Abstract
Basal cell carcinoma (BCC) is the most common skin cancer. Skin cancers may present either as a non-invasive tumor or an invasive malignancy. The terminology of carcinoma in situ is used when the tumor is either just limited to epidermis or not present as single cells or nests in the dermis. However, currently the terminology superficial BCC is inappropriately used instead of BCC in situ when the skin cancer is limited to epidermis. In this study we compare the pathologic changes of superficial, nodular, and infiltrative BCCs using electron microscopy to identify the ultrastructural characteristics and validate the previously proposed terminology. Three cases of BCC (superficial BCC, nodular BCC, and infiltrative BCC) diagnosed by dermatopathologists at our institute were selected for review. Paraffin block tissues from these cases were sent for electron microscopy studies which demonstrated disruption of basal lamina in both nodular and infiltrative type of BCC, while it remains intact in BCC superficial type after extensive examination. Therefore, similar to other in situ skin cancers, there is no invasion of the neoplasm in superficial BCC into the dermis. Hence, the older term superficial BCC should be appropriately replaced with the newer terminology BCC in situ.
Avoid common mistakes on your manuscript.
Basal cell carcinoma is the most common skin cancer; it has been classified into distinctive morphologic and pathologic subtypes. |
Superficial basal cell carcinoma only shows extension of tumor that is contiguous with the overlying epidermis into the dermis; there is no invasion of individual tumor cells or isolated nests of cancer cells into the dermis. |
Electron microscopy of superficial basal cell reveals that the basal lamina of the epidermis remains intact; in contrast, ultrastructural evaluation of nodular basal cell carcinoma and infiltrative basal cell carcinoma show disruption of the basal lamina. |
Basal cell carcinoma in situ should replace the older term superficial basal cell carcinoma since the basal lamina is intact and there is no invasion of the neoplasm into the underlying dermis. |
Introduction
Keratinocyte-derived carcinomas are by far the most common malignancies worldwide and exceed the prevalence of all other cancers combined. Approximately 80% of keratinocytes carcinomas are basal cell carcinoma (BCC) and 20% are squamous cell carcinoma (SCC) [1,2,3,4]. They most commonly present in patients between 40 and 70 years of age; the male to female ratio ranges from 1.5:1 to 2:1 [5].
Historically, a basal cell carcinoma was referred to as a basal cell epithelioma. An in situ variant was initially designated as an intraepidermal epithelioma of Borst-Jadassohn. Eventually the cells composing the intraepidermal islands in the presumed intraepidermal basal cell epithelioma were observed to possess intercellular bridges; indeed, the benign tumor was reclassified as a clonal seborrheic keratosis. Subsequently, the term epithelioma was replaced by carcinoma and an in situ variant of basal cell carcinoma was not established [6, 7].
Nodular, superficial, infundibulocystic, fibroepithelial, morpheaform (sclerosing, desmoplastic), and infiltrative are well-defined subtypes with distinct clinical and histopathologic findings. Nodular BCC is the most common subtype; however superficial BCC is the second most common subtype, accounting for 10–30% of tumors. The origin or the differentiation or both of a basal cell carcinoma may influence its pathologic subtype and development into an invasive neoplasm [8].
Superficial BCCs commonly present as an erythematous, scaly, well-circumscribed thin plaque. They can initially appear as red patch. Their clinical morphology can be mistaken for other cutaneous tumors such as SCC in situ [9].
The histopathologic examination of a superficial BCC demonstrates multiple lobular foci of palisading basaloid tumor cells attached to the epidermis without any invasion of noncontiguous nests of tumor cells into the underlying dermis. This is analogous to a squamous cell carcinoma in situ of the skin that presents with a thickened epidermis and may push beyond the papillary dermis into the reticular dermis. Importantly, the neoplasm is confined by the epidermal basement membrane and remains in situ. In contrast, skin carcinoma invasion may be described as the presence of noncontiguous nests of tumor cells or individual tumor cells in the dermis that have breached the epidermis with penetration of the epidermal basement membrane [9,10,11].
The integrity of basal lamina is thin and labile. These factors of the basal lamina are often difficult to assess with traditional histopathological techniques. Indeed, transmission electron microscopy is necessary to image its matrix components [12].
Traditionally, the term “basal lamina” is usually used with electron microscopy. However, the term “basement membrane” is used with light microscopy. Our goal was to investigate the basal lamina integrity in different types of BCC using electron microscopy.
Cases
Materials
This institutional review board (IRB)-approved study was based on a retrospective analysis of archival tissue; all of the patients gave consent for being part of study or being part of subsequent publications. A total of three surgical pathology specimens diagnosed as either “superficial BCC” or “nodular BCC” or “infiltrative BCC” were selected for review. All selected cases were diagnosed by the dermatopathologists in our institution and reviewed prior to this study by one of the authors (BRS).
Clinical Presentation and Light Microscopy
The clinical presentation and pathologic findings on light microscopy are summarized in Table 1.
Case 1—A 77-year-old woman presented with an asymptomatic lesion on her forearm. Clinically she had a single lesion which appeared as red scaly plaque. A shave biopsy was taken for examination. Light microscopy showed several basaloid tumor nodules restricted to lower layer of epidermis with no invasion of the tumor cells into the underlying dermis (Fig. 1).
Light microscopy evaluation of hematoxylin and eosin stained section of basal cell carcinoma (BCC) in situ, previously referred to as a superficial basal cell carcinoma, showing tumor lobules attached to the overlying epidermis (A). The BCC in situ shows the following ultrastructural features by electron microscopy, including lower magnification of tumor nodules demonstrate numerous euchromatic nuclei (arrows) of the basaloid tumor cells (B) and a higher magnification of tumor nodules showing intact basal lamina (arrow) (C). Magnifications: A ×100; B ×3000; C ×8000
Case 2—A 58-year-old woman presented with flesh-colored papule on her clavicle. She also has a history of squamous cell carcinoma of scalp that was excised a year ago. A shave biopsy from current lesion was taken for examination. Light microscopy showed tumor nodules deep in the dermis that are not contiguous with epidermis (Fig. 2).
Light microscopy evaluation of hematoxylin and eosin stained section of basal cell carcinoma (BCC) shows tumor nodules in the dermis (A). Electron microscopy of lower magnification (B) and higher magnification (C) views show breakage in the basal lamina (arrow) of the tumor nodule. Magnifications: A ×100; B ×15,000; C ×30,000
Case 3—An 86-year-old man presented with pearly telangiectatic papule on his forehead. A shave biopsy was taken for examination. Light microscopy showed tumor strands deep in the dermis that are not contiguous with epidermis (Fig. 3).
Light microscopy evaluation of hematoxylin and eosin stained section of basal cell carcinoma (BCC) shows cords and nests of tumor cells in the dermis (A). Electron microscopy of lower magnification (B) and higher magnification (C) views show breakage in the basal lamina (arrow) of the tumor nests. Magnifications: A ×100; B ×15,000; C ×30,000
Electron Microscopy Method
Paraffin block tissues from these cases were cored out using a bone marrow biopsy needle and placed into vials with xylene overnight. The next day the tissue was exchanged three times in xylene (30 min each) and then rehydrated through a graded series of ethanol (100% to 50%, 20 min each) to water, fixed in 0.1 M sodium cacodylate buffered 2.5% glutaraldehyde for 24 h and then post-fixed in 1.0% buffered osmium tetroxide for 60 min. The tissue was rinsed in distilled water and dehydrated through a graded series of ethanol to 100%, transitioned into propylene oxide, and finally EPON/Araldite epoxy resin overnight. The next day the tissue was embedded into fresh epoxy resin in BEEM capsules and polymerized for 48 h at 60 °C. The blocks were trimmed with a razor blade to a trapezoid face for 1-μm sectioning onto glass slides which were stained with toluidine blue to confirm the region of interest to be thin sectioned at 70 nm onto copper formvar/carbon-coated slot grids. The grids were stained with aqueous uranyl acetate and lead citrate. The grids were examined using a Hitachi 7650 transmission electron microscope and micrographs were captured using an attached Gatan Erlangshen 11-megapixel digital camera.
Electron Microscopy Results
The basal lamina integrity was evaluated in three cases of basal cell carcinoma: a superficial BCC, a nodular BCC, and an infiltrative BCC. The electron microscopy features of these tumors are summarized in Table 1. In the superficial BCC, the basal lamina is intact and completely surrounds all the tumor nodules (Fig. 1). In the nodular and infiltrative BCCs, the basal lamina is focally disrupted (Figs. 2 and 3).
Discussion
BCC has previously only been considered to be an invasive neoplasm. Indeed, we have demonstrated that an in situ variant of the tumor exists. The origin of BCC has most commonly been attributed to embryonic follicular germinative cells which may also influence its pathologic subtype [13,14,15].
Superficial BCC is characterized by proliferation of tumor cells parallel to the epidermis without noncontiguous invasion into the dermis. They often demonstrate slit-like spaces from the subjacent stroma. The tumor cells may also colonize the hair follicle depicting its origin [16].
Nodular BCC is characterized by discrete large or small nests of tumor cells in either the papillary or reticular dermis. The surrounding stroma of a nodular BCC may show myxoid change, calcification, and abundant slit-like spaces surrounding the tumor nests [16].
In contrast, infiltrative BCC comprises irregularly sized and shaped nests of tumor cells. There are occasional foci of slit-like retraction. In addition, the cancer may extend beyond subcutis into the underlying and adjacent tissue such as muscles [16].
Ultrastructural examination of the basal lamina helps in understanding the pathogenesis and subtype characteristics of BCC. Previous studies have concluded that both the superficial and nodular variants of BCC are surrounded by a continuous basal lamina which consist of collagen IV and collagen V admixed with laminin. However, the infiltrative pattern lacked a continuous basal lamina [17, 18]. It was speculated that the basal lamina may act as a trap for activated cytokines derived from tumor cells, stromal cells, and inflammatory cells. These cytokines when released may act as promotors for tumor growth [19].
Importantly, in contrast to the prior studies that demonstrated a continuous basal lamina in nodular BCC, our results show breaks in the basal lamina in both the nodular and the infiltrative BCC subtypes. However, basal lamina continuity remained in the superficial BCC. Disruption of the basal lamina was more limited in the nodular BCC than in the infiltrative BCC. Yet, no example of basal lamina disruption could be detected in our superficial BCC after extensive examination.
These results support the concept that in situ and invasive tumors would be the appropriate terminology for BCC, as it occurs in other carcinomas. The older term superficial BCC might better be replaced with BCC in situ; however, the designation of an invasive neoplasm would be appropriate for the nodular and infiltrative subtypes of BCC. The term “in situ” in Latin means “in its (original) place or position” [20]. Similarly, The National Cancer Institute defined “in situ” as abnormal cells that are confined to their site of origin and have not invaded neighboring tissue or gone elsewhere in the body [21, 22].
Multiple treatment modalities are potentially available for the management of BCC including surgery. Recent advances in our understanding of BCC pathogenesis have led to the discovery of systemic treatments for this cutaneous neoplasm with Hedgehog inhibitors (such as vismodegib and sonidegib) and an anti-PD1 agent (cemiplimab). However, for BCC in situ, localized therapeutic interventions may include destructive interventions (such as cryotherapy, or electrodissection and curettage, or laser), or a topical antineoplastic agent (5-fluorouracil), or a topical immunologic drug (imiquimod) [23].
A potential limitation to our case series is that our observations included the examination of only a single superficial BCC, nodular BCC, and infiltrative BCC. However, we were able to demonstrate a completely intact basal lamina in the non-invasive variant of BCC. Therefore, our study provides scientific evidence to support using the term BCC in situ instead of superficial BCC.
Conclusion
BCCs have previously been classified into several subtypes including superficial, nodular, and infiltrative. Carcinomas are defined by either being in situ or invasive. In situ skin carcinomas demonstrate the malignant changes only within the epidermis; extension of tumor into the dermis is always contiguous with the overlying epidermis. Disruption of the basal lamina on electron microscopic evaluation is associated with invasive malignancy. We observed breaks in the basal lamina of both nodular and invasive BCC. However, the basal lamina of superficial BCC remained intact. In conclusion, on the basis of our findings, we recommend that superficial BCC is more appropriately referred to as BCC in situ.
Data Availability
All data generated or analyzed during this study are included in this published article.
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Acknowledgements
We thank the participants of the study. We also thank the University of Rochester Medical Center (URMC) Electron Microscopy Resource in the Center for Advanced Resource Technologies (CART).
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All authors (Harsimran Kaur, MD, MBBS, Karen L. de Mesy Bentley, MS, Syed Minhaj Rahman, BS, Philip R. Cohen, MD, and Bruce R. Smoller, MD) participated in the concept and design, drafting the manuscript, and have read and approved the final version.
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Harsimran Kaur, MD, MBBS, Karen L. de Mesy Bentley, MS, Syed Minhaj Rahman, BS, MD and Bruce R. Smoller, MD have nothing to disclose. Philip R. Cohen is an Editorial Board member of Dermatology and Therapy. Philip R. Cohen was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions.
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All of the patients gave consent for being part of study or being part of subsequent publications. This study was approved by the Institutional Review Board (IRB) of the University of Rochester Medical Center (URMC), Research Subjects Review Board (STUDY00007788).
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Kaur, H., de Mesy Bentley, K.L., Rahman, S.M. et al. Cutaneous Superficial Basal Cell Carcinoma is a Basal Cell Carcinoma In Situ: Electron Microscopy of a Case Series of Basal Cell Carcinomas. Dermatol Ther (Heidelb) 14, 1359–1366 (2024). https://doi.org/10.1007/s13555-024-01151-x
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DOI: https://doi.org/10.1007/s13555-024-01151-x