Data Set for the Reporting of Mucosal Melanomas of the Head and Neck: Explanations and Recommendations of the Guidelines From the International Collaboration on Cancer Reporting

Mucosal melanoma is recognized as a distinct histopathologic entity that represents less than 1% of all melanomas. However, about 60% of mucosal melanomas arise in the upper aerodigestive tract, with sinonasal tract accounting for 66%, oral cavity about 25%, and the remaining in the nasopharynx, oropharynx, and larynx; mucosal melanoma represents about 4% of all sinonasal malignancies.⁴  Within the sinonasal tract, the nasal cavity was affected twice as often as paranasal sinuses in a series of more than 20 years of data collected through the Surveillance Epidemiology and End Results database in the United States.⁵  Presenting sinonasal tract symptoms are most commonly epistaxis or obstructive symptoms,^6,7  whereas oral cavity presentation is as a painless pigmented lesion of the palate or alveolus, although maybe as a raised mucosal colored and/or ulcerated lesion.^8–10  The median age for head and neck mucosal melanoma is 67 to 73 years without a sex predilection (0.8:1.3 male to female ratio).^4,5 

Factors contributing to the development of mucosal melanoma remain largely undefined, although an association with melanosis is possible.¹¹  Biologically, mucosal melanomas are distinct from cutaneous melanomas. Many histopathologic findings used in cutaneous melanoma for risk stratification are not applicable to mucosal melanoma, and thus are not included in the head and neck mucosal melanoma data set, as will be highlighted below.

The overall outcomes in head and neck mucosal melanoma remain poor regardless of disease extent at presentation.⁸  This aggressive disease course is reflected in the TNM classification discussed in the staging section. The overall survival is less than 30% at 5 years.¹² 

This data set is to be used for biopsy and resection specimens of primary mucosal melanomas of the upper aerodigestive system; subsites include nasal cavity and paranasal sinuses, nasopharynx, oropharynx, larynx, hypopharynx, and oral cavity. Importantly, tumors arising from cutaneous sites extending to involve the mucosa should not be included in this data set. Similarly, melanoma metastases to the aerodigestive tract are excluded. Challenging cases involving the lips and nares should be clinically correlated in an attempt to distinguish cutaneous melanomas from mucosally derived tumors, recognizing that cutaneous melanomas are significantly more common than mucosal melanomas. When neck lymph node dissections are included, a separate, linked data set for Nodal Excisions and Neck Dissection Specimens for Head & Neck Tumours would be completed.⁴⁴ 

The head and neck mucosal melanoma data set is composed of 11 total data elements. Table 2 shows the distribution of these data elements into the 6 core (required) and 5 noncore (recommended) elements. Core elements signify information that should be included in all reports and is used for clinical care. Additional elements that relate to the disease but are not universally available and/or for which the significance is not clearly established are designated as noncore. Although noncore elements are optional, including this information is encouraged for future validation. All elements have predefined, standardized terminology and options listed, with free text available when necessary. These standardized data elements and response terminology have been unified across all ICCR data sets, enhancing communication with clinicians and the comparison of patients' data between institutions.

Because this data set/template is used for both biopsy and resection specimens, the extent of the surgery is documented in the operative procedure element. Biopsy should be further clarified as an excisional or incisional biopsy, whereas resection specimens are also specifically stated (eg, maxillectomy). If a neck dissection is performed or lymph nodes are removed as part of the surgery, this is recorded in the operative procedure section. However, reporting of the lymph node findings is recorded on a separate, linked data set: Nodal Excisions and Neck Dissection Specimens for Head & Neck Tumours.⁴⁴  “Other” is also included if a different procedure has been performed or if another anatomic site was surgically evaluated (eg, distant metastatic site) not captured in the primary resection.

Specimens submitted to pathology associated with the primary tumor resection are recorded. Where this includes multiple separate specimens, each should be listed for completeness. Multiple specimens are a particularly common occurrence for resection of sinonasal primary mucosal melanomas. All specimens related to the primary tumor site should be listed, including both specimens with and without tumor. Submitted lymph node specimens would be separately reported on the corresponding neck dissection data set.

Mucosal melanomas of the upper aerodigestive tract may arise at the following primary tumor sites: sinonasal, oral cavity, larynx, nasopharynx, and other. Multiple sites should be selected if a tumor extends between locations (eg, sinonasal primary with extension into nasopharynx). To further characterize the primary tumor site, laterality of the tumor (right, left, midline, or not specified) aids in the description of the primary tumor location and extent. Additionally, detailing the anatomic subsites involved is encouraged in an open text box by site (eg, septal or turbinate for sinonasal tract; gingiva or hard palate for oral cavity).

There is a predilection of mucosal melanoma to specific sites within the head and neck mucosae. Within the sinonasal cavity, 62% to 66% of primary mucosal melanomas involved only the nasal cavity, septum, and/or turbinate,^6,7  whereas upper gingiva and/or hard palate accounted for most oral cavity tumors.^13,14  The distinction of mucosal lip versus cutaneous lip is highlighted because cutaneous primaries would require a different data set and staging elements.

Tumor size remains a core data element of pathologic reporting for all tumor types. The recommendation in mucosal melanoma is to report the largest single, linear tumor dimension in the specimen with the largest tumor volume (core element), irrespective of overlying mucosal orientation (additional dimensions of the largest tumor are noncore). This guideline applies even if the tumor is removed in multiple components, as may occur in the sinonasal region. Although the limitation of using only a single specimen is noteworthy, the additive value of combining multiple specimens potentially overestimates the size and has no added value. Mucosal melanomas, particularly of the sinonasal region, are often polypoid and thereby may be removed initially to improve visualization of the remaining nasal cavity for further surgical resection. Unlike cutaneous melanomas where Breslow thickness or Clark level is used, these are not easily determined in mucosal sites.¹⁵  Several studies have correlated larger tumor size (>3 cm) with a worse prognosis.^6,13,16,17  However, tumor size is not included in pT staging categorization.

Mucosal melanoma diagnosis is established through histologic review and additional ancillary studies, as needed. Only about 60% of mucosal melanomas will have pigment to aid in the histologic diagnosis.^6,7,9  Therefore, mucosal melanomas should be considered in the differential diagnosis of undifferentiated or small round blue cell tumors, particularly in the sinonasal region. Importantly, the distinction to clearly delineate mucosal melanoma from melanoma of cutaneous origin is critical for staging, prognosis, and tumor biology. Therefore, correlation with clinical history, including the presence of skin involvement and/or prior cutaneous resections, may aid in favoring a primary cutaneous origin over a mucosal origin. Similarly, distinction from metastatic melanomas to a mucosal site is important. In the oral cavity, criteria to establish a primary mucosal melanoma of the oral cavity were first proposed by Greene et al,¹⁸  which required both histologic evaluation for an intraepithelial component and clinical exclusion of another primary site (Figure 1). However, in sinonasal tract melanomas, an in situ/junctional component is infrequently encountered (<25%).⁶ 

Although there may be limited data to inform clinical management or prognosis at this time, noncore elements still provide meaningful data for further study and evaluation.

Mucosal melanomas may be multifocal, and this has been shown in rare case reports of patients with underlying melanosis.^9,11  The added challenge in the sinonasal tract region is determining whether multiple specimens are contiguous or indeed multifocal. If true multifocal tumors exist, the recommendation is to complete separate data sets for each tumor. The guidance for indeterminate cases of possible contiguous versus multifocal tumors is to use 1 template.

Head and neck mucosal melanomas show great diversity in both cellular morphology and growth patterns. Patterns include peritheliomatous/perivascular, solid, fascicular, storiform, papillary, and alveolar, whereas cytomorphologic features include epithelioid, spindled, plasmacytoid, rhabdoid, meningothelial, pleomorphic, and undifferentiated (Figure 2). The main significance of this marked histologic variability is to consider mucosal melanoma in the broad differential diagnosis of head and neck neoplasms, even though these patterns or cytologic features do not seem to correlate with patient prognosis.^6,16  Importantly, these observations allow for meaningful comparison with potential metastases, which are often amelanotic.⁹ 

The specific subtypes of melanoma included in this data set are balloon cell melanoma,¹⁹  mixed epithelioid and spindle cell melanoma, epithelioid, spindled, amelanotic, undifferentiated, and other, specify. The specific subtype of melanoma is associated with prognosis in uveal melanoma, but not yet correlated to outcome for mucosal sites.^20–22  Amelanotic melanomas show little to no appreciable pigmentation, a finding that makes the diagnosis more challenging, especially in the sinonasal tract (Figures 1 through 3).^6,7,9  Desmoplastic melanoma is characterized by amelanotic invasive spindled cells in a fibrotic stroma and seems to show a high propensity for perineural invasion (up to 83%).²³ 

Both pathologists and clinicians use margin status to determine the adequacy of surgery, and in many cancers this correlates with rates of local recurrence and overall outcome. Additionally, in many tumor types, margin status may trigger adjuvant therapy or augmented therapy when surgery was viewed as incomplete. However, in mucosal sites, resections are often performed by obtaining multiple separate specimens, making margin assessment unreliable. Some studies have shown the prognostic value of margin status^7,24 ; however, the very high propensity for vascular invasion may contribute to earlier distant metastasis, which contributes to overall mortality in this patient population, irrespective of margin status. Further, even when tumors have limited submucosal disease, outcomes are still poor, and thus margin status is not an independent prognostic factor.^8,25  If margins are evaluable, invasive versus in situ tumor should be reported. Submucosal tumor is considered invasive, whereas atypical melanocytic cells either in increased numbers and/or confluent along the epithelial basement membrane junction or with upward (Pagetoid) mucosal spread would constitute an in situ component.^8,26,27 

Factors that contribute to mucosal melanoma remain largely unknown; however, recording coexisting pathology may over time provide insight into this disease. Findings such as melanosis may occur with mucosal melanoma, as noted in case reports, and this warrants further study.^11,28–30 

Supplemental studies, most often in the form of immunohistochemistry, are used to confirm the diagnosis of mucosal melanoma, especially if amelanotic, rather than for their prognostic value. The neoplastic cells usually react with S100 protein (about 90% of tumors), SOX10, HMB-45 (about 75% of tumors), Melan-A, and tyrosinase (Figure 3, B), among others, although positivity rates vary^6,22,31  and other tumors may also show immunoreactivity for these markers.

Increasingly, ancillary studies (immunohistochemistry or molecular assessment) may be performed for possible targeted therapies. Importantly, the genetic profile of mucosal melanomas is unique and does not align with that of cutaneous melanomas.^32–34  Mucosal melanomas have shown 18% and 12% rates of KIT (CD117) and NRAS mutations, respectively, with infrequent BRAF alterations.^32–36 

The AJCC/UICC 8th edition staging systems, unchanged from the 7th edition, are based on the pathologic extent of disease (TNM), supported by several studies.^16,37,38  However, site-specific staging of sinonasal melanomas also stratified patients into prognostic groups.³⁹  This data set is applied to all upper aerodigestive tract sites, even though sinonasal tract disease forms the basis for the staging,^2,6  and previous staging proposals have been rendered obsolete.^40–42 

The UICC 8th edition staging is provided in Table 3, also reflecting the current AJCC criteria. Reflecting the poor prognosis and high recurrence rates, the pT categorization is truncated, with no T1 or T2 designations. Specifically, all head and neck mucosal melanomas are classified as either T3 for localized disease limited to the epithelium and/or submucosa, or T4 for advanced tumors. T4 is further divided into T4a for tumors extending into the deep soft tissue, cartilage, bone, or overlying skin, and T4b for extension of tumors into the central nervous system (brain, dura), skull base, lower cranial nerves (IX, X, XI, XII), prevertebral or masticator space, carotid artery, or mediastinal structures.

Because size is not the discriminating factor, a polypoid nasal mass may qualify as a pT3 tumor when the evaluation of the stalk shows limited submucosal involvement (Figure 4), whereas documentation of bone invasion places the tumor in pT4 (Figure 5).

Lymph node metastases are found in 15% of oral cavity and up to one-third of sinonasal mucosal melanomas at initial presentation. Despite an association with worse outcomes in multiple studies, the number or size of lymph nodes does not further stratify patients.^6,8,37,42  Therefore, regional lymph node disease (N category) is defined as either absent (N0) or present (N1). If lymph nodes are present as part of a mucosal melanoma case, reporting of the lymph nodes is captured via the separate but linked Nodal Excisions and Neck Dissection Specimens for Head & Neck Tumours data set.⁴⁴  Although the 8th edition of AJCC/UICC has incorporated extranodal extension into many head and neck tumor types for N determination, the significance of this finding in mucosal melanoma is unknown and does not modify the N category in this disease.

Although distant metastasis (M1) has been identified as the most important factor determining patient outcome, with 100% mortality (death with disease) by 5 years,⁶  the 8th edition of AJCC/UICC does not designate prognostic stage groupings, even though there is support for such a determination.² 

The goal of the ICCR is to allow for the standardization of data elements reported across each tumor site. In rare diseases, such as head and neck mucosal melanoma, the literature is mixed on what may be prognostic elements in this disease. To date, there are no well-developed prospectively validated prognostic factors in head and neck mucosal melanoma. Thus, the move toward global implementation of standardized data sets would allow for the collection of data that may achieve better identification of frequency, distribution, and prognostic factors, while documenting geographic, genetic, and other underlying global differences. These data could then permit improved communication within and between institutions and allow for harmonized therapeutic approaches and improved outcome for these rare neoplasms when presented and compared based on uniform terminology and standardized criteria.

The authors would like to express their appreciation to the sponsoring societies and organizations and give special thanks to Fleur Webster and Hannah B. Canlas for their exceptional organizational and editing contributions. The views expressed are those of the authors solely.