A Frequent Diagnostic Pitfall: Dermatological Clinical Features and Pathological Results in Diagnosing Pagetoid Squamous Cell Carcinoma in situ (Case Series).

Squamous cell carcinoma (SCC) in situ can occur on any skin or mucus surface and is more commonly found in elderly patients on areas of skin that have been sunburnt. Most previous case reports are from dermatologists, with few published reports from pathologists. In this study, three patients underwent pathological routine and auxiliary immunohistochemical (IHC) examination and were ultimately diagnosed with pagetoid SCC in situ - a different diagnosis from the initial clinical assessment. All three patients received a complete resection of the skin mass. After follow-up, as of June 2023, the patients had no tumour recurrence or metastasis. Pagetoid SCC in situ is a particular type of SCC in situ that has no specific features in clinical manifestations, gross diagnosis or histopathological sections. The final diagnosis depends on IHC staining. Pagetoid SCC in situ expresses EMA, CK5/6 and p63 but not CEA, CK8 or S-100, which are expressed in extramammary Paget's disease. Pagetoid SCC in situ is usually only locally invasive, and the main treatment is complete surgical resection. The prognosis is related to human papillomavirus infection, surgical margin closure, disease location, tumour thickness and other factors.

Assessing outcomes of topical 5-fluorouracil as primary and adjuvant therapy for squamous cell carcinoma in-situ.

Cutaneous squamous cell carcinoma in-situ (SCCis) is an intraepithelial tumor with a good prognosis. Standard treatment includes both surgical and non-surgical interventions. We determined the clearance rate for SCCis and residual SCCis identified on frozen section during Mohs micrographic surgery (MMS) after treatment with topical fluorouracil 5% cream (5-FU). All MMS cases were initiated for biopsy-proven invasive squamous cell carcinoma (SCC). A retrospective chart review was conducted from January 2017-February 2024 at Columbia University Irving Medical Center (CUIMC) to identify patients with SCCis who were treated with topical 5-FU as primary therapy or adjuvant therapy (AT) for residual SCCis post-MMS for invasive SCC. 41 patients were included (80% males, 70.1 ± 11.8 years). The average follow-up time for the primary therapy group was 25.4 ± 12.8 months, and for the post-MMS AT group 22.5 ± 11.1 months. In the group treated with topical 5-FU as primary therapy (n = 28), 27 patients (96.43%, 95% confidence interval: 81.65-99.91%) achieved complete clearance. One patient had recurrence at 8 months post-treatment. Of the patients in the post-MMS adjuvant treatment group (n = 13), 12 (92.3% clearance, 95% confidence interval 63.97-99.81%) achieved complete clearance. One patient had recurrence at 8 months post-treatment. This study found that topical 5-FU cream is effective as both primary therapy for SCCis and as adjuvant therapy for residual SCCis following MMS of invasive SCC.

Photodynamic Therapy for the Treatment of Bowen's Disease: A Review on Efficacy, Non-Invasive Treatment Monitoring, Tolerability, and Cosmetic Outcome.

Bowen's disease represents the in situ form of cutaneous squamous cell carcinoma; although it has an excellent prognosis, 3-5% of lesions progress to invasive cutaneous squamous cell carcinoma, with a higher risk in immunocompromised patients. Treatment is therefore always necessary, and conventional photodynamic therapy is a first-line option. The aim of this review is to provide an overview of the clinical response, recurrence rates, safety, and cosmetic outcome of photodynamic therapy in the treatment of Bowen's disease, considering different protocols in terms of photosensitizers, light source, and combination treatments. Photodynamic therapy is a valuable option for tumors at sites where wound healing is poor/delayed, in the case of multiple and/or large tumors, and where surgery would be difficult or invasive. Dermoscopy and reflectance confocal microscopy can be used as valuable tools for monitoring the therapeutic response. The treatment is generally well tolerated, with mild side effects, and is associated with a good/excellent cosmetic outcome. Periodic follow-up after photodynamic therapy is essential because of the risk of recurrence and progression to cSCC. As the incidence of keratinocyte tumors increases, the therapeutic space for photodynamic therapy will further increase.

Esophageal squamous cell carcinoma with pagetoid spread: a clinicopathologic study.

Pagetoid spread in esophageal squamous epithelium associated with underlying esophageal adenocarcinoma (EAC) has been well studied. Case reports describing pagetoid spread of esophageal squamous cell carcinomas (ESCC) also exist in the literature. The latter, however, has not been systematically studied. In this study, we report seven cases of pagetoid spread associated with ESCC. The clinical, morphologic, and immunophenotypic profiles of pagetoid spread in the context of ESCC and EAC are compared. Cases of pagetoid spread of ESCC were identified through computerized search of pathology archives at five institutions. Additional cases were identified through manual review of surgical resection cases of treatment naive ESCC in Mass General Brigham (MGB) pathology archive. Clinical history was collected via chart review. Immunohistochemistry for CK7, CK20, CDX2, p53, p63, and p40 was performed on selected cases. A computerized search of pathology archives of five institutions revealed only two cases. A manual review of 76 resected untreated ESCC revealed five additional cases with unequivocal pagetoid spread of ESCC, indicating the condition was not uncommon but rarely reported. Patient age ranged from 54 to 78 years (median, 65). There were six women and one man. One case had in situ disease, five had pT1 (1 pT1a and 4 pT1b), and one had pT3 disease. One of the patients with pT1 tumor had a positive lymph node, while the remaining six patients were all N0. Four tumors were in the proximal to mid esophagus, and three in the distal esophagus. Patient survival ranged from 25 months to more than 288 months. The pagetoid tumor cells demonstrated enlarged, hyperchromatic nuclei with variable amounts of eosinophilic cytoplasm. The cytoplasm was often condensed to the perinuclear area, creating peripheral clearing. By immunohistochemistry, the pagetoid cells were positive for p40 (6/6) and p63 (7/7) and negative for CDX2 (7/7). The tumor cells showed mutant-type staining for p53 in five of seven cases. One of the patients had pagetoid tumor cells at the resection margin and subsequently had recurrent disease 2 years later. All other patients had negative resection margins and did not have local recurrence. Four cases of pagetoid spread in the context of EAC were used as a comparison group. Previously published studies were also analyzed. These tumors were all located in the distal esophagus or gastroesophageal junction. All cases were associated with underlying invasive EAC. Pagetoid spread associated with EAC often had cytoplasmic vacuoles or mucin. They were more frequently positive for CK7 than pagetoid ESCC (p = 0.01). Both ESCC and EAC may give rise to pagetoid spread of tumor cells within surface squamous epithelium. Pagetoid spread from ESCC and EAC have overlapping morphologic features. P40 and p63 immunostains can facilitate the distinction between ESCC and EAC. P53 immunostain can aid in confirmation of malignancy. Understanding their overlapping pathologic features will help pathologists avoid pitfalls and diagnose these lesions correctly on biopsy specimens.

Merkel cell carcinoma overlapping Bowen's disease: two cases report and literature review.

PURPOSE: Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin, which mainly occurs in the sun exposed sites of white patients over 65 years, with a higher recurrence and metastasis rate. Clinically, MCC overlapping Bowen's disease (BD) is a very rare subtype of MCC. Few cases in the literature have been described and the management is not well defined. We summarize and update the epidemiology, clinical and histopathological features, metastasis characteristics, local recurrence rate and management of it by presenting two cases of MCC overlapping BD and reviewing the literature over the last 11 years. DESIGN: We consulted databases from PubMed, ResearchGate and Google Scholar by MeSh "Merkel cell carcinoma" and "Bowen's disease", "Bowen disease" or "squamous cell carcinoma in situ", from January 2013 to December 2023 and reviewed the literatures. We reported two additional cases. RESULTS: Total 13 cases of MCC overlapping BD were retrospectively analyzed, in whom mainly in elderly women over 70 years, the skin lesions were primarily located on the faces, followed by the extremities and trunk. Most of them were asymptomatic, firm, dark red nodules arising on rapidly growing red or dark brown patches, or presenting as isolated nodules. Dermoscopy evaluation was rarely performed in the pre-operative diagnostic setting. All cases were confirmed by histopathology and immunohistochemistry. The most definitive treatment was extended local excision, but local recurrences were common. Of the 13 cases, 4 cases experienced local or distant metastasis. One suffered from an in-transit recurrence of MCC on the ipsilateral leg after local excision and lymph node dissection, whose metastasis completely subsided after avelumab treatment and without recurrence or metastasis during 6 months of follow-up. CONCLUSIONS: MCC overlapping BD is a very rare skin tumor mainly predisposed on the faces, with high misdiagnosis rate and recurrence rate. Advanced disease at diagnosis is a poor prognostic factor, suggesting that earlier detection may improve outcome. The acronym, AEIOUN, has been proposed to aid in clinical identification. Our reports and the literature review can provide a better awareness and management of it.

Condyloma and Anal Dysplasia.

Anal intraepithelial neoplasia (AIN) are precancerous lesions and are sequela of human papilloma virus (HPV) infection. AIN is classified as low-grade squamous intraepithelial lesion or high-grade squamous intraepithelial lesion. Screening with anal cytology and anoscopy should be considered for high-risk populations. Diagnosis is made through high resolution anaoscopy and biopsy. Options for treatment include ablation and several topical therapies; however, recurrence rates are high for all treatment options, and an ongoing surveillance is necessary to prevent progression to anal squamous cell carcinoma. HPV vaccination is recommended to prevent disease.

Bowen disease with sebaceous differentiation arising from clonal seborrheic keratosis.

We present a rare case of clonal seborrheic keratosis (SK) with focal Bowen disease (BD) (squamous cell carcinoma in situ) accompanied by sebaceous differentiation. An 89-year-old woman presented with a pale reddish-brown plaque on the left buttock. Histopathological examination of the excisional specimen revealed hyperkeratosis, acanthosis, and intraepidermal epithelioma. In some areas of the tumor, we observed proliferation of basaloid keratinocytes within the intraepidermal nests and pseudohorn cysts. This area was diagnosed as clonal SK. However, in other areas, the tumor cells within the intraepidermal nests showed nuclear pleomorphism, abnormal mitoses, dyskeratotic cells, and clumping cells, consistent with BD with a nested/clonal pattern (clonal BD). The SK and BD areas were contiguous with the transitional zone. Some nests within the BD area contained vacuolated cells with bubbly cytoplasm and scalloped nuclei, suggestive of sebaceous differentiation. Therefore, we made the diagnosis of clonal BD with sebaceous differentiation arising from clonal SK. All areas contained intraepidermal nests, which revealed that the lesions were not the result of accidental collision, but that the neoplastic cells in the intraepidermal nests of the SK transformed into BD and underwent sebaceous differentiation.

Bowen disease is not synonymous with intraepidermal squamous cell carcinoma.

The terms 'Bowen disease' and 'intraepidermal squamous cell carcinoma' are sometimes considered synonymous. In this paper we present historical, clinical, histological and molecular evidence that this is incorrect. The term Bowen disease should be reserved for a subset of intraepidermal squamous cell carcinoma with a distinctive and reproducible morphological pattern, described in detail by Bowen in 1912. One other common subset of intraepidermal squamous cell carcinoma represents progression of actinic keratosis. In some cases the separation of these two common patterns of intraepidermal squamous cell carcinoma can be challenging and there are patterns of intraepidermal squamous cell carcinoma which appear to represent other distinct pathways. However, there is emerging biological evidence to support this distinction and reason to suspect that the types of invasive squamous cell carcinoma which arise from these different pathways may show important clinical and biological differences, particularly in the era of targeted and immunomodulatory therapy for advanced disease.

Squamous Neoplastic Precursor Lesions of the Esophagus.

Clinicopathological and molecular studies have demonstrated that dysplasia is a precancerous and/or neoplastic lesion with malignant potential. Further, it is subclassified into two grades: high-grade and low-grade dysplasia. High-grade dysplasia is a clinically significant lesion requiring resection or ablation. Low-grade dysplasia has a much lower risk of carcinoma; thus, it should be followed by endoscopic surveillance. Because squamous dysplasia may progress to squamous cell carcinoma, periodic endoscopy is useful to detect the lesion in patients with risk factors. Squamous dysplasia is diagnosed histopathologically by evaluating both cytologic and structural changes.

Extra-Ocular Sebaceous Carcinoma in Situ of the Arm of an Elder Male: An Unusual Presentation in an Atypical Location.

Background. Sebaceous carcinoma in situ outside the ocular region is an exceedingly uncommon. It is an intraepidermal neoplasm originating from sebaceous glands limited to the epidermis with no invasion into the underlying dermis or beyond. Although sebaceous carcinoma in situ is predominantly observed in ocular regions, particularly the eyelids, instances of its occurrence in extraocular locations are infrequent, with only a limited number of examples reported in the literature. Case Presentation. A 63-year-old man presented with a left posterior arm lesion. Microscopic examination revealed a proliferation of poorly differentiated atypical neoplastic sebocytes confined to the epidermis with pleomorphic nuclei, prominent nucleoli, and clear cell changes. The neoplastic cells demonstrated positive staining for adipophilin, androgen receptor, epithelial membrane antigen, P63, BerEP4, and keratin 7. Microsatellite instability markers showed preserved nuclear staining for MLH1, PMS2, MSH2, and MSH6. A definitive diagnosis of sebaceous carcinoma in situ was rendered. Discussion. The distinctive histopathologic characteristics typically involve the presence of atypical sebaceous cells confined within the epidermis. Atypical cells often exhibit enlarged nuclei, increased mitotic activity, and prominent nucleoli. A panel of epithelial membrane antigen, adipophilin, and androgen receptors is essential for ensuring an accurate diagnosis. Conclusion. This report underscores the importance of considering sebaceous carcinoma in situ in diagnosis in atypical locations, emphasizing the need for a comprehensive histopathologic examination and immunohistochemical staining panel. This article aims to demonstrate the rarity of sebaceous carcinoma in situ in extraocular sites to broaden our understanding of its diverse clinical presentations.

Survival of patients with basal cell carcinoma, squamous cell carcinoma, and squamous cell carcinoma in situ: A whole population study.

BACKGROUND: Keratinocyte carcinoma (KC) is the commonest type of malignancy in humans; however, the impact of KC on survival is poorly understood. OBJECTIVES: This study characterizes the impact of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and squamous cell carcinoma in situ (SCCis) on the survival of Icelanders. METHODS: This whole population study evaluated relative survival of KC in Iceland by using a cancer registry containing records of all BCC, SCCis, and SCC cases recorded in Iceland between 1981 and 2015. RESULTS: Between 1981 and 2015, 8767 Icelanders were diagnosed with their first localized KC. A total of 6473 individuals with BCC, 1194 with SCCis, and 1100 with invasive SCC, respectively. BCC was not associated with decreased survival except for men diagnosed with BCC between 1981 and 1995 for whom decreased 10-year relative survival was observed (85.3, 95% CI [77.9-92.7]). SCC and SCCis were both associated with a decrease in relative survival for certain population subgroups such as individuals <50 years of age at time of diagnosis. CONCLUSION: Our whole population cohort survival study examining the Icelandic Cancer Registry supports prior studies demonstrating that BCC is not associated with a reduction in relative survival and that SCC and SCCis are associated with comparatively poor relative survival in certain population subgroups.

Incidence of Squamous Cell Carcinoma in Situ Upstaged to Invasive Squamous Cell Carcinoma During Mohs Surgery.

Objective: We sought to record the incidence and risk factors associated with upstaging squamous cell carcinoma in situ (SCCIS) to squamous cell carcinoma (SCC) during Mohs surgery with the largest sample size to date. Methods: Patient records of preoperative biopsy-proven SCCIS being treated with Mohs between January 2019 to March 2022 were identified and reviewed. Postoperative diagnoses of invasive SCC proven by dermal infiltration on pathology were identified as upstaged SCCIS. Results: From 2,043 cases of preoperative diagnosed SCCIS, 47 (2.3%) were upstaged to SCC during Mohs surgery. Of the 47 invasive tumors, a large proportion on the hands (29.8%) and lesions with larger preoperative sizes had a higher risk of being upstaged to invasive SCC in this study. Limitations: All of the patients included were from rural and suburban areas of North Carolina. The only sections obtained were those reviewed for margin analysis, which may significantly underestimate the actual number of invasive SCC, as only the deepest and furthest portions were examined. Conclusion: This retrospective study concluded that 2.3 percent of preoperatively diagnosed SCCIS were upstaged to SCC during treatment with Mohs surgery. Large lesions (>2cm) and lesions on the hand were more likely to be upstaged (29.8%). Treatment must be individualized considering the size of the lesion, the anatomic location, and the possibility that in some cases the initial biopsy may not have been able to accurately distinguish SCCIS from SCC. Although there is a myriad of treatment options for SCC, select patients with increased risk factors for upstaged SCC must be considered for margin assessed treatment modalities.

Efficacy of Fractionated Erbium Laser in Treating Radiation-Induced Dermal Atrophy: A Case Report.

Radiation dermatitis is a common side effect of radiotherapy in patients with acute and chronic changes affecting the skin. While acute changes occur within 90 days of radiation exposure, chronic changes manifest thereafter. This paper presents a case of a 70-year-old male with squamous cell carcinoma in situ (SCCIS) on the right zygoma who was treated with superficial radiation therapy (SRT), which resulted in a hypo-pigmented atrophic scar. The scar was successfully treated with a single session of Erbium:YAG laser therapy. The findings highlight the need for improved treatment options for radiation-induced skin changes and demonstrate the efficacy of fractionated laser therapy in addressing SRT-induced dermal atrophy.

A case of coexistent poorly differentiated adenosquamous carcinoma (glassy cell carcinoma), usual-type adenocarcinoma, and squamous cell carcinoma in situ of the cervix.

Poorly differentiated adenosquamous carcinoma (glassy cell carcinoma) of the cervix is extremely rare, accounting for 1-2% of all cervical cancers. Herein, we report a case with coexistent poorly differentiated adenosquamous carcinoma (glassy cell carcinoma), "usual-type" adenocarcinoma, and squamous cell carcinoma in situ of the cervix. A female patient in her 60 s was referred to our hospital and diagnosed with poorly differentiated adenosquamous carcinoma based on cervical cytology and biopsy. The tumor was classified as clinical stage IB1 cervical cancer following magnetic resonance imaging; radical hysterectomy was performed. Histopathological examination revealed poorly differentiated adenosquamous carcinoma (glassy cell carcinoma), usual-type adenocarcinoma, and squamous cell carcinoma in situ, all coexisting. All carcinoma regions showed identical sizes to high-risk human papillomavirus (HPV) in fragment analysis. The patient is currently alive, without evidence of recurrence, 31 months post surgery. In this case, three different carcinomas coexisted. Fragment analysis of the patient's HPV status suggested that all carcinomas were related to an infection with the same high-risk HPV type. To determine the precise mechanism of tumor development, i.e., whether the tumors were of the mixed or collision type, further studies are needed, including clonal analysis for the loss of heterozygosity pattern.

The utility of p63, CK7, and CAM5.2 staining in differentiating pagetoid intraepidermal carcinomas.

BACKGROUND: Extramammary Paget disease (EMPD), pagetoid squamous cell carcinoma in situ (PSCCIS), and Paget disease of the breast (PD) are intraepidermal carcinomas with overlapping histopathologic features. CK7 and CAM5.2 stains are frequently utilized to distinguish PSCCIS from EMPD and PD. However, some cases of PSCCIS can stain positively for CAM5.2 and CK7, indicating a potential pitfall with these stains. p63 has been shown to distinguish PSCCIS from EMPD. We assessed p63 staining in PD and compared it to p63 staining of PSCCIS and EMPD. METHODS: A retrospective search for 15 examples each of PSCCIS, EMPD, and PD with remaining tissue in the paraffin block was performed. The diagnosis was confirmed by a board-certified dermatopathologist and immunostaining for p63, CK7, and CAM5.2 was performed. Staining >55% was scored as positive. Staining <55% was scored as negative and an approximate percentage of positive cells was recorded. RESULTS: Diffuse nuclear expression for p63 was detected in 100% (15/15) of PSCCIS cases, 0% (0/15) of PD cases, and 0% (0/15) of EMPD cases. CK7 and CAM5.2 stains were positive in 100% of PD. CAM5.2 was positive in 100% of EMPD and CK7 was positive in 93% of EMPD. CAM5.2 was positive in 0% of PSCCIS biopsy specimens, but partial staining was seen in 20%. CK7 was positive in 13%, but partial staining was seen in 47%. CONCLUSIONS: p63 immunostaining is a highly sensitive and specific method for differentiating between PSCCIS and PD or EMPD. While CAM5.2 and CK7 are also useful ancillary stains in this differential diagnosis, false-positive and false-negative staining occurs with these two markers.

Bladder squamous cell carcinoma in situ in the background of condyloma acuminatum in a kidney transplant recipient.

Condyloma acuminatum with synchronous squamous cell carcinoma in situ (CIS) rarely occurs in the bladder. In developed countries, bladder squamous cell carcinoma (SCC) is uncommon. Among the various noninvasive squamous bladder lesions, there is significant morphological overlap, which further complicates accurate diagnosis. Immunosuppression and human papilloma virus increase the risk of bladder condyloma acuminatum, which has a strong association with bladder SCC. Herein, we describe a case of a 79-year-old man with a history of end-stage renal disease with kidney transplantation and anal SCC who presented with bladder squamous cell CIS arising in the background of condyloma acuminatum.

Squamous carcinogenesis: potential truncal mutations.

Squamous carcinogenesis is incompletely understood, but more recent genetic studies support that the order of acquired mutations is important. This paper will review more recent genetic studies with an emphasis on the potential truncal mutations, mutations critical to the trunk of the cancer evolutionary tree, in actinic keratosis, squamous cell carcinoma in situ, cutaneous squamous cell carcinoma, keratoacanthoma, and keratoacanthoma-like squamous proliferation.

Long-term follow up of ALA 10% gel and red-light photodynamic therapy for the treatment of squamous cell carcinoma in situ.

Photodynamic Therapy (PDT) with 10% aminolevulinic acid (ALA) gel and narrow-band red light has been previously shown to be safe and effective for the treatment of squamous cell carcinoma in situ (SCCis) on the trunk and extremities. However, there is a paucity of data in the literature evaluating long-term disease recurrence after PDT. Hence, we performed a follow-up study in which nine of the original twelve patients from our pilot study returned 29-40 months after their last PDT treatment. All patients were clinically clear of disease and only one of seven patients biopsied had residual disease, indicating a long-term clearance rate of 88%. Cosmetic outcomes and patient satisfaction were favorable. Our data supports that red-light PDT with 10% ALA gel can achieve long-term clinical and histopathologic disease clearance and is a viable alternative to surgery for select SCCis.