This Medicare contractor will provide limited coverage for the Pigmented
Lesion Assay / PLA (DermTech, Inc., La Jolla, CA), RNA gene expression test
conducted on skin samples obtained noninvasively via adhesive patches.

This test is intended to help rule out primary cutaneous melanoma and guide
biopsy decisions of melanocytic skin lesions with one or more clinical or
historical characteristics suggestive of melanoma. The evaluation with the PLA
is limited to order by a physician or other qualified health care professional
with expertise in melanoma.

**Specific Coverage Criteria**

The PLA is indicated for use on melanocytic skin lesions with 1 or more
clinical or historical characteristics suggestive of melanoma, including 1 or
more ABCDE criteria when a clinician trained in the clinical diagnosis of skin
cancer is considering the need for biopsy to rule out melanoma. The PLA should
not be used on clinically obvious melanoma. The PLA result is 1 element of the
overall clinical assessment, and should be used in combination with clinical
and historical signs of melanoma to obtain additional information prior to a
decision to biopsy.

(PLA positive lesions [LINC (LINC00518) and/or PRAME (preferentially expressed
antigen of melanoma) detected] should be considered for biopsy. The biopsy
decision of a PLA negative lesion should be based on the remainder of the
entire clinical context.)

The PLA is indicated only for use on:

  * Primary melanocytic skin lesions between 5mm and 19mm
  * Lesions where the skin is intact (i.e., non-ulcerated or non-bleeding lesions)
  * Lesions that do not contain a scar or were previously biopsied
  * Lesions not located in areas of psoriasis, eczema or similar skin conditions
  * Lesions not clinically diagnosed as melanoma
  * Lesions in areas other than palms of hands, soles of feet, nails, mucous membranes and hair covered areas that cannot be trimmed

The PLA is not intended to be used as a screening test in patients without
melanocytic skin lesions. It is also not covered as an adjunctive test in
lesions that are considered to already warrant a biopsy. The PLA is a decision
tool for atypical melanocytic lesions prior to the decision to biopsy.

The evaluation with the PLA is limited to order by a physician or other
qualified healthcare professional.

**Background**

Invasive and _in situ_ cutaneous melanoma is a type of skin cancer that is
diagnosed in over 178,000 patients annually in the United States. Over 9,300
people die from cutaneous melanoma in the US per year.1 Detecting melanomas at
their earliest stages (melanoma _in situ_ (MIS) / Stage 1) impacts disease
outcome and patient survival. The 5-year relative survival rate from diagnosis
for localized, early melanoma is over 98%, but less than 20% for melanoma that
has spread to distant sites.2 The generally well accepted approach to
assessing pigmented lesions includes visual inspection followed by surgical
biopsy and histopathologic analysis of the biopsied tissue.3-12 One large
study assessing dermatologists' biopsy decisions using existing decision
making tools is approximately 25.3 In another study, roughly 24 biopsies were
needed to diagnose 1 invasive melanoma, and roughly 12 biopsies were needed to
detect either invasive melanomas or MIS.13 In summary, this approach results
in many biopsies that do not lead to a melanoma diagnosis. Guidelines from the
American Academy of Dermatology recommend that a prebiopsy photograph be taken
to help with clinical / pathologic correlation.14

Additionally, the diagnostic yield of early stage melanoma on biopsied tissue
is limited. Histopathologic assessment of early stage biopsied melanoma tissue
is challenging and has significant discordance between pathologists.15-17 It
also appears that underinterpretation is more common than over-interpretation
of a patient who has had a biopsy,16,17 which is tantamount to missed
diagnoses. Additionally, while fellowship-trained or board certified
dermatopathologists tend to have a higher accuracy than other pathologists,
even among this group, under-interpretation is highly prevalent.16

In summary, conventional melanoma care may lead to both biopsies of non-
malignant lesions, and even in those patients who do have a biopsy the
diagnosis of a malignancy may be missed. As such, there is potential clinical
utility for a test that can either spare a patient the need for a biopsy.

The Pigmented Lesion Assay (PLA) was developed to address fill the niche of
reducing the biopsy rate of non-malignant lesions.

**  
PLA Test Description**

  
It is a gene expression test using samples collected via adhesive patches
providing a non-invasive alternative to the surgical biopsy pathway in the
assessment of pigmented skin lesions.17-24 The test is positive if LINC00518
and/or PRAME (2 genes known to be overexpressed in melanoma) are
detected.29-30 The PLA is based on a platform technology for non-invasive
genomic testing of the skin that allows the analysis of samples collected with
an adhesive patch.24 Four patches are placed on a lesion. For each patch, the
margin of the lesion is outlined by the clinician. This outlined tissue is
dissected away from the surrounding tissue by the processing laboratory, and
RNA is extracted only from the lesional tissue. In contrast to histopathologic
sectioning, the adhesive patch method of tissue sampling allows the collection
of tissue from the entire the lesion in the plane of the skin surface.
Further, genomic information obtained by adhesive patch sampling of the
stratum corneum contains information from deeper epidermal cells.

**Bioplausibility**

  
The PLA has been validated against hotspot driver mutations in melanoma (
_e.g.,_ BRAF other than V600E, NRAS, and the TERT promoter) that are
associated with disease progression and histopathologic findings, such as
mitotic counts and ulceration.25-32



**Analytical and Clinical Validation**

  
The analytical and clinical performance of the PLA is supported by multiple
investigational studies as discussed below.

  
As noted above, trained pathologists may disagree over their assessments of
pigmented skin lesions, and comparisons of pathologists opinions to each other
or to a consensus group have been used as reference standard in studies. The
clinical validity for the PLA has been assessed both using pathologist opinion
and longitudinal patient outcomes.

  
Following early work identifying that the expression of LINC and PRAME can
accurately classify pigmented lesions using a simple 2-gene detection
methodology, a classifier method based on these 2 genes was used in an
independent test set.20

  
The performance metrics of the PLA were validated by Gerami et al. against
consensus panel histopathologic assessment clearly demonstrating the test's
clinical validity in the assessment of early stage pigmented lesions.19 In
this study samples were collected _prospectively_ from multiple dermatology
practices and centers, in patients 18 years of age or older, and from
pigmented lesions that were suspicious for melanoma, meeting one or more ABCDE
criteria. Clinically obvious or frank melanomas were excluded. Lesions were
simultaneously sampled using the adhesive patch and surgically biopsied.
Biopsy specimens underwent pathologic diagnosis from 3 independent
dermatopathologists, and lesions that received a concordant diagnosis from all
3 dermatopathologists were enrolled in the study. Overall, 11% of lesions
sampled had a discordant pathological read and were excluded, creating a
reference set upon which there was diagnostic agreement among pathologists. A
blinded evaluation of these concordant biopsy samples was performed against
the PLA result. An initial training set of 157 lesions was tested and
demonstrated a 91% sensitivity, 53% specificity. An independent validation set
was subsequently studied that included 398 pigmented lesion samples (87
melanomas, 253 atypical pigmented lesions, 53 non-melanocytic lesions). All
melanomas enrolled in the study were classified as very early stage and were
either MIS or Stage 1 with a median Breslow thickness <0.5 mm. The PLA
demonstrated a sensitivity of 91% and a specificity of 69%.

  
A separate study assessing the clinical performance of the PLA in patients who
received longitudinal follow-up was also done. This study included available
outcomes and clinical management decisions for PLA- and PLA+ cases at 4 US
dermatology practices using the PLA commercially.17 Cases were reviewed with a
minimum of 6 months to 9 months follow-up, with 273 samples of this ongoing
effort having 12 months follow up. Serial dermatoscopy studies indicate that
melanomas have detectable visual changes within 3 months and recommended
surveillance guidelines are 3-6 months.33 For the 381 lesions evaluated in
this study, the sensitivity was 95% and the specificity was 91%. While the
sensitivity in this study is similar to that found in the histopathologic
validation19, the specificity is higher.

Table 1 below summarizes the publications regarding analytical and clinical
validation.

**Summary of Performance and Utility (Table 1)**



  |

**Published Studies and Manuscripts Demonstrating PLA Validation and Utility**  
  
---|---  
  
**1.** **Analytical Validity** **23**

|

Yao Z, et al. (2016). "Analytical Characteristics of a Noninvasive Gene
Expression Assay for Pigmented Skin Lesions." **_Assay and Drug Development
Technologies_** 14.6 (2016): 355-363.

  
  
**2.** **Clinical Validity** **24**

|

Yao Z, et al. "An Adhesive Patch-Based Skin Biopsy Device for Molecular
Diagnostics and Skin Microbiome Studies." **_Journal of Drugs in
Dermatology_** 16.10 (2017): 611-618.  
  
**3.** **Clinical Validity** **19**

|

Gerami P, et al. "Development and validation of a noninvasive 2-gene molecular
assay for cutaneous melanoma." **_J Am Acad Dermatol_** 76.1 (2017): 114-120
_._

* _398 validation samples, 157 training samples._

* _PLA performance accuracy: 91% sensitive and 69% specific, NPV 99%._  
  
**4.** **Clinical Validity and Utility** **17**

|

Ferris L, et al. (2017). Real-World Performance and Utility of a Non-Invasive
Gene Expression Assay to Evaluate Melanoma Risk in Pigmented Lesions.
**_Melanoma Research_** 2018.

* _Analysis of 381 patients, yielding 51 PLA+ and 330 PLA- tests._

* _PLA sensitivity 95%, specificity 91%._

* _The test guides clinical management of lesions:_

 _99% of PLA- tests underwent surveillance pathway_

 _100% of PLA+ tests received biopsy_

* _Zero missed melanomas in the follow up period_

* _Number of biopsies needed per melanoma found 2.7_

* _Number of excisions needed per melanoma found 1.6_

* _Visual assessment/histopathology pathway sensitivity 84%_  
  
**5.** **Clinical Validity** **18**

|

Ferris et al. (2017) Utility of a noninvasive 2-gene molecular assay for
cutaneous melanoma and effect on the decision to biopsy **. _JAMA
Dermatology_** 153:675-680.

* _45 dermatologists evaluated 60 clinical and dermatoscopic images plus patient and lesion history._

* _Both sensitivity and specificity improved with PLA results over clinical evaluation alone (specificity 32% -> 57%; sensitivity 95% ->99%)._  
  
**Clinical Utility**

A review of over 20,000 commercial PLA results indicated that 88% of reported
PLA tests were negative and 12% were positive22. This combined with the
finding in a 2017 study of 18,715 surgical biopsies of pigmented lesions
showing that 83% of the lesions biopsied were either benign or mildly atypical
lesions13, suggests that if the test has sufficient clinical performance to
rule out melanoma (i.e _.,_ adequate sensitivity and negative predictive
value), and treating clinicians use the test results as intended, it should
result in significantly fewer unnecessary biopsies without compromising
melanoma outcomes. Clinical performance is reviewed above. Here clinical
decision making following the use of the test is reviewed.

In the Ferris longitudinal follow-up study mentioned above,18 99% of the 330
PLA negative lesions were managed by dermatologists with surveillance. Three
of the PLA- lesions that were biopsied in the follow-up period were done so at
the patient's insistence. One PLA- lesion was simultaneously surgically
biopsied (not the intended use of the test) and adhesive patch sampled and was
diagnosed as MIS. There were 0 missed melanomas found in the follow-up period.
Of 51 PLA+ test results, 100% were managed by dermatologists with a surgical
biopsy. Nineteen (37%) of these cases were MIS / Stage 1 invasive melanomas
with a thickness of <0.5 mm and demonstrating a Number needed to biopsy (NNB)
of 2.7 (51/19).

In an additional utility study by Ferris et al., 45 dermatologists who
regularly evaluate pigmented lesions, assessed 60 cases containing
dermatoscopic and lesional images (8 melanoma and 52 nevi with known
pathologic concordance) with full patient and lesion history.18 The
photographic/dermatoscopic analysis design of this study provided information
nearly identical to the dermatologist's primary clinical visual assessment
used to make biopsy decisions and is therefore more relevant than typical
decision impact studies that involve select case information review with and
without a test result. Cases/images were initially presented without PLA
results, and the dermatologists were asked to make a biopsy decision for
suspicion of melanoma. The 60 cases were then shuffled and presented again,
including the PLA test data. Again, dermatologists were asked to make a biopsy
decision for suspicion of melanoma. Outcomes included changes in biopsy
decisions, specificity, and sensitivity. Biopsy decisions increased from 750
to 1331. Assuming correctness of the reference diagnosis, the specificity of
the biopsy decision increased by 1.8-fold with the PLA (32%-56%, p<0.001). The
sensitivity also improved to approximately 99% (p=0.01) with the PLA, even
with significant increases in specificity.

Most recently, a 2019 study by Ferris reviewed 12 month management decisions
and outcomes for patients testing using the PLA.35 The study involved
retrospective chart reviews of 734 lesions that were PLA(-) and a registry of
175 pigmented lesions tested using the PLA. Among the 734 PLA(-) lesions, 13
were biopsied within one year. Of these 13 biopsied lesions, 11 were nevi with
various degrees of atypia, 1 was a basal cell carcinoma and 1 was a squamous
cell carcinoma. None were melanomas. In the registry cohort, 1433 of 1575
total lesions were PLA(-), and in follow-up only 2 had a surgical evaluation
within a year. One of these had a scoop excision and was found to be a
melanocytic nevus. The other was a squamous cell carcinoma removed by Mohs
surgery. Of the 142 PLA(+) lesions in the registry cohort 96.5% were biopsied.



**Level of Evidence**

Quality of evidence - Moderate  
Strength of evidence - Moderate  
Weight of evidence - Low

The diagnosis of pigmented skin lesions is challenging both for dermatologists
examining a lesion _in vivo_ in a clinical setting and for pathologists
examining tissue specimens following biopsy. As such, pigmented skin lesions
may be biopsied in many cases where the biopsy did not need to be done.
Additionally, once a skin lesion has been biopsied, diagnostic concordance
among pathologists for a given lesion is limited.

This test is not actually a replacement for histopathological examination, but
rather a tool to help clinicians decide if a patient requires histopathologic
examination. As such, evidence reviewed regarding alternative diagnostic
approaches was reviewed for both clinical examination of a lesion prior to a
biopsy and for histopathologic examination post-biopsy. The diagnostic
accuracy of a melanoma for a patient is driven by both of these things,
however we did not find adequate literature examining the joint probability of
correct diagnosis based on both clinical examination and histopathology to
allow us to use a comparison for the PLA.

**Coverage Criteria**

The PLA is indicated only for use by dermatologists on pigmented skin lesions,
for which a diagnosis of melanoma is being considered. The specific
characteristics that the lesion must have are as follows:

  * The lesion must meet one or more ABCDE criteria ( _A_ symmetry, _B_ order, _C_ olor, _D_ iameter, _E_ volving)
  * Primary melanocytic skin lesions between 5mm and 19mm
  * Lesions where the skin is intact (i.e. non-ulcerated or non-bleeding lesions)
  * Lesions that do not contain a scar or were previously biopsied
  * Lesions not located in areas of psoriasis, eczema or similar skin conditions
  * Lesions not already clinically diagnosed as melanoma or for which the clinical suspicion is sufficiently high that the treating clinician believes melanoma is a more likely diagnosis than not
  * Lesions in areas other than palms of hands, soles of feet, nails, mucous membranes and hair covered areas that cannot be trimmed

Additional coverage requirements:

  * The ordering dermatologist must also have a plan at the time of ordering the test to continue to monitor the skin lesion for changes if the test is negative.
  * The ordering physician must clearly document the lesion site on the patient's body
  * The test may not be ordered for the same lesion a second time.
  * Only one test may be used per patient per clinical encounter.

The PLA is not intended to be used as a screening test in patients without
melanocytic skin lesions. It is also not covered as an adjunctive test in
lesions that are considered to already warrant a biopsy. The PLA is a decision
tool for atypical melanocytic lesions prior to the decision to biopsy.

Given the existing evidence for the PLA and alternative diagnostic approaches,
the evidence is sufficient to indicate that the pigmented lesion assay
provides adequate sensitivity and negative predictive value for malignant
pigment lesions to be used as a clinical decision tool in select pigmented
lesions where there is a question as to whether or not a biopsy is needed.

The area of pigmented skin lesion diagnosis is rapidly changing with new
developments to better aid in diagnosis, and standards of care may change, and
better outcomes may be definitively demonstrated as additional diagnostic
evidence emerges. Additionally, the field of melanoma diagnosis currently has
a paucity of studies comparing diagnostic methods with long term (i.e. >5
years) outcomes. As such, MolDX will continue to monitor the evidence for not
only the PLA test, but also for diagnostic performance or outcomes of
alternative diagnosis and management approaches. Such developments may have an
impact on this coverage policy.

Additionally, while this coverage decision is presently based on only the
published evidence discussed above, the test developer notes plans to publish
longer term outcome data. This data will be considered when available and may
result in changes to the coverage policy.