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Original Investigation |

Detection of Occult Invasion in Melanoma In Situ ONLINE FIRST

Michael J. Bax, MD1; Timothy M. Johnson, MD1,2,3; Paul W. Harms, MD, PhD1,4; Jennifer L. Schwartz, MD1; Lili Zhao, PhD5; Douglas R. Fullen, MD1,4; May P. Chan, MD1,4
[+] Author Affiliations
1Department of Dermatology, University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor
2Department of Otolaryngology, University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor
3Division of Plastic Surgery, Department of Surgery, University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor
4Department of Pathology, University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor
5Department of Biostatistics, University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor
JAMA Dermatol. Published online August 10, 2016. doi:10.1001/jamadermatol.2016.2668
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Importance  It is unclear why some patients with in situ melanoma develop metastases. Few reports demonstrate occult invasion with immunohistochemistry staining, which were discordant with reports interpreting such staining as false-positive.

Objective  To investigate the occurrence of occult invasive disease within in situ melanoma by using methods to circumvent potential limitations in prior study designs.

Design, Setting, and Participants  Unequivocal in situ melanoma without associated nevi or regression was identified using a consecutive sample of 33 cases plus 1 index case in an academic medical center. After cutting deeper into the most representative tissue block, 3 sequential slides were stained with hematoxylin-eosin (H-E), melanoma antigen (melan-A), and again with H-E. Melan-A–stained slides showing definitive invasion were double-stained with Sry-related HMg-Box gene 10 (SOX10) to confirm the melanocytic nature of the cells of interest. The study evaluated the possibilities of occult invasion detected by immunohistochemistry, sectioning deeper into the tissue block, or both. Slides were independently scored by 3 dermatopathologists with interrater reliability assessed. The study was conducted from January 1, 2012, to July 31, 2014.

Main Outcomes and Measures  Assessment of the occurrence of occult invasion, diagnosis of invasion by immunohistochemistry alone vs cutting deeper into the tissue block, and occurrence of false-positive results using immunohistochemistry alone.

Results  Occult invasive melanoma was detected in 11 of 33 consecutive cases (33%) of previously diagnosed unequivocal in situ melanoma. Six of 11 melanomas (55%) were diagnosable only by immunohistochemistry. The remaining 5 tumors (45%) were diagnosable by both melan-A and H-E staining, likely as a result of simply cutting deeper into the tissue block. Four cases (12%) showed a few melan-A–positive cells in the dermis, which was insufficient for a diagnosis of invasive melanoma and most consistent on a cytomorphologic basis with occult nevi.

Conclusions and Relevance  Although rare, in situ melanoma may metastasize. Occult microinvasion was demonstrated in up to one-third of the specimens in the present study, which provides a plausible explanation for this adverse event. Thus, history and physical examination including regional lymph nodes, education, and surveillance recommendations should be based on a very low, but not zero, risk of metastasis.

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Figure 1.
Invasive Melanoma Detected on Hematoxylin-Eosin (H-E) Stain (Case 5)

A, H-E stain reveals a discrete nest of atypical epithelioid melanocytes in the superficial dermis (arrowhead). These cells contain ample cytoplasm, enlarged nuclei, and central nucleoli, cytologically identical to the overlying in situ component and therefore consistent with microinvasive melanoma (H-E score, 2) (original magnification ×400). B, Melanoma antigen (melan-A) immunostain highlights these melanoma cells (melan-A score, 2) (original magnification ×400).

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Figure 2.
Invasive Melanoma Suspicious on Hematoxylin-Eosin (H-E) Stain Confirmed by Melanoma Antigen (Melan-A) and SOX10 Immunostains (Case 7)

A, H-E stain shows large nests within the epidermis (top left) consistent with in situ melanoma. Rare, similarly appearing cells are seen in the dermis (arrowheads). Although suspicious for invasion, these cells are obscured by admixed lymphocytes and histiocytes that preclude definitive diagnosis (H-E score, 1) (original magnification ×400). B, Double-staining with melan-A and SOX10 immunostains highlight these cells (arrowheads) with cytoplasmic staining for melan-A (brown) and nuclear staining for SOX10 (red), confirming the presence of microinvasion (melan-A score, 2) (original magnification ×400).

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Figure 3.
Invasive Melanoma Detected on Melanoma Antigen (Melan-A) and SOX10 Immunostains Only (Case 10)

A, Hematoxylin-eosin (H-E) stain reveals numerous atypical melanocytes within the epidermis, consistent with in situ melanoma. No dermal invasion was identified (H-E score, 0) (original magnification ×200). B, Melan-A immunostain highlights the in situ melanoma as well as a few atypical cells with similar cytomorphology in the superficial dermis (arrowhead) (melan-A score, 2). Double melan-A/SOX10 immunostains shown in the inset confirm the melanocytic origin of these cells by demonstrating both cytoplasmic staining for melan-A (brown) and nuclear staining for SOX10 (red). These findings support the diagnosis of microinvasive melanoma (original magnification ×200; inset, ×400).

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Figure 4.
In Situ Melanoma With Occult Dermal Nevus Cells (Case 13)

A, Hematoxylin-eosin (H-E) stain reveals an increased number of atypical epithelioid melanocytes disposed singly along the dermoepidermal junction with foci of pagetoid spread, consistent with in situ melanoma. No dermal melanocytes were identified (H-E score, 0) (original magnification ×200). B, Melanoma antigen (melan-A) immunostain highlights the in situ melanoma and also rare single cells in the dermis (melan-A score, 1). These dermal cells (black arrowhead) are significantly smaller and blander than the in situ melanoma cells (white arrowhead) and are best interpreted as occult dermal nevus cells (original magnification ×200).

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