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. Author manuscript; available in PMC: 2022 Jun 1.
Published in final edited form as: Surg Pathol Clin. 2021 Apr 28;14(2):165–175. doi: 10.1016/j.path.2021.01.001

PRAME Immunohistochemistry as an Ancillary Test for the Assessment of Melanocytic Lesions

Cecilia Lezcano 1, Achim A Jungbluth 1, Klaus J Busam 1
PMCID: PMC8152939  NIHMSID: NIHMS1665025  PMID: 34023098

Synopsis

PRAME (PReferentially expressed Antigen in MElanoma) is a melanoma-associated antigen that is expressed in cutaneous and ocular melanomas as well as in some other malignant neoplasms while its expression in normal tissue and benign tumors is limited. Detection of PRAME protein expression by immunohistochemistry in a cohort of 400 melanocytic tumors showed diffuse nuclear immunoreactivity for PRAME in most metastatic and primary melanomas. In contrast, most nevi were completely negative for PRAME or showed non-diffuse immunoreactivity. The marked difference in the extent of immunoreactivity for PRAME in unambiguous melanocytic tumors, prompted the study of PRAME as an ancillary tool in the evaluation of melanocytic lesions in more challenging scenarios.

Keywords: PRAME, immunohistochemistry, melanoma, nevus

Background

PRAME (PReferentially expressed Antigen in MElanoma) is a tumor-associated antigen that was identified by Ikeda et al. by autologous T-cell epitope cloning in a patient with metastatic cutaneous melanoma(1). The expression of PRAME mRNA was detected by the authors and others not only in cutaneous and ocular melanomas, but also in various non-melanocytic malignant neoplasms, including carcinomas of pulmonary, renal, and mammary origin, leukemia, synovial sarcoma, and myxoid liposarcoma(2–10). Conversely, most benign adult tissue showed low or absent PRAME mRNA expression with the exception of testis, ovary, placenta, adrenals, and endometrium(1, 11). The expression profile of the PRAME gene, being expressed in malignant lesions but largely restricted to testis in non-neoplastic tissue, places PRAME in the category of cancer testis antigens (CTA)(12). This expression profile and its high prevalence in melanoma and other malignant tumors make PRAME particularly attractive for the development of targeted therapies and clinical trials related to tumor expression of CTAs, including PRAME, are on-going (7, 13–15).

As for most CT antigens, PRAME gene expression regulation is not yet entirely understood; however, it has been shown to be modulated by epigenetic mechanisms like DNA methylation, being hypermethylated in most normal tissues and hypomethylated in malignant cells(16–19). Regarding its cellular functions, PRAME has been identified as a repressor of the retinoic acid receptor (RAR) signaling. Retinoic acid through RAR signaling induces proliferation arrest, differentiation, and apoptosis in many cell types. These tumor-suppressive activities are normally mediated by retinoids, and impaired RAR signaling has been implicated in carcinogenesis. PRAME has been shown to interact with RAR in a ligand-dependent manner repressing the expression of RAR-target genes. Thus, overexpression of PRAME in many malignant neoplasms appears to contribute to cellular mechanisms of growth and tumor survival by antagonizing RAR signaling(20–22).

PRAME mRNA expression levels have been identified as an important biomarker for metastatic risk stratification of uveal melanomas(23, 24) and is part of a 12-gene expression prognostic assay (23). PRAME is also included in a 23-gene panel assay for cutaneous melanoma diagnosis (25, 26), and in a 2-gene non-invasive molecular assay to assess the need for biopsy of melanocytic lesions (27).

The availability of commercial monoclonal antibodies for immunohistochemical detection of PRAME protein in formalin-fixed paraffin-embedded tissue has facilitated the in situ evaluation of PRAME expression in histologic sections and allowed us to explore possible applications in dermatopathology.

PRAME IHC in primary cutaneous melanoma and nevi.

In a series of 155 primary cutaneous melanomas, the prevalence and extent of PRAME expression detected by immunohistochemistry was assessed. These included in situ and invasive melanoma of a wide variety of histologic subtypes including superficial spreading melanoma, lentigo maligna melanoma, acral melanoma, desmoplastic melanoma, non-desmoplastic nodular melanoma, as well as a few cases of melanomas less frequently encountered such as nevoid melanoma and melanoma-ex-blue nevus. In this series, PRAME immunoreactivity was diffuse (i.e. present in >75% of tumor cells) in 129 (83.2%) of all primary melanoma cases. Considering a subgroup of only melanoma in situ cases, forty-five out of forty-eight (93.8%) of them expressed PRAME in a diffuse pattern (Figure 1). When taking together all histologic subtypes of melanoma with an invasive component, the frequency of diffuse staining for PRAME was 78.5%. However, a marked difference in prevalence of diffuse PRAME expression was seen in desmoplastic versus non-desmoplastic melanoma subtypes. While diffuse PRAME expression was observed in 88.2 to 90.9% of superficial spreading, acral, nodular, and lentigo maligna melanomas (Figure 2); only 35% of desmoplastic melanomas were diffusely positive for PRAME. In cases of desmoplastic melanoma where only a subset of tumor cells were PRAME-positive, these frequently corresponded to the in situ component of the tumor or to the invasive non-desmoplastic component of mixed desmoplastic melanomas (Figure 2)(28). A similarly high prevalence of PRAME expression in invasive lentigo maligna melanoma has also been reported by others, although the same study found much lower PRAME expression rates in lentigo maligna-type in situ melanoma (29).

Figure 1.

Figure 1.

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(A) Melanoma in situ (H&E stain). (B) Sox10 immunostain included for comparison with the extent of staining seen with (C) PRAME, showing nuclear immunoreactivity diffusely in virtually all tumor cells in this case.

Figure 2.

Figure 2.

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Primary melanoma. (A) H&E stain showing in situ and invasive melanoma. (B) Both in situ and invasive melanoma are strongly and diffusely immunoreactive for PRAME in the majority of cases. (C) Desmoplastic melanoma, mixed type (H&E), (D) shows PRAME immunoreactivity of the in situ component and subset of the non-desmoplastic invasive tumor cells.

In contrast, of 140 cutaneous nevi most (86.4%) lacked staining for PRAME. However, a subset of benign nevi showed PRAME immunoreactivity that in the majority of the cases was limited to <50% of melanocytes (Figure 3). In this initial series, only one lesion of a pigmented junctional Spitz nevus from the cheek of a 6-year-old child showed diffuse PRAME staining. In melanomas found to be associated with a melanocytic nevus, only the melanoma tumor cells showed diffuse immunoreactivity for PRAME (Figure 4).

Figure 3.

Figure 3.

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PRAME immunoreactivity in a nevus. (A & B) Compound melanocytic nevus with architectural disorder (H&E stain) (C) shows a subset of PRAME-positive melanocytes at the dermoepidermal junction and in the superficial dermis. Note the melanin pigment within adjacent keratinocytes which at lower magnification could give a false impression of more extensive PRAME nuclear expression in melanocytes (if using a brown chromogen); examination at medium and high magnification prevents this potential pitfall.

Figure 4.

Figure 4.

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(A) Primary melanoma with associated nevus underlying invasive melanoma cells (H&E). (B) IHC for PRAME stains only melanoma cells and is negative in the associated nevus.

Our results have been replicated in a more recent study that reported most malignant melanomas (23/24; 95.8%) with PRAME immunoreactivity in over 60% of tumor cells while most nevi including traumatized, recurrent/persistent, dysplastic, and mitotically active nevi were negative for PRAME (43/45; 95.6%). This study also reported a single case of a Spitz nevus showing diffuse PRAME expression, although the majority of Spitz nevi (15/20) lacked staining for PRAME (30).

In non-neoplastic skin, nuclear PRAME staining is usually absent, or limited to few scattered melanocytes most frequently encountered in actinically damaged skin (28, 29). We have also noted occasional weak nuclear immunoreactivity of stromal cells in scars. Additionally, cytoplasmic PRAME staining is typically seen highlighting the cytoplasm of sebocytes in sebaceous glands. The significance of this finding is unclear. It is consistently observed with the EPR20330 clone, but not with all anti-PRAME antibodies (personal observations).

Uses

  • Support a suspected diagnosis of melanoma or nevus in conjunction with careful morphologic evaluation on H&E and correlation with clinical findings and/or additional ancillary tests when applicable.

  • Assist in the evaluation of primary tumor staging and Breslow tumor thickness measurement when a dermal melanocytic population with nevoid features is encountered underlying melanoma in situ or a combination of invasive melanoma and dermal nevic cells is suspected.

  • Margin assessment of melanoma in situ with broad predominantly lentiginous junctional growth and diffuse immunoreactivity for PRAME. Different from other melanocytic markers such as Melan A and Sox10 that highlight all melanocytes, PRAME preferentially highlights melanoma cells and is typically negative in most background non-neoplastic melanocytes.

Limitations and Pitfalls

  • Not all melanomas are diffusely positive for PRAME, some are completely negative while others show only focal or patchy expression.

  • Nevi can show PRAME immunoreactivity, but typically in only a subset of tumor cells. Rarely, benign nevi show diffuse PRAME expression.

  • Larger series of less frequent tumor subtypes such as melanoma ex-blue nevus, deep penetrating nevi, etc. are needed to draw conclusions on the use of PRAME in these melanocytic tumor subsets.

  • Intensity of staining can vary and interpretation of weak immunoreactivity can be difficult.

  • Occasional non-neoplastic melanocytes, especially in actinically-damaged skin, can be PRAME-positive, complicating the use of PRAME IHC for margin assessment particularly in lower-cellularity tumors with irregular borders.

  • If a DAB-detection system is used, care should be taken to not mistake melanin pigment within adjacent keratinocytes for PRAME nuclear expression in melanocytes; particularly when examining sections at scanning magnification. A closer look with a higher magnification objective lens should suffice to avoid this pitfall (Figure 3).

  • Tissue sections that underwent decalcification can show a significant decrease in PRAME tumor staining.

PRAME IHC in challenging cutaneous melanocytic tumors

The majority of melanocytic tumors can be readily classified as benign or malignant based on H&E histomorphology and clinical findings. However, ambiguous microscopic features and clinical context occasionally make classification and definitive diagnosis of melanocytic tumors challenging. Cytogenetic tests, including fluorescence in situ hybridization (FISH) for melanoma, genome-wide array comparative genomic hybridization (CGH), and single nucleotide polymorphism (SNP) array have been proven valuable in the assessment of melanocytic tumors (31–37). Limitations related to these tests include their cost, turnaround time, relatively limited availability, as well as limitations in their sensitivity and specificity.

In light of the markedly different results of PRAME immunostaining in unequivocally benign versus malignant melanocytic neoplasms(28), a role for PRAME IHC in the assessment of ambiguous melanocytic tumors was explored. These included melanocytic neoplasms with spitzoid and nevoid features, as well as lesions with dysplastic, combined, or deep-penetrating nevus-like morphology. Given the intrinsic difficulty in confidently classifying the lesions solely on histomorphology and clinical findings (38, 39), evaluation of results concordance with other established ancillary tests (FISH for melanoma and SNP-array) was pursued. A threshold of >75% of tumor cells positive for PRAME was established as in support of a melanoma diagnosis. Absence of PRAME or less than 75% of tumor cells immunoreactive for PRAME was interpreted as insufficient to support melanoma or in favor of an indolent lesion.

There was agreement between PRAME IHC and cytogenetic (FISH and/or SNP-array) results in 90 out of 100 cases (90% concordance) and agreement of 92.7% (102 out of 110 cases) between PRAME IHC results and final diagnostic interpretation that incorporated all available histomorphologic, clinical, PRAME IHC, and cytogenetic data (Figure 5). Of 10 cases with discordant PRAME IHC and cytogenetic results, 6 corresponded to lesions with non-diffuse PRAME immunoreactivity in which cytogenetic results and final diagnostic interpretation favored melanoma. In 2 cases with diffuse PRAME immunoreactivity and negative cytogenetic results, the final diagnostic interpretation favored malignant melanoma. Conversely, in 2 cases with final diagnostic interpretation favoring an indolent Spitz tumor in pediatric patients, PRAME IHC was negative while cytogenetic studies were suggestive of melanoma. In this cohort of highly challenging melanocytic tumors, the sensitivity of diffuse PRAME immunoreactivity for melanoma was 75%, while its specificity was 98.8%(40).

Figure 5.

Figure 5.

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PRAME IHC in challenging melanocytic tumors. (A&B) Atypical compound melanocytic tumor with a junctional component simulating a dysplastic nevus and an unusual dermal component with nevoid features, impaired maturation, and a rare mitotic figure. (C) PRAME immunostain diffusely highlights the intraepidermal and dermal tumor cells. (D) SNP-array showed several genomic aberrations including gains in chromosome 1 q, chromosome 6p, chromosome 9q, and segmental losses in chromosome 11p and 11q. FISH for melanoma confirmed that gains in 6p (RREB1) were present in both junctional and dermal components (FISH not shown). Chr= chromosome, seg= segmental.

Uses and Advantages

  • Additional evidence for diagnostic interpretation of difficult cutaneous melanocytic tumors.

  • Ancillary test that is easy to adopt given technical expertise in immunohistochemistry in most pathology laboratories and commercial availability of reagents including anti-PRAME monoclonal antibody.

  • Immunohistochemistry offers advantages over molecular tests including more rapid turn-around time, lower cost, and familiarity of pathologists with test interpretation.

Limitations and Pitfalls

  • “False negative”: Tumors with absent or focal immunoreactivity for PRAME that in light of other findings are ultimately favored to represent malignant melanoma.

  • “False positive”: A few cases with diffuse PRAME immunoreactivity upon review of all combined findings (i.e. histomorphology, clinical, and other ancillary studies such as cytogenetic tests) are indolent tumors (nevi or melanocytomas) with aberrant PRAME expression.

  • Intermediate extent of PRAME staining (present in >50% but <75% of tumor cells) and/or weak immunoreactivity can be very difficult to interpret, limit reproducibility, and ultimately be of little to no value to inform a final diagnosis.

  • Despite high concordance in results, PRAME IHC is not interchangeable with cytogenetic tests for melanoma.

  • PRAME IHC cannot replace expert histomorphologic evaluation and correlation with relevant clinical findings.

PRAME in the assessment of nodal melanocytic deposits

In the evaluation of 100 lesions of metastatic cutaneous melanoma to lymph nodes, soft tissue, and viscera we found most of them (92%) were immunoreactive for PRAME, the majority (87%) of which showed diffuse PRAME nuclear staining (i.e. present in >75% of tumor cells). When PRAME expression was compared in 14 paired specimens of primary cutaneous and corresponding metastatic melanoma, the extent of PRAME expression was retained or increased in the metastatic lesions (28).

This prompted the investigation of PRAME as a possible ancillary test for the assessment of nodal melanocytic deposits as metastatic melanoma to lymph nodes can on occasion be difficult to distinguish from nodal nevi. Scenarios where this can pose a challenge include the diagnosis of subcapsular and intraparenchymal nodal nevi, metastatic melanoma confined to the fibrous capsule, and the co-existence of nodal nevi and metastatic melanoma (41–48).

30 lymph nodes with nodal nevi, including 8 cases where nevic melanocytes were present in subcapsular and intraparenchymal location, were negative for PRAME and showed benign cytomorphologic features i.e. small cellular and nuclear size, regular nuclear membranes, inconspicuous or small nucleoli, and absent mitotic activity. Conversely, all 15 melanoma metastases to lymph node examined were diffusely positive for PRAME. These included 10 cases where metastatic melanoma deposits were seen in perinodal fibrous tissue (so-called lymph node capsule). The remainder 5 cases showed metastatic melanoma and nodal nevi co-existing in the same lymph node; in these cases, PRAME highlighted only metastatic melanoma cells and was negative in the benign melanocytes of the associated nodal nevus (Figure 6).

Figure 6.

Figure 6.

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Melanocytic deposits in a sentinel lymph node for melanoma. (A) Excision of a primary melanoma (H&E) that showed (B) diffuse immunoreactivity for PRAME. (C) The corresponding sentinel lymph node showed capsular and focally subcapsular nevic rests (H&E) (D) highlighted only by Melan A with a Melan A/PRAME double immunostain. (E) In the same lymph node, an adjacent focus of subcapsular metastatic melanoma is present (F) and shows co-labeling of red cytoplasmic Melan A and brown nuclear PRAME (Melan A/PRAME double immunostain).

A more recent series comparing the performance of PRAME to p16 IHC in the distinction of nodal melanocytic deposits, found similarly high sensitivity and specificity of PRAME immunostaining for nodal metastatic melanoma, being diffusely positive in 87% of metastatic tumor deposits. The majority of nodal nevi (43 out of 44) were negative for PRAME, only one nodal nevus was reported to show very weak focal staining (49).

Morphologic assessment of nodal melanocytic deposits on H&E routine sections remains paramount. Additionally, correlation of morphologic features between the primary tumor and suspected metastasis as well as knowledge of the PRAME expression status of the primary melanoma are always important. PRAME IHC may not be informative in the assessment of a nodal melanocytic deposit in the setting of a PRAME-negative primary melanoma.

Uses

  • PRAME immunostaining of a nodal melanocytic deposit is evidence in support of metastatic melanoma.

  • Absence of staining for PRAME in a nodal melanocytic deposit is evidence in support of a morphologically suspected nodal nevus, in particular when the primary melanoma is known to be diffusely positive for PRAME.

Limitations and Pitfalls

  • Not all metastatic melanomas are PRAME positive.

  • Lack of PRAME expression in a nodal melanocytic deposit is non-informative in the context of a sentinel lymph node for a PRAME-negative primary melanoma.

  • Non-specific PRAME labeling of scattered hematolymphoid cells in lymph nodes, which could complicate the use of PRAME IHC as single label in this setting. A PRAME/Melan A double-label immunostain (PRAME nuclear labeling by DAB -brown chromogen- and Melan A cytoplasmic labeling by FastRed -red chromogen) helps circumvent this issue.

  • Less frequently encountered variants of nodal nevus, such as blue nevus in lymph nodes, have not yet been evaluated with PRAME IHC.

  • Other non-melanocytic malignant tumors also express PRAME, thus assessment of lymph node metastases of poorly differentiated tumors of unclear primary requires evaluation of other immunohistochemical markers to establish tumor lineage.

PRAME IHC in conjunctival melanocytic nevi and mucosal melanomas

PRAME expression by immunohistochemistry was found to have value in the distinction of conjunctival nevi from conjunctival melanomas in a study that used a polyclonal rabbit anti-PRAME antibody that showed some cytoplasmic labeling in addition to the expected nuclear immunoreactivity. Using a score that combined staining intensity and extent of immunoreactivity in tumor cells, conjunctival melanomas showed significantly higher levels of PRAME protein expression than conjunctival nevi (50). A more recent study including mucosal melanomas of sinonasal, gastrointestinal, genitourinary, and oropharyngeal origin also found a high prevalence of PRAME expression (51).

PRAME IHC in other malignant neoplasms

From the initial studies identifying PRAME it has been known that PRAME mRNA is expressed in a wide variety of malignant neoplasms besides melanoma (1). Intermediate to occasionally high levels of PRAME protein expression have also been detected by immunohistochemistry in carcinomas of various origins including ovary, lung, and breast. In mesenchymal tumors, diffuse PRAME IHC staining is seen in most synovial sarcomas and myxoid liposarcomas (52). Clear cell sarcomas, which are relevant to the differential diagnosis of melanoma due to similarities in histomorphology and expression of most melanocytic differentiation markers, have been found to be negative or show limited PRAME expression (53).

Uses and advantages

  • PRAME IHC may become a helpful time- and cost-efficient tool in the selection of best candidates for novel therapies targeting PRAME based on the detected presence and extent of PRAME protein expression across several tumor types.

  • High prevalence of diffuse immunoreactivity for PRAME in malignant melanoma versus limited to absent expression in clear cell sarcoma shows potential value for diagnosis.

Limitations and Pitfalls

  • PRAME can be expressed in malignant tumors of various lineages, thus a panel of markers of differentiation -as well as molecular data in certain cases- is required when assessing malignant neoplasms of unknown origin (i.e. diffuse PRAME immunostaining does not always equal melanoma!).

Summary

Diffuse labeling with PRAME IHC in melanocytic neoplasms is strongly associated with melanoma. Thus, when other findings including histomorphology, clinical context, and -when applicable- additional ancillary studies favor melanoma, diffuse immunostaining for PRAME is additional supportive evidence for melanoma. However, it is critical for practicing pathologists to keep in mind that the sensitivity and specificity of PRAME IHC for melanoma is certainly not perfect and does not replace expert histopathologic evaluation.

The potential of PRAME IHC to inform the selection of cases for therapeutic purposes represents an exciting prospect where pathologists may further contribute to patient care.

Key Points.

  • PRAME is a tumor-associated antigen first identified in a melanoma patient and found to be expressed in the majority of melanomas as well as other malignant neoplasms.

  • Detection of PRAME expression in formalin-fixed paraffin-embedded tissue is possible through immunohistochemistry (IHC) with commercially available monoclonal anti-PRAME antibodies.

  • PRAME frequent diffuse pattern of immunoreactivity in in situ and invasive melanoma contrasts with the infrequent and typically focal staining seen in nevi.

  • Most metastatic melanomas are positive for PRAME, whereas nodal nevi are not.

  • PRAME IHC results showed high concordance with cytogenetic studies in a cohort of melanocytic neoplasms with ambiguous histomorphology; however, these tests are not interchangeable.

  • PRAME IHC is a valuable tool in the evaluation of melanocytic lesions; nevertheless, limitations in sensitivity and specificity as well as possible pitfalls need to be kept in mind by practicing pathologists.

Acknowledgements:

The authors wish to thank Denise Frosina for excellent technical assistance with the characterization of the antibody. They also thank Yesenia Gonzalez and Maria Sanchez for their assistance with digital images.

Footnotes

Disclosures: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

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