EBS 22-2-8

Evidence Summary #22-2-8 ARCHIVED 2017

A Quality Initiative of the Program in Evidence-Based Care (PEBC), Cancer Care Ontario (CCO)

Best Practices for Oncologic Pathology Secondary Review: Cutaneous Melanoma and Other Skin Cancers

Suhas Joshi, Glenn G Fletcher, Danny Ghazarian, Jadranka Jambrosic,

Denise Kam, Sudha Rajagopal, John Toye, Aaron Pollett, and John Srigley *

Report Date: June 26, 2014

An assessment conducted in October 2017 ARCHIVED Evidence Summary

22-2-8. This means that the document will no longer be maintained but may still

be useful for academic or other information purposes. The PEBC has a formal and

standardized process to ensure the currency of each document

(PEBC Assessment & Review Protocol)

This Evidence Summary is part of an eleven-report series.

Please refer to #22-2-M for background and methodology.

#22-2-M: Methods and Overview

#22-2-1: Breast Cancer

#22-2-2: Gastrointestinal Cancers

#22-2-3: Genitourinary Cancers

#22-2-4: Gynecologic Cancers

#22-2-5: Head and Neck Cancers

#22-2-6: Hematologic Cancers

#22-2-7: Lung Cancer

#22-2-8: Cutaneous Melanoma and Other Skin Cancers

#22-2-9: Central Nervous System (CNS) Tumours

#22-2-10: Bone and Soft Tissue Cancers (Sarcoma)

EBS 22-2-8

* Author affiliations are given in Appendix I

For information about the PEBC and the most current version of all reports, please visit the

CCO Web site at http://www.cancercare.on.ca/ or contact the PEBC office at: Phone: 905-527-4322 ext. 42822 Fax: 905 526-6775 E-mail: ccopgi@mcmaster.ca

22-2-8 Melanoma & Other Skin Cancers Evidence Summary Page 1

QUESTION What types of specimens suspected to be or diagnosed as cutaneous melanoma or

other skin cancer1 should or should not have routine secondary pathology review?

INTRODUCTION This report is part of a series of reports on secondary pathology review in cancer

diagnosis. The reader should consult document #22-2-M: Methods and Overview for a more detailed background to the project, definitions and limitations of secondary review, and the methodology used. Only a brief summary of the methods is given below, along with any details specific to this skin cancer pathology. METHODS

The evidence-based reports developed by the CCO Program in Evidence-Based Care (PEBC) use the methods of the Practice Guidelines Development Cycle (1). For this project, the core methodology used to develop the evidentiary base was the systematic review. Evidence was selected and key details extracted by DK and reviewed by GF of the PEBC.

The body of evidence in this review is primarily comprised of comparative studies on interobserver accuracy or agreement. The systematic review is intended to promote evidence-based practice in Ontario, Canada. The PEBC is supported by the Ontario Ministry of Health and Long-Term Care through CCO. All work produced by the PEBC is editorially independent from the Ministry. Definition of Secondary Pathology Review

In this series of documents, secondary pathology review is defined as review of pathology specimens by a second pathologist that is usually initiated at the request of the patient or treating clinician, multidisciplinary case conference (MCC) process, quality control protocol, or as standard practice to review all cases at a cancer centre prior to treatment. Consultation or review at the request of the primary pathologist or prior to finalization of the primary pathologist’s report is NOT included in this definition. Literature Search Strategy and Study Selection Criteria

Details of the search strategy and inclusion/exclusion criteria are provided in report #22-2-M of this series and only a brief summary is included here. In December 2009, a search for practice guidelines was conducted in the National Guideline Clearing House (USA), National Institute for Health and Clinical Excellence (NICE, UK), Scottish Intercollegiate Guidelines Network (SIGN), American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN, USA), National Health and Medical Research Council (NHMRC, Australia), New Zealand Guidelines Group (NZZG), Canadian Medical Association’s CMA Infobase: Clinical Practice Guidelines, Association of Directors of Anatomic and Surgical Pathology, College of American Pathologists (CAP), and the Canadian Association of Pathologists (CAP-ACP). The SAGE Directory of Cancer Guidelines was searched in May 2012.

MEDLINE and EMBASE databases were searched from 1995 to May 7, 2013. Articles with terms related to both pathology (including cytology or histology) and diagnostic discrepancy were retrieved. For inclusion in this report, articles had to include review of the same samples by a second pathologist (excluding review at the original pathologist’s request), be related to the diagnosis of cutaneous melanoma or other skin cancers, and report on diagnostic discrepancy or agreement between two (or more) pathologists. 1 Cancer includes precancerous conditions that need to be distinguished from cancer, which may progress to cancer, or for which there is not general agreement as to whether they should be termed as cancer.

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RESULTS

For cutaneous melanoma and other skin cancers, the search resulted in 49 articles, of which 36 were reproducibility studies. The 13 studies (2-14) that report agreement or disagreement between the initial and secondary pathology review are summarized in Table 1. Sample size in the 11 diagnostic studies ranged from 14 to 5136. Five of the studies indicated changes that would affect management (major changes). An additional seven studies include skin cancer along with other cancers (15-21). Several of the studies include all lesions detected or cases referred to a cancer centre for treatment. In those studies, discrepancy rates ranged from 3% to 54%. Studies did not indicate the way in which the original diagnoses were sorted (i.e., grade, type of tumour, and so on). Major changes were indicated in four of the studies and included changes between benign and malignant diagnoses (19), clinical significance (15), or a change in therapy/prognosis (17,20). While data were not extracted from the reproducibility studies, these may be of interest to some readers and address specialized areas of pathologic interpretation and especially areas where more research or standardization is necessary. The publications are therefore listed separately in Appendix II. 1. Sentinel Lymph Nodes

Two studies reported on sentinel lymph node biopsies (SLNB) in primary cutaneous melanoma (2,3). In both studies, the SLNB were initially reported as negative, but upon a secondary review, there was a 12% and 32% discrepancy, respectively. Neither study made mention of whether discrepancies were major or minor. 2. Melanoma

The study by McGinnis et al (8) reported an 11% discrepancy rate in the diagnosis of melanocytic lesion (significant changes only). Discrepancy rates were 2.3% for critical

revisions (benign ↔ malignant melanoma) and 8.5% for upgrade or downgrade (same category of benign or malignant), with significant impact on treatment or prognosis. Shoo et al (9) studied cases initially diagnosed with thin melanoma (melanoma in situ, stage IA, stage IB) or benign nevi, and found a 14% discrepancy among the categories of benign, malignant, or

ambiguous (5% ambiguous ↔ malignant/benign, 9% benign ↔ malignant). The initial diagnosis was by a dermatopathologist in 55% of the discordant cases. Heal et al (10) report a 9% discrepancy rate in samples initially diagnosed as cutaneous melanoma by histopathologists who received specific training prior to the study. Butler et al (11) reported discrepancy rate of 2.2% (1.3% resulting in a change in management) for patients referred for Mohs surgery; melanomas (malignant melanoma [MM] and malignant melanoma in situ [MMIS]) represented a small portion of total tumours but 17% of misdiagnosed tumours. Hawryluk et al (7) reviewed melanocytic tumours and found a 21% major discrepancy rate for specimens initially diagnosed by a general pathologist compared to 12% for specimens initially diagnosed by a dermatopathologist. 3. Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC)

Heal et al (10) reported high discrepancy rates; however, the discrepancies (e.g., SCC to actinic keratosis [AK]) are not considered clinically significant and would not affect treatment. 4. Rare Cutaneous Cancers

No studies were found that reported the discrepancy rate between initial and secondary review for rare cutaneous cancers.

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5. Other Features McGinnis et al (8) reported changes in margins from clear to involved (5.8%) and

involved to clear (6.2%) in re-excision specimens. Murali et al (12) reported discrepancies of 8% in Breslow thickness and 8% in ulceration; however, they noted 36% of original reports and 9% of review reports failed to mention ulceration. Of those samples where ulceration was not mentioned, 5.5% were found on review to have non-traumatic ulceration. This contradicts their assumption that no mention of ulceration equates to no ulceration. Murali et al also reported a 25% discrepancy rate in Clark level. While this feature is often used for melanoma, it is considered to be irreproducible. It is optional in the CAP report, though may become important in the future for certain cancer types.

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Table 1. Pathologic discrepancy rates between primary and secondary review pathologists: cutaneous melanoma and other skin cancers.

(Note: For ease of reading please print this table or enlarge (zoom) it to 120% on the computer monitor.)

Author

Year

# 2nd Reviewers

# Specimens

2nd Reviewer Profession/Training

(1st pathologist if noted)

Type of Review, Notes

Sample Description, Notes

Sample Subtype, Change or Item Compared

# Samples of Subtype

Discrepancy, % Agreement

All Major Minor % Kappa

Lymph Nodes Yu (2) 1999 94 deeper sections and IHC on

negative sentinel lymph nodes (SLN)

235 SLN reported as negative for melanoma metastasis from 94 patients with AJCC Stage I and II cutaneous melanoma

microscopic metastasis found in SLNs previously diagnosed as negative

94 12 88

Li (3) 2003 2 22 Histopathologists experienced in diagnosis and reporting of melanoma and SLN specimens did both primary and secondary review

re-examine slides plus deeper sections and IHC on negative sentinel lymph nodes (SLN)

patients with primary melanoma and negative SLN on initial pathologic examination with subsequent development of regional node field recurrence of melanoma (26/957 patients; 22 had slides and blocks available for re-examination)

melanoma cells found in SLNs previously reported as negative

22 32 68

Diagnosis

Monshizadeh (4) 2012 1 (+ show

difficult cases to others in

group)

721 (598 pts)

Pathologists with special interest in melanocytic lesions, 3 of 4 pathologists are full time dermatopathologists

Referrals to WAMAS (a multidisciplinary service providing advice on management of patients with melanoma) from clinicians, 75% from general practitioners, mainly for more complex melanomas (WAMAS reviews ≈8% of new melanoma cases in Western Australia)

When calculating concordance cases were excluded if data were missing from either pathology report (initial pathology report or WAMAS database)

Cases with data reported by both pathologists Histologic type Nodular melanoma (NM) SSM Unclassified Other (< 15 cases each type) Melanoma ↔ non-melanoma In situ versus invasive Tumour Thickness within 0.1 mm Breslow thickness staging group Mitotic Rate Clark Level Vascular Invasion (absent/present) present Ulceration (absent/present) present Predominant cell type TMN stage, pathologic Completeness of excision (total/complete) Regression (absent/present) Neurotropism (absent/present) Tumour infiltrating lymphocytes Growth Phase (vertical/radical) Microsatellites (absent/present)

584 90

162 260 72

583 551

585 585 35

271 91 9

89

57 551 136 75 53 74 43 30

43 58 20 52 43 2.7 3.2

29 9.2 20 24 5.5 56 5.6 20 18 18 13 24 3.8 49 2.3 0

57 42 80 48 57 97 97

71 91 80 76 95 44 94 80 82 82 87 76 96 51 98

100

0.40

0.10 0.86

0.86 0.69 0.68 0.59

0.85

0.43 0.79 0.67 0.49 0.65 0.12 0.95 1.00

Missing Information Ulceration Mitotic rate Presence/absence of microsatellites Growth phase Neurotropism Predominant cell type Tumour infiltrating lymphocytes Regression Vascular invasion

42 41 79 76 64 58 51 49 38

58 59 21 24 36 42 49 51 62

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Author

Year

# 2nd Reviewers

# Specimens

2nd Reviewer Profession/Training

(1st pathologist if noted)

Type of Review, Notes

Sample Description, Notes

Sample Subtype, Change or Item Compared

# Samples of Subtype

Discrepancy, % Agreement

All Major Minor % Kappa

Nobre (5) 2013 2 89 1 general pathologist, 1 dermatopathologist

Retrospective analysis of all histological specimens diagnosed as dysplastic nevus 1978-2006

Review of H&E slides using criteria for diagnosis of dysplastic nevi, 89 lesions from 54 patients

change from dysplastic melanocytic nevus general pathologist dermatopathologist

89 89

12 16

88 84

Haws (6) 2012 1 14 dermatopathologist Patients referred for SLNB associated with melanoma, Merkel cell carcinoma, or adnexal carcinoma and who had pathology reports from both referring institution and review at institution where SLNB was to be performed

Of 68 identified cases, 2nd review of diagnostic specimens in order to determine whether SLNB was needed was only performed in 14 cases; these were at the request of a surgeon or oncologist

requirement for SLNB (2nd review indicated SLNB not required in 3/14 cases due to misdiagnosis)

14 21 21 79

Hawryluk (7) 2012 1 (more than one when referral and MGH diagnosis differed significantly)

478 dermatopathologists Routine review of melanocytic tumours from patients referred to the Massachusetts General Hospital Pigmented Lesion Clinic (MGH PLC) in the MGH Dermatopathology Unit; not blinded

Consecutive cutaneous melanocytic tumors from 1996-97(n=126) and 2010-11 (n=352) Benign includes dysplastic nevi, spitz nevi, benign acquired nevi Major = change in therapy

change in diagnosis Initial diagnosis by general pathologist Initial diagnosis by dermatopathologist malignant, all discrepancies Malignant → benign Melanoma thickness Melanoma, other prognostic factors benign (nevi), all discrepancies Benign → malignant Nevus type Grade of atypia for dysplastic nevi

478 72

406 321 321 247 247 157 157 157 117

35 51 32 29 5.0 30

12.6 37 7.6 9.6 26

13 21 12 7.8 1.6 4.9 2.4 22 5.7 5.7 14

65 49 68 71 95 70 87 63 92 90 74

McGinnis (8) 2002 1 5136 dermatopathologist interinstitutional: retrospective review; consensus with other intrainstitutional dermatopathologists for difficult lesions

Review of melanocytic lesions of patients referred to Pigmented Lesion Clinic after established outside diagnosis

significant change -critical revision (benign to/from

malignant melanoma) -upgrade or downgrade within same

category (benign or malignant) with significant impact on treatment, prognosis, and research

-Reexcision specimens: change in margins

-clear to involved -involved to clear

5136

257

12.1

6.2 5.8

11 2.3

8.5

88

94 94

Shoo (9) 2010 1 392 dermatopathologist (first seen by dermatopathologist, 31/56 discordant cases; or general surgical pathologist 20/56)

cases referred to pigmented lesion clinic at UCSF and re-evaluated by routine histopathologic exam

patients diagnosed with thin melanoma (melanoma in situ, stage IA, stage IB) or benign nevus

difference in category of benign, malignant, or ambiguous (cases interpreted as ambiguous or atypical by both groups were not considered discordant) ambiguous to/from benign or malignant

benign to/from malignant

392

14

5 9

86

95 91

Heal (10) 2009 1 407 dermato-histopathologist (first seen by local histopathologist)

stratified random sample of all excised and histologically confirmed skin cancers collected from 3 local pathology labs

originally diagnosed by histopathologists who received training prior to this study at a workshop by a dermato-histopathologist (who later did the 2nd review)

Overall (all diagnoses, 5 categories) -basal cell carcinoma -squamous cell carcinoma (all discrepancies were SCC→AK) -actinic keratosis -cutaneous melanoma -common nevus

407 83

179

92 23 30

18 7

27

17 9 7

82 93 73

83 91 93

Butler (11) 2009 2 3345 dermatopathologist (first seen by either dermatopathologists, 48%, just under ½ of all discrepancies; 28%

interinstitutional: review by dermatopathologists (1 for all samples, 2 if discrepancy)of all outside biopsy slides before Mohs surgery

only reports discrepancies in which more than one dermatopathologist disagreed with the original diagnosis; major = results in a change in management

overall diagnosis Of 74 discrepancies, 32 (43%) were between types of malignant tumors, 27 (36%) malignant to benign, 9 (12%) malignant to premalignant, 7% benign to malignant

3345 2.2 1.3 98

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Author

Year

# 2nd Reviewers

# Specimens

2nd Reviewer Profession/Training

(1st pathologist if noted)

Type of Review, Notes

Sample Description, Notes

Sample Subtype, Change or Item Compared

# Samples of Subtype

Discrepancy, % Agreement

All Major Minor % Kappa

dermatologists; 25% pathologists)

Authors note that melanomas (MM and MMIS) represent a small portion of total tumours but 17% of misdiagnosed tumours

Murali (12)

2009 panel 912 expert pathologist (first seen by pathologist, type not specified)

interinstitutional: review of all outside cases referred to Sydney Melanoma Unit for definitive treatment following a diagnosis of melanoma

biopsy proven dermal-invasive primary cutaneous melanomas; excluded cases where Breslow thickness and Clark level were not included; Breslow thickness stratified into 4 groups (<= 1.00mm, 1.01-2.00 mm, 2.01 to 4.00 mm, > 4 mm); ulceration (no, non-traumatic, traumatic, not reported), Clark level (I-V)

Breslow thickness Clark level Ulceration overall pathologic stage (I or II) substage (IA, IB, IIA, IIB, IIC) T Stage (T1a-T4b)

912 912 912 912 912 912

8 25 8 4

16 18

92 75 92 96 84 82

0.883 0.627 0.768

Olhoffer (13) 2002 panel 336 4 dermatopathologists at conference (1-4 ?) (physicians at pathology labs approved by 3

rd party payers)

interinstitutional: retrospective review 2/3 of errors made by physicians who were not specialists in dermatopathology

cases referred to Yale University dermatopathology lab by dermatologic surgery section prior to surgery; major = change in management

change in diagnosis 11 overdiagnosed (10 non-melanoma skin cancer, 1 AK) 7 underdiagnosed (2 missed melanoma, 4 non-melanoma skin cancer, 1 AK)

336 5.7 5.4 94

Jagdeo (14) 2007 1 (≈10%

randomly selected to

be read by 2 pathologists)

3926 dermatopathologist (local pathologist for 1st review)

trial of topical tretinoin for prevention of keratinocyte carcinoma; blinded review by local central reference dermatopathologist

lesions biopsied from the face or ears of high-risk individuals; diagnosis placed into 5 categories (data in different tables of article does not match)

Overall (all diagnoses, 5 categories) BCC SCC invasive SCC in situ Actinic keratosis Other

3926 1641 523 219 854 716

25 9

31 51 40 30

75 91 69 49 60 70

0.66

Studies that reported on skin and other cancers, specific types not indicated Lind (15) 1995 1 975 pathologists 2nd opinion in the same lab compared 1st and 2nd pathology

readings; exclude samples where 2 pathologists could not reach consensus

major = clinical significance 975 4.5 0.7 95

Prescott (16) 1995 1 16 Pathologist with specialist interest in neoplastic conditions

review at regional cancer treatment centre

cases with confident 1st diagnosis, excluded cases where 2nd opinion sought

16 25 13 13 75

Kronz (17) 1999 1 103 mandatory 2nd opinion; all cases referred to treating institution, excludes consult cases with uncertain diagnosis

major modification in therapy or prognosis, does not include change only in histologic grade or stage; limited number of cases as most were seen by the dermatology department

103 3 97

Ahmed (18) 2004 1 13 2nd opinion at major referral centre

reviewed at Aga Khan University, Pakistan; most sent by clinicians, some by primary pathologists

13 54 46

Tsung (19) 2004 1 24 pathologists All patients receiving treatment or seeking second opinion before therapy at Sun Yat-Sen Cancer Center

major discrepancies (benign to malignant or vice versa), different type of neoplasm, change in N or M of TMN classification

24 13 87

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Author

Year

# 2nd Reviewers

# Specimens

2nd Reviewer Profession/Training

(1st pathologist if noted)

Type of Review, Notes

Sample Description, Notes

Sample Subtype, Change or Item Compared

# Samples of Subtype

Discrepancy, % Agreement

All Major Minor % Kappa

Renshaw (20)

2006 1 4728 Internal blinded review; 1/6 of cases from new pathologists, rest random

major error leads to amendment, minor error requires no action

all discrepancies reviewer missed lesion

4728 7.4 0.3

0.1

7.3 93

Lu (21) 2009 1 23 external consultation 23 13

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Clinical Practice Guidelines No guidelines were located that dealt specifically with secondary pathology review in

melanoma or other skin cancers, though several dealt more broadly with the management of melanoma or skin cancers. They include a section on pathology or diagnosis (22-29) and recommend secondary review or specialist review.

The most extensive guideline is the evidence-based NCCC/NICE guideline (29), which indicates that “patients with invasive skin cancer associated with a greater risk or rarity should be managed by SSMDTs [specialist skin cancer multidisciplinary team].” Most of the pathology recommendations concern the qualification of those involved and only address secondary review for a subset (e.g., malignant melanoma). The NICE guideline was considered important but could not be considered for endorsement as it did not cover the full scope of the current guideline.

The NICE guideline indicates a specialist skin cancer multidisciplinary team (SSMDT) should have at least two specialist dermatopathologists or histopathologists with a special interest in dermatopathology, and all referred cases should have a specialist histopathology review.

Patients for review by SSMDTs [reproduced from (29)]

• Patients referred from the LSMDT [local hospital skin cancer multidisciplinary team] • Patients with high-risk SCCs …that pose difficulty in management • Patients with MM managed by other site specialist teams (e.g. gynaecological, mucosal and head and neck (excluding ocular)) • Patients newly diagnosed with MM stage 2B or higher (American Joint Committee on Cancer (AJCC) staging system) • Patients with MM stage 1 or above who are eligible for clinical trials that have been approved at cancer network level • Patients with multiple MM • Children younger than 19 years with MM • Any patient with metastatic MM or SCC diagnosed at presentation or on follow-up • Patients with giant congenital naevi where there is suspicion of malignant transformation • Patients with BCCs that are metastatic • Patients with malignant skin lesions of uncertain pathological diagnosis • Patients with rare skin cancers, including lymphoma and sarcoma • For periodic review, patients developing skin cancers who are immunocompromised, have Gorlin’s syndrome or other genetic predisposition syndromes) • Patients needing nodal dissection including sentinel lymph node biopsy (SNB) – these patients should be seen and referred by the LSMDT • Patients who may benefit from radiotherapy, if not available at the LSMDT • Patients who may be eligible for entry into clinical trials • Patients who require adjuvant treatment (where this is shown to be beneficial)

The guideline recommends that “all MMs and severely atypical naevi should be double-reported if resources allow the report to be generated within 2 weeks”. While double-reporting is recommended and is a long-term goal, the inference is that the treatment should not be delayed due to a shortage of specialist pathologists. Observational studies report difficulty with diagnostic accuracy and consistency for childhood melanoma, atypical nevi, Spitz nevi, and melanocytic lesions that are considered borderline for malignancy. Skin lymphomas, because of their rarity and complexity in diagnosis, should be reviewed by a dermatopathologist with expertise in cutaneous lymphoma. Close liaison should be maintained with a hemato-oncopathologist, as appropriate. Cutaneous sarcomas require specialist histopathology review (see Improving Outcomes for People with Sarcoma (30-32)). Management of children and young people diagnosed with skin cancer should be within an MDT including a dermatologist expert in skin malignancies (see Improving Outcomes in Children and Young People with Cancer (33,34).

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Several other guidelines agree with or are based on the NICE guideline, though they are not as comprehensive. The British Association of Dermatologists guideline (28) is based on the NICE guideline. SIGN (25) concludes that there is significant discrepancy between general pathologists and experts in the reporting of melanocytic tumours. The Australian Cancer Network (22) recommends that lesions in children and young adults, including melanocytic and Spitz-like lesions, be reviewed by histopathologists highly experienced in the diagnosis of such lesions. The NCCN (24,33) recommends referral to a pathologist with expertise in atypical melanocytic lesions for suspected cases of atypical melanocytic proliferation (AMP), melanocytic tumor of uncertain malignant potential (MELTUMP), superficial melanocytic tumour of uncertain significance (SAMPUS), atypical Spitz tumour, and atypical cellular blue nevus as these are all diagnostically challenging. An experienced dermatopathologist should examine the entire lesion when pure desmoplastic melanoma is suspected. The German Cancer Society and the German Dermatologic Society (26), and the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization for Research and Treatment of Cancer (EORTC) (27) recommend that a dermatopathologist experienced in the interpretation of pigmented lesions should review suspected cases of melanoma. DISCUSSION

An initial (primary) pathology review should include synoptic reporting, as stipulated in the CAP protocols (see http://www.cap.org) and based on the American Joint Commission on Cancer (AJCC) standards (35). CCO and CAP/APC have endorsed the CAP cancer checklists as the content standard for pathology reporting (36,37). Synoptic reporting can help ensure that reports are complete, and in Ontario such reports are currently required for hospital laboratories for the diagnoses of melanoma (biopsy, excision, re-excision), Merkel Cell carcinoma (incisional biopsy, excision, re-excision, lymphadenectomy), and squamous cell carcinoma (biopsy, excision, re-excision, lymphadenectomy) (37).

The quality and completeness of the reports has a direct impact on their usefulness. There is greater variation in the completeness of reports from private laboratories in Ontario, as only some currently have synoptic-like reporting, and they have not implemented the CAP electronic checklists. When a feature such as ulceration is not reported, it is often assumed to be absent, but this may be incorrect and result in inappropriate treatment. Some laboratories do not have the capability to perform immunohistochemistry (IHC) and this component may be omitted or subcontracted to other facilities. In the latter case, the two reports do not always get combined, and the surgeon or oncologist may not be aware of the complete data. In the absence of a complete report, it is sometimes more expedient to have a secondary review by the specialist at the treating facility. While these are important issues, they do not directly relate to diagnostic uncertainties that should be the main reason for performing a secondary pathology review, and the conclusions regarding secondary review assume that the primary pathologist has issued a complete report.

While the evidence suggests that secondary pathology review is warranted for some cancers, this must be balanced by delays in diagnosis that may have a significant impact on outcome, especially for fast-growing cancers.

In Canada there is no definitive standard for a subspecialist or pathologist with recognized expertise in skin pathology. Some considerations are given in the methods/overview document. Pathologists with expertise in skin pathology may include those who have completed a fellowship or specialized training in dermatopathology, certification in dermatopathology from other jurisdictions, or with special interest in this area. Such experts should participate in MCC or MDT and quality assurance programs, attend meetings of relevant specialist societies, and keep up to date in the field through professional

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development activities. They will often devote a substantial amount of time to this area of practice and provide specialist opinion to colleagues.

Most of the studies involved interinstitutional review, with secondary review by a dermatopathologist at a specialized centre (pigmented lesion or melanoma clinic, dermatopathology lab, treating institution). Most studies did not usually specify the qualifications/specialty of the first pathologist, but some indicated that diagnoses by dermatopathologists were more consistent. Most guidelines indicated that a specialist/expert pathologist was necessary.

Review of the data in Table 1 indicated a wide range of discrepancy rates between the initial and secondary pathology review. The Working Group was unable to decide on an acceptable discrepancy rate (see report #22-2-M for further discussion).

Overall Diagnosis Melanoma

A complete report for melanoma should include margins (including distance in mm of closest margin of the excision to invasive melanoma), ulceration, tumour thickness, mitotic rate, and lymphovascular invasion (LVI). Ulceration (yes or no) plus thickness are the most important features in determining the risk of metastasis. An amendment or second review is necessary if any of these elements are missing. Synoptic reporting is strongly encouraged. In the case of a diagnostic punch biopsy, the synoptic report should be as complete as possible, and at a minimum should include histologic type, Breslow thickness, ulceration, and mitotic rate.

Discrepancies in cases of melanoma were 9% to 14% (8-10). Shoo et al (9) noted that 55% of discordant cases had been first seen by a dermatopathologist (though the proportion of overall cases first seen by a dermatopathologist was not stated). Butler et al (11) noted that melanomas represented a small portion of the tumours reviewed but accounted for 17% of the misdiagnosed tumours. Initial and secondary reviews were by dermatopathologists in 48% of cases and accounted for just under half of all discrepancies. This level of discrepancy suggests that a routine secondary review is required for cutaneous melanomas. Guidelines recommend review by a specialist dermatopathologist or histopathologist with special interest in dermatopathology and/or experience in the interpretation of pigmented lesions. We suggest that review should be by an experienced pathologist with special interest and expertise in diagnosing skin cancers, including melanoma. Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC)

Little data was available for basal cell carcinoma and SCC. Heal et al (10) reported high discrepancy rates, but all discrepancies for SCC were changes to AK, which is considered not clinically significant. While the data in Table 1 is insufficient to make conclusions regarding secondary review, our experience indicates that it should be considered for poorly differentiated SCCs and for BCCs of special types such as sclerosing, infiltrative, or metaplastic; those with adnexal differentiation; and when there is discordance between clinical and pathological results. We suggest that routine secondary review of other cases of BCC and SCC is not required. The NICE guideline recommends patients with malignant SCC or BCC, or with high-risk SCC should have specialist histopathology review by a dermatopathologist or histopathologist with special interest in dermatopathology (29). Rare Cutaneous Cancers No studies were found that dealt with discrepancy rates for rare cancers. The consensus of the group is that adnexal carcinoma, Merkel cell carcinoma, malignant spindle cell tumours, and any other rare cancers should be reviewed by a dermatopathologist or

22-2-8 Melanoma & Other Skin Cancers Evidence Summary Page 11

pathologist with a special interest in skin cancer. Due to their low incidence, general pathologists are unlikely to have expertise in these tumours, which is consistent with other guidelines (e.g., NICE (29)). The NICE guideline (29) also indicates that skin lymphomas, because of their rarity and complexity in diagnosis, should be reviewed by a dermatopathologist with expertise in cutaneous lymphoma. Close liaison should be maintained with a hemato-oncopathologist, as appropriate. Cutaneous sarcomas require specialist histopathology review ((30-32); see also report #22-2-10 in this series). Cancers in Children

While no studies were found comparing initial and secondary pathology review, childhood cancers are addressed in several guidelines. The Australian Cancer Network Melanoma (22) recommends that melanocytic and Spitz-like lesions in children/young adults be reviewed by histopathologists highly experienced in the diagnosis of such lesions. NICE recommends review by dermatopathologists or histopathologists with a special interest in dermatopathology for patients under 19 with malignant melanoma, and that all children and young people diagnosed with skin cancer should be managed, within the context of an MDT including a dermatologist expert in skin malignancies (33,34). The NCCN recommends specimens suspected to be melanocytic tumours of uncertain malignant potential (MELTUMP), atypical melanocytic proliferation (AMP), superficial melanocytic tumour of uncertain significance (SAMPUS), atypical Spitz tumour, and atypical cellular blue nevus be referred to a pathologist with expertise in atypical melanocytic lesions (23,24). Due to the lower incidence in children, and diagnostic difficulty and differential features compared to some adult cancers, we conclude that all cases of cutaneous cancers in children or young adults should be reviewed by an experienced pathologist with special interest and expertise in diagnosing skin cancers, including melanoma. (Sentinel) Lymph Node Evaluation

Lymph node status is of clinical relevance, as a false negative would result in removal of fewer nodes and patients would not receive adjuvant therapy. Only two small studies involved discrepancies in SLN evaluation and suggested that routine secondary review is required (2,3). The high discrepancy rates may not reflect the current situation due to advances in the field and technique since the time of the studies. Difficulties are mainly due to such technical issues as how to prepare and stain samples and the number and type of antibodies for IHC. Li et al (3) used two antibodies, while current procedures may use five. There is, therefore, insufficient evidence to evaluate the use of a secondary pathology review in SLNB with current methodology.

The consensus of the group was that SLN evaluation must follow a full and current protocol including IHC (see the CCO guideline on SLNB in clinically node-negative melanoma (38)). Secondary pathology review including IHC is recommended for SLNs resected in relation to melanoma if the full SLN protocol (22,38,39) including IHC, was not followed.

CONCLUSIONS 1. Overall

Secondary pathology review should be performed whenever there is discordance between the pathologic diagnosis and clinical or other features that raise doubt as to the accuracy of the pathology results.

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2. Diagnosis of Melanoma Secondary pathology review by an experienced pathologist with special interest and

expertise in diagnosing skin cancers including melanoma should be considered for all samples diagnosed as or suspected to be cutaneous melanoma. 3. Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC)

Second review should be considered for poorly differentiated SCCs and for BCCs of special types such as sclerosing, infiltrative, or metaplastic, and those with adnexal differentiation. Routine secondary review is not required for other basal cell and squamous cell carcinomas. 4. Rare Cutaneous Cancers

All samples diagnosed as or suspected to be rare cutaneous tumours, including Merkel cell carcinoma, adnexal carcinoma, and malignant spindle cell tumours, should be reviewed by an experienced pathologist with special interest and expertise in diagnosing skin cancers, including melanoma. 5. Cancers in Children

All cases of cutaneous cancers in children or young adults should be reviewed by an experienced pathologist with special interest and expertise in diagnosing skin cancers including melanoma. 6. Sentinel Lymph Node (SLN) Biopsy

Secondary pathology review including immunohistochemistry (IHC) is recommended for SLNs resected in relation to melanoma if the full SLN protocol (22,38,39) including IHC, was not followed. OTHER ISSUES AND FUTURE RESEARCH

Development of standards regarding the minimum facilities required for reviewing cutaneous pathology samples and some assurance by CCO that these are met.

Determination of a standard battery of IHC testing (e.g., HMB-45, S100, melanoma cocktail) for adequate assessment of samples.

Research study on the rate of discrepancies in major Ontario hospitals, using synoptic reports and secondary pathology review. Are the rates similar to those in the literature or lower due to the use of synoptic reporting? Is there an effect on outcome? Results may reveal areas where training sessions would be beneficial. Training sessions by CCO would be useful if people could be convinced to attend.

RELATED PEBC GUIDELINES

Wright F, Spithoff K, Easson A, Murray C, Toye J, McCready D, et al. Primary excision margins and sentinel lymph node biopsy in clinically node-negative cutaneous melanoma of the trunk or extremities: guideline recommendations. Toronto (ON): Cancer Care Ontario (CCO); 2010 May 17. Program in Evidence-based Care Evidence-Based Series No.: 8-2.

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UPDATING This series of evidence summaries on secondary pathology review will be considered

current for three years. The evidence summaries will then be designated as archived and indicated as such on the CCO website. These reports will not undergo annual assessment. They will not be updated unless required as the basis of a new guideline by the Pathology and Laboratory Medicine Program (PLMP).

CONFLICT OF INTEREST

In accordance with the PEBC Conflict of Interest (COI) Policy, the authors, and internal reviewers were asked to disclose potential COIs. Potential COIs that were declared are summarized in Appendix I. The COIs declared did not disqualify any individuals from performing their designated role in the development of this guideline, in accordance with the PEBC COI Policy. To obtain a copy of the policy, please contact the PEBC office by email at ccopgi.mcmaster.ca ACKNOWLEDGEMENTS AND AUTHORSHIP

The Pathology & Medicine Program and the Working Group would like to thank the following individuals for their assistance in developing this report:

Dr John Srigley, Dr Sandy Boag, Glenn Fletcher, Dr Suhas Joshi, Dr Mahmoud Khalifa, and Dr Brendan Mullen for taking the lead in the overall pathology secondary review project.

Melissa Brouwers, Adam Haynes, Nofisat Ismaila, Sheila McNair, and Hans Messersmith for providing feedback on draft versions.

Denise Kam for providing research assistance and for managing communication among the Working Group and with the reviewers.

Harkanwal Randhawa for conducting a data audit.

Carol De Vito for copyediting.

Jennifer Hart and Dana Wilson-Li of Cancer Care Ontario. A complete list of the members of the Best Practices for Oncologic Pathology

Secondary Review: Cutaneous Melanoma and other Skin Cancers Working Group with their affiliations and conflict of interest information is provided in Appendix 1.

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Funding The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health

and Long-Term Care. All work produced by the PEBC is editorially independent from the Ontario Ministry of Health and Long-Term Care.

Copyright

This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

Disclaimer

Care has been taken in the preparation of the information contained in this report. Nonetheless, any person seeking to apply or consult the report is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer

Care Ontario makes no representation or guarantees of any kind whatsoever regarding the report content or use or application and disclaims any responsibility for its application or use in any way.

Contact Information

For information about the PEBC and the most current version of all reports, please visit the CCO website at http://www.cancercare.on.ca/ or contact the PEBC office at:

Phone: 905-527-4322 ext. 42822 Fax: 905 526-6775 E-mail: ccopgi@mcmaster.ca

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29. Verne J, Roberts D, Allan E, Caswell A, Godsell G, Jackson A, et al. Guidance on cancer services. Improving outcomes for people with skin tumours including melanoma. The manual. London (UK): National Institute for Health and Clinical Excellence (NICE); 2006 [modified 2010 May, cited 2012 May 31]. Available from: www.nice.org.uk/nicemedia/live/10901/28906/28906.pdf.

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Appendix I. Members of the Pathology Secondary Review Working Group. Pathology Secondary Review Working Group: Melanoma

Dr. Danny Ghazarian, Director of Dermatopathology and Director of Education, Department of Pathology, University Health Network (Princess Margaret /Toronto General/Toronto Western Hospitals); Associate Professor, Laboratory and Medicine and Pathobiology, University of Toronto,

Dr. Jay Jambrosic, Dermatologist, Kingsway Dermatology and Cosmetic Clinic; Pathologist/Dermatologist, Pigmented Lesions Clinic, Women’s College Hospital; Department of Dermatology, University of Toronto

Dr. Suhas Joshi, Chief of the Department of Pathology and Regional Director of Laboratories, Niagara Health System, St Catharines General Site, St Catharines

Dr. Aaron Pollett, Pathologist, Mount Sinai Hospital, Toronto; Assistant Professor, Laboratory and Medicine and Pathobiology, University of Toronto; Chair, Pathology and Laboratory Medicine Program (PLMP), Cancer Care Ontario

Dr. Sudha Rajagopal, Medical Oncologist, Credit Valley Hospital; Lecturer, Division of Medical Oncology, Department of Medicine, University of Toronto

Dr. John Srigley, Pathologist and Chief of Laboratory Medicine, Credit Valley Hospital, Mississauga; Professor (part-time), Pathology and Molecular Medicine, McMaster University; Chair (until April 2013), Pathology and Laboratory Medicine Program (PLMP), Cancer Care Ontario

Dr. John Toye, Plastic Surgeon, Orillia Soldiers Memorial Hospital

Glenn G. Fletcher, Health Research Methodologist, PEBC, Cancer Care Ontario/McMaster University, Hamilton, Ontario

Denise Kam, Research Assistant, PEBC, Cancer Care Ontario/McMaster University, Hamilton, Ontario

Jennifer Hart, Manager - Clinical Programs, Cancer Care Ontario, Toronto, Ontario

Dana Wilson-Li, Policy and Research Analyst, Pathology and Laboratory Medicine Program, Cancer Care Ontario, Toronto, Ontario

No conflicts of interest were declared by the Working Group members.

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Appendix II. Reproducibility studies (data not extracted). 1. Barnhill RL, Argenyi Z, Berwick M, Duray PH, Erickson L, Guitart J, et al. Atypical

cellular blue nevi (cellular blue nevi with atypical features): Lack of consensus for diagnosis and distinction from cellular blue nevi and malignant melanoma ("malignant blue nevus"). Am J Surg Pathol. 2008;32(1):36-44.

2. Barnhill RL, Argenyi ZB, From L, Glass LF, Maize JC, Mihm MC, Jr., et al. Atypical Spitz nevi/tumors: Lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome. Hum Pathol. 1999;30(5):513-20.

3. Belousova II, Kazakov DV, Samtsov AV, Kempf W. [Assessment of the significance of histological, immunohistochemical and clinical data in the diagnosis of lymphoproliferative skin diseases in conformance with a consensus by international experts]. Arkh Patol. 2004;66(2):11-6.

4. Braun RP, Gutkowicz-Krusin D, Rabinovitz H, Cognetta A, Hofmann-Wellenhof R, Ahlgrimm-Siess V, et al. Agreement of dermatopathologists in the evaluation of clinically difficult melanocytic lesions: How golden is the 'gold standard'? Dermatology. 2012;224(1):51-8.

5. Brochez L, Verhaeghe E, Grosshans E, Haneke E, Pierard G, Ruiter D, et al. Inter-observer variation in the histopathological diagnosis of clinically suspicious pigmented skin lesions. J Pathol. 2002;196(4):459-66.

6. Busam KJ, Antonescu CR, Marghoob AA, Nehal KS, Sachs DL, Shia J, et al. Histologic classification of tumor-infiltrating lymphocytes in primary cutaneous malignant melanoma. A study of interobserver agreement. Am J Clin Pathol. 2001;115(6):856-60.

7. Cerroni L, Kerl H. Tutorial on melanocytic lesions. Am J Dermatopathol. 2001;23(3):237-41.

8. Cook MG, Clarke TJ, Humphreys S, Fletcher A, McLaren KM, Smith NP, et al. The evaluation of diagnostic and prognostic criteria and the terminology of thin cutaneous malignant melanoma by the CRC Melanoma Pathology Panel. Histopathology. 1996;28(6):497-512.

9. Corona R, Mele A, Amini M, De Rosa G, Coppola G, Piccardi P, et al. Interobserver variability on the histopathologic diagnosis of cutaneous melanoma and other pigmented skin lesions. J Clin Oncol. 1996;14(4):1218-23.

10. CRC Melanoma Pathology Panel. A nationwide survey of observer variation in the diagnosis of thin cutaneous malignant melanoma including the MIN terminology. CRC Melanoma Pathology Panel. J Clin Pathol. 1997;50(3):202-5.

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12. Ferrara G, Argenyi Z, Argenziano G, Cerio R, Cerroni L, Di Blasi A, et al. The influence of clinical information in the histopathologic diagnosis of melanocytic skin neoplasms.[Erratum appears in PLoS One. 2009;4(6). doi: 10.1371/annotation/512cb17b-934c-4a06-9dbb-114d43052a2b]. PLoS ONE. 2009;4(4):e5375.

13. Ferrara G, Argenziano G, Soyer HP, Corona R, Sera F, Brunetti B, et al. Dermoscopic and histopathologic diagnosis of equivocal melanocytic skin lesions: An interdisciplinary study on 107 cases. Cancer. 2002;95(5):1094-100.

14. Florell SR, Boucher KM, Leachman SA, Azmi F, Harris RM, Malone JC, et al. Histopathologic recognition of involved margins of lentigo maligna excised by staged excision: An interobserver comparison study. Arch Dermatol. 2003;139(5):595-604.

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15. Gerami P, Barnhill RL, Beilfuss BA, Leboit P, Schneider P, Guitart J. Superficial melanocytic neoplasms with pagetoid melanocytosis: A study of interobserver concordance and correlation with FISH. Am J Surg Pathol. 2010;34 (6):816-21.

16. Guitart J, Kennedy J, Ronan S, Chmiel JS, Hsiegh YC, Variakojis D. Histologic criteria for the diagnosis of mycosis fungoides: Proposal for a grading system to standardize pathology reporting. J Cutan Pathol. 2001;28(4):174-83.

17. Kazakov DV, Bisceglia M, Calonje E, Hantschke M, Kutzner H, Mentzel T, et al. Tubular adenoma and syringocystadenoma papilliferum: A reappraisal of their relationship. An interobserver study of a series, by a panel of dermatopathologists. Am J Dermatopathol. 2007;29(3):256-63.

18. Kempf W, Haeffner AC, Mueller B, Panizzon RG, Burg G. Experts and gold standards in dermatopathology: Qualitative and quantitative analysis of the self-assessment slide seminar at the 17th colloquium of the International Society of Dermatopathology. Am J Dermatopathol. 1998;20(5):478-82.

19. Lock-Andersen J, Hou-Jensen K, Hansen JP, Jensen NK, Sogaard H, Andersen PK. Observer variation in histological classification of cutaneous malignant melanoma. Scand J Plast Reconstr Surg Hand Surg. 1995;29(2):141-8.

20. Lodha S, Saggar S, Celebi JT, Silvers DN. Discordance in the histopathologic diagnosis of difficult melanocytic neoplasms in the clinical setting. J Cutan Pathol. 2008;35(4):349-52.

21. Massi D, Carli P, Franchi A, Santucci M. Naevus-associated melanomas: Cause or chance? Melanoma Res. 1999;9(1):85-91.

22. Massone C, Peter Soyer H, Lozzi GP, Di Stefani A, Leinweber B, Gabler G, et al. Feasibility and diagnostic agreement in teledermatopathology using a virtual slide system. Hum Pathol. 2007;38 (4):546-54.

23. McDermott NC, Hayes DP, al-Sader MH, Hogan JM, Walsh CB, Kay EW, et al. Identification of vertical growth phase in malignant melanoma. A study of interobserver agreement. Am J Clin Pathol. 1998;110(6):753-7.

24. Mooney E, Kempf W, Jemec GBE, Koch L, Hood A. Diagnostic accuracy in virtual dermatopathology. J Cutan Pathol. 2012;39(8):758-61.

25. Murali R, Cochran AJ, Cook MG, Hillman JD, Karim RZ, Moncrieff M, et al. Interobserver reproducibility of histologic parameters of melanoma deposits in sentinel lymph nodes: Implications for management of patients with melanoma. Cancer. 2009;115(21):5026-37.

26. Puri PK, Ferringer TC, Tyler WB, Wilson ML, Kirchner HL, Elston DM. Statistical analysis of the concordance of immunohistochemical stains with the final diagnosis in spitzoid neoplasms. Am J Dermatopathol. 2011;33(1):72-7.

27. Ramos-Ceballos FI, Ounpraseuth ST, Horn TD. Diagnostic concordance among dermatopathologists using a three-tiered keratinocytic intraepithelial neoplasia grading scheme. J Cutan Pathol. 2008;35(4):386-91.

28. Schettini FA, Ferreira LCL, Schettini APM, Camelo RT. Reproducibility of histopathologic diagnosis of skin diseases by digital photomicrographs versus conventional optical microscopy. An Bras Dermatol. 2011;86(3):491-6.

29. Scolyer RA, Shaw HM, Thompson JF, Li L-XL, Colman MH, Lo SK, et al. Interobserver reproducibility of histopathologic prognostic variables in primary cutaneous melanomas. Am J Surg Pathol. 2003;27(12):1571-6.

30. Silletti A, Peserico E, Mantovan A, Zattra E, Peserico A, Belloni Fortina A. Variability in human and automatic segmentation of melanocytic lesions. Conference proceedings : . 2009;Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2009:5789-92.

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31. Spatz A, Cook MG, Elder DE, Piepkorn M, Ruiter DJ, Barnhill RL. Interobserver reproducibility of ulceration assessment in primary cutaneous melanomas. Eur J Cancer. 2003;39(13):1861-5.

32. Urso C, Rongioletti F, Innocenzi D, Saieva C, Batolo D, Chimenti S, et al. Interobserver reproducibility of histological features in cutaneous malignant melanoma. J Clin Pathol. 2005;58 (11):1194-8.

33. Wechsler J, Bastuji-Garin S, Spatz A, Bailly C, Cribier B, Andrac-Meyer L, et al. Reliability of the histopathologic diagnosis of malignant melanoma in childhood. Arch Dermatol. 2002;138(5):625-8.

34. Wechsler J, Zanetti R, Schrameck C, Rosso S, Pippione M, Linares J, et al. Reproducibility of histopathologic diagnosis and classification of non-melanocytic skin cancer: A panel exercise in the framework of the multicenter southern European study HELIOS. Tumori. 2001;87(2):95-100.

35. Weinstock MA, Barnhill RL, Rhodes AR, Brodsky GL, The Dysplastic Nevus Panel. Reliability of the histopathologic diagnosis of melanocytic dysplasia. Arch Dermatol. 1997;133(8):953-8.

36. Yeh YA, Hudson AR, Prieto VG, Shea CR, Smoller BR. Reassessment of lymphocytic atypia in the diagnosis of mycosis fungoides. Mod Pathol. 2001;14(4):285-8.