When the Skin Tells a Bigger Story: Distinguishing Cutaneous Metastases from Primary Adnexal Carcinomas in Dermatopathology

Elsayed Ibrahim; Phyu P. Aung

doi:10.20944/preprints202606.0816.v1

Submitted:

09 June 2026

Posted:

11 June 2026

You are already at the latest version

Abstract

Cutaneous metastases represent a relatively rare but clinically significant manifestation of advanced internal malignant neoplasms, occurring in approximately 0.7% to 10.4% of all cancer patients. Because cutaneous metastases can occasionally serve as the first indication of an occult internal malignant neoplasm, their accurate and timely diagnosis is of paramount importance. However, distinguishing cutaneous metastases from primary cutaneous neoplasms, particularly malignant cutaneous adnexal tumors, poses a diagnostic challenge in dermatopathology due to significant clinical and histomorphologic overlap. Here, we review the current literature on the epidemiology and clinical presentation of cutaneous metastases, emphasizing the importance of clinicopathologic correlation. While histologic features such as a purely dermal/subcutaneous location, intravascular tumor emboli, and a "bottom-heavy" architecture suggest metastasis, the presence of an in situ component or morphologic transition from a benign precursor lesion strongly supports a primary cutaneous origin. Furthermore, we detail the utility of optimized immunohistochemical panels, highlighting the diagnostic value of markers such as p63, cytokeratin 15, calretinin, and D2-40 (podoplanin) in confirming primary adnexal lineage. We also explore recent advances in molecular biology and comprehensive genomic profiling, discussing how the identification of specific gene fusions (e.g., MYB::NFIB, CRTC1::MAML2, YAP1 fusions) and mutational signatures can resolve ambiguous cases and provide critical insights into lineage. Finally, we provide a comprehensive, practical diagnostic algorithm for differentiating primary cutaneous adnexal carcinomas from cutaneous metastases of adenocarcinomas. By integrating traditional histopathologic techniques with modern immunohistochemical and molecular techniques, pathologists and clinicians can successfully navigate this complex differential diagnosis and thereby facilitate appropriate patient management and therapeutic intervention.

Keywords:

cutaneous metastases

;

adnexal carcinoma

;

dermatopathology

;

immunohistochemistry

;

p63

;

calretinin

;

D2-40

;

cytokeratin 15

;

gene fusions

;

Muir-Torre syndrome

;

diagnostic algorithm

Subject:

Medicine and Pharmacology - Pathology and Pathobiology

Introduction

Metastasis of internal malignant neoplasms to the skin is uncommon but clinically significant. Cutaneous metastases occur in approximately 0.7% to 10.4% of all patients with cancer and account for roughly 0.2% to 0.5% of all specimens evaluated in a typical dermatopathology practice [1,2]. While usually cutaneous metastases manifest in patients with a known history of widespread metastatic disease, in up to 17% of cases cutaneous metastases are the initial presenting sign of an occult internal malignant neoplasm [2,3]. The diagnosis of cutaneous metastases generally carries a poor prognosis, with median survival times often measured in months, underscoring the critical need for prompt and accurate identification [1].

One of the greatest diagnostic challenges in dermatopathology is distinguishing cutaneous metastases from primary cutaneous neoplasms, particularly malignant cutaneous adnexal tumors [4]. Primary adnexal carcinomas encompass eccrine, apocrine, follicular, and sebaceous lineages and exhibit a wide spectrum of morphologic patterns that can perfectly mimic cutaneous metastases from adenocarcinomas of the breast, lung, gastrointestinal tract, and kidney [4,5]. Because the clinical management, staging, and prognosis of a primary cutaneous neoplasm differ drastically from those of a metastatic visceral malignant neoplasm, distinguishing between the 2 entities is of paramount importance [1]. A misdiagnosis in either direction carries serious consequences: misidentifying a primary adnexal carcinoma as a metastasis may deny the patient a potentially curative surgical resection, while misidentifying a metastasis as a primary tumor may lead to inappropriate local treatment and delay in systemic workup.

In this review, we explore the epidemiological patterns and clinical presentations that provide initial diagnostic clues to differentiating between cutaneous metastases and primary adnexal carcinomas. We then detail the key histopathologic features that favor a primary versus metastatic origin. We emphasize the critical role of immunohistochemistry (IHC), including the utility of markers such as p63, cytokeratin 15 (CK15), D2-40, and calretinin, in establishing adnexal lineage. We discuss recent advances in molecular pathology, such as the identification of recurrent gene fusions and mutational signatures, that have revolutionized the classification of adnexal tumors and provided new tools for resolving diagnostically ambiguous cases [6,7]. Finally, we offer a robust, practical algorithm for differentiating cutaneous metastases from primary adnexal carcinomas.

Biology of Metastasis

To fully appreciate the diagnostic challenge posed by cutaneous metastases, it is essential to understand the biological mechanisms that drive tumor dissemination. The metastatic cascade is a highly inefficient but ultimately lethal process that requires cancer cells to overcome numerous physical and biological barriers. This process can be broadly divided into local invasion, intravasation, survival in the circulation, extravasation, and colonization of the distant microenvironment [8].

The initial step of the metastatic cascade is local invasion: the detachment of tumor cells from the primary mass and their invasion into the surrounding stroma. This step is largely driven by epithelial-mesenchymal transition, a process characterized by loss of epithelial features (such as cell-cell adhesion) and acquisition of a migratory, mesenchymal phenotype [9]. A hallmark of epithelial-mesenchymal transition is downregulation of E-cadherin, mediated by transcription factors such as SNAIL, TWIST, and ZEB [9]. This loss of E-cadherin dismantles adherens junctions, allowing cells to detach. Concurrently, tumor cells upregulate matrix metalloproteinases, which degrade the extracellular matrix and facilitate invasion toward local blood or lymphatic vessels [10].

Following local invasion, tumor cells must intravasate into the vasculature. This process is often facilitated by tumor-associated angiogenesis, driven by factors like vascular endothelial growth factor, which creates leaky, poorly formed blood vessels that are easier for tumor cells to penetrate [10].

Once in the bloodstream, tumor cells are termed circulating tumor cells (CTCs). The circulatory environment is highly hostile; CTCs face immense shear stress, anoikis (apoptosis induced by loss of cell-matrix attachment), and immune surveillance by natural killer cells [8]. To survive, CTCs often associate with platelets and coagulation factors, forming microthrombi that shield CTCs from immune detection and physical stress [8]. Furthermore, CTCs frequently travel in clusters, which exhibit significantly higher metastatic potential than single cells due to enhanced survival and stemness properties [8].

Upon reaching a distant capillary bed, such as the dermal microvasculature, CTCs arrest and extravasate into the surrounding tissue. However, successful extravasation does not guarantee metastasis.

The "seed and soil" hypothesis, originally proposed by Stephen Paget, posits that metastasis requires both a viable tumor cell (the seed) and a receptive microenvironment (the soil) [11]. Recent research has revealed that primary tumors actively prepare this "soil" even before CTCs arrive, creating a pre-metastatic niche [12]. The primary tumor secretes soluble factors (e.g., vascular endothelial growth factor, transforming growth factor-β) and extracellular vesicles (exosomes) that travel to distant organs. These factors induce vascular hyperpermeability, remodel the local extracellular matrix, and recruit bone marrow–derived cells, such as myeloid-derived suppressor cells and regulatory T cells, to create an immunosuppressive environment [12]. In the context of cutaneous metastases, the dermal microenvironment is altered to support the survival and proliferation of arriving CTCs, which ultimately leads to the macroscopic lesions encountered in dermatopathology.

Epidemiology and Timing of Diagnosis of Cutaneous Metastases

The sites of origin of cutaneous metastases differ significantly by patient sex. In women, breast carcinoma is by far the most common source of cutaneous metastases, accounting for up to 70% of cases, followed by melanoma, ovarian cancer, and lung cancer [3,13]. In men, melanoma is the most frequent source of cutaneous metastases, accounting for approximately 32% of cases, followed by carcinomas of the head and neck (16%), lung (12%), and colon (11%) [3,13]. Cutaneous metastases in children are rare, and most are associated with rhabdomyosarcoma and neuroblastoma [3].

The temporal relationship between diagnosis of the primary tumor and diagnosis of cutaneous metastases is also diagnostically relevant. Approximately 60% of cutaneous metastases are diagnosed after the primary tumor, 32% are diagnosed at the same time as the primary tumor, and only 8% are diagnosed before the primary tumor [3]. Diagnosis of cutaneous metastases before the primary tumor, while uncommon, has been documented in prostate cancer, rectal carcinoma, and thyroid carcinoma, among others [3].

Morphology of Cutaneous Metastases

Clinically, cutaneous metastases exist along a wide morphologic spectrum. They most commonly present as firm, painless, rapidly growing nodules or plaques that are flesh-colored to erythematous [13]. However, they can also mimic a variety of benign or inflammatory dermatologic conditions. For instance, metastatic lesions may resemble lipomas, epidermoid cysts, or pyogenic granulomas [3]. Cutaneous metastases from inflammatory carcinoma (carcinoma erysipelatoides), most commonly from breast primary tumors, present as an erythematous, edematous plaque that closely mimics cellulitis due to extensive lymphatic permeation in the dermis [1]. The Sister Mary Joseph nodule, a periumbilical metastasis, is a classic presentation of an intra-abdominal or pelvic malignant neoplasm and should prompt a thorough systemic workup [1].

Dermoscopy can provide useful clinical clues to the origin of cutaneous neoplasms. Nonpigmented cutaneous metastases typically have highly vascularized structures with atypical vessels (dotted, irregular, or glomerular); pigmented patterns may be observed in metastases from melanoma or breast carcinoma [14]. Despite these clinical clues, the definitive distinction between a primary adnexal tumor and a cutaneous metastasis relies heavily on histopathologic and ancillary testing.

Interpretation of Histopathologic Findings in Cutaneous Neoplasms

The initial evaluation of a cutaneous neoplasm using routine hematoxylin and eosin staining remains the cornerstone of diagnosis. Several architectural and cytologic features can help guide the pathologist toward diagnosis of a primary or metastatic tumor.

Features Favoring Metastasis

Metastatic lesions typically present as well-circumscribed nodules located in the deep reticular dermis or subcutaneous fat, often described as having a "bottom-heavy" architecture [1]. Key features of metastases are lack of connection to the overlying epidermis or native adnexal structures and absence of an in-situ component or benign precursor lesion [4]. The tumor cells often appear discordant or "foreign" relative to the adjacent normal skin. The presence of tumor emboli within dermal lymphatic vessels or blood vessels is a strong indicator of metastatic spread [1]. Additionally, the following specific cytologic features should immediately raise suspicion of metastasis: "dirty necrosis" (suggestive of carcinoma of colorectal origin), prominent signet ring cells (suggestive of carcinoma of gastric or lobular breast origin), clear cells with a prominent sinusoidal vascular network (suggestive of renal cell carcinoma [RCC]), and neuroendocrine nuclear features with salt-and-pepper chromatin (suggestive of small cell lung carcinoma or Merkel cell carcinoma) [1,4].

Features Favoring Primary Adnexal Carcinoma

Conversely, primary cutaneous adnexal carcinomas often demonstrate a connection to the epidermis or to native hair follicles, sebaceous glands, or sweat ducts [4]. The presence of an in situ component such as intraepidermal pagetoid spread in extramammary Paget disease (EMPD) or porocarcinoma strongly supports a primary tumor [1]. Primary tumors frequently exhibit a morphologic transition from a benign precursor lesion (e.g., a benign poroma transitioning into a porocarcinoma) or exhibit a spectrum of differentiation ranging from well-differentiated adnexal structures to frank carcinoma [4]. The presence of a desmoplastic stroma and perineural invasion are common in certain primary adnexal tumors, most notably microcystic adnexal carcinoma, a locally aggressive tumor that rarely metastasizes but exhibits extensive perineural spread in up to 80% of cases [15].

Morphologic Patterns Commonly Causing Confusion

Several specific morphologic patterns are notorious for causing confusion about whether cutaneous neoplasms are primary or metastatic (Table 1). Several of these patterns are discussed here; immunohistochemical markers used in such cases are discussed below in the section Immunohistochemical Panels.

Clear Cell Tumors. Primary cutaneous clear cell tumors, such as sebaceous carcinoma, clear cell hidradenoma, and clear cell porocarcinoma, can closely mimic metastatic clear cell RCC [4]. Distinguishing between primary clear cell tumors and metastatic RCC is particularly difficult because both RCC and some primary sebaceous tumors can express CD10 and EMA [1]. The identification of sebaceous lobules, comedonecrosis, or an epidermal connection favors a primary sebaceous neoplasm, while PAX8 positivity and CK7 negativity are characteristic of RCC [16].

Mucinous Tumors. Primary mucinous carcinoma of the skin is a rare adnexal tumor that is histologically indistinguishable from metastatic mucinous carcinoma of the breast or gastrointestinal tract [4]. Both present as islands of atypical epithelial cells floating in large pools of extracellular mucin. The presence of an in situ component within adnexal structures and the absence of a breast or gastrointestinal primary tumor are essential for establishing a primary cutaneous diagnosis.

Extramammary Paget Disease. Primary EMPD and secondary EMPD are particularly difficult to distinguish from one another. Primary EMPD arises as an intraepithelial neoplasm from pluripotent keratinocyte stem cells or adnexal glandular cells, while secondary EMPD results from the epidermotropic spread of an underlying adenocarcinoma (most commonly rectal or urothelial) [1]. The 2 forms share a pagetoid intraepidermal growth pattern with large cells containing abundant pale cytoplasm and prominent nucleoli. The distinction between primary and secondary EMPD is critical because the diagnosis of secondary EMPD mandates treatment of the underlying visceral malignant neoplasm.

Immunohistochemical Panels

IHC is an indispensable adjunct in the differential diagnosis of cutaneous neoplasms. While no single marker is entirely specific for primary adnexal lineage, a carefully selected panel can significantly improve diagnostic accuracy.

Markers Favoring Primary Adnexal Carcinoma

The most robust panel for confirming a primary cutaneous adnexal carcinoma includes p63, CK15, D2-40 (podoplanin), and calretinin [17]. When a tumor exhibits positive staining for all or most of these markers, a primary cutaneous adnexal neoplasm is strongly favored [17].

p63 and p40. The p53 homologue p63 is expressed in the basal and myoepithelial cells of normal skin appendages and is highly sensitive for primary adnexal carcinomas; it is expressed in over 90% of primary adnexal carcinomas but only approximately 8% of metastatic adenocarcinomas [17]. The truncated isoform p40 (ΔNp63) has a sensitivity of approximately 84% and a specificity superior to that of p63 in distinguishing primary cutaneous adnexal carcinomas from cutaneous metastases [18].

Cytokeratin 15. CK15 is a marker of follicular stem cells located in the bulge region of the hair follicle. It is highly specific (up to 98%) for primary adnexal carcinomas, although its sensitivity is lower (approximately 40%) [17]. Its high specificity makes it a valuable confirmatory marker when positive.

D2-40 (Podoplanin). D2-40 is a transmembrane mucoprotein expressed in lymphatic endothelium, the basal cells of the epidermis, and the outer root sheath of hair follicles. D2-40 expression is seen in approximately 44% of primary adnexal carcinomas but is virtually absent in metastatic adenocarcinomas and has a specificity of approximately 96% for primary adnexal carcinomas [17,19].

Calretinin. Calretinin is a calcium-binding protein of the EF-hand family that is expressed in the innermost cell layer of the outer root sheath in normal anagen hair follicles, as well as in both the duct and secretory portions of eccrine sweat glands [20]. In the context of cutaneous neoplasms, calretinin is frequently positive in tumors with follicular differentiation (e.g., tricholemmoma, trichilemmal carcinoma, and pilomatricoma) and is positive in a significant proportion of sweat gland tumors [20,21]. Mahalingam et al. demonstrated calretinin expression in approximately 14% of primary adnexal carcinomas versus 10% of cutaneous metastases, suggesting a modest but real contribution to the panel [17]. However, other studies have reported calretinin positivity in up to 64% of cutaneous adnexal tumors, particularly those with follicular or eccrine differentiation [21]. The inclusion of calretinin in the diagnostic panel, alongside p63, CK15, and D2-40, provides additional support for a primary cutaneous origin. An important caveat is that calretinin is also strongly expressed in malignant mesothelioma; therefore, in the rare scenario of calretinin positivity in combination with p63 negativity, cutaneous mesothelioma metastasis should be considered [22].

Markers for Metastases from Tumors in Specific Organs

When a metastatic origin is suspected on the basis of morphology or negative findings of a primary adnexal tumor panel, markers for tumors in specific organs are employed to identify the primary tumor site (Table 1).

Breast. Metastatic breast carcinoma is the most common source of cutaneous metastases in women. A panel including GATA3, estrogen receptor, progesterone receptor, and mammaglobin is highly sensitive and specific for breast carcinoma [23]. GATA3 is particularly useful as it is expressed in most breast carcinomas (sensitivity ~91%) but is typically negative in primary sweat gland carcinomas, though it may be expressed in urothelial carcinoma [23]. Loss of E-cadherin expression is characteristic of lobular breast carcinoma and its metastases and can help distinguish lobular breast carcinoma metastases from signet ring cell adnexal tumors [1].

Lung. Metastatic lung adenocarcinoma typically expresses TTF-1, Napsin A, and CK7 [1]. The combination of TTF-1 and Napsin A positivity is highly specific for a pulmonary origin [24]. It should be noted that squamous cell carcinoma of the lung expresses p40 and CK5/6, markers that overlap with primary cutaneous squamous carcinoma and primary cutaneous adnexal carcinoma, necessitating careful clinical correlation.

Gastrointestinal Tract. Metastatic colorectal carcinoma is classically positive for CK20 and CDX2 and negative for CK7 [1]. The combination of "dirty necrosis" on hematoxylin and eosin staining and a CK20-positive, CDX2-positive, CK7-negative profile is virtually diagnostic of colorectal origin.

Kidney and Genitourinary Tract. Metastatic clear cell RCC is typically positive for PAX8 and CD10 and negative for CK7 and CK20 [1]. PAX8 is a highly sensitive and specific marker for tumors of renal, Müllerian (ovarian), or thyroid origin, making it invaluable in distinguishing metastases from such tumors from primary adnexal tumors [16].

Extramammary Paget Disease. The IHC profile of EMPD is particularly instructive of the value of IHC in identifying tumor origin. Primary EMPD typically is CK7 positive, CK20 negative, TRPS1 positive, and GCDFP-15 positive, reflecting its apocrine glandular origin. Secondary EMPD associated with an anorectal malignant neoplasm typically exhibits the opposite staining pattern for these markers, i.e., CK7 negative, CK20 positive, TRPS1 negative, and GCDFP-15 negative, along with CDX2 positivity. Secondary EMPD associated with urothelial carcinoma typically is CK7 positive, CK20 positive, uroplakin positive, and GCDFP-15 negative.

Molecular Advances and Genomic Profiling of Cutaneous Adnexal Tumors

Recent advances in molecular pathology have revolutionized the classification of cutaneous adnexal tumors, revealing that many of these neoplasms harbor specific recurrent genetic alterations. These discoveries not only aid in resolving diagnostically challenging cases but also highlight the biological similarities between cutaneous adnexal tumors and homologous tumors in the salivary and mammary glands [6].

Recurrent Gene Fusions in Primary Adnexal Neoplasms

Several primary adnexal carcinomas are now defined by specific gene fusions, which can be detected via fluorescence in situ hybridization, RT-PCR, or next-generation sequencing. Table 2 summarizes the major molecular alterations in adnexal tumors.

Adenoid Cystic Carcinoma. Cutaneous adenoid cystic carcinoma is characterized by recurrent MYB::NFIB or MYBL1::NFIB gene fusions in up to 83% of cases, identical to its salivary gland counterpart [6]. MYB and SOX10 detected on IHC can serve as surrogate markers for fusion, with SOX10 showing intense and diffuse nuclear positivity in the vast majority of cases [6].

Poroma and Porocarcinoma. In poroma and porocarcinoma, YAP1 fusions are present in a significant majority of cases and serve as strong diagnostic markers [6]. IHC for YAP1 C-terminus (showing cytoplasmic loss) and NUT (showing nuclear positivity) can be used as surrogate markers for the fusion in routine practice [6].

Hidradenoma and Hidradenocarcinoma. Hidradenoma and hidradenocarcinoma are characterized by CRTC1::MAML2 or CRTC3::MAML2 fusions, similar to mucoepidermoid carcinoma of the salivary gland [6]. This molecular overlap can cause diagnostic confusion when a MAML2-rearranged tumor presents in the skin as it may represent either a primary adnexal tumor or a metastasis from a salivary gland mucoepidermoid carcinoma.

Secretory Carcinoma. Cutaneous secretory carcinoma is defined by the ETV6::NTRK3 gene fusion, which is also the hallmark of secretory carcinoma of the breast and salivary gland [6]. The identification of this fusion is diagnostically critical as it not only confirms the diagnosis but also identifies patients who may benefit from TRK inhibitor therapy (e.g., larotrectinib, entrectinib).

Sebaceous Neoplasms and Muir-Torre Syndrome

Sebaceous neoplasms are of special concern because they are associated with Muir-Torre syndrome, a variant of Lynch syndrome caused by germline mutations in mismatch repair (MMR) genes, most commonly MSH2 and MSH6 [25] (Table 2). IHC for MMR proteins (MLH1, PMS2, MSH2, and MSH6) should be performed on sebaceous neoplasms especially from the non-head and neck area as loss of expression of MMR genes identifies patients who require genetic counseling and screening for synchronous or metachronous visceral malignant tumors, particularly colorectal, endometrial, and urothelial carcinomas [25]. Importantly, the presence of sebaceous differentiation in a carcinoma does not automatically indicate a primary cutaneous origin; metastatic carcinomas with sebaceous-like differentiation have been reported, and the clinical context must always be considered.

Comprehensive Genomic Profiling

Comprehensive genomic profiling has provided further insights into the pathogenesis of adnexal tumors. Sebaceous tumors exhibit the highest frequency of genomic alterations among adnexal carcinomas, including frequent mutations in RB1 (38.2%) and TP53 (76.4%), as well as microsatellite–high status in approximately 15.7% of cases [7]. In contrast, sweat gland tumors generally exhibit lower genomic alteration burdens, reflecting their distinct pathogenesis driven by specific gene fusions rather than widespread genomic instability [7]. The tumor mutational burden across most adnexal carcinoma types ranges from 10.4 mutations per megabase to 38.8 mutations per megabase [7]. Unlike basal cell and squamous cell carcinomas, which are driven by ultraviolet-induced mutational signatures, many deep-seated adnexal tumors lack ultraviolet signatures, further supporting their distinct biology [6,7].

Practical Diagnostic Algorithm

To navigate the complex problem of distinguishing between primary adnexal carcinomas and cutaneous metastases, we propose the following practical, stepwise algorithm:

Step 1: Clinical and Historical Assessment. Begin with a thorough review of the patient's age and sex, anatomic site of the lesion, and, most important, any history of a prior malignant neoplasm. Determine the temporal relationship (synchronous vs. metachronous) and the number and distribution of lesions. A solitary lesion in a patient without a prior malignant neoplasm favors a primary tumor, while multiple dermal nodules in a patient with known advanced cancer strongly favor metastasis.

Step 2: Low-Power Histologic Evaluation. Assess the architectural pattern on hematoxylin and eosin staining. Look for an epidermal connection, an in situ component, or a transition from a benign precursor, which strongly favors a primary adnexal origin. Conversely, a purely dermal/subcutaneous location, a "bottom-heavy" architecture, and intravascular tumor emboli favor metastasis.

Step 3: High-Power Cytologic Evaluation. Identify specific cytomorphologic features that suggest a particular lineage, such as clear cells, mucin production, signet ring cells, basaloid nesting, neuroendocrine chromatin, or sebaceous differentiation.

Step 4: Initial IHC Panel (Primary Adnexal Screen). Employ a panel of IHC markers for primary adnexal carcinoma, including p63 (or p40), CK15, D2-40, and calretinin. Strong, diffuse positivity for these markers strongly suggests a primary cutaneous adnexal neoplasm. A negative result for all 4 markers strongly favors metastasis and should prompt an organ-specific workup.

Step 5: Lineage-Specific IHC Markers. If the initial panel is negative or equivocal or if morphology strongly suggests metastasis, employ organ-specific markers based on the suspected primary tumor site: GATA3 and estrogen receptor for breast; TTF-1 and Napsin A for lung; CK20 and CDX2 for colorectal; PAX8 for renal or Müllerian; NKX3.1 and prostate-specific antigen for prostate; and CK20 paranuclear dot-like pattern for Merkel cell carcinoma.

Step 6: Molecular Testing. In diagnostically ambiguous cases or when a specific fusion–driven adnexal tumor is suspected, utilize fluorescence in situ hybridization or next-generation sequencing to identify defining molecular alterations (e.g., MYB, YAP1, CRTC1, or ETV6 fusions). Perform IHC or PCR studies for MMR genes on all sebaceous neoplasms to screen for Muir-Torre syndrome.

Conclusions

Distinguishing primary cutaneous adnexal carcinomas from cutaneous metastases from adenocarcinomas remains one of the most challenging tasks in dermatopathology. A purely morphologic assessment is often insufficient due to the profound histologic overlap between these entities. However, by integrating careful clinicopathologic correlation with an optimized immunohistochemical panel including p63/p40, CK15, D2-40, and calretinin, pathologists can accurately establish the diagnosis, which will be a primary cutaneous neoplasm in the majority of cases. The rapid expansion of molecular pathology has provided a new dimension to the classification of adnexal tumors, offering definitive diagnostic biomarkers in the form of recurrent gene fusions and mutational signatures. As our understanding of the molecular landscape of primary cutaneous adnexal tumors continues to evolve, the integration of traditional histopathology with advanced genomic profiling will undoubtedly become the standard of care, ensuring accurate diagnosis and guiding optimal therapeutic management for patients presenting with malignant cutaneous neoplasms.

Acknowledgments

Ms. Stephanie Deming, ELS, Senior Scientific Editor, Research Medical Library, The University of Texas MD Anderson Cancer Center, assisted us with editing of this manuscript.

Conflict of Interest and Source of Funding

All authors declare no conflicts of interest.

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Table 1. Common Morphologic Patterns Seen in Both Primary Adnexal Carcinomas and Cutaneous Metastases.

Morphologic Pattern	Primary Adnexal Tumors With Pattern	Cutaneous Metastases With Pattern	Key Distinguishing Features
Clear cell	Sebaceous carcinoma, clear cell hidradenoma	Clear cell RCC	Primary adnexal tumor: epidermal connection, sebaceous lobules, PAX8−, CD10+
Mucinous	Primary mucinous (eccrine) carcinoma	Mucinous breast carcinoma, mucinous colorectal adenocarcinoma	Primary adnexal tumor: p63+ Breast: ER+, GATA3+ Colorectal: CDX2+, CK20+
Glandular/ductal	Apocrine carcinoma, eccrine carcinoma	Breast, lung, pancreatic adenocarcinoma	Primary adnexal tumor: p63+, CK15+ Breast: ER+, GATA3+ Lung: TTF-1+, Napsin A+
Basaloid/nested	Adenoid cystic carcinoma, spiradenocarcinoma	Small cell lung carcinoma, Merkel cell carcinoma	Small cell lung: TTF-1+, synaptophysin+ MCC: CK20 paranuclear dot-like pattern
Pagetoid intraepidermal	Primary EMPD, porocarcinoma	Secondary EMPD (colorectal, urothelial)	Primary EMPD: CK7+, GCDFP-15+ Colorectal: CDX2+, CK20+ Urothelial: uroplakin+
Signet ring cell	Signet ring cell hidradenoma	Gastric, lobular breast carcinoma	Gastric: CDX2+, CK20+ Lobular breast: GATA3+, E-cadherin loss

—, negative; +, positive; ER, estrogen receptor; MCC, Merkel cell carcinoma.

Table 2. Key Molecular Alterations in Primary Cutaneous Adnexal Tumors and Their Extracutaneous Homologues.

Tumor Type	Molecular Alteration	Frequency	Homologous Extracutaneous Tumor
Adenoid cystic carcinoma	MYB::NFIB or MYBL1::NFIB fusion	73–83%	Salivary gland ACC
Poroma and porocarcinoma	YAP1 fusion (e.g., YAP1::MAML2)	~88%	—
Hidradenoma and hidradenocarcinoma	CRTC1::MAML2 or CRTC3::MAML2 fusion	50–75%	Mucoepidermoid carcinoma (salivary gland)
Secretory carcinoma	ETV6::NTRK3 fusion	~100%	Secretory carcinoma (breast, salivary gland)
Cylindroma	CYLD inactivation	~100%	—
Spiradenoma	CYLD inactivation or ALPK1 mutation	~70% combined	—
Mixed tumor (chondroid syringoma)	PLAG1 fusion	~33%	Pleomorphic adenoma (salivary gland)
Myoepithelioma	EWSR1 or FUS fusion	~100%	Myoepithelioma (salivary gland, soft tissue)
Sebaceous tumors (Muir-Torre syndrome)	MMR loss (MSH2, MSH6), MSI-H	~15–20%	Lynch syndrome–associated visceral cancers

ACC, adenoid cystic carcinoma; MSI-H, microsatellite instability–high.

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