A Novel Artificial Intelligence-based Parameterization Approach of the Stromal Landscape in Merkel Cell Carcinoma: a Multi-Institutional Study.

BACKGROUND: Tumor-Stroma Ratio (TSR) has been recognized as a valuable prognostic indicator in various solid tumors. This study aimed to examine the clinicopathological relevance of TSR in Merkel cell carcinoma (MCC) using artificial intelligence (AI)-based parameterization of the stromal landscape and validate TSR scores generated by our AI model versus human-assessed. METHODS: 112 MCC cases with Whole Slide Images (WSIs) were collected from four different institutions. WSIs were first partitioned into 128x128-pixel "mini-patches" then classified by a novel framework, termed Pre-TumOr And STroma (Pre-TOAST) and TOAST, whose output equaled the probability of the mini-patch representing tumor cells rather than stroma. Hierarchical random samplings of 50 mini-patches per region were performed throughout 50 regions per slide. TSR and Tumor-Stromal Landscape (TSL) parameters were estimated by the maximum-likelihood algorithm. RESULTS: Receiver Operating Characteristic (ROC) curves showed the areas under the curve (AUCs) of Pre-TOAST in discriminating classed of interest (COI) including tumor cells, collagenous stroma, and lymphocytes from non-classes of interest (non-COI) including hemorrhage, space, and necrosis were 1.00. AUCs of TOAST in differentiating tumor cells from related stroma were 0.93. MCC stroma was categorized into TSR-high (TSR≥50%) and TSR-low (TSR<50%) using both AI- and human pathology-based methods. AI-based TSR-high subgroup exhibited notably shorter Metastasis-Free Survival (MFS) with a statistical significance of p=0.029. Interestingly, pathologist-determined TSR subgroups lacked statistical significance in Recurrence-Free Survival (RFS), MFS, and Overall Survival (OS) (p>0.05). Density-based spatial clustering of applications with noise (DBSCAN) analysis identified two distinct Tumor-Stroma Landscape (TSL) clusters: TSL1 and TSL2. TSL2 showed significantly shorter RFS (p=0.045) and markedly reduced MFS (p<0.001) compared to TSL1. CONCLUSION: TSL classification appears to offer better prognostic discrimination than traditional TSR evaluation in MCC. TSL can be reliably calculated using an AI-based classification framework and predict various prognostic features of MCC.

Clinical implication of PRAME immunohistochemistry in differentiating melanoma in situ and dysplastic nevus in non-acral nevus-associated melanoma in situ: An institutional experience and meta-analysis.

INTRODUCTION: PReferentially expressed Antigen in MElanoma (PRAME) has shown utility in differentiating benign from malignant melanocytic neoplasms. In this study, we investigated the clinical significance of PRAME expression in dysplastic nevi (DN) and nevus-associated melanoma in situ (MIS). METHODS: We included 172 DN and 38 nevus-associated MIS from our institutional archive. PRAME positive expression was defined as nuclear staining in at least 75% of melanocytes. In addition, relevant studies from PubMed and Web of Science were incorporated into a meta-analysis using the random-effects model to assess PRAME expression in MIS and DN. RESULTS: Our institutional data revealed that 71.1% of nevus-associated MIS cases exhibited positive PRAME expression in the MIS components, whereas all DN components were negative for PRAME. 5.7% of cases diagnosed as DN in our cohort demonstrated diffuse positivity for PRAME. Notably, MIS associated with DN displaying epidermal and dermal components displayed a higher likelihood of PRAME positivity compared to those arising on a background of DN with solely epidermal (junctional) components (84% vs. 46%, p = 0.024). The meta-analysis indicated that the pooled PRAME positivity in MIS and DN was 54.5% and 1.9%, respectively. CONCLUSION: PRAME is a valuable immunohistochemical marker for differentiating MIS from DN, particularly in the context of nevus-associated MIS.

FLI-1/Melan-A dual stain is an alternative to PRAME in differentiating metastatic melanoma from nodal nevus: A monocentric retrospective study.

Melanocytic nevi existing in lymph nodes create a diagnostic challenge by mimicking metastases. PReferentially expressed Antigen in MElanoma (PRAME) immunohistochemical (IHC) stain can differentiate one from another. FLI-1 IHC expression has been shown in malignant melanoma with variable sensitivity while melanocytic nevi were reported to be negative. We hypothesized that FLI-1/Melan-A dual IHC staining may be used in the distinction of metastatic melanoma from nodal nevi and can be an alternative and/or complementary to PRAME. In this study, we examined 13 lymph nodes with metastatic melanoma and 13 lymph nodes with benign deposits. We stained all of the lymph nodes with FLI-1, FLI-1/Melan-A dual, and PRAME IHC stains. In addition, we stained paired skin samples of the metastatic lymph nodes with FLI-1 and PRAME. In primary cutaneous melanomas, 11 of 13 were positive for FLI-1 and PRAME expression (85%). Malignant cells in 12 and 13 lymph nodes showed positive expression of PRAME and FLI-1, respectively. Only one case with a nevic cell deposit was weakly positive for FLI-1 and the remaining benign cases were negative for both FLI-1 and PRAME. Our results show that FLI-1/Melan-A dual stain is as sensitive and specific as PRAME in distinguishing lymph nodes with metastatic melanoma from nodal nevi. Further studies with larger case numbers are needed to support our significant results.

Two distinct pathogenic pathways of digital papillary adenocarcinoma - BRAF mutation or low-risk HPV infection.

Digital papillary adenocarcinoma (DPA) is a rare neoplasm that can exhibit local recurrence and distant metastasis. We present a series of eight cases of DPA showing two distinct clinical presentations, morphologies, immunophenotypes, and molecular features. Four cases were characterized by painless, slow-growing nodules located on the digits. The lesions were small, well-defined, and confined in the dermis. Histopathologically, these tumors were composed of glandular structures lined by cuboidal epithelium with luminal papillary infoldings. Only rare mitotic figures and minimal squamoid differentiation were present, and cellular necrosis was absent. All four cases were positive for the BRAF V600E immunohistochemistry but negative for p16, low-risk and high-risk HPV in situ hybridization (ISH). In contrast, the remaining four cases were characterized by painful, rapidly growing masses on the digits. These four lesions were located in the deep dermis and consisted of a solid, tightly packed papillary architecture lined by atypical epithelioid cells with inconspicuous nucleoli. Cellular necrosis, numerous mitotic figures, and prominent squamoid differentiation were seen. All cases were negative for the BRAF V600E IHC. However, they showed strong, patchy to diffuse reactivity for p16 and were positive for low-risk HPV ISH and negative for high-risk HPV ISH. Our findings suggest that the current classification of DPA encompasses tumors that show two discrete pathogenic pathways - BRAF mutation or low-risk HPV infection. DPAs with low-risk HPV infection exhibit aggressive clinical features, high-grade morphology, marked squamoid differentiation, and wild-type BRAF. DPAs with BRAF V600E have less aggressive clinical features, low-grade morphologic findings, mild to absent squamoid differentiation, and negative HPV infection.

Acantholytic Squamous Cell Carcinoma Arising From Lichen Sclerosus: A Rare Case Affecting Vulvar Skin.

We present the case of an 82-year-old female with acantholytic squamous cell carcinoma affecting vulvar skin. The patient had a history of perineal lichen sclerosus for 5 years before presentation. She was referred to a dermatologist for intractable severe pain associated with the lesions. Biopsies showed an infiltrative squamous cell carcinoma with histology consistent with the acantholytic subtype. Acantholytic squamous cell carcinoma is a rare histologic variant characterized by dyscohesive keratinocytes with pseudoglandular formation and dyskeratosis. It is associated with sun-damaged skin and most commonly occurs in the head and neck of elderly men. Few cases have been reported at nondermal sites and non-sun-exposed dermis. The patient underwent a radical vulvectomy and bilateral inguinal node dissection. The 1.6 cm tumor was diffusely acantholytic and pseudoglands were present. The tumor cells were diffusely positive for p63 immunohistochemical stain. As expected at this site, there was no solar elastosis identified histologically. However, vulvar intraepithelial neoplasia and chronic lichen sclerosus were apparent. This case represents a rare histologic subtype of squamous cell carcinoma in an unusual site associated with lichen sclerosus instead of solar elastosis.

Weak immunohistochemical expression of galectin-3 near blisters in Hailey-Hailey disease.

BACKGROUND: Hailey-Hailey disease (HHD) is an uncommon hereditary and benign skin condition characterized by blisters and erosions on intertriginous areas. It is related to a mutation of the ATP2C1 gene, which encodes a Ca2+ pump. It is characterized by multiple foci of skin acantholysis in the epidermis, with dyskeratosis and suprabasilar clefting. Galectin-3 is a beta-galactoside-binding protein that has an essential role in cell-to-cell and cell-to-matrix adhesion. We assessed galectin-3 immunohistochemical expression in HHD to explore its impact on the pathogenesis of this hereditary blistering disorder. METHOD: In a retrospective study, seven specimens from seven patients diagnosed with HHD were stained with antibodies to galectin-3. We evaluated the nuclear and cytoplasmic expression of galectin-3, as well as the staining intensity around blisters and distant normal skin. RESULTS: We observed a significant decrease in cytoplasmic and nuclear expression of galectin-3 as well as stain intensity around blisters compared with distant normal skin. CONCLUSIONS: While the acantholysis process in HHD is related to abnormality in cadherin expression caused by altered Ca2+ pump concentration, lower expression of galectin-3 may cause the extension of blisters by initiating cell-to-cell disassembly in the epidermis.

A previously undescribed variant of cutaneous clear-cell squamous cell carcinoma with psammomatous calcification and intratumoral giant cell granulomas.

Cutaneous clear-cell squamous cell carcinoma (ccSCC) is a rare variant of SCC composed of clear cells that lack cytoplasmic glycogen or evidence of tricholemmal keratinization. We report a previously undescribed variant of ccSCC with psammomatous calcification and intratumoral giant cell granulomas. The differential diagnosis with trichilemmal carcinoma is outlined according to the criteria of the fourth edition of World Health Organization (WHO) classification. Our findings outline that psammomatous calcification may occur inside the keratinous pearls of the neoplastic lobules triggering an intratumoral giant cell granulomatous reaction. The prognostic significance of this histopathological presentation is unknown but the potential for formation of psammoma bodies in cSCC should be considered to avoid diagnostic pitfalls.

Oral white lesion in patients post-hematopoietic stem cell transplantation: a case series demonstrating the diagnostic dilemma.

The current National Institutes of Health (NIH) consensus paper excluded "white hyperkeratotic plaque" from the diagnostic criteria for oral chronic graft-versus-host disease (cGVHD) in order to ensure malignant transformation is not overlooked. Therefore, an isolated oral white plaque is recommended to be subjected to biopsy and pathologic examination. The cases described in this paper shed a new light on the clinical approach to oral white plaque post-hematopoietic stem cell transplantation. The objectives of this article are to demonstrate that a white plaque does not contradict a diagnosis of oral cGVHD, and to highlight the clinical considerations for taking a biopsy.

Immunohistochemical Expression of Galectin-3 in Pemphigus Vulgaris.

ABSTRACT: Pemphigus vulgaris (PV) is an autoimmune bullous disorder related to immunoglobulin-G autoantibodies against desmoglein-3. Galectin-3 is one of the main elements of the immunoglobulin-E group which is essential in the cell-cell or cell-matrix adhesion. Although the presence of immunoglobulin-E autoantibodies in PV has been observed, no studies have been performed to describe the role of galectin-3 in PV. We evaluated galectin-3 expression in PV as a first step in assessing its impact in the pathogenesis of this autoimmune blistering process. In a retrospective study, 56 specimens from 45 patients diagnosed with PV were stained with antibodies to galectin-3. The percentages of nuclear and cytoplasmic galectin-3 expression as well as staining intensity were evaluated around blisters and adjacent unaffected skin. We observed a significant decrease in galectin-3 cytoplasmic and nuclear expression as well as stain intensity around blisters compared with adjacent unaffected skin. Although autoantibodies against desmogleins trigger the blister formation in PV patients, loss of galectin-3 may play a role in the extension of blister formation by initiating cell-cell disassembly at the level of the intercellular keratinocyte desmosome. We demonstrated a lower expression of galectin-3 around the blisters in PV. The pathogenesis of the blister formation may be related to lower expression of galectin-3. Additional studies are necessary to clarify the result of this outcome and determine the accurate pathogenesis of blister formation in PV.

TLE1 expression fails to distinguish between synovial sarcoma, atypical fibroxanthoma, and dermatofibrosarcoma protuberans.

Transducin-like enhancer of split 1 (TLE1) belongs to the Groucho/TLE/Grg family. It functions as a transcriptional corepressor and is widely used as a biomarker of synovial sarcoma (SS). Within the skin, atypical fibroxanthoma (AFX) and dermatofibrosarcoma protuberans (DFSP) often enter the histopathologic differential diagnosis. TLE1 expression has not been evaluated in these neoplasms. We examined archived tissues sections from the surgical pathology files from 10 adult patients diagnosed with AFX and 10 adult patients diagnosed with DFSP. We found nuclear staining in 10 of 10 AFX and 2 of 10 DFSP. We also noticed three patterns of staining in AFX: predominantly spindle component, predominantly epithelioid component, or mixed pattern of both epithelioid and spindle components. The group with the predominantly spindle pattern expressed the strongest nuclear TLE1 staining. In the DFSP group, one lesion demonstrated staining of epithelioid cells, with strong, diffuse nuclear TLE 1 expression, and the second lesion stained only the spindled cells, with weak nuclear TLE1 marking. In conclusion, TLE1, while a sensitive marker for SS, is not specific. A wide range of cutaneous spindle cell neoplasms also express TLE1. AFX and DFSP should be added to this list. TLE1 might be added to a diagnostic panel in this differential diagnosis.

Membrane attack complex (C5b-9 complex or Mac), is strongly present in lesional skin from patients with endemic pemphigus foliaceus in El Bagre, Colombia.

BACKGROUND: El Bagre endemic pemphigus foliaceus (El Bagre-EPF) is a new variant of endemic pemphigus foliaceus present in the El Bagre area of Colombia, South America. Here, we investigate the presence of complement/C5-b9 in lesional skin of patients and matched controls from the endemic area. We also aim to compare the patient's autoantibody levels using indirect immunofluorescent titers (IIF) and correlate with the lesional presence of complement/C5b-9. METHODS: A case-control study was carried out by testing for the presence of complement/C5b-9 in lesional skin in 43 patients affected by El Bagre-EPF, as well as 43 matched, healthy controls from the endemic area. Skin biopsies were obtained and evaluated via hematoxylin and eosin staining, and immunohistochemistry. RESULTS: The presence of complement/C5b-9 was observed in all cases of the patients affected by El Bagre-EPF and was not observed in the controls from the endemic area (P < 0.001). The patients' autoantibody titers utilizing IIF for IgG and IgM showed correlation between higher autoantibody titers and stronger intensity of staining with complement/C5-b9 staining (P < 0.001). CONCLUSION: Patients affected by El Bagre-EPF have lesional deposition of complement/C5b, which correlates with disease severity and previously established serologies.

A diagnostically challenging case of CD8+ primary cutaneous gamma/delta T-cell lymphoma.

Primary cutaneous gamma/delta T-cell lymphoma (PCγδTCL) is a rare form of cutaneous lymphoma characterized by abnormal clonal proliferation of mature, activated gamma-delta T cells expressing the γδ heterodimer of the T-cell receptor (TCR). As an entity, PCγδTCL has recently undergone diagnostic revision since its introduction in the 2008 WHO classification of cutaneous lymphomas and confirmedin 2016. Nonetheless, diagnosis remains difficult both clinically and histologically, given its broad range of clinical manifestations and immunohistochemical phenotypes. Herein, we present a rare case of CD8+ PCγδTCL with a discussion highlighting theheterogeneity within this entity.

Nuclear factor XIIIa staining (clone AC-1A1 mouse monoclonal) is a sensitive and specific marker to discriminate sebaceous proliferations from other cutaneous clear cell neoplasms.

Sebaceous carcinoma is a rare but serious malignancy that may be difficult to diagnose when poorly differentiated. Other epithelial tumors with clear cell change may mimic sebaceous carcinoma. Few useful or specific immunohistochemical markers for sebaceous differentiation are available. Nuclear staining with factor XIIIa (clone AC-1A1) was recently found to be a highly sensitive marker of sebaceous differentiation. We evaluated nuclear factor XIIIa (AC-1A1) staining in sebaceous neoplasms vs. other cutaneous clear cell tumors. We stained 27 sebaceous proliferations: sebaceous hyperplasia (7), sebaceous adenoma (8), sebaceoma (5), sebaceous carcinoma (7). We also stained 67 tumors with clear cell change: basal cell carcinoma (8), squamous cell carcinoma (8), hidradenoma (7), desmoplastic trichilemmoma (2), trichilemmoma (10), trichilemmal carcinoma (3), clear cell acanthoma (9), atypical fibroxanthoma (1), syringoma (8), trichoepithelioma (1), metastatic renal cell carcinoma (2), and nevi with balloon cell change (8). Nuclear factor XIIIa (AC-1A1) staining was present in 100% of sebaceous proliferations; 96% displayed strong staining. Non-sebaceous clear cell tumors were negative or only weakly positive with factor XIIIa (AC-1A1) in 95.5%; only 4.5% showed strong staining. This suggests that strong nuclear factor XIIIa (AC-1A1) staining is a sensitive and specific marker of sebaceous neoplasms vs. other clear cell tumors.

Nuclear factor XIIIa staining (clone AC-1A1 mouse monoclonal) is a highly sensitive marker of sebaceous differentiation in normal and neoplastic sebocytes.

BACKGROUND: Sebaceous proliferations are common and may be confused with other cutaneous neoplasms. Few useful or specific immunohistochemical markers for sebaceous differentiation are available. We incidentally observed strong factor XIIIa (Ventana clone AC-1A1 on Ventana Benchmark Ultra stainer) nuclear staining in normal sebaceous glands and hypothesized that this might be a useful marker in sebaceous proliferations. METHODS: Immunohistochemistry for factor XIIIa (AC-1A1) was performed on seven sebaceous hyperplasias, eight sebaceous adenomas, five sebaceomas, seven sebaceous carcinomas. RESULTS: Strong nuclear factor XIIIa (AC-1A1) staining was present in 100% of normal sebaceous glands, 100% of sebaceous hyperplasia, adenoma and carcinoma, and 80% of sebaceoma. Moderately or poorly differentiated squamous cell carcinomas (SCCs) (n = 26) were also stained for factor XIIIa (AC-1A1); two showed focal strong staining (8%), but the remainder showed only weak or negative staining (92%). In contrast, factor XIIIa clones from Abcam, Cambridge, MA, USA (EP3372) and Vector Laboratories, Burlingame, CA, USA (E980.1) were negative in sebocyte nuclei. CONCLUSIONS: We report the novel finding of consistent nuclear factor XIIIa (AC-1A1) staining in normal, hyperplastic and neoplastic sebocytes. Factor XIIIa (AC-1A1) is a highly sensitive marker of sebaceous differentiation. It may have potential clinical utility as a specific marker to distinguish sebaceous carcinoma from poorly differentiated SCC.

Characterization of dermatopathology fellowship applicants: a 5-year single institution experience.

BACKGROUND: Although much data have been documented on the characteristics of medical school applicants for dermatology and pathology residency programs in the United States and select medical and surgical fellowship applicants through the National Residency Matching Program, little is known about the dermatopathology applicant demographics. METHODS: We examined a 5-year pool of dermatopathology fellowship applicants from a single institution (University of Arkansas for Medical Sciences) and compiled background profile data of the applicants to characterize an 'average dermatopathology fellow' applicant. RESULTS: A total of 229 applicants over a 5-year period were included in the assessment. The majority were of pathology background with medical school and residency training based in the southern United States. One-third of the applicants had original research publications, case reports or had given an oral or poster presentation in the field of dermatopathology. CONCLUSIONS: Knowledge regarding the average applicant statistics for a dermatopathology fellowship will allow prospective applicants to evaluate their own applications for strengths and weaknesses. This will also provide institutions information regarding anticipated statistics for a competitive applicant pool.

Epithelioid melanocytic nevus with tubule and pseudoacini formation.

A 26-year-old female presented with a 7 mm irritated pink-red papule on the left posterior shoulder. A shave biopsy revealed a dermal proliferation of epithelioid cells arranged in small nests with central lumen-like structures resembling glands set in a densely sclerotic stroma. S100 and Melanoma antigen recognized by T cells 1 (MART-1) immunohistochemical positivity confirmed a dermal melanocytic neoplasm. Pan-cytokeratin and cytokeratin 7 were negative within the nests ruling out an adnexal neoplasm or metastatic adenocarcinoma. A Spitz nevus variant characterized by the presence of focal tubular structures (tubular epithelioid cell nevus) has rarely been described in the literature and is of uncertain biological significance. Similar structures have also been observed in Clark/dysplastic nevi and melanoma. Glandular differentiation is seen in a wide variety of benign and malignant epithelial neoplasms; however, melanocytes are not known to be capable of forming true glands. The exact mechanism and significance of this phenomenon are currently unknown. Certain postulations include central melanocyte apoptosis, autocrine or paracrine factor secretion or retraction artifact caused by tissue fixation. This distinctive finding is important to recognize in order to avoid misdiagnosis as a glandular neoplasm.

Acquired cutis laxa associated with cutaneous mastocytosis.

Cutis laxa is characterized by dramatic wrinkling of skin that is lacking in elasticity due to inherent defects in dermal elastic fibers. Cutis laxa can be caused by genetic and metabolic disorders. It can also be acquired, possibly resulting from inflammatory processes with destruction of elastic fibers. This report describes a 26-year old woman who developed acquired cutis laxa and cutaneous mastocytosis leading to premature aging. She represents a unique co-occurrence of these two separate disease entities. To our knowledge, there has been only one published case report of acquired cutis laxa occurring in association with urticaria pigmentosa in a 4-year old girl. Our case would be a second case that exhibits the coexistence of these two disorders in an adult female.

Diagnosing Cutaneous Melanocytic Tumors in the Molecular Era: Updates and Review of Literature.

Over the past decade, molecular and genomic discoveries have experienced unprecedented growth, fundamentally reshaping our comprehension of melanocytic tumors. This review comprises three main sections. The first part gives an overview of the current genomic landscape of cutaneous melanocytic tumors. The second part provides an update on the associated molecular tests and immunohistochemical stains that are helpful for diagnostic purposes. The third section briefly outlines the diverse molecular pathways now utilized for the classification of cutaneous melanomas. The primary goal of this review is to provide a succinct overview of the molecular pathways involved in melanocytic tumors and demonstrate their practical integration into the realm of diagnostic aids. As the molecular and genomic knowledge base continues to expand, this review hopes to serve as a valuable resource for healthcare professionals, offering insight into the evolving molecular landscape of cutaneous melanocytic tumors and its implications for patient care.

'Eczematous' dermatitis of the nipple: clinical and histopathological differential diagnosis of Paget disease.

The nipple can be affected by many malignant and benign entities. A wide variety of diseases including Paget disease, atopic dermatitis and nipple candidiasis can cause eczema-like changes in the nipple. In cases of diagnostic uncertainty, tissue sampling may be indicated. A true eczematous lesion, such as atopic dermatitis, typically shows a spongiotic dermatitis pattern. Paget disease, on the other hand, presents with infiltration of the nipple epidermis by neoplastic cells. The presence of atypical cells scattered in the epidermis in a pagetoid pattern opens up a histopathological differential diagnosis encompassing squamous cell carcinoma in situ and malignant melanoma, among others. Immunohistochemistry is commonly used to render a diagnosis. The objective of this article is to discuss Paget disease and highlight relevant clinical and histopathological differential diagnoses.

Cutaneous Superficial Basal Cell Carcinoma is a Basal Cell Carcinoma In Situ: Electron Microscopy of a Case Series of Basal Cell Carcinomas.

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.