False Negative Diagnosis
- 1 Basal cell carcinoma (BCC)
- 2 Squamous cell carcinoma (SCC)
- 3 Melanoma
- 3.1 In situ melanoma. Main false negative diagnosis: Clark nevus
- 3.2 Nevoid melanoma. Main false negative diagnosis: Dermal nevus
- 3.3 Spitzoid melanoma. Main false negative diagnosis: Spitz/Reed nevus
- 3.4 Verrucous melanoma. Main false negative diagnosis: Seborrheic keratosis
- 3.5 Reggressive melanoma. Main false negative diagnosis: Lichen planus-like keratosis (LPLK)
- 3.6 Amelanotic melanoma. Main false negative diagnosis: Pyogenic granuloma, inflammatory nodules et al.
False negative diagnosis in dermoscopy is an error occurring when a malignant tumor displays characteristics suggestive of a benign tumor. Obviously, as compared to false positive diagnosis, this type of error is significantly more important, since overlooking a cancer might result in undesirable consequences both for the patient and the doctor. It has to be mentioned that the term “dermoscopically false negative” cancer should not be considered equivalent to the term “dermoscopically featureless” cancer. A “featureless” malignant tumor does not display any of the expected dermoscopic criteria, whereas a “false negative” one, not only lacks expected criteria, but also shows criteria suggestive of a benign tumor. Therefore, false negative cancers are much more likely to escape detection. All the main malignant skin tumors might occasionally be dermoscopically false negative.
Basal cell carcinoma (BCC)
Of the 3 main skin cancers, BCC is less frequently mimicking a benign tumor. This is because the dermoscopic characteristics of BCC are quite peculiar and are rarely confused with structures suggestive of benign tumors. Therefore, most BCCs are dermoscopically evident from a very early stage. Exceptions, however, do exist:
Non-pigmented BCC. Main false negative diagnosis: Dermal nevus
The dermoscopic hallmark of BCC is its vascular pattern, which consists of the so-called “arborizing” vessels. These are ideally stem vessels of large caliber, projecting sharply in focus, branching in thinner vessels and finally terminal capillaries and typically cross the centre of the tumor. However, deviations of this “ideal” pattern are frequent. Occasionally, the branches might be not very evident and the vessels might project as multiple short linear curved structures, somehow mimicking the so-called “comma vessels” of dermal nevi. Often, this is just an optical illusion caused by pressure applied during dermoscopic examination. Thus, dermoscopic examination of nodular lesions should be either non-contact (polarized) or at least with the use of an immersion fluid or gel to minimize the applied pressure.
Pigmented BCC. Main false negative diagnosis: Blue nevus
As compared to non-pigmented BCC, pigmented variants are even easier to recognize, based on the unique morphology of BCC-specific pigmented structures (leaf-like structures, spoke-wheel, areas, concentric structures, blue dots/globules/nests). However, when the pigmented basaloid nests are very large and heavily pigmented, they might result in diffuse blue pigmentation, which could mimic the pattern of blue nevi. To address this problem, it has been suggested that the diagnosis of a blue nevus should always be confirmed by the history of a long-standing stable lesion.
Squamous cell carcinoma (SCC)
The dermoscopic pattern of SCC depends on the grade of histopathologic differentiation. Well-differentiated SCC is dermoscopically typified by white color, and the main structures are white perifollicular circles (highly specific), white perivascular halos, white structureless areas and hyperkeratosis/keratin. In contrast, poorly differentiated SCC is displays an unspecific dermoscopic pattern consisting of a red predominant colour, numerous polymorphic vessels and/or bleeding. Rarely, SCC might mimic a benign tumor.
Well-differentiated SCC. Main false negative diagnosis: Seborrheic keratosis, common wart
Well-differentiated SCC is a highly keratinizing tumor. When keratinisation is very extensive, not allowing the visualisation of underlying features, SCC might be quite similar to benign keratinizing tumors, mainly seborrheic keratosis and common wart. A simple clue to minimize this problem is the removal of the superficial keratin (ex with an alcoholic solution). Another confounding dermoscopic feature is the so-called “white perivascular halo”, since this structure can be seen in virtually all keratinizing tumors. Therefore, an SCC showing numerous whitish halos might be misinterpreted as an irritated seborrheic keratosis or a common wart (false negative). Some clues to discriminate between SCC and irritated SK do exist: irritated SK is usually characterized by a symmetric distribution of structures (vessels surrounded by halos), in contrast to the more uneven arrangement of features in SCC. Furthermore, SCC rarely displays multiple white halos surrounding vessels as the only dermoscopic feature. If present, usually white halos in SCC are combined with white circles surrounding hair follicles or structureless whitish areas.
Poorly differentiated SCC. Main false negative diagnosis: None
The dermoscopic pattern of poorly differentiated SCC is highly unspecific, since the same features can also be seen in several other malignant tumors like Merkel cell carcinoma, atypical fibroxanthoma, melanotic melanoma, adnexal carcinomas etc. However, poorly differentiated SCC is almost never false negative, since no benign tumor is known to display a similar dermoscopic pattern.
In the field of melanoma, the terms “featureless” and “false negative” are quite overlapping. This is because melanoma and nevi share several similar dermoscopic criteria, and the main difference is their asymmetric or symmetric distribution, respectively (ex. regular network vs irregular network, regular globules vs irregular globules etc). Therefore, a melanoma lacking melanoma-specific dermoscopic criteria might very possibly be interpreted as a nevus.
In situ melanoma. Main false negative diagnosis: Clark nevus
The morphologic overlap between early melanomas and “atypical” nevi is also discussed in the chapter “false positive diagnosis”. It should be underlined that the majority of the known melanoma-specific dermoscopic criteria are usually absent in melanoma in situ. Therefore, it might be possible that a melanoma in situ might be dermoscopically assessed as a nevus. To minimize this risk, management rules based on the overall patient’s context have been suggested. Furthermore, 3 new predictors of melanoma in situ have been recently introduced: dark, irregularly-shaped small structures (DISSS), prominent skin markings and angulated lines (polygons), the latter 2 mainly seen on sun-damaged skin.
Nevoid melanoma. Main false negative diagnosis: Dermal nevus
Nevoid melanoma represents a rare melanoma subtype that clinically and histopathologically mimics a nevus. Dermoscopy might improve the recognition of nevoid melanomas, since some of them display a multicomponent pattern, which is considered suggestive of melanoma. A proportion of nevoid melanomas, however, mimic dermoscopically a dermal nevus, displaying a relatively symmetric globular pattern. A possible clue might be the presence of polymorphic vessels instead of the “comma” vessels that would be expected in a dermal nevus.
Spitzoid melanoma. Main false negative diagnosis: Spitz/Reed nevus
The potential of spitzoid melanoma to perfectly mimic a Spitz or Reed nevus has been extensively reported in the literature. Due to this significant morphologic overlap, specific strategies and guidelines on the management of spitzoid-looking tumors have been released by the International Dermoscopy Society.
Verrucous melanoma. Main false negative diagnosis: Seborrheic keratosis
Occasionally, melanoma might have a verroucous surface, because of hyperkeratosis and epidermal hyperplasia, acquiring an overall aspect similar to a seborrheic keratosis. A recent study highlighted that the majority of seborrheic keratosis-like melanomas can be uncovered by dermoscopy, since they display one or more of the following melanoma specific criteria: blue-white veil, pseudopods, streaks, atypical network and the blue-black sign. However, approximately 20% of melanomas displayed dermoscopic features suggestive of seborrheic keratosis (false negative). The multivariate analysis revealed than only the blue-black sign remained a potent melanoma-predictor.
Reggressive melanoma. Main false negative diagnosis: Lichen planus-like keratosis (LPLK)
Regression structures (white scar-like depigmentation and blue/gray granules/peppering) are included among the classic melanoma-specific criteria. However, in fact they represent criteria suggestive of the regression process, since very similar features are seen in regressive nevi and regressive seborrheic keratoses/solar lentiggines (LPLK). The feasibility to accurately classify a regressive lesion depends on the stage (extension) or regression. When the regression is partial and parts of the initial tumor are still present, then the diagnosis might be possible. If, in contrast, the regression is so extensive that no remnants of the primary tumor are evident, a safe diagnosis is impossible. The only safe strategy to address this problem is to perform a biopsy/exciosion of any fully regressive lesion.
Amelanotic melanoma. Main false negative diagnosis: Pyogenic granuloma, inflammatory nodules et al.
Amelanotic melanoma represents the most important trap for clinicians. In fact melanotic melanoma is usually featureless, but very rarely acquires a pattern highly suggestive of a benign tumor. Strategies on how to approach non-pigmented tumors can be found in other chapters. The main false negative diagnosis of melanotic melanoma is pyogenic granuloma, which led experts to suggest that the diagnosis pyogenic granulomas should be histopathologically confirmed in all (if possible) cases.
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