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Nodular Melanoma


Any melanoma, including the common variants superficial spreading, lentigo maligna, and acral lentiginous melanoma, may form an invasive tumor nodule. However, the presence of a prominent nodule does not equate a nodular melanoma (NM) subtype ( Fig. 15.1 ). According to the World Health Organization (WHO) classification of skin tumors, the NM subtype is defined conceptually as “malignant melanoma exclusively in vertical growth phase.” Or in other words, it is defined by the “absence of a radial growth phase.” Microscopically this could mean (a) the presence of invasive melanoma without associated in situ melanoma ( Fig. 15.2 ), or (b) invasive melanoma associated with in situ melanoma of limited horizontal extension in the epidermis and/or follicles ( Figs. 15.3–15.5 ). According to WHO criteria for NM, if in situ melanoma is present, it should not extend horizontally beyond the periphery of the invasive tumor component (see Figs. 15.3–15.5 ).

Fig. 15.1
Superficial Spreading Melanoma With Large Invasive Tumor Nodule.
(A) Large polypoid nodule of melanoma. (B) The tumor is not a nodular melanoma because it is associated with melanoma in situ, which extends broadly beyond the perimeter of the invasive melanoma, displaying a nested and pagetoid growth pattern.

Fig. 15.2
Nodular Melanoma Without Associated Melanoma in Situ (Aka Primary Dermal Melanoma).
(A) Silhouette of an entirely intradermal tumor nodule. (B) There is no intraepidermal melanocytic neoplasm. (C) Cytology of the intradermal melanoma.

Fig. 15.3
Nodular Melanoma With Associated Melanoma in Situ.
(A) Plaque-like silhouette of a melanoma. Invasive melanoma extends farther peripherally than the associated in situ melanoma. (B) In situ melanoma displays a nested and pagetoid growth pattern. It is confined to the epidermis overlying the invasive melanoma.

Fig. 15.4
Nodular Melanoma With Only Focal in Situ Melanoma.
(A) The amelanotic nodular melanoma invades dermis and subcutis. (B) Only a small part of the epidermis contains melanoma cells. They are associated with a dermal scar from a prior biopsy.

Fig. 15.5
Primary Nodular Melanoma With Intrafollicular Melanoma in Situ.
(A) Asymmetric silhouette of invasive melanoma clustered around follicular structures. (B) Most of the tumor is in the dermis. Melanoma in situ is focally seen at the infundibular dermal stromal junction.

The WHO definition allows for significant heterogeneity of tumors that qualify for the set parameters. It includes de novo intradermal (primary dermal) melanomas of any phenotype—epithelioid, fusiform, spitzoid, blue nevus-like, other, nodular dermal melanomas associated with a melanocytic nevus, and various other melanoma subtypes, in which the intraepidermal or intra-adnexal melanoma cells do not extend beyond the dermal invasive component. The WHO definition also accepts as NM tumors which may have started as conventional (superficial spreading, acral, or lentigo maligna) melanoma, but the invasive component quickly matched and reached the in situ component in horizontal extension at the time of diagnosis. In other words, NM does not represent a unique melanoma variant, but a combination of primary dermal melanomas and melanomas with a shared pathway of rapid tumor progression from an intraepithelial neoplastic proliferation of superficial spreading, acral lentiginous, or lentigo maligna melanoma.

Although NM includes pathologically heterogeneous group of tumors, it is a clinically useful category. NMs are more difficult to diagnose clinically than other conventional melanomas, especially in the absence of melanin pigment. They tend to grow faster and are thicker at the time of diagnosis.

Clinical Findings

The pathologic definition of NM affects the clinical phenotype: a papule, nodule, or plaque is present (visible or palpable). If there is an associated nevus precursor ( Fig. 15.6 ), there may be a flat lesion adjacent to the nodule. However, for most lesions of NM ( Figs. 15.7 and 15.8 ), this is usually not the case. The clinical diagnosis is often challenging, because NMs may be relatively symmetric and circumscribed, thereby defying the ABCD rules for recognition (see Fig. 15.7 ). This difficulty has been documented by the fact that usually more doctor visits are needed for the diagnosis of NM than superficial spreading melanomas. The diameter and color of the nodules vary, as well as the speed of growth, but in general NMs tend to grow faster than other conventional melanoma types. For NM the EFG ( e levated, f irm, g rowing progressively) rule has been proposed to assist in the diagnosis. However, these features have limited specificity. Amelanotic NM may be confused with a range of other lesions (e.g., basal cell carcinoma, cyst, fibroma, angioma). Pigmented NMs (see Fig. 15.8 ) are more readily recognized as malignant, but may be confused with pigmented basal cell carcinoma.

Fig. 15.6, Primary Nodular Melanoma Arising in Association With a Congenital Melanocytic Nevus.

Fig. 15.7, Amelanotic Primary Dermal Nodular Melanoma.

Fig. 15.8, Pigmented Nodular Melanoma.

From a clinical perspective, any enlarging papule or nodule—particularly if multicolored, firm, ulcerated, or with a history of bleeding—should be considered suspicious. There are a number of dermoscopic clues that can assist in the recognition of pigmented NM: asymmetric pigmentation, blue-black structureless areas (especially if they involve more than 10% of the lesional surface), a disorganized pigment pattern throughout the lesion, abnormal vascular structures, and milky-red globules or irregular dots. Dermoscopic findings of amelanotic or hypomelanocytic lesions that raise suspicion for melanoma include a blue-white veil, focal blue-black color which may not be readily visible to the naked eye, polymorphous vessels, and pseudolacunes.

Studies from both the United States and Australia show that NMs are responsible for a disproportionate number of tumor-related deaths. NMs constituted 14% of all diagnosed melanomas, but were responsible for 37% and 43% of melanoma-related deaths. NMs seem to progress and invade faster than other melanoma subtypes. Thus, even for patients being followed by dermatologists, the growth of NMs may proceed so quickly in intervals between visits that a dermatologist may not catch the tumor early. The difficulty of clinically recognizing NMs early is another factor contributing to the later stage at time of diagnosis for NM compared with the other subtypes. In one study of 5775 melanomas covering 5 years from the Australian tumor registry, the average Breslow depth at the time of diagnosis was 0.6 mm for superficial spreading melanoma (SSM) compared with 2.6 mm for NM . One study specifically aimed at assessing rate of growth estimated a rate of growth in mm of Breslow/month of 0.49 mm for the nodular types compared with 0.12 for SSM and 0.13 for lentigo maligna (LM). The greatest risk for delayed diagnosis is likely associated with amelanotic NM. Importantly, the findings in these studies primarily refer to more conventional patterns of NM, rather than spitzoid neoplasms or melanoma arising in blue nevi, as these subtypes of lesions are less frequent and have their own patterns of typical biologic behavior.

Histopathologic Findings

Histopathologically, NMs may be divided into tumors with and without associated in situ melanoma. They can be further subdivided into de novo NMs and those associated with a melanocytic nevus.

Nodular Melanoma Associated With In Situ Melanoma

The intraepidermal component of an NM may be well developed (see Fig. 15.3 ) or focal (see Figs. 15.4 and 15.5 ). By definition, the in situ melanoma should not extend beyond the periphery of the invasive tumor nodule at the time of diagnosis. Otherwise, the tumor is disqualified as nodular subtype. Accordingly, the distinction of NM or other type of melanoma with a dominant invasive tumor nodule is best made on an excisional specimen, which permits review of the entire epidermis surrounding the tumor nodule. At times, there may not be melanoma in situ visible peripheral to the tumor nodule in a given two-dimensional plane of sectioning, but melanoma in situ may be seen in subsequent sections along the longitudinal plane of an elliptical excision ( Figs. 15.9 and 15.10 ).

Fig. 15.9, Pitfall of Melanoma Classification Due to Sampling.

Fig. 15.10, Pitfall of Melanoma Classification Due to Sampling.

We therefore caution against attempts to subtype a melanoma as nodular on a small partial shave biopsy. It is clinically not necessary since NM, SSM, and lentigo maligna melanoma (LMM) with an identical stage have the same prognosis, and subtyping of melanomas on limited material is not uncommonly inaccurate. While there may be no melanoma in situ visible peripheral to a melanoma nodule, the subsequent excision may reveal adjacent melanoma in situ extending over many rete ridges peripheral to the invasive component (see Fig. 15.10 ).

In terms of histopathologic appearances, NM may display a range of sizes and architectural and cytologic features. A tumor may be small (see Fig. 15.2 ) or large (see Figs. 15.8 and 15.11 ). It may display a plaque-like, nodular (see Fig. 15.11 ), or polypoid silhouette ( Fig. 15.12 ), or be predominantly endophytic with diffusely infiltrative growth ( Fig. 15.13 ). The tumor may be solid and of high cell density, containing nests and/or fascicles, or the tumor cells may be dispersed and cell aggregates may be less dense and of low density. Any melanoma phenotype may be seen. Nodular tumors close to the epidermis are often associated with an epidermal collarette (see Figs. 15.11B and 15.14 ). Ulceration is common with mitotically active tumors.

Fig. 15.11, (A) Large amelanotic nodular melanoma in dermis and subcutis. (B) Nodular melanoma with an epidermal collarette.

Fig. 15.12, Polypoid Nodular Dermal Melanoma.

Fig. 15.13, Nodular neurotropic melanoma in dermis and subcutis with infiltrative growth.

Fig. 15.14, Ulcerated nodular melanoma with an epidermal collarette and adjacent compound melanocytic nevus. (A) Silhouette of the ulcerated melanoma located to the left of a melanocytic nevus. (B) Cytologically atypical melanoma cells juxtaposed to the bland cell population of the associated melanocytic nevus.

Cytologically the tumor cells may be epithelioid, spindle shaped, or various combinations of both cell types, small and/or large. Melanin pigment may be absent or present in variable amounts from paucimelanotic to heavily pigmented. Any phenotype of melanoma (e.g., small or large epithelioid, spindle cell, spitzoid, nevoid, blue nevus-like, deep penetrating nevus-like) may be found in an NM ( Box 15.1 ).

Box 15.1
Variants of Nodular Melanoma

Nodular Melanoma Associated With In Situ Melanoma

  • De novo

  • Associated with a melanocytic nevus

  • Various phenotypes: epithelioid, fusiform, nevoid, spitzoid, desmoplastic plexiform (DPN-like), other

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