Chapter IV.3 Amelanotic Melanoma Jürgen Kreusch IV.3

Contents

IV.3.1 Introduction and Definition...... 204 IV.3.2 Hypomelanotic and Amelanotic Melanoma...... 204 IV.3 IV.3.4 Clinical Features...... 205 IV.3.5 Dermoscopic Criteria...... 207 IV.3.6 Adequate Dermoscopic Inspection of Non-pigmented Lesions ...... 208 IV.3.7 Dermoscopic Features of Amelanotic Melanoma ...... 208

IV.3.8 Vascular Patterns Fig. IV.3.1. Amelanotic melanoma (center; SSM, L III, in Amelanotic Melanoma...... 208 0.6 mm) IV.3.9 Morphological Changes of Vessels During Tumor Growth...... 209 summarized under this general term; however, IV.3.10 Relevant Clinical Differential amelanotic melanoma will not be identified by Diagnosis...... 210 dermoscopy nor by any other diagnostic meth- IV.3.10.1 The Way to Diagnosis od if a lesion is not considered worth inspection of Amelanotic Melanoma ...... 210 with the particular instrument – a screening IV.3.10.2 Strategies for Detecting Amelanotic strategy including knowledge of clinical fea- Melanoma...... 211 tures, dermoscopic techniques and criteria is References...... 212 ­essential to spot amelanotic melanoma among the variety of non-pigmented lesions of the skin (Figs. IV.3.1, IV.3.5a).

IV.3.1 Introduction and Definition IV.3.2 Hypomelanotic and Amelanotic Melanoma “Amelanotic melanoma” is a clinical and de- scriptive term frequently used for any melano- Frequently, melanoma are classified “amelanot- ma lacking melanin pigmentation. These tu- ic” regardless of the degree and nature of hy- mors represent a large fraction of the so-called popigmentation. One must distinguish two rea- “featureless” or “undiagnosable” melanoma [3– sons for a melanoma to contain little melanin. 5, 7, 13]. This chapter gives details on the der- There are tumors which produce little or no moscopic features of amelanotic melanoma melanin. On the other hand, there are melano- which may help to classify the variety of tumors ma which have lost more or less of their melanin Chapter IV.3 Amelanotic Melanoma Chapter IV.3 205

content mostly due to regression. Both phenom- melanin in all segments warrants description as Amelanotic Melanoma ena may even occur within the same lesion. The “slightly pigmented melanoma.” Lesions with Jürgen Kreusch IV.3 varied reasons for hypopigmentation should circumscribed hypopigmentation may be char- find their equivalent in clinical and, more im- acterized as “partially hypomelanotic” or “par- portantly, in dermoscopic terminology. tially amelanotic” melanoma (Table IV.3.1). There exist tumors with great differences in melanin content, be it the proportion of the hy- IV.3.4 Clinical Features popigmented area in partially pigmented mela- noma or the intensity of pigmentation within a Completely amelanotic melanoma are quite slightly pigmented melanoma. As a proposal, a rare: estimates between 2 and 8% are given [14]. melanoma may be considered “partially pig- In general, the descriptive clinical term “amela- mented” if the section containing melanin is no notic” melanoma is used imprecisely, as it is fre- larger than 30% of the tumoral area. A melano- quently attributed to a wide variety of tumors ma should be described as “slightly pigmented” with a broad spectrum of intensity and variable if the intensity of pigmentation is an estimated distribution of their pigmentation. Hypopig- 30% of a “regular” dark-brown tumor as judged mentation may refer to the entire lesion or just by visual inspection. Colorimetric and quanti- to a segment of the tumor, and may develop or tative measurements of these details appear de- change with time [8]. One should differentiate sirable for classification of melanoma for scien- between tumors lacking melanin just in circum- tific purposes. scribed segments, and other ones which are of Regressive melanoma may best be spotted by homogenous structure and contain little mela- means of grayish or whitish areas, the white ar- nin within the entire lesion. The extreme vari- eas being whiter than the neighboring skin. Re- ant of the latter are completely “amelanotic” ports of the patient that a dark spot or nodule melanoma. A lesion containing a low amount of has become paler may be helpful.

Flow-chart IV.3. For classifying hypopigmented melanoma and diagnosing amelanotic melanoma 206 J. Kreusch

Table IV.3.1. Phenotypes of hypomelanotic and amelanotic melanoma Description of lesion Category of melanoma Melanoma not producing Amelanotic melanoma any trace of melanin (sensu strictu)

Melanoma consisting Hypopigmented melanoma exclusively of a cell line with low production of melanin IV.3

Melanoma consisting Partially pigmented melanoma of a section (mostly a nodule) with no or little melanin content within a pigmented tumor

Hypomelanotic melanoma Partially pigmented melanoma with amelanotic components

Amelanotic / hypomelanotic Partially pigmented melanoma melanoma associated to junctional or compound nevus Amelanotic Melanoma Chapter IV.3 207

Table IV.3.1. (continued) Description of lesion Category of melanoma Partially regressive melanoma Partially pigmented melanoma associated to dermal nevus

Amelanotic cell line/metastasis No images available in regressive melanoma

Collision tumors of amelanotic No images available melanoma and non-pigmented lesions (e.g. BCC, seborrheic keratosis)

In order to complete the listing of hypopig- It is therefore suggested to follow the pathway mented variants of melanoma, collision tumors given in this chapter to distinguish the two ba- of a regressive or amelanotic melanoma (or a sic types of hypomelanotic melanoma before melanoma metastasis) next to or within a poor- analyzing the morphology any further. ly pigmented benign lesion, e.g., a dermal nevus Loss of melanin due to regression can be rec- or a seborrheic keratosis, might be taken for an ognized easily in almost any case, as it is indi- amelanotic melanoma despite the fact that the cated by the presence of melanophages visible as components are of different origin and biologi- tiny grayish granules of approximately 0.01– cal behavior. Such cases of collision tumors are 0.02 mm diameter (“peppering”), or by the pres- somewhat hypothetical and certainly very rare. ence of gray-blue veils. Progress of regression They are not dealt with any further here. results in disappearance of grayish areas and melanophages, leaving behind whitish fibrous tissue resembling a scar. These lesions should be IV.3.5 Dermoscopic Criteria excluded from the suspicion of amelanotic mel- anoma. They show differences in vasculariza- There are few reports in the literature which tion as compared with amelanotic melanoma. describe dermoscopic features of truly amela- Truly amelanotic melanoma do not contain notic melanoma [1, 2, 6, 12, 14, 15]. The diag- any melanin; thus, all features related to details nostic importance of vascular structures is of pigmented lesions must be absent. Size, asym- stressed in each contribution. In several papers metry, irregular border, and ulceration are fea- cases of hypomelanotic melanoma due to re- tures of secondary diagnostic importance as gression are viewed jointly with completely they are not restricted to melanocytic tumors; amelanotic melanoma; however, intermingling however, as vascular structures are easily visible, melanoma with different origin of hypopig- amelanotic melanoma can be diagnosed with a mentation in morphological studies will result dermoscope, provided they are inspected prop- in loss of sensitivity and specificity of features. erly. 208 J. Kreusch

Theoretically, there might exist melanoma amelanotic melanoma. If reddish or pink areas consisting of a regressive section joint with an are observed, the magnification might be too amelanotic component (and even in collision low to distinguish terminal capillaries, or the with further hypopigmented tumors such as vessels might be out of focus; therefore, instru- seborrheic keratoses or basal cell carcinoma). ments permitting focus control are quite helpful They must be identified by stepwise analysis of for better analysis of vascular structures. The the various components and certainly are a only features visible dermoscopically are vessels challenge even for the experienced dermosco- and whitish structures which resemble pseudo- pist. horn cysts (Fig. IV.3.5b); the latter are somewhat misleading, as they might be taken as signs of seborrheic keratoses, basal cell carcinoma, or IV.3.6 Adequate Dermoscopic Inspec- ordinary nevi. They are present in melanoma of tion of Non-pigmented Lesions several millimeters in vertical diameter. In his- tological sections they revealed mucoid degen- Instruments with glass front plate must be set eration and no keratin (unpublished observa- onto the tumoral surface very carefully in order tions); thus, the remaining features of diagnostic to avoid compression of the soft vascular struc- importance are vascular patterns. IV.3 tures and squeezing out the blood, rendering them invisible. Ultrasound gel is recommended as a contact medium due to its low viscosity and IV.3.8 Vascular Patterns non-volatility. This helps to inspect the vessels in Amelanotic Melanoma with as little pressure as possible. Use of instru- ments with polarized light may serve better if The vascular patterns in amelanotic melanoma the light source emits an appropriate spectrum have been described as pinpoint, point-like, dot- of wavelengths for visualizing reddish struc- ted vessels, and as hairpin, loop-like, linear ir- tures such as blood vessels and the magnifica- regular vessels. In principle, all point-like or tion permits viewing small capillaries of 10 µm looped vessels are variants of the basic structure in diameter; however, most dermoscopes using of a vascular loop; however, loop-like terminal polarized light operate with low magnification, capillaries are encountered in melanocytic le- which is inadequate for analysis of vasculariza- sions (Spitz nevi, melanoma) [5] as well as in all tion. If a non-pigmented lesion does not reveal keratinizing lesions (vulgar warts, seborrheic any vessels upon dermoscopic inspection, the keratoses, keratoacanthoma, squamous cell car- first idea should be to control the pressure of the cinoma, etc.). Of course, vessels encountered in instrument. Any non-pigmented lesion (with dermal papillae are not to be considered as tu- the exception of, for example, hyperkeratoses) moral vessels. The appearance of vascular loops must present at least some vascular structures depends on their length and the angle of view- upon appropriate examination. In the literature ing them. Upon viewing in axial direction, ver- one finds many cases with obvious compression tical to the tumoral surface, short loops are vis- artifacts: no vessels are visible within whitish ible as tiny red dots. Longer loops resemble areas, preferably within the most elevated re- hairpins, especially if the direction of view is gions of nodular lesions. somewhat oblique. Increasing tumoral thick- ness requires elongation of the feeding vessels. The longer the vascular loops, the more mor- IV.3.7 Dermoscopic Features phological variations are to be seen. Twisting, of Amelanotic Melanoma splintering, glomerular-like winding of the loops is observed; however, a loop is the basic In truly amelanotic melanoma all features re- structure of these peculiarities. There is a ten- lated to pigmentation are absent. Observations dency to describe too many details within the of grayish veils, traces of network, etc., refer to vascular structures, thus confounding the ob- regressive, hypomelanotic or partially hypo-/ servers. Another descriptor of vessels is the Amelanotic Melanoma Chapter IV.3 209 mode of their arrangement within the tumor, e. g., regular or irregular, arranged at the periph- ery or distributed evenly over the tumoral sur- face, etc. Vascular loops (point-like rather than hairpin-like) in amelanotic melanoma are dis- persed quite regularly across the entire area of the tumor; however, this is the case only in early lesions.

IV.3.9 Morphological Changes of Vessels During Tumor Growth

The fact that dermoscopic analysis of vessels in Fig. IV.3.2. Partially pigmented, hypomelanotic mela- melanoma must consider time-dependent noma (SSM in situ). Bar: 5 mm changes which occur during tumor growth has attracted too little attention: As horizontal di- ameter and vertical thickness of melanoma in- crease with time, vessels in advanced stages will be longer, coarser, and more variable according to the tumoral thickness. Examples for the ­evolution of vascularization of melanoma are given in Figs. IV.3.2–IV.3.5. All thin melanoma (<0.5 mm Breslow thickness) are supplied by point-like vessels in a quite regular arrangement across the entire tumoral area (Figs. IV.3.2, IV.3.3). Tumors of 0.5- to 2-mm thickness re- veal vessels of point-like and hairpin appear- ance, yet the arrangement of vessels is quite regular (Fig. IV.3.4). Beyond 2 mm thickness, Fig. IV.3.3. Amelanotic melanoma (SSM, L III, 0.4 mm) the hairpin loops become increasingly more twisted and splintered, and their arrangement is not as regular as in thin tumors; hence, they were described as irregular vessels (Figs. IV.3.3, IV.3.5a,b). Melanoma of more than approxi- mately 3 mm thickness develop a different structure of vascular supply. As vertical growth apparently cannot be maintained by further elongation of the capillary loops, vessels arising from the adjacent dermal plexus appear on the tumoral surface. These vessels resemble arbo- rizing vessels of basal cell carcinoma; however, their winding and branching is less bizarre and irregular as compared with basal cell carcino- Fig. IV.3.4. Amelanotic melanoma (NM, L IV 1.2 mm) ma. Reports published on amelanotic melanoma frequently note that tumors were ulcerated [7, 10, 13]. This secondary phenomenon may dis- amelanotic melanoma with visible vasculariza- turb the morphology of the vessels and make it tion. This may be ascribed to non-standardized more difficult to characterize them. Studies fre- imaging techniques and low magnification, and quently report a surprisingly low percentage of to mixing truly amelanotic, regressive, and hy- 210 J. Kreusch

cal” and “irregular.” As a rule – and surprising- ly – advanced cases of amelanotic melanoma may be more difficult to identify by dermoscopy than early lesions of low vertical diameter.

IV.3.10 Relevant Clinical Differential Diagnosis Confounding amelanotic melanoma and basal cell carcinoma should not occur if the vascular patterns are viewed correctly – arborizing ves- sels of basal cell carcinoma can easily be distin- guished from point-like or loop-like vessels. The vascularization of dermal nevi consists of coarse and “comma-shaped” vessels in a sur- prisingly irregular arrangement. The vessels in IV.3 pyogenic granuloma appear blurred and are of unspecific morphology. In regressive tumors (regressive melanoma as well as in regressive so- lar keratoses, “lichenoid” keratoses, etc.) the vascular pattern also cannot be ascribed to a certain geometrical structure. Keratinizing tumors represent a large group Fig. IV.3.5. a Amelanotic melanoma (NM, L IV, 2.8 mm). of non-pigmented lesions and their loop-like b Amelanotic melanoma (NM, L IV, 2.8 mm): irregular vessels, some of hairpin shape. Note absence of white vessels may resemble the ones of amelanotic halo and presence of whitish spots. Histopathology: no melanoma. Depending on their vertical diame- pseudo-horn cysts but mucoid degeneration ter, flat lesions display point-like vessels, where- as thicker ones are supplied by hairpin-like lon- ger loops. Characteristically, in all keratinizing pomelanotic melanoma. Nevertheless, the im- tumors the vessels are embedded into a whitish portance of vascular structures is underlined. halo. The halo represents the vital keratinocytes Pizzichetta et al. [14] consider vascular patterns supplied by the feeding capillary. The whitish the only relevant ones for diagnostic purposes. zone in most cases merges into a yellowish sub- The presence of point-like, hairpin-like, linear, stance, which is keratin. This observation is and linear-irregular vessels is reported. Diame- most helpful for excluding non-pigmented le- ter, asymmetry, and ulceration are considered sions from suspicion of melanoma. An instru- less valuable for diagnosis. ment more powerful than just tenfold magnifi- Few studies separate thin (<1 mm) and thick cation is particularly helpful for viewing faint (>1 mm) melanoma [2, 14]. One of the few pa- white halos. pers which deals with amelanotic melanoma of low thickness is that by Bono et al. [2], with the prevailing vascular pattern in accordance with IV.3.10.1 The Way to Diagnosis own observations being dotted vessels. This of Amelanotic Melanoma pattern appears to be the most valuable for iden- tification of early amelanotic melanoma. Other A pathway to diagnosis of amelanotic melano- studies present cases of considerable thickness, ma based exclusively on analysis of vascular mostly more than 1 mm [15]. As explained structures was published in 1996 [9, 11]. It is ap- above, vessels in these lesions tend to be split, plicable to truly amelanotic melanoma provided splintered, and twisted, thus appearing “atypi- the lesions are not ulcerated. Regressive mela- Amelanotic Melanoma Chapter IV.3 211 noma and compression artifacts should be ex- IV.3.10.2 Strategies for Detecting cluded by means of the procedure summarized Amelanotic Melanoma in the flow chart below. Analysis of vascularized lesions can be sum- Spotting amelanotic melanoma is one of the marized in a series of 5 + 2 questions leading challenges for a dermatologist and possibly a directly to diagnosis. This pathway is best ap- life-saving diagnostic procedure if performed plicable to flat lesions. In cases of thick, pink, early enough. It is not possible to identify these and nodular tumors one must always consider tumors positively by clinical criteria; however, the morphological changes in vascular patterns, in the present author’s opinion, dermoscopy is rule out frequently occurring non-pigmented effective in diagnosing suspicious lesions in al- lesions as mentioned above, and treat the re- most all cases of amelanotic melanoma, espe- maining ones with special attention. cially early ones. But dermoscopy is not the first In the list below the presence of a certain type step in diagnosing amelanotic melanoma. The of vessel is asked for – if the answer is “no,” one major obstacle in our own strategy in selecting may proceed to the next question: lesions for dermoscopic examination is that we have been trained to consider large and dark tu- 1. Presence of arborizing vessels (basal cell mors as suspicious, and the idea of using a der- carcinoma)? moscope arises when we come over such lesions. 2. Presence of crown vessels (sebaceous Small and non-pigmented objects escape our at- hyperplasia)? tention and are not considered worthy of fur- 3. Presence of “comma” vessels (dermal ther examination. This approach represents a nevus)? filter mechanism toward large and dark lesions. 4. Presence of unspecific vessels (Kaposi Small and hypopigmented lesions (“atypical sarcoma, regressive lesions)? melanoma”) are neglected. “Atypical melano- 5. Presence of point-like or hairpin vessels? ma” frequently are not examined by dermosco- 5.1 Absence of white halos? py and neither photographed nor excised, thus 5.2 Presence of traces of melanin? escaping early diagnosis and our visual memo- ry. Most studies are based on cases of melanoma If question no. 5 is answered, in the affirmative with high thickness, mostly reddish or pink (i.e., presence of point-like or loop-like vessels), nodules, frequently ulcerated [10, 13], which are additional questions must ask for the absence of eye-catching. The lack of images of early non- white halos and presence of traces of melanin. If pigmented melanoma leads us back to diagnos- the answer is “yes,” suspicion of melanoma is tic recommendations and procedures, and red- raised. If traces of brownish melanin, which dish macules too frequently are not inspected may not be visible clinically, are present focally dermoscopically. In the working routine of the within the lesion, they support the diagnosis of present author, elimination of the amelanotic melanoma or Spitz nevus, the only other diag- melanoma filter mechanism, i.e., not restricting nosis, which has to be considered. It is very dif- dermoscopy to large and dark tumors (“pig- ficult, often impossible, to discriminate reliably mented lesions of the skin”), has changed the amelanotic melanoma and Spitz nevus by der- spectrum of melanoma phenotypes. This ap- moscopy. As histopathological judgment faces proach, best described as “non-selective der- the same problem, consequently all lesions with moscopy,” has raised the proportion of poorly point-like or loop-like vessels without white pigmented melanoma to a constant of 20% of all halo must be considered suspicious and re- cases per annum during the past 7 years, among moved. them 6% truly amelanotic melanoma (unpub- lished observations). 212 J. Kreusch

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(1996) Frequency and morphologic characteristics of invasive melanoma lacking specific surface mi- croscopic features. Arch Dermatol 132:1178–1182 Acknowledgement: The author gratefully 13. Neuber H, Lippold A, Hundeiker M (1991) Nichtdi- acknowledges Evelyn Kreusch-Shah for care- agnostizierbare maligne Melanome. (Non-diagnos- fully reading the manuscript and for valuable able malignant melanoma) Hautarzt 42:220–222 advice. Reprint permission for all images was 14. Pizzichetta MA, Talamini R, Stanganelli I, Puddu P kindly granted by Sur Prise, POB 111107, et al. (2004) Amelanotic/hypomelanotic melanoma: D-23521 Luebeck, Germany. clinical and dermoscopic features. Br J Dermatol 150:1117–1124 15. Zalaudek I, Argenziano G, Kerl H, Soyer HP, Hof- mann-Wellenhof R (2003) Amelanotic/hypomela- notic melanoma: Is dermatoscopy useful for diag- nosis? J Dt Dermatol Ges 5: 369–373