Cytokine levels in breast cancer are highly dependent on cytomegalovirus (CMV) status.

PURPOSE: Breast cancer accounts for 30% of all female cancers in the US. Cytomegalovirus (CMV), a herpesvirus that establishes lifelong infection, may play a role in breast cancer. CMV is not oncogenic, yet viral DNA and proteins have been detected in breast tumors, indicating possible contribution to tumor development. CMV encodes cmvIL-10, a homolog of human cellular IL-10 (cIL-10) with potent immunosuppressive activities. We investigated the relationship between CMV infection, cytokines, and breast cancer. METHODS: We evaluated CMV serostatus and cytokine levels in plasma of women with benign breast disease (n = 38), in situ carcinoma (n = 41), invasive carcinoma, no lymph node involvement (Inv/LN-; n = 41), and invasive with lymph node involvement (Inv/LN+; n = 37). RESULTS: Fifty percent of the patient samples (n = 79) were CMV seropositive. There was no correlation between CMV status and diagnosis (p = 0.75). For CMV+ patients, there was a trend toward higher CMV IgG levels in invasive disease (p = 0.172). CmvIL-10 levels were higher in CMV+ in situ patients compared to the Inv/LN- and Inv/LN+ groups (p = 0.020). Similarly, cIL-10 levels were higher in CMV+ in situ patients compared to the Inv/LN- and Inv/LN+ groups (p = 0.043). The results were quite different in CMV- patients where cIL-10 levels were highest in Inv/LN- compared to benign, in situ, or Inv/LN+ (p = 0.019). African American patients were significantly associated with CMV+ status (p = 0.001) and had lower cmvIL-10 levels than Caucasian patients (p = 0.046). CONCLUSION: No association was observed between CMV IgG and diagnosis, but CMV infection influences cytokine production and contributes to altered cytokine profiles in breast cancer.

Using colorimetric in situ hybridisation method for FcaPV-2 to estimate postsurgical prognosis in feline Bowenoid in situ carcinoma.

BACKGROUND: Feline Bowenoid in situ carcinoma (BISC) is frequently associated with Felis catus papillomavirus-2 (FcaPV-2). Although surgical excision of BISC is expected to be curative, recurrent lesions are reported and it is not known whether it is a consequence of incomplete surgery or residual viral load. OBJECTIVES: To combine colorimetric in situ hybridisation (CISH) and quantitative (q)PCR for the detection of viral DNA, and to correlate the clinical outcome of cats with BISC in which FcaPV-2 DNA is detected at surgical margins. ANIMALS: Twenty-seven cats with a histopathological diagnosis of BISC. MATERIALS AND METHODS: Sections including core and margins of the lesions were used for histopathological evaluation, qPCR and CISH. After surgical removal of the lesion, clinical follow-up data were recorded for 6 months. RESULTS: Six of 12 cases in which all four histological margins were evaluable were used to correlate the infection status at the margins with the follow-up data. Four showed margin positivity, of which half relapsed as expected and half cured; two cases were negative, of which one cured as expected while the other relapsed. Fifteen cases where only three, two or one of the histological margins were evaluable, were considered to adequately correlate the status of infection with the follow-up data if CISH was positive. Follow-up data were available for three with positive margins: one relapsed while the other two were cured. CONCLUSIONS AND CLINICAL RELEVANCE: Wide clinical surgical margins are always recommended for neoplastic conditions, yet there was no evidence that CISH margin examination would be beneficial in predicting recurrence in this viral-induced lesion.

Identification of Stage-Specific microRNAs that Govern the Early Stages of Sequential Oral Oncogenesis by Strategically Bridging Human Genetics with Epigenetics and Utilizing an Animal Model.

Oral squamous cell carcinoma (OSCC) is a highly prevalent and aggressive malignancy, with mortality rates reaching 60%, mainly due to its excessive diagnostic delay. MiRNAs, a class of crucial epigenetic gene-expression regulators, have emerged as potential diagnostic biomarkers, with >200 molecules exhibiting expressional dysregulation in OSCC. We had previously established an in silico methodology for the identification of the most disease-specific molecules by bridging genetics and epigenetics. Here, we identified the stage-specific miRNAs that govern the asymptomatic early stages of oral tumorigenesis by exploiting seed-matching and the reverse interplay between miRNA levels and their target genes' expression. Incorporating gene-expression data from our group's experimental hamster model of sequential oral oncogenesis, we bioinformatically detected the miRNAs that simultaneously target/regulate >75% of the genes that are characteristically upregulated or downregulated in the consecutive stages of hyperplasia, dysplasia, and early invasion, while exhibiting the opposite expressional dysregulation in OSCC-derived tissue and/or saliva specimens. We found that all stages share the downregulation of miR-34a-5p, miR124-3p, and miR-125b-5p, while miR-1-3p is under-expressed in dysplasia and early invasion. The malignant early-invasion stage is distinguished by the downregulation of miR-147a and the overexpression of miR-155-5p, miR-423-3p, and miR-34a-5p. The identification of stage-specific miRNAs may facilitate their utilization as biomarkers for presymptomatic OSCC diagnosis.

In situ squamous cell carcinoma of the gingiva and nictitating membrane associated with Felis catus papillomavirus type 3 in a cat.

Oral squamous cell carcinomas (OSCCs) are common cancers of cats. While papillomaviruses (PVs) are an important cause of human OSCCs, there is currently little evidence that PVs cause squamous cell carcinomas (SCCs) of the mouth or other mucosal surfaces in cats. In the present cat, in situ carcinomas developed on the gingiva and nictitating membrane. Neoplastic cells within both cancers contained prominent PV-induced cellular changes consistent with those caused by Felis catus PV3 (FcaPV3), and FcaPV3 DNA was amplified from both cancers. Neoplasms also contained intense nuclear and cytoplasmic p16CDKN2A protein (p16) immunolabeling, suggesting PV-induced degradation of retinoblastoma protein. The molecular and histological features strongly suggested the cancers were caused by FcaPV3 infection. This is the first report of an association between PV infection and the development of an in situ carcinoma of the mucosa of cats. The identification of these lesions suggests that PVs might cause a proportion of OSCCs, and SCCs from other mucosal surfaces, in cats.

Which type of cancer is detected in breast screening programs? Review of the literature with focus on the most frequent histological features.

Breast cancer is the most frequent type of cancer affecting female patients. The introduction of breast cancer screening programs led to a substantial reduction of mortality from breast cancer. Nevertheless, doubts are being raised on the real efficacy of breast screening programs. The aim of the present paper is to review the main pathological type of cancers detected in breast cancer screening programs. Specifically, attention will be given to: in situ carcinoma, invasive carcinoma histotypes and interval cancer.

Rabbit monoclonal E-cadherin antibody: A cost-effective alternative to mouse monoclonal antibody in distinguishing ductal carcinoma in situ from lobular carcinoma in situ.

Rabbit monoclonal antibody (RabMAb) demonstrates higher sensitivity without sacrificing specificity than mouse monoclonal antibody (MMAb). MMAb against E-cadherin stain is heavily utilized in distinguishing ductal carcinoma in situ (DCIS) from lobular carcinoma in situ (LCIS). We aimed to compare the E-cadherin stain using RabMAb vs MMAb in distinguishing DCIS from LCIS. One hundred and seventeen in situ breast carcinomas (55 DCIS, 58 LCIS, and 4 DCIS and LCIS) were studied. Sections from a representative block of each were stained with RabMAb [EP700Y] and MMAb [36B5]. Scanned images of stained slides were compared in tandem. All DCIS cases (59/59) showed comparable staining by RabMAb and MMAb. Comparable staining was also observed in all but one case of LCIS (61/62; 98%). One case of pleomorphic LCIS showed mostly complete, weak to moderately intense membranous staining with RabMAb and fragmented, weak membranous staining with MMAb. Consistently better staining quality was observed in slides stained by RabMAb vs MMAb. RabMAb and MMAb against E-cadherin were diagnostically equivalent with the exception of one case where RabMAb may have led to diagnostic misinterpretation. However, the not insignificant cost savings and easier interpretation using RabMAb may justify the risk of misinterpretation of increased staining in rare cases, largely avertable with proper training.

In situ carcinoma in a hybrid cyst: a case report.

Follicular hybrid cysts including two or more components of the epithelial skin adnexa are very rare. The epithelial lining of hybrid cysts varies, and either contains epidermis, and trichilemmal squamous epithelium, or other epithelia of the skin adnexa. Hybrid cysts may also be associated with neoplasia, such as in situ carcinoma, Bowen's disease and squamous cell carcinoma. A 37-year-old female was complaining of a cyst on her scalp. The unilocular cystic lesion was lined with markedly atypical squamous cells with trichilemmal differentiation. Marked nuclear and cytological atypia, pleomorphism, numerous mitotic figures and atypical mitosis was detected in the squamous epithelium. The epithelium of the cyst was also composed of ductal structures lined with cuboidal epithelium. Immunohistochemical staining was positive for cytokeratin 7 (CK7) in both squamous and glandular epithelium. Luminal staining was shown by carcinoembryonic antigen (CEA), although gross cystic disease fluid protein-15 (GCDFP-15) was negative in the glandular epithelium. In addition, p16 tumor suppressor gene was strongly positive in both the squamous and glandular epithelium. Overall, the unique cystic lesion reported contained pilar squamous epithelium with in situ carcinoma and eccrine ductal structures, which was interpreted as a hybrid cyst composed of in situ trichilemmal carcinoma and a ductal eccrine component.

Multiple viral plaques with sebaceous differentiation associated with an unclassified papillomavirus type in a cat.

CASE HISTORY AND CLINICAL FINDINGS A 15-year-old neutered male domestic short-haired cat was presented due to multiple 0.5-2 cm-diameter crusting plaques in the left preauricular region, over the bridge of nose, and in the right periocular region. The plaques did not appear to cause discomfort. HISTOPATHOLOGICAL FINDINGS Biopsy samples of four plaques were examined histologically. Three plaques consisted of well-demarcated foci of mild epidermal hyperplasia overlying markedly hyperplastic sebaceous glands. Approximately 60% of the hyperplastic cells contained a large cytoplasmic vacuole that ranged from being clear to containing prominent grey-blue fibrillar material. The fourth plaque was composed solely of epidermal hyperplasia, consistent with previous descriptions of feline viral plaques. MOLECULAR BIOLOGY Papillomavirus DNA was amplified from all four plaques using PCR. A single DNA sequence was amplified from the plaques with sebaceous differentiation. This sequence was identical to the FdPV-MY sequence previously suggested to be from a putative unclassified papillomavirus type. Felis catus papillomavirus type 2 sequences were amplified from the plaque typical of feline viral plaques. Immunohistochemistry to detect p16CDKN2A protein (p16) showed marked immunostaining throughout the hyperplastic epidermis and adnexal structures within the plaques with sebaceous differentiation. DIAGNOSIS Multiple feline viral plaques with variable sebaceous differentiation. CLINICAL RELEVANCE Feline viral plaques with sebaceous differentiation have not been previously reported in cats. The presence of unique cell changes within these lesions, the detection of an unclassified papillomavirus type, and the p16 immunostaining within these plaques suggest that they may have been caused by the papillomavirus that contains the FdPV-MY sequence.

An Unusual Case of Recurrent Cutaneous Carcinomas Over Extragenital Multicentric Pigmented Bowen's Disease.

Bowen's disease is a slowly progressive squamous cell carcinoma (SSC) in situ with high potential for malignant transformation. In this case, we describe a patient with multicentric Bowen's disease for the past 26 years, developing growths over his left buttock. The patient had a previous history of growth developing over his right thigh, and was diagnosed with metatypical basal cell carcinoma (BCC). The points that make this case noteworthy are recurrent cutaneous carcinomas over the multicentric generalized occurrence of in situ SCC of extragenital type, the rarity of the site, and the nature of its morphological presentation in the skin of color.

Hospitalization burden associated with anus and penis neoplasm in Spain (2016-2020).

In 2020, there were approximately 50,865 anal cancer cases and 36,068 penile cancer cases worldwide. HPV is considered the main causal agent for the development of anal cancer and one of the causal agents responsible for the development of penile cancer. The aim of this epidemiological, descriptive, retrospective study was to describe the burden of hospitalization associated with anal neoplasms in men and women and with penis neoplasms in men in Spain from 2016 to 2020. The National Hospital Data Surveillance System of the Ministry of Health, Conjunto Mínimo Básico de Datos, provided the discharge information used in this observational retrospective analysis. A total of 3,542 hospitalizations due to anal cancer and 4,270 hospitalizations due to penile cancer were found; For anal cancer, 57.4% of the hospitalizations occurred in men, and these hospitalizations were also associated with significantly younger mean age, longer hospital stays and greater costs than those in women. HIV was diagnosed in 11.19% of the patients with anal cancer and 1.74% of the patients with penile cancer. The hospitalization rate was 2.07 for men and 1.45 for women per 100,000 in anal cancer and of 4.38 per 100,000 men in penile cancer. The mortality rate was 0.21 for men and 0.12 for women per 100,000 in anal cancer and 0.31 per 100.000 men in penile cancer and the case-fatality rate was 10.07% in men and 8,26% in women for anal cancer and 7.04% in penile cancer. HIV diagnosis significantly increased the cost of hospitalization. For all the studied diagnoses, the median length of hospital stays and hospitalization cost increased with age. Our study offers relevant data on the burden of hospitalization for anal and penile cancer in Spain. This information can be useful for future assessment on the impact of preventive measures, such as screening or vaccination in Spain.

Prevalence, molecular markers, and outcome of bronchial squamous carcinoma in situ in high-risk subjects.

Bronchial squamous carcinoma in situ (CIS) is a preinvasive lesion that is thought to precede invasive carcinoma. We conducted prospective autofluorescence and white light bronchoscopy trials between 1992 and 2016 to assess the prevalence, molecular markers, and outcome of individuals with CIS and other preneoplastic bronchial lesions. Biopsies were evaluated at multiple levels and selected biopsies were tested for aneuploidy and DNA sequenced for TP53 mutation. Thirty-one individuals with CIS were identified. Twenty-two cases of CIS occurred in association with concurrent invasive carcinomas. Seven of the invasive tumors were radiographically occult. In two cases, CIS spread from the focus of invasive carcinoma into contralateral lung lobes, forming secondary invasive tumors. In nine cases, CIS occurred as isolated lesions and one progressed to invasive squamous carcinoma at the same site 40 months after discovery. In a second case, CIS was a precursor of carcinoma at a separate site in a different lobe. In seven cases CIS regressed to a lower grade or disappeared. High level chromosomal aneusomy was often associated with TP53 mutation and with invasive carcinoma. CIS most often occurs in association with invasive squamous carcinoma and may extend along the airways into distant lobes. In rare cases, CIS may be observed to directly transform into invasive carcinoma. CIS may be indicative of invasive tumor at a separate distant site. Isolated CIS may regress. Molecular changes parallel histological changes in CIS and may be used to map clonal expansion in the airways.

Squamous Cell Carcinoma In Situ of the Breast With the Configuration of an Intraductal Papilloma.

A 64-year-old woman presented to our institution with a palpable and painful left breast mass. She denied any other breast symptoms. Subsequent imaging classified it as a US Breast Imaging-Reporting and Data System (BI-RADS) 4A lesion. A core needle biopsy was performed showing atypical proliferating fragments of squamous epithelium suspicious for malignant neoplasm. An excisional biopsy was recommended. Gross examination showed a well-circumscribed pink soft mass measuring 2.0 x 1.4 x 1.3 cm. The entire lesion was submitted for histologic evaluation, demonstrating a neoplasm with branching stroma and exuberant squamous differentiation. The lesion exhibited obvious cytologic features of malignancy like mitotic figures, prominent nucleoli, irregular nuclei, and multinucleation. Collagen IV stain ruled out invasion. The lesion was finally classified as squamous cell carcinoma (SCC) in situ with the configuration of an intraductal papilloma. The possibility of metastatic disease was suggested. A PET scan was negative, and no other foci of disease were found in the remainder of the specimen. The mass was also independent of nipple and skin. Based on the architectural features, we believe that this is a case of an intraductal papilloma that underwent complete squamous metaplasia with no residual adenomyoepithelial components and transformation into an SCC in situ demonstrated by stains. Papillomas can undergo reactive metaplastic changes, usually benign and in small foci. This is the first reported case of exuberant squamous epithelium that transformed into carcinoma in situ with papillary architecture in the breast.

Variants of in situ carcinoma of the endometrium: Clear cell and gastrointestinal types, with a review of the literature.

Two precursor lesions are commonly associated with endometrial carcinoma. Atypical endometrial hyperplasia/endometrial intraepithelial neoplasia is a known precursor lesion of endometrial endometrioid carcinoma, while endometrial intraepithelial carcinoma, is a recognized precursor lesion of endometrial high-grade serous carcinoma. Other than these two recognized entities, other rare precursor lesions for endometrial carcinoma do exist, although reported cases are relatively few and not universally recognized. This therefore poses diagnostic challenges in clinical practice. Here, we describe a series of rare precursor lesions of the endometrium identified at our institution, including clear cell and gastrointestinal variants, their morphologic and immunohistochemical characteristics, and review current literature regarding these variants. The information provided may guide the proper diagnosis and ultimately lead to effective clinical management in every-day practice.

Intracystic Papillary Carcinoma: A Case Report.

Intracystic papillary carcinoma (IPC) of the breast is a rare form of in-situ carcinoma, which is contained within a dilated duct. Mammography and ultrasound may provide clues to its presence, but formal diagnosis always requires histologic evidence. Although IPC is associated with an excellent prognosis, surgical resection is important in order to rule out the possibility of any invasive component, which would result in the need for more aggressive treatment. In this paper, we review the radiographic and histologic features of this interesting diagnosis, present a patient case, and explore the possible reason why IPC does not require the same treatment modalities as the more common ductal carcinoma in situ (DCIS).

Apocrine lesions of the breast.

Apocrine change is recognised in benign, atypical and malignant lesions of the breast. Apocrine metaplasia, a frequent finding in the breast of women over the age of 25 years, is most commonly seen in benign cysts with a simple or papillary configuration. Apocrine change is also recognised in other benign lesions including sclerosing adenosis, now known as apocrine adenosis. Apocrine atypia usually refers to cytological atypia in which there is at least threefold variation in nuclear size but architectural atypia may also occur. The distinction between atypical apocrine hyperplasia and non-high-grade apocrine ductal carcinoma in situ may be difficult due to the relative rarity of these entities and the lack of validated diagnostic criteria. Lobular carcinoma in situ (LCIS) with apocrine change is considered to be a variant of pleomorphic LCIS. An apocrine variant of encapsulated papillary carcinoma is also recognised. Apocrine change is described in invasive carcinoma, including no special type, lobular, micropapillary and mucinous variants. The recent WHO 2019 update recognises 'carcinoma with apocrine differentiation' as a special type breast carcinoma based on the presence of apocrine morphology in at least 90% of the tumour. Tumours with apocrine morphology are usually but not always hormone receptor negative. Human epidermal growth factor receptor 2 (HER-2) status is variable. Molecular studies have identified breast tumours with apocrine features and high expression of androgen receptor mRNA including 'luminal androgen receptor tumours' and 'molecular apocrine tumours'. The term 'pure apocrine carcinoma' has been proposed to describe an invasive carcinoma with apocrine morphology that is oestrogen and progesterone receptor negative and androgen receptor positive. HER-2 status may be positive or negative. This article reviews the pathology of benign, atypical and malignant apocrine lesions of the breast, with emphasis on diagnostic criteria including an approach to evaluation of apocrine lesions on needle core biopsy, and recent advances in our understanding of invasive apocrine carcinoma.

Papillomaviral skin diseases of humans, dogs, cats and horses: A comparative review. Part 2: Pre-neoplastic and neoplastic diseases.

Papillomaviruses (PVs) are well recognized to cause pre-neoplastic and neoplastic diseases in humans. Similarly, there is increasing evidence that PVs play a significant role in the development of pre-neoplastic and neoplastic diseases of the haired skin of dogs and cats, and the mucosa of horses. As the mechanisms by which PVs cause neoplasia are well studied in humans, it is valuable to compare the PV-induced neoplasms of humans with similar PV-associated neoplasms in the companion animal species. In the second part of this comparative review, the pre-neoplastic and neoplastic diseases thought to be caused by PVs in humans, dogs, cats, and horses are described. This includes PV-induced cutaneous plaques, cutaneous squamous cell carcinomas (SCCs) and mucosal SCCs within the four species. The review concludes with a discussion about the potential use of vaccines to prevent PV-induced diseases of dogs, cats, and horses.

Intra-Cystic (In Situ) Mucoepidermoid Carcinoma: A Clinico-Pathological Study of 14 Cases.

AIMS: To report on the clinico-pathological features of a series of 14 intra-oral mucoepidermoid carcinomas showing exclusive intra-cystic growth. Materials and methods: All mucoepidermoid carcinomas diagnosed in the period 1990­2012 were retrieved; the original histological preparations were reviewed to confirm the diagnosis and from selected cases, showing exclusive intra-cystic neoplastic components, additional sections were cut at three subsequent 200 m intervals and stained with Hematoxylin­Eosin, PAS, Mucicarmine and Alcian Blue, to possibly identify tumor invasion of the adjacent tissues, which could have been overlooked in the original histological preparations. Additionally, pertinent findings collected from the clinical charts and follow-up data were analyzed. Results: We identified 14 intraoral mucoepidermoid carcinomas treated by conservative surgery and with a minimum follow up of five years. The neoplasms were located in the hard palate (nine cases), the soft palate (two), the cheek (two) and the retromolar trigone (one). In all instances, histological examination revealed the presence of a single cystic space, containing clusters of columnar, intermediate, epidermoid, clear and mucous-producing cells, the latter exhibiting distinct intra-cytoplasmic mucin production, as confirmed by PAS, Mucicarmine and Alcian Blue stains. The cysts were entirely circumscribed by fibrous connective tissue, and no solid areas or infiltrating tumor cell clusters were detected. Conservative surgical resection was performed in all cases, and no recurrences or nodal metastases were observed during follow up. Conclusions: Mucoepidermoid carcinomas showing prominent (>20%) intra-cystic proliferation currently are considered low-grade tumors. In addition, we also unveil the possibility that mucoepidermoid carcinomas, at least in their early growth phase, may display an exclusive intra-cystic component and might be considered as in situ carcinomas, unable to infiltrate adjacent tissues and metastasize.

Pathologic characterization of Felis catus papillomavirus type 5 (FcaPV-5)-associated viral plaques and Bowenoid in situ carcinoma in a Domestic Shorthair cat.

The present paper describes Felis catus papillomavirus (FcaPV) type 5-associated cutaneous mass in a Domestic Shorthair cat. Histological examination revealed multicentric epidermal acanthosis with papillomavirus-associated cytopathic changes, which progressed to a tumor lobule with intact basement membrane. An association between FcaPV-5 and the cutaneous lesions was confirmed by detection of virus antigen and genes using immunohistochemistry, polymerase chain reaction (PCR), sequencing analysis, and in situ hybridization. Based on these findings, the lesions were diagnosed as FcaPV-5-associated viral plaques and Bowenoid in situ carcinoma (BISC). To date, this is the first reported case of FcaPV-5 infection in a cat in Japan, and the second case reported worldwide. For the first time this papillomavirus type is associated with BISC development.

Novel viruses: Update on the significance of papillomavirus infections in cats.

PRACTICAL RELEVANCE: Prior to 1990 papillomaviruses (PVs) were not recognised to infect or cause disease in domestic cats. Since this time, the use of histology, immunohistochemistry and, more recently, molecular techniques has revealed that PVs almost certainly cause feline viral plaques and Bowenoid in situ carcinomas, oral papillomas and feline sarcoids. In addition, there is increasing evidence that PVs play a significant role in the development of feline cutaneous squamous cell carcinomas, one of the most common skin cancers of cats. Recent studies have also revealed that most cats are asymptomatically infected with PVs. This raises a critical question that is currently unanswered: why do only a small proportion of infected cats develop disease? In the future it may be possible to prevent PV-induced diseases by using a vaccine to prevent PV infection. Alternatively, novel therapies may be developed that prevent PVs from causing clinical disease by stimulating the host immune response. CLINICAL CHALLENGES: A recognition of the skin diseases caused by PVs is important to more accurately predict disease progression. Unfortunately, there are currently no non-surgical treatments that have been proven to be beneficial in cats and clinical management of PV-induced skin disease in cats can be challenging. GLOBAL IMPORTANCE: PVs have a worldwide distribution and negatively impact feline health and welfare globally. AUDIENCE: This review is aimed at clinicians, especially those who regularly treat cats with skin disease. The review will also be useful to oncologists and researchers who have an interest in how cancer develops in cats. EVIDENCE BASE: In producing this update the authors have drawn on recently published peer-reviewed literature.