscured in pigmented NM -- abundant eumelanin in dermis and epidermis blocks visualization of neoangiogenic vessels.

• NMs represent only 14% of invasive melanomas but are the predominant contributor to melanoma-related deaths.
• Thick melanomas (greater than 3 mm Breslow thickness) are predominantly NMs (56%).
• Between 30% and 40% of NMs are amelanotic or hypomelanotic, making them especially prone to diagnostic delay.
• A proportion of early NMs escape detection because they lack the classic ABCD clinical features of SSM.
• NM is widely regarded as the most commonly missed melanoma subtype.

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NMs account for approximately 14% of invasive melanomas but carry the worst prognosis of any melanoma subtype due to their rapid vertical growth and the frequent delay in diagnosis. They are the largest contributor to melanoma-related deaths. Thick melanomas (greater than 3 mm Breslow thickness) are predominantly NMs (56%), underscoring the clinical urgency of early detection.

Clinically, NMs may lack the "ABCD" features more typical of SSMs. The classic dermoscopy features of SSMs (see Module 21) -- including features correlating with radial growth and pagetoid spread (streaks, pseudopods, radial streaming) and those features found in thin melanomas (atypical network, regression features including multiple blue-gray fine dots/peppering, and scarlike areas) -- are often lacking in NMs.

The histopathology and growth dynamics of pigmented NMs explain their dermoscopic morphology. NMs are characterized by prominent vertical growth with a relative lack of radial growth. Thus, dermoscopic features associated with radial growth (network structures, streaks) are not often seen. In contrast, dermoscopic features associated with vertical growth -- including matrix alterations (shiny white lines) and tumor cell aggregates (globules) -- are commonly present.

It is uncommon for NMs to spontaneously regress or involute; therefore, regression structures (scarlike depigmentation and granularity/peppering) are not a prominent feature. Although these tumors have neoangiogenic vessels in the dermis, the vessels are virtually invisible with dermoscopy due to the abundant eumelanin pigment present in the dermis and epidermis, which obscures the observer's ability to see the dermal vessels. The pigment is often so extensive that no dermoscopic structures can be appreciated, and the lesion simply appears as a blue-black nodule with an intermix of different hues of blue, red, and gray color.

NMs can display a clinically symmetric shape with an asymmetric pigmentation pattern under dermoscopy. However, the asymmetry of pattern may be less marked compared with SSM, and a small percentage of pigmented NMs (5.8%) can show symmetry of pigmentation pattern across all axes. Nevertheless, the majority of pigmented NMs can be diagnosed using standard dermoscopy criteria.

Dermoscopic structures that positively correlate with NM include:

1. Areas of homogeneous blue pigmentation -- Reflecting deep dermal melanin deposition from vertical growth. Unlike blue nevi, which display a relatively "homogeneous blue" hue, pigmented NMs typically show an intermix of different hues of blue, red, and gray.

2. Asymmetrical pigmentation pattern -- Though less marked than in SSM, present in the vast majority of pigmented NMs (approximately 94%).

3. Atypical peripheral black dots/globules with irregular size and distribution -- Representing tumor cell aggregates in the epidermis. Irregular brown dots/globules are predictive of NM less than 2 mm in thickness.

4. Blue-white veil -- The defining feature of the nodular component in many NMs. It reflects acanthosis with compact orthokeratosis overlying confluent nests of heavily pigmented melanocytes and melanophages in the dermis.

5. Pink, blue, or black color -- Multiple (five to six) colors are frequently present, scored from tan, dark brown, black, blue, gray, and red. The multicolored appearance reflects varied melanin depth and vascularity.

6. Atypical vascular structures -- Including polymorphous vessels, milky-red globules/areas, and homogeneous red areas. Vessel types include hairpin (looped) vessels, dotted vessels (indicative of melanocytic origin), and linear irregular vessels.

7. Blue-black structures -- Defined as the presence of a combination of blue and black pigmented areas involving at least 10% of the lesion surface. This is the basis of the "blue-black rule" (see Section 4.5).

8. Shiny white structures (shiny white streaks or lines) -- Visible only with polarized dermoscopy. These result from collagen matrix alteration caused by the invasive vertical growth component. Also known as crystalline structures.

9. Ulceration/erosion -- Indicating epidermal destruction overlying the vertically expanding tumor mass.

Check Your Understanding

Why is nodular melanoma particularly challenging to diagnose with dermoscopy?

Nodular melanoma often lacks the classic dermoscopic features of superficial spreading melanoma (atypical network, irregular streaks) because it grows vertically from the outset, bypassing the radial growth phase. It may appear as a symmetric, structureless nodule with blue-white veil or may be amelanotic, making recognition with pattern-analysis algorithms difficult.

Key Takeaways

• Nodular melanoma (NM) frequently presents with blue-black color corresponding to dense dermal melanin, and this blue-black homogeneous pattern may be the only dermoscopic clue.
• Atypical vessels in NM include irregular linear, dotted, and hairpin vessels, often in a polymorphous pattern reflecting the chaotic tumor vasculature.
• Ulceration in NM corresponds to epidermal disruption overlying the tumor and is associated with thicker, more aggressive tumors with worse prognosis.

Clinical Scenario

A 62-year-old man presents with a rapidly growing 12 mm blue-black nodule on his left calf that appeared 3 months ago. Dermoscopy reveals homogeneous blue pigmentation with intermixed areas of black, gray, and red, a blue-white veil covering most of the lesion, and shiny white lines visible under polarized light. No network or streaks are visible.

What is the most likely diagnosis, and why are network and streaks absent?

Nodular Melanoma (NM)

The blue-black nodule with blue-white veil, shiny white lines, and absent network/streaks is classic for NM. Network and streaks are absent because NM grows vertically from the outset, lacking the radial growth phase that produces these features. The blue-white veil reflects acanthosis overlying deep dermal melanocytes, and shiny white lines indicate collagen matrix alteration from vertical invasion. The blue-black rule (blue and black areas involving >10% of the lesion) further supports melanoma. Urgent excision is required given the rapid growth (EFG rule: Elevated, Firm, Growing).

A diagnostically significant proportion of NMs are hypomelanotic or amelanotic compared with invasive non-NM (37.3% vs. 7.5%). This is the single most important factor contributing to diagnostic delay.

Nonpigmented NMs can be classified as:

• Pure amelanotic NM (ANM): No discernable eumelanin production.
• Hypomelanotic NM: Appears mainly amelanotic to the naked eye but reveals subtle melanin pigmentation under dermoscopy.

Since there is minimal to no eumelanin pigment to block dermoscopic light, amelanotic NMs almost always display:

• Polymorphous vascular pattern -- The polymorphous vessels usually consist of dotted and serpentine vessels. Rarely will there be vessels with a comma shape (as seen in intradermal nevi) or an arborizing configuration (as seen in BCC). The presence of serpentine vessels is highly predictive of thicker NMs (greater than 2 mm).
• Shiny white structures -- Visible under polarized light, representing dermal matrix alteration.
• Milky-red/pink areas -- An important feature reflecting neoangiogenesis and altered dermal stroma.
• Linear irregular vessels and hairpin vessels -- The most important single vascular structures in amelanotic/hypomelanotic NM.

In amelanotic NMs, atypical vascular structures may be the only clues for diagnosis and are indicative of angiogenesis. Thicker melanomas tend to show more peripheral vessels than thin melanomas.

Key distinguishing point: If blue-gray globules or vessels are visualized in a heavily pigmented nodule, it is more likely that the lesion will prove to be a pigmented nodular BCC than a NM. This is because in pigmented nodular BCC, the epidermis is not heavily melanized -- only the dermal BCC tumor islands are. Therefore, dermoscopic light can still reach the superficial dermis, allowing the observer to see vessels and blue-gray BCC tumor islands.

The dermoscopic pattern of NM is often characterized as:

• Homogeneous disorganized -- dermoscopically asymmetric despite sometimes appearing clinically symmetric.
• Featureless with atypical vessels -- structureless pink or blue-black background with scattered vascular structures.

This reflects the fundamental nature of NM: vertical growth without the structured patterns (network, streaks) that characterize radial growth melanomas.

Check Your Understanding

What are the dermoscopic clues that help identify nodular melanoma?

Key clues include blue-white veil over a raised portion, atypical vascular pattern (dotted and/or linear-irregular vessels), peripheral black dots or globules, milky-red or pink globules/areas, and ulceration. The combination of blue-white structures with polymorphous vessels in a nodular lesion should raise suspicion even without a pigment network.

The "blue-black rule" is a simplified dermoscopic clue specifically developed for recognizing pigmented nodular melanoma.

Definition: The presence of a combination of blue and black pigmented areas involving at least 10% of the lesion surface.

Performance:

• Sensitivity for the diagnosis of melanoma: 78.2%
• Specificity for the diagnosis of melanoma: 80.5%

Application: When encountering a pigmented nodule with combined blue and black areas covering at least 10% of its surface, melanoma must be strongly considered and biopsy is generally indicated. This rule is particularly useful for less experienced dermoscopists as it provides a simple, binary criterion for raising suspicion.

Key Takeaways

• The EFG criteria (Elevated, Firm, Growing) were developed specifically for NM because nodular melanoma frequently lacks the ABCD clinical features used for flat melanomas.
• Amelanotic NM may show only milky-red or pink structureless areas with polymorphous vessels and is one of the most commonly missed melanoma subtypes.
• Symmetric pigmented nodules (blue-black) still require the blue-black rule: any nodule with blue and black color and no other definitive benign features should be excised.

Clinical Scenario

A 70-year-old woman presents with a 10 mm pink, dome-shaped, firm nodule on her right shin that has been growing for 6 weeks. Dermoscopy reveals a milky-red structureless background with polymorphous vessels (dotted, hairpin, and linear irregular) and shiny white lines under polarized light. There is no pigment visible.

What is the most likely diagnosis, and what clinical rule applies?

Amelanotic Nodular Melanoma

Approximately 37% of NMs are amelanotic or hypomelanotic. The polymorphous vascular pattern (multiple vessel types in one lesion) combined with shiny white lines is highly suspicious for amelanotic melanoma. The EFG rule applies: Elevated, Firm, and Growing for more than one month -- all three criteria are met. Amelanotic NM is the most commonly missed melanoma subtype because it lacks pigment-based dermoscopic criteria. Key mimics include pyogenic granuloma and BCC, but the polymorphous vessels with shiny white lines favor melanoma.

Because a proportion of early NMs escape detection due to their lack of classic ABCD features, the "EFG" criteria were proposed to supplement the ABCD rule:

• E -- Elevated: The lesion is raised above the skin surface.
• F -- Firm: The lesion feels firm to palpation (not soft or compressible).
• G -- Growing: The lesion has been continuously growing for more than one month.

Any elevated, firm, and continuously growing lesion that does not match the pattern recognition morphology of a common benign lesion warrants biopsy. This rule underscores the importance of growth as a key feature of NM, as evolution ("E" for evolution) was also added to the ABCD rule to improve early detection. Amelanotic NMs in particular present as pink, elevated, firm, fast-growing tumors that fit the EFG criteria.

Multiple factors contribute to NM being the melanoma subtype most prone to diagnostic delay:

1. Absence of classic ABCD features: NMs may lack asymmetry, border irregularity, color variegation, and the larger diameter typical of SSM.
2. High rate of amelanosis/hypomelanos: 30-40% of NMs are amelanotic or hypomelanotic, compared with only 7.5% of non-nodular invasive melanomas.
3. Relatively symmetric shape: NMs can present as symmetric nodules, failing to trigger the "ugly duckling" alarm.
4. Symmetric dermoscopic pigmentation: 5.8% of pigmented NMs show symmetry across all axes under dermoscopy.
5. Lack of radial growth features: Network, streaks, and regression structures -- the features most clinicians look for -- are absent.
6. Mimicry of benign lesions: Pigmented NM can mimic blue nevus; amelanotic NM can mimic pyogenic granuloma, dermal nevus, or cyst.
7. Featureless morphology: Some NMs appear as feature-poor or structureless lesions under dermoscopy, making them difficult to categorize as concerning.
8. Rapid growth: The very speed of NM progression means the window for early detection is inherently shorter than for SSM.

Pigmented NM vs. Blue Nevus

The critical differential for a heavily pigmented blue-black nodule. Blue nevi display a relatively "homogeneous blue" hue, while pigmented NMs typically show an intermix of different hues (blue, red, gray) and are more likely to exhibit multicolored areas, blue-white veil, and atypical vessels when present.

Pigmented NM vs. Pigmented Basal Cell Carcinoma (BCC)

A hypomelanotic nodule with features resembling pigmented BCC (large blue-gray ovoid nests, ulceration) but lacking arborizing vessels typical of BCC -- and instead showing brown globules and dotted vessels (indicative of melanocytic origin) along with milky-red globules (specific for melanoma) -- should raise concern for NM. If blue-gray globules or vessels are visible in a heavily pigmented nodule, pigmented nodular BCC is more likely than NM, because the non-melanized epidermis in BCC allows dermoscopic light to reach dermal structures.

Amelanotic NM vs. Pyogenic Granuloma

Both present as rapidly growing pink-red vascular nodules. Amelanotic NM will show polymorphous vascular patterns with multiple vessel morphologies (dotted, serpentine, hairpin), shiny white structures under polarized light, and milky-red areas. Pyogenic granuloma typically shows a more homogeneous vascular pattern with red lacunae or a collarette of scale.

NM vs. Spitz Nevus

Both may present as pigmented or amelanotic papules/nodules. Spitz nevi typically show a symmetric starburst pattern with circumferential radial lines or pseudopods, a regular dotted vascular pattern, and organized globular patterns. NM shows asymmetric pattern, polymorphous vessels, and blue-white veil.

NM vs. Thrombosed Hemangioma/Angiokeratoma

Thrombosed hemangiomas display homogeneous dark-red to blue-black lacunae with clearly defined borders and septa. NM lacks lacunae and septae and instead shows multicolored areas, blue-white veil, and atypical vessels when present.

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Key Takeaways

• NM must be differentiated from pigmented BCC (arborizing vessels present), blue nevus (stable and homogeneous), and thrombosed hemangioma (lacunae visible under dermoscopy).
• The combination of blue-white veil, irregular vessels, and any pigmented structureless areas in a nodule is highly specific for melanoma and should prompt immediate excision.
• Any rapidly growing nodule (weeks to months) should be biopsied regardless of dermoscopic findings, as NM can evolve faster than surveillance intervals.