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Ghost cell
Ghost cell
Ghost cell
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Endometrial adenocarcinoma with necrotic ghost cells of keratinocytes at right in image, leaving pink keratin and clear spaces at the prior locations of the nuclei.

A ghost cell is an enlarged eosinophilic epithelial cell with eosinophilic cytoplasm but without a nucleus. It has lost its nucleus and cytoplasmic contents, leaving behind only the cell membrane and sometimes remnants of the cell's structure. In pathology, ghost cells are often associated with certain types of tumors, such as pilomatricomas and calcifying odontogenic cysts, where they appear as pale, anucleate cells that have undergone degeneration or calcification.

The ghost cells indicate coagulative necrosis where there is cell death but retainment of cellular architecture. In histologic sections ghost cells are those which appear as shadow cells. They are dead cells. For example, in peripheral blood smear preparations, the RBCs are lysed and appear as ghost cells.

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References

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Ghost cell

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A ghost cell is a degenerated epithelial cell characterized by its enlarged, swollen, pale cytoplasm, absence of a visible nucleus, and preservation of the cellular outline, often resulting from aberrant keratinization or , and commonly observed under hematoxylin-eosin staining as translucent structures with possible remnants of nuclear membranes or organelles. These cells were first described in the context of pilomatricomas (also known as pilomatrixomas) by Highman and Ogden, and later linked to odontogenic lesions by researchers such as Praetorius, highlighting their role in epithelial pathology. In oral and maxillofacial pathology, ghost cells are a hallmark feature of various developmental, cystic, and neoplastic conditions, including the calcifying odontogenic cyst (COC), dentinogenic ghost cell tumor, and ghost cell odontogenic carcinoma, where they may undergo or contribute to the tumor's aggressive behavior. They can also appear in other odontogenic lesions such as odontomas and ameloblastomas, and in non-odontogenic lesions such as craniopharyngiomas and pilomatrixomas, underscoring their association with keratinizing epithelial transformations.

Definition and Characteristics

Definition

A ghost cell is defined as an enlarged, epithelial cell that exhibits a preserved cytoplasmic outline but lacks a nucleus and intracellular contents as a result of degenerative changes. These cells appear swollen and pale due to the loss of nuclear material and cytoplasmic organelles, while retaining the basic cellular architecture. The concept of ghost cells was first introduced in 1946 by Thoma and Goldman in their description of odontogenic lesions, highlighting their characteristic "ghost-like" appearance in histological sections. This terminology gained prominence in the mid-20th century through studies on calcifying odontogenic cysts, where such cells were identified as a key pathological feature. In distinction from other forms of cellular degeneration, ghost cells do not display (nuclear fragmentation) or (nuclear dissolution), instead presenting a uniform ballooned, pale morphology that underscores their unique degenerative pathway. They are briefly associated with aberrant keratinization processes within odontogenic epithelium.

Histological Features

Ghost cells are characterized microscopically by their swollen, pale-staining on hematoxylin and eosin (H&E) , often exhibiting a faint cellular outline with a pyknotic or absent nucleus, imparting a shadowy or translucent appearance. Also known as shadow cells, this quality arises from intracytoplasmic keratinization, where coarse tonofilament bundles accumulate, leading to clear, vacuolated areas within the cell that contribute to the "ghostly" translucency. These cells adopt an elliptical or rounded, balloon-like shape, either singly or in sheets. Special staining techniques further highlight these features: ghost cells show positive reactivity with periodic acid-Schiff (PAS) due to or altered content, while remaining negative for Alcian blue, indicating an absence of acidic mucopolysaccharides. Immunohistochemically, they demonstrate strong positivity for cytokeratins such as AE1/AE3 and 34βE12, confirming their epithelial and keratinized nature, but are negative for proliferation markers like Ki-67, consistent with their anucleate, non-viable state. In odontogenic lesions, such as calcifying odontogenic cysts, these histological traits aid in distinguishing ghost cells from viable epithelium.

Pathophysiology

Formation Mechanisms

Ghost cells arise through a degenerative process characterized by aberrant keratinization and an in odontogenic epithelial cells, involving partial squamous differentiation followed by selective nuclear dissolution that leaves the intact. This transformation begins with enlargement of mural epithelial cells, progressing to accumulation of altered material and loss of nuclear details, resulting in the characteristic shadow-like appearance with preserved cell outlines. Molecular dysregulation plays a central role, particularly in cytokeratin expression; ghost cells typically exhibit positivity for high-molecular-weight cytokeratins (e.g., AE1/AE3) but show reduced or absent reactivity to low-molecular-weight variants like CK13 and CK19, indicative of faulty terminal differentiation. Mutations in keratin genes, such as (e.g., Y281H), have been identified in lesions with prominent ghost cell clusters, potentially contributing to perinuclear condensation and cytoplasmic persistence. The cell death mechanism is caspase-independent, as demonstrated by negative for cleaved caspase-3 and lamin A in transitional cells, distinguishing it from classical while sharing features like DNA double-strand breaks and Bax positivity. In the context of cystic or tumoral lesions, environmental factors such as local hypoxia trigger this by promoting metaplastic changes in epithelial cells. Wnt pathway activation leading to β-catenin accumulation has also been implicated in ghost cell formation. The formation unfolds gradually during neoplastic proliferation, evolving from basaloid precursors through transitional stages to mature ghost cells over the course of tumor development, in contrast to the rapid onset of acute . This cytoplasmic remnant arises from the keratin-rich degeneration, contributing to the cells' distinctive histological profile.

Biological Role

Ghost cells play a crucial role in modulating the growth dynamics of epithelial-derived neoplasms by contributing to tumor indolence. Through terminal differentiation and apoptosis-like processes, they reduce the overall proliferative activity within the , leading to slower expansion and diminished malignant potential. This indolent behavior is evidenced by the absence of proliferative markers in ghost cells, distinguishing them from surrounding viable epithelial cells. In pathological contexts, ghost cells function as a mechanism for stress relief in , serving as repositories for accumulated produced during aberrant keratinization. This process allows adjacent viable cells to avoid excessive buildup, which could otherwise trigger and compromise neoplasm survival. By sequestering excess , ghost cells promote the persistence of the tumor mass without immediate cellular demise. Immunohistochemical analyses further support the senescent-like state of ghost cells, revealing low or negligible expression of proliferation markers such as Ki-67, typically below 5% in affected regions. This contrasts with higher expression in peripheral epithelial components, underscoring the non-proliferative nature of ghost cells. Such findings indicate a post-mitotic, differentiated that aligns with reduced metabolic activity.

Associated Pathological Conditions

Odontogenic Cysts and Tumors

Ghost cells are prominently associated with and tumors of dental origin, particularly the calcifying odontogenic cyst (COC), also known as the Gorlin cyst, where they represent a defining histological component often undergoing . In COCs, ghost cells typically appear as clusters of anucleate, epithelial cells within the ameloblastoma-like lining, contributing to the lesion's characteristic calcified structures and distinguishing it from other odontogenic cysts. These cells are present in all cases, with reviews indicating their consistent occurrence in documented COCs. Within odontogenic tumors, ghost cells are a key feature of the dentinogenic ghost cell tumor (DGCT), a rare solid variant of COC characterized by ameloblast-like epithelial islands interspersed with clusters of ghost cells and associated dentinoid material. In DGCT, ghost cells often form focal aggregates that induce surrounding dentinoid deposition, reflecting an aberrant odontogenic differentiation process. Similarly, the ghost cell odontogenic (GCOC), a malignant , exhibits ghost cells amid infiltrative ameloblastic epithelium, typically arising de novo or from preexisting benign lesions like COC or DGCT. These ghost cells in GCOC maintain their anucleate morphology but occur in a more disorganized stromal context, underscoring the tumor's aggressive potential. Ghost cells have also been observed in odontomas, particularly complex odontomas, where they arise from metaplastic transformation of odontogenic epithelium and are present in most cases. The prevalence of ghost cells underscores their diagnostic significance in these entities; for instance, they are identified in all COCs based on comprehensive case reviews, while their presence in ameloblastomas remains rare, limited to exceptional ghost cell variants that mimic COC features. This selective occurrence highlights ghost cells as a hallmark of specific odontogenic pathologies rather than a ubiquitous trait. The recognition of ghost cells as integral to these lesions traces back to the 1970s, when the World Health Organization's 1971 classification of odontogenic tumors formally described the , emphasizing their role in lesion identification.

Non-Odontogenic Lesions

Ghost cells, also known as shadow cells, are a prominent histological feature in pilomatricomas, benign skin tumors arising from hair matrix cells, where they result from abrupt keratinization of basaloid matrical cells, leading to anucleated cells with a central pale area corresponding to the lost nucleus. In these lesions, often referred to as calcifying epitheliomas of Malherbe, ghost cells form sheets or clusters within epithelial islands, frequently surrounded by reactions and stromal , with dystrophic calcium deposits observed in approximately 75% of cases, increasing with tumor age. This in pilomatricomas is typically dystrophic and associated with debris, distinguishing it from the more structured enamel- or dentin-like calcifications seen in odontogenic counterparts. In non-odontogenic craniofacial lesions, ghost cells appear rarely in adamantinomatous craniopharyngiomas, intracranial tumors derived from remnants, where they manifest as plump, anucleate squamous cells forming nodules of wet within lobules of stratified , often accompanied by that are a hallmark of the tumor and visible on imaging. These ghost cells in craniopharyngiomas can mimic odontogenic patterns due to their squamous differentiation and association with stellate reticulum-like areas, but they exhibit variable protein expression, such as low levels, suggesting distinct formation pathways from those in skin tumors. here is frequently extensive, involving ghost cell clusters and contributing to the tumor's characteristic radiographic appearance. Ghost cells are systemically rare outside odontogenic and cutaneous contexts, with occasional reports in salivary gland tumors, such as or basaloid squamous cell carcinoma of the parotid, where they comprise significant portions of the (up to 62% in documented cases) and display prominent shadow cell differentiation with stromal and osseous . In metastatic s, ghost cells have been noted infrequently, particularly in basaloid variants, showing faded nuclei and with occasional , though less consistently than in primary salivary or lesions. Overall, non-odontogenic ghost cells tend to exhibit higher rates of and responses compared to odontogenic ones, reflecting differences in keratinization and stromal interactions.

Diagnosis and Identification

Microscopic Diagnosis

Microscopic diagnosis of ghost cells begins with appropriate tissue sampling through incisional of suspected cystic or tumoral lesions, particularly targeting the epithelial lining and solid components where ghost cells are most likely to occur. Extensive sampling is recommended, as the distribution of ghost cells can be focal, potentially leading to underdiagnosis if only limited areas are examined. In routine hematoxylin and eosin (H&E) stained sections, ghost cells are identified as enlarged, polyhedral cells with sharply outlined, and a central pale or empty space representing the lost nucleus, often appearing as a shadowy outline. The requires the conspicuous presence of these cells within sheets or islands of odontogenic , typically confirmed by the absence of nuclear (no hematoxylin uptake) and immunoreactivity for cytokeratins, indicating their epithelial origin despite altered keratinization. for cytokeratins, such as CK14 or broad-spectrum markers, highlights the cytoplasmic positivity, while standard antibodies may show reduced due to aberrant keratin formation. Ancillary techniques enhance confirmation and characterization. Transmission electron microscopy reveals ultrastructural details, including bundles of tonofilaments (60–400 nm in diameter) filling the and empty or collapsed nuclear spaces devoid of , distinguishing true ghost cells from viable . Digital pathology tools, such as image analysis software integrated with whole-slide scanners, facilitate quantification by segmenting ghost cells based on morphological features like cytoplasmic and nuclear absence, aiding in assessing their proportion relative to total epithelial cells. A common pitfall in identification is mistaking artifactual cytoplasmic or nuclear clearing in poorly fixed or processed tissues for cells; such artifacts often result from improper fixation leading to hydropic degeneration or loss of cellular detail, but lack the uniform cytoplasm and epithelial context of true ghost cells. Careful review of fixation quality and correlation with clinical-radiographic features helps avoid this error.

Differential Diagnosis

Ghost cells in odontogenic lesions must be differentiated from deposits, which can appear as acellular eosinophilic material in various pathologies. Unlike , which exhibits apple-green under polarized light following staining, ghost cells are negative and demonstrate an epithelial origin through (IHC) positivity for cytokeratins such as AE1/AE3 and 34βE12. Additionally, ghost cells express enamel-related proteins like and enamelysin, features absent in . Distinguishing ghost cells from calcified bodies, such as psammoma bodies, relies on the absence of mineral cores in true ghost cells, which initially present as anucleate epithelial remnants with preserved cellular outlines before potential passive . Psammoma bodies, in contrast, feature concentric laminated calcifications without an epithelial ghost structure and may show variable staining patterns, including Alcian blue positivity in some cases, whereas ghost cells are typically Alcian blue negative. Ghost cells also differ from necrotic debris, which appears as amorphous, unstructured material often accompanied by infiltrates. In comparison, ghost cells maintain distinct cellular borders, contain tonofilament bundles ultrastructurally, and lack significant , with IHC confirming keratin expression that is absent in pure necrotic debris. Key discriminators in diagnosis include an IHC panel revealing positivity (e.g., AE1/AE3) and negativity (e.g., ), combined with clinical correlation to an odontogenic history, such as association with cysts or tumors in the .

Clinical and Prognostic Implications

Tumor Behavior and Malignancy

In odontogenic tumors featuring ghost cells, such as dentinogenic ghost cell tumors (DGCT), the presence of a high proportion of ghost cells is associated with relatively indolent behavior and lower recurrence rates compared to ghost cell-poor counterparts like conventional ameloblastomas. For instance, central DGCT exhibits a recurrence rate of approximately 30%, while peripheral variants show rates as low as 2%, contrasting with recurrence rates of up to 65% in conservatively treated ameloblastomas. This correlation suggests that abundant ghost cells may contribute to reduced tumor aggressiveness by promoting differentiation and limiting proliferative activity. Ghost cell odontogenic carcinoma (GCOC), the malignant counterpart, retains ghost cells but is characterized by their persistence alongside atypical epithelial proliferation, increased invasiveness, and mitotic activity. In GCOC, ghost cells often constitute a minor component in recurrent lesions, accompanying nuclear atypia and local invasion, with a reported 5-year survival rate of about 73%. The overall recurrence rate for GCOC is around 40%, higher than in benign DGCT, underscoring the shift toward despite ghost cell presence. Prognostically, ghost cell density serves as a marker inversely related to in these neoplasms, with higher ghost cell proportions linked to lower mitotic rates (e.g., 4% in DGCT versus 94% in GCOC) and reduced risk. Studies from the early , including case series analyses, indicate that tumors with dense ghost cell clusters exhibit diminished metastatic potential, with distant spread occurring in only about 17% of GCOC cases, primarily to the lungs. Malignant transformation from benign ghost cell lesions to GCOC is rare, with approximately 8% of reported GCOC cases arising from prior DGCT, typically after an average of 6 years and based on case series spanning multiple recurrences. This rarity highlights the generally favorable for benign entities but necessitates vigilant monitoring.

Therapeutic Considerations

The management of lesions containing ghost cells varies based on their classification as benign cyst-like entities, such as dentinogenic ghost cell tumors (DGCTs), or malignant neoplasms like ghost cell odontogenic carcinomas (GCOCs). For cyst-like lesions, simple enucleation or is often employed as the initial surgical approach, though this carries a high of local recurrence due to the tumor's infiltrative nature. In cases of incomplete removal, a combination strategy involving followed by wider resection with at least 5 mm margins may be necessary to achieve better outcomes and reduce recurrence. For GCOCs, which exhibit local aggression and potential for , wide surgical excision with clear margins is the standard treatment to address the malignant behavior. Composite resection, such as maxillectomy or mandibulectomy depending on the site, is commonly performed, with approximately 45.8% of reported cases utilizing . Adjuvant radiotherapy is employed in select instances, accounting for about 18.8% of treated cases, particularly following incomplete excision or in aggressive presentations, though it is not routinely recommended as the primary modality. Long-term follow-up is essential for all ghost cell-containing lesions given their propensity for recurrence, with monitoring typically involving periodic clinical examinations and imaging such as panoramic radiographs or CT scans at intervals of 6 months initially, extending to annually thereafter. Recurrence rates can reach up to 73% after conservative enucleation in benign variants, underscoring the need for vigilant surveillance over 1 to 20 years. Emerging therapeutic options for advanced or inoperable GCOCs include systemic therapies such as immunotherapy combined with chemotherapy; for instance, toripalimab (a PD-1 inhibitor) alongside albumin-paclitaxel and cisplatin has shown partial remission in locally invasive cases, though these approaches remain investigational and non-standard as of post-2020 reports.

Non-Odontogenic Conditions

In non-odontogenic contexts, ghost cells in conditions like pilomatrixomas (calcifying epitheliomas of the skin) are associated with benign behavior, with low recurrence rates (<5%) following complete surgical excision and excellent prognosis. Craniopharyngiomas, which may contain ghost cells, have variable prognosis depending on location and extent, with 5-year survival rates of 80-90% after surgical resection combined with radiotherapy if needed. In , ghost cells resulting from vitreous hemorrhage can lead to ghost cell , a secondary open-angle due to outflow obstruction by degenerated red blood cells. If untreated, it may cause elevated and vision loss, but is favorable with timely intervention such as pars plana or , preventing progression in most cases.

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