IV.5.1 Definition
False negative is defined as a negative test result when the attribute for which the subject is being tested actually exists. Clinically, dermoscopi- cally, and/or histopathologically the diagnosis of melanoma is not made, yet, the patient has a melanoma.
IV.5.2 Clinical Features
It has been reported that amelanotic melanoma is the great masquerader; however, any melano- ma has the potential to fool the most experi- enced clinician. It is not possible to make the diagnosis 100% of the time no matter what clin- ical aids one uses.
Experienced clinicians can diagnose mela- noma clinically 60–75% of the time. In a meta- analysis it was shown that the diagnostic accu- racy can be improved by as much as 49% with dermoscopy. The sensitivity of clinical evalua- tion plus dermoscopy can be as high as 97%.
As many as 15% of melanomas can be false negative, mimicking melanocytic and non-me- lanocytic lesions or non-melanoma skin can- cers. At times, the only way to suspect the diag- nosis is by finding clinical and/or dermoscopic changes over time.
In general, false-negative melanoma incog- nito could be a solitary macule, papule, nodule, or plaque that can have a smooth or scaly sur- face with or without ulceration. Polymorphous lesions can be seen with cutaneous metastatic melanoma.
A single relatively innocuous color or multi- ple colors can be present with various shades of black, brown, gray, or blue. The ABCD clinical
False-Negative Melanomas
Robert Johr and Giuseppe Argenziano IV.5
Contents
IV.5.1 Definition . . . .221 IV.5.2 Clinical Features . . . .221 IV.5.3 Dermoscopic Criteria . . . .222 IV.5.4 Melanoma Simulating
Seborrheic Keratosis . . . .223 IV.5.5 Melanoma Simulating Basal Cell
Carcinoma . . . .224 IV.5.6 Melanoma Simulating
Vascular Lesions . . . .224 IV.5.7 Melanoma Simulating
Dysplastic Nevi . . . .224 IV.5.8 Melanoma Simulating Spitz Nevi . . . .224 IV.5.9 Melanoma Simulating Blue Nevi . . . .225 IV.5.10 Melanoma Simulating
a Combined Nevus. . . .225 IV.5.11 Melanoma Simulating
a Recurrent Nevus . . . .225 IV.5.12 Melanoma Simulating Ink Spot Lentigo . .225 IV.5.13 Melanoma Simulating Actinic Lentigo
and Pigmented Actinic Keratosis . . . .225 IV.5.14 Feature Poor and Featureless
Melanomas . . . .225 IV.5.15 Relevant Clinical Differential
Diagnosis . . . .225
IV.5.16 Management . . . .225
References . . . .227
222 R. Johr, G. Argenziano
IV.5
criteria might not be helpful for small-diameter lesions less than 6 mm, desmoplastic, nodular lesions, or patients with multiple dysplastic nevi.
Hypomelanotic and amelanotic melanoma can be clear, skin colored, or pinkish red. At times, surface vasculature can be seen with the naked eye or with typical magnification clinicians use. More specifically, melanoma incognito could have the clinical characteristics of a seborrheic keratosis, basal cell carcinoma, hemangioma, pyogenic granuloma, ink spot, or actinic lenti- go. They can also be mistaken clinically for der- mal, combined, blue, Spitz, recurrent, Unna, Meishner, or dysplastic nevi.
IV.5.3 Dermoscopic Criteria
At times, it is not possible to determine if a le- sion is melanocytic, non-melanocytic, benign, or malignant. A non-specific dermoscopic pat- tern should always include melanoma in the dif- ferential diagnosis. It is important to not only use dermoscopy for clinically suspicious lesions.
Melanoma incognito might not look high risk clinically yet have well-developed melanoma- specific criteria or subtle clues, such as pinpoint telangiectatic blood vessels, that lead to the cor- rect histopathological diagnosis.
The most difficult case scenario is a melano- ma that has the dermoscopic criteria of non-me-
Fig. IV5.1. a A pink plaque resembling a dermal nevus located on the back of a 66-year-old man. b On dermos- copy, instead of the “comma-shaped” vessels expected in a dermal nevus, there are atypical vessels, which in- creased our index of suspicion to perform a biopsy. Histo- pathologically, the lesion was diagnosed as a 1-mm-thick amelanotic melanoma
Fig. IV5.2. a A flat pigmented lesion resembling a com- mon nevus located on the abdomen of a 56-year-old man.
b On dermoscopy, there is an atypical pattern composed
of a reticular depigmentation and grayish pepper-like pig-
mentation; thus, the lesion was excised and subsequent
histopathological examination revealed a 0.45-mm-thick
melanoma
lanocytic lesions such as seborrheic keratosis, basal cell carcinoma, or hemangioma. The false- negative criteria can dominate the entire lesion.
Foci of melanoma-specific criteria may or may not be present in these lesions. A final group can stimulate the spectrum of benign melanocytic nevi from dermal nevi to Spitzoid lesions (Figs. IV.5.1–IV.5.4).
IV.5.4 Melanoma Simulating Seborrheic Keratosis
Most melanomas that simulate seborrheic kera- tosis clinically can be diagnosed with dermos- copy. If criteria used to diagnose both patholo- gies are present, the clinical decision making will be problematic.
In-situ amelanotic pink macular melanoma can be featureless and side by side with what ap- pears to be seborrheic keratosis. A high index of suspicion will lead to the excision and histo- pathological diagnosis of collision lesions.
The most difficult case scenario is a melano- ma in which the predominant criteria are milia-
Fig. IV.5.3. a A small banal pigmented macule located on the lower arm of a 60-year-old woman. b On dermos- copy, the lesion is strikingly asymmetric, with evident regression structures and atypical vessels. The lesion was thus excised and subsequent histopathological examina- tion revealed a melanoma in situ with regression
Fig. IV5.4. a A pigmented lesion clinically diagnosed as
nevus on the back of a 29-year-old woman. b On dermos-
copy, the lesion is asymmetric with features of regression
and irregular dots/globules. The lesion was thus excised
and subsequent histopathological examination revealed
an in situ melanoma arising within a pre-existing mela-
nocytic nevus
224 R. Johr, G. Argenziano
IV.5
like cysts and comedo-like openings. It is not always possible to differentiate pigmented com- edo-like openings of a seborrheic keratosis from the dots and globules of a melanocytic lesion.
These lesions tend to be uniformly black or grayish. One should always search for foci of melanoma-specific criteria such as irregular dots and globules or streaks. A history of change or the patient’s concern for the lesion might be the only reason for an excision. Comedo-like openings and milia-like cysts are not exclusively seen in seborrheic keratosis. They can also be found in banal nevi and in melanomas.
IV.5.5 Melanoma Simulating Basal Cell Carcinoma
Rarely, melanoma can be characterized by the typical in-focus arborizing blood vessels char- acteristic of basal cell carcinoma. Areas of re- gression and pigmentation that vary in size, shape, and color may or may not be present. The histopathological surprise could be in-situ or deeply invasive melanoma masquerading as a basal cell carcinoma.
IV.5.6 Melanoma Simulating Vascular Lesions
Are the vascular spaces that you see in other- wise typical hemangioma sharply in focus and well demarcated or poorly defined? If they are poorly defined, it could be a melanoma mas- querading as a banal hemangioma. Whitish color that is diffuse or localized might represent hyperkeratosis seen in hemangiomas or areas of regression of a hemangioma-like melanoma.
The dermoscopic appearance of amelanotic melanoma simulating a pyogenic granuloma is non-specific. They are pinkish or red nodules that are featureless or feature poor with poly- morphous vascular pattern with pin-point, ir- regular linear, and other shaped small telangi- ectatic vessels with or without ulceration.
IV.5.7 Melanoma Simulating Dysplastic Nevi
Patients with multiple dysplastic nevi and a his- tory of melanoma are the number one group in which a dysplastic nevus-like melanoma could be found or missed. They can have a polymor- phous dermoscopic appearance usually without well-defined melanoma-specific criteria. One might only find asymmetry of different shades of color with or without barely perceptible foci of regular pigment network or small dots. Vari- ous presentations of hyper- and hypopigmenta- tion without true regression can also be present, indistinguishable from the typical benign dys- plastic nevus. If pink color is seen, a red flag of concern should be raised that the lesion could be a dysplastic nevus-like melanoma.
IV.5.8 Melanoma Simulating Spitz Nevi
Not all melanomas with a Spitzoid dermoscopic pattern turn out to be Spitzoid melanomas his- topathologically, and not all Spitzoid melano- mas histopathologically have a Spitzoid dermo- scopic pattern. A symmetrical starburst pattern with streaks and/or dots and globules at most points along the periphery is the hallmark of a benign Spitz nevus. A small percentage of mela- nomas can have a symmetrical starburst pat- tern.
Melanoma incognito can also have a globular pattern reminiscent of the globular pattern that can be seen with banal and Spitz nevi. In this case, the dots and globules are irregular in size, shape, and color. Other melanoma-specific cri- teria, such as blue-white color or foci of irregu- lar pigment network, might also be present.
Spitzoid melanomas histopathologically can
have a non-specific dermoscopic pattern that
can be feature poor with subtle foci of dots,
globules, streaks, and pink color.
IV.5.9 Melanoma Simulating Blue Nevi Different shades of homogeneous blue and brown color, plus foci of irregular dots and glob- ules, could be seen in this category. The dermo- scopic differential diagnosis of a blue nevus in- cludes nodular melanoma and cutaneous metastatic melanoma.
IV.5.10 Melanoma Simulating a Combined Nevus
A black or bluish-gray blotch of pigmentation associated with what appears to be banal mela- nocytic nevus has a dermoscopic differential diagnosis that includes melanocytic atypia or melanoma and could be confused with a com- bined nevus.
IV.5.11 Melanoma Simulating a Recurrent Nevus
Blotches of pigmentation in a surgical scar could represent melanoma masquerading as a recur- rent nevus. There is nothing diagnostic about this dermoscopic picture and it is essential to be aware of the histopathological diagnosis of the lesions that was originally excised.
IV.5.12 Melanoma Simulating Ink Spot Lentigo
General asymmetry of color and structure plus a prominent dark thickened pigment network with foci of other melanoma specific criteria, such as blue-white color or irregular dots and globules, can be seen.
IV.5.13 Melanoma Simulating
Actinic Lentigo and Pigmented Actinic Keratosis
Annular–granular structures consisting of black, brown, or gray fine dots surrounding ap- pendigeal openings has a dermoscopic differen- tial diagnosis that includes melanoma. Melano-
ma could be associated with an actinic lentigo or pigmented actinic keratosis. Multiple skin bi- opsies might be necessary to make the diagno- sis. A feature-poor lesion with moth-eaten bor- ders and asymmetry of various shades of brown color could be a melanoma masquerading as an actinic lentigo.
IV.5.14 Feature Poor and Featureless Melanomas
There can be a complete absence of local criteria with different shades of color in featureless mel- anomas. Feature-poor melanomas do not have well-developed melanoma-specific criteria such as irregular network, dots, globules, or streaks.
A polymorphous vascular pattern with pin- point, linear irregular, and other shaped telan- giectatic vessels should raise a red flag of con- cern, especially if the lesion is pink or red clinically.
IV.5.15 Relevant Clinical Differential Diagnosis
For false-negative melanoma incognito the clin- ical differential diagnosis is extensive. Any soli- tary pink or red macule, papule, nodule, or plaque with or without scale or skin markings could be melanocytic, non-melanocytic, benign malignant, or inflammatory. Lesions with pig- mentation encompass the same clinical differ- ential diagnosis. The patient’s personal and family history, plus the history of the lesion as well as the clinical and dermoscopic appear- ance, should all be taken into consideration when formulating a clinical diagnosis.
IV.5.16 Management
Melanoma can be found from head to toe, and
comprehensive skin examinations of patients
are sometimes essential. A thorough history is
also recommended to find out if a lesion is new,
changing, or bothersome to the patient, and
should never be ignored no matter how banal
the lesion might appear. It is not uncommon for
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a patient with melanoma to seek several derma- tologists’ opinions or insist on an excision of a lesion against their physician’s advice. Dermos- copy is a readily available tool that should be used on both clinically suspicious and banal-ap- pearing skin lesions. There should always be a good clinico-dermoscopic correlation and non- specific dermoscopic patterns could be seen in false-negative melanomas. Total-body photog- raphy and/or digital dermoscopy should be used for patients at risk of multiple atypically pig- mented skin lesions that are not sufficiently atypical to warrant excision yet cannot be for- gotten. Short-term digital dermoscopic moni- toring at 3- to 4-month intervals or intervals up to 1 year represents currently the highest level of patient care. Side-by-side comparisons of baseline dermoscopic images that have been mapped out can be performed with the same le- sion at follow-up. Even the most insignificant change over time should be taken into consider- ation and not ignored. Most lesions that change are not melanomas, yet they could be. Melano- mas found with digital follow-up tend to be in situ or less invasive than melanomas found at a typical office visit. Digital follow-up for a nod- ular lesion that raises some sort of suspicion is not recommended. Even with short-term moni- toring, waiting a few months with nodular mel- anoma incognito could worsen the patient’s chances for survival. Any Spitzoid pattern, es- pecially if it is found in an adult, should be ex- cised. If there is any mention of atypicality in the pathology report, more histopathological opinions should be sought and the lesion should be considered melanoma until proven other- wise. Attention should be focused on all aspects of the patient, because melanoma can masquer- ade as almost anything, and attentive examina- tion will increase the chances of diagnosing false-negative melanomas.
Clinically banal-looking pigmented skin lesion. On dermoscopy there is asymmetry of color and structure, a focus of atypical network on the left side and a small area of blue-white color at the upper pole of the lesion.
Despite the banal clinical appearance, the constellation of
dermoscopic criteria is strongly suggestive of melanoma
C
