Benign Papillomas Research Articles

Characterisation of breast papillary neoplasm on automated breast ultrasound

Intraductal papillary neoplasms of the breast form a wide spectrum of pathological changes with benign intraductal papilloma and papillary carcinoma. They can occur anywhere within the breast ductal system. This review illustrates some characteristic appearances of breast papillary neoplasms on coronal planes reconstructed by automatic breast volume scan. Such manifestations are not uncommon in papillary neoplasms, and familiarity will enable confident diagnosis.

Indian Hedgehog Controls Proliferation and Differentiation in Skin Tumorigenesis and Protects against Malignant Progression

Mutations in the hedgehog pathway drive the formation of tumors in many different organs, including the development of basal cell carcinoma in the skin. However, little is known about the role of epidermal Indian hedgehog (Ihh) in skin physiology. Using mouse genetics, we identified overlapping and distinct functions of Ihh in different models of epidermal tumorigenesis. Epidermal deletion of Ihh resulted in increased formation of benign squamous papilloma. Strikingly, Ihh-deficient mice showed an increase in malignant squamous cell carcinoma and developed lung and lymph node metastases. In a sebaceous gland tumor model, Ihh deficiency inhibited tumor cell differentiation. More mechanistically, IHH stimulated cell proliferation by activating the transcription factor GLI2 in human keratinocytes and human tumors. Thus, our results uncover important functions for Ihh signaling in controlling proliferation, differentiation, malignant progression, and metastasis of epithelial cancer, establishing Ihh as a gatekeeper for controlling the grade of tumor malignancy.

Human Papillomavirus Infections: Warts or Cancer?

Human papillomaviruses (HPVs) are prevalent pathogens of mucosal and cutaneous epithelia. Productive infections of squamous epithelia lead to benign hyperproliferative warts, condylomata, or papillomas. Persistent infections of the anogenital mucosa by high-risk HPV genotypes 16 and 18 and closely related types can infrequently progress to high-grade intraepithelial neoplasias, carcinomas-in-situ, and invasive cancers in women and men. HPV-16 is also associated with a fraction of head and neck cancers. We discuss the interactions of the mucosotropic HPVs with the host regulatory proteins and pathways that lead to benign coexistence and enable HPV DNA amplification or, alternatively, to cancers that no longer support viral production.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Comparison of Sonographically Guided Core Needle Biopsy and Excision in Breast Papillomas

The aim of this study was to evaluate the clinical factors and sonographic features of benign papillomas of the breast proven by sonographically guided 14-gauge core needle biopsy and their upgrade or malignancy rate after sonographically guided vacuum-assisted excision or surgical excision. We reviewed the medical records of patients who underwent core needle biopsy from July 2005 to December 2011. We evaluated 39 benign papillomas without atypia in 34 patients. The papillomas were diagnosed by core needle biopsy and underwent surgical or vacuum-assisted excision. After core needle biopsy, imaging-histologic correlation was performed to determine concordance. The upgrade and malignancy rates were assessed after surgical or vacuum-assisted excision, and associated clinical and radiologic factors, including patient age, lesion size, distance from the nipple, sonographic features, and American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) category were evaluated. Three lesions (7.7 %) among 39 papillomas were upgraded to papilloma with atypia after surgical excision. There was no malignancy after excision. The upgrade rates for BI-RADS categories 3, 4a, 4b, and 4c were 0%, 6.9%, 0%, and 20%, respectively. There were no significant differences in the upgrade to papilloma with atypia in terms of the presence of symptoms, lesion size, distance from the nipple, BI-RADS category, or imaging-histologic correlation. Prediction of papilloma with atypia, not malignancy, was challenging because there were no associated clinical or radiologic factors to predict papilloma with atypia before excision. However, there was no malignancy after excision. Therefore, intensive surveillance is preferable to immediate surgical excision for benign papillomas diagnosed on core needle biopsy.

Management of Benign Intraductal Solitary Papilloma Diagnosed on Core Needle Biopsy

The purpose of this study was to determine whether surgical excision of benign solitary intraductal papillomas (BSIP) diagnosed by core needle biopsy (CNBx) without an associated high-risk lesion and concordant with imaging is justified. A review of all papillary lesions diagnosed by CNBx from January 2003 to June 2010 was performed. Available histologic and radiologic materials were evaluated in a blinded fashion by three pathologists and three dedicated breast radiologists, respectively, to assess for concordance. The papillary lesions were designated as benign, atypical, or malignant. There were 16 BSIPs excluded because of an adjacent high-risk lesion or same-quadrant ipsilateral cancer. All immediate and delayed excisional specimens were reviewed. Clinical and radiologic data were recorded. A total of 299 papillary lesions diagnosed on CNBx and concordant with imaging were identified. Of these, 240 (80%) were classified as benign, 49 (16%) atypical, and 10 (3%) malignant. After exclusions, 77 of 224 women in our study cohort (34%) underwent surgical excision with no atypical or malignant upgrades. Of the remaining 147 women diagnosed with a BSIP on CNBx, 47 (32%) were lost to follow-up and 100 (68%) were observed. All 100 observed patients had stable imaging findings at follow-up (4.8-93.8months, mean 36.0months). The likelihood of diagnosing atypia or malignancy after surgical excision of a BSIP diagnosed on CNBx without associated high-risk lesion or ipsilateral quadrant malignancy is extremely low. For this distinct subset of patients with a BSIP, these data justify close imaging follow-up, rather than surgical excision.

Can additional immunohistochemistry staining replace the surgical excision for the diagnosis of papillary breast lesions classified as benign on 14-gage core needle biopsy?

To evaluate whether the upgrade-to-malignancy rate of benign papillary lesions on ultrasonographically (US)-guided 14-gage core needle biopsy (CNB) can be decreased using immunohistochemistry staining (IHC) for pathologic diagnosis, and to determine whether additional IHC can replace surgical excision for the diagnosis of papillary breast lesions classified as benign on 14-gage CNB. A total of 274 consecutive papillary lesions were studied, including available imaging findings, CNB specimens and surgical specimens. Two rounds of retrospective review of the pathologic slides from CNB were performed by a pathologist, including H&E staining (first round; 1R, n=274) and IHC of the benign papillomas (second round; 2R). The upgrade-to-malignancy rate was assessed for benign papillomas with comparison between 1R and 2R. The final diagnosis was based on surgical pathology. The clinicoradiologic findings were compared between the benign and malignant papillomas at the time of final diagnosis. In 1R, 204 benign papillomas were identified. During 2R using IHC, three carcinomas and ten atypical papillomas were diagnosed. Among the 204 benign papillomas from 1R, 15 were found to be carcinomas (upgrade-to-malignancy rate, 7.4%) at the time of final diagnosis. With 2R, the overall upgrade-to-malignancy rate was decreased to 4.7% (9/192, p=0.3680). Older age and upgrades made after IHC review resulted in higher upgrade-to-malignancy rates (odds ratio, 4.133, 95% CI 1.393-12.267, p=0.0106; 134.46, 95% CI 17.886-infinity, p<0.0001, respectively). The use of IHC may decrease the upgrade-to-malignancy rate for benign papillary lesions after US-guided 14-gage CNB and help to more accurately predict malignancy at the time of surgery. Despite these findings, a misdiagnosis still occurred in our study, suggesting that IHC cannot replace surgical excision for diagnosis of benign papillary lesions of the breast.

Mammotome biopsy in diagnosing and treatment of intraductal papilloma of the breast

Intraductal papilloma is a benign breast tumor which needs histopathological verification because of the risk of cancer coincidence. To assess the value of the mammography-guided and ultrasound-guided vacuum-assisted core biopsy in the diagnosis and treatment of intraductal papillomas of breast and to answer the question if mammotome biopsy allows to avoid surgery in these patients. In the period 2000-2011, a total of 2246 vacuum-assisted core biopsies were performed, of which 1495 were ultrasound-guided and 751 were mammography-guided (stereotaxic). In 76/2246 patients (3.4%), aged 19-88 years (mean age was 51,5) histopathological examination confirmed intraductal papilloma. Atypical lesions were accompanying intraductal papilloma in 16/76 cases (21%). Open surgical biopsy performed in these group revealed invasive cancer in 3 women. In all 60 cases (79%) with benign papilloma in biopsy specimens, further clinical observation did not show recurrence or malignant transformation of lesions. Vacuum-assisted core biopsy is a minimally invasive and efficient method used for diagnosing intraductal papilloma of the breast. If histopathological examination confirms a benign character of the lesion, surgery may be avoided but regular follow-up is recommended. However, in all cases histopathological diagnosis of papilloma with atypical hyperplasia, should always be indication for surgical excision.

One Lung Wheezing due to Endobronchial Solitary Papilloma

A 55-year-old man was referred to our hospital due to intolerant severe short of breathing and persistent cough for two hours. He had similar attacks in the past two years which were treated with bronchodilators. Computed tomography revealed endobronchial mass, which was endoscopically resected by laser. Histology revealed benign squamous papilloma. In this paper we will deal with the various nonspecific clinical presentations, etiopathology, predisposing factors, and diagnosing tests of these benign tumors, especially the important role of computed tomography.

Squamous Cell Papilloma of the Urinary Bladder Endoscopically Mimicking Cancer

Squamous cell lesions of the urinary bladder are generally rare. Herein we describe a case of 74-year-old male patient with a benign squamous cell papilloma. Histologically, the tumor presented extensive keratinization at its surface and showed no nuclear atypia or stromal invasion. The tumor cells were negative for HPV DNA. These lesions are extremely rare, and even though they are considered benign and non-HPV related, they should be followed, since recurrence has been reported.

Fibroepithelial Polyp of the External Auditory Canal: A Case Report and a Literature Review

This paper reports the first case of fibroepithelial polyp arising independently of the external auditory canal. A 16-year-old female patient presented to our clinic for aural fullness of the left side. Physical examination revealed a papillomatous tumor at the posterior wall of the inlet of the left external auditory canal. After biopsy, which yielded a diagnosis of benign papilloma, the patient underwent tumor excision. Final diagnosis was fibroepithelial polyp. One week after resection, aural fullness had resolved. Fibroepithelial polyp is a benign lesion and occurs mainly in the skin, ureteropelvic system, and genitals. In the head and neck area, there are reports on fibroepithelial polyp of the tongue, piriform fossa, inferior nasal turbinate, and tonsil, in addition to the skin, but none on independent fibroepithelial polyp of the external auditory canal. Excision of fibroepithelial polyp of the external auditory canal is advisable, especially in the presence of any symptoms, and should be preceded by confirmation of nonmalignancy by biopsy, if possible.

Non-melanoma skin cancer in mouse and man

As a frontier organ, skin is exposed to different environmental and/or occupational chemicals which cause cutaneous cancers in experimental animals. In mice, 7,12-dimethylbenz[a]anthrancene (DMBA) and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) are frequently used as skin model tumor initiator and promoter, respectively. The sequential administration of DMBA and TPA leads to the appearance of a large number of benign papillomas, of which some convert later into invasive squamous cell carcinomas (SCC). At the molecular level, initiation of carcinogenesis in mouse skin consists in the mutational activation of the Ha-ras oncoprotein. HA-RAS mutations are rare in human SCC, but HA-RAS-mutated tumors appear in melanoma patients treated with B-raf inhibitors, indicating that initiated, HA-RAS-mutated stem cells also reside in human skin. Similarly, UV-induced human SCC show footprint mutations in the tumor suppressor gene TP53 which are also observed in UV-induced mouse SCC. Strong species differences exist with respect to phorbol ester-mediated tumor promotion. While certain mouse strains are very susceptible, other rodent species are much less sensitive. Likewise, humans appear to be much more resistant to phorbol ester-mediated skin toxicity. Papilloma formation as a result of a chemical insult is uncommon in men, questioning the relevance of this preneoplastic lesion for humans. However, skin tumorigenesis in the experimental situation and in humans appears to follow common molecular mechanisms, even though there are species differences in the morphological correlates to the preneoplastic state. Therefore, we recommend not simply labeling them as irrelevant for human risk assessment.

Cav1 Suppresses Tumor Growth and Metastasis in a Murine Model of Cutaneous SCC through Modulation of MAPK/AP-1 Activation

Caveolin-1 (Cav1) is a scaffolding protein that serves to regulate the activity of several signaling molecules. Its loss has been implicated in the pathogenesis of several types of cancer, but its role in the development and progression of cutaneous squamous cell carcinoma (cSCC) remains largely unexplored. Herein, we use the keratinocyte cell line PAM212, a murine model of cSCC, to determine the function of Cav1 in skin tumor biology. We first show that Cav1 overexpression decreases cell and tumor growth, whereas Cav1 knockdown increases these attributes in PAM212 cells. In addition, Cav1 knockdown increases the invasive ability and incidence of spontaneous lymph node metastasis. Finally, we demonstrate that Cav1 knockdown increases extracellular signaling-related kinase 1/2 mitogen-activated protein kinase/activator protein-1 pathway activation. We attribute the growth and invasive advantage conferred by Cav1 knockdown to increased expression of activator protein-1 transcriptional targets, including cyclin D1 and keratin 18, which show inverse expression in PAM212 based on the expression level of Cav1. In summary, we demonstrate that loss of Cav1 affects several characteristics associated with aggressive human skin tumors and that this protein may be an important modulator of tumor growth and invasion in cSCC.

Upping the stemness during tumour progression

Using four mouse models of squamous skin cancer and limiting dilution serial transplantation, Lapouge and colleagues found that cells from benign papillomas formed tumours in recipient mice at a low frequency and only when cancer-associated fibroblasts or endothelial cells were present in the transplanted mixture. This indicates that there are few cancer stem cells (CSCs) in papillomas, which grow rapidly. Conversely, the number of CSCs increased with tumour invasiveness, indicating that the proportion of CSCs in squamous skin tumours changes as they progress.

Benign papilloma diagnosed on image-guided 14 G core biopsy of the breast: Effect of lesion type on likelihood of malignancy at excision

To ascertain the negative predictive value (NPV) for atypia and malignancy of 14G core biopsy of papillomas and to determine whether lesion type influences the likelihood of malignancy at lesion excision. Ninety-six lesions with a 14G core biopsy diagnosis of benign papilloma without atypia in 95 women were included. The imaging features (mass or microcalcification), biopsy mode, and number of core samples taken were documented. All patients subsequently underwent lesion excision with either extensive vacuum-assisted biopsy (VAB; 72 lesions) or surgery (24 lesions). Mammographic follow-up of at least 2 years was available for 32 lesions that were benign at VAB. Atypia or malignancy was found more commonly in association with microcalcification (six of 29 lesions: 21%; median number of nine 14G cores) than a mass (five of 67 lesions: 7%; median number of three 14G cores), although the difference does not reach statistical significance (p=0.088). The NPV of a 14G core biopsy diagnosis of papilloma for atypia or malignancy is 89% (85/96). Disease underestimation may be more common in microcalcification lesions despite the greater number of cores obtained. Excision (using VAB or surgically) of all papillomas diagnosed as benign on 14G needle core biopsy is recommended. Surgery may be more appropriate than VAB for some microcalcification lesions unless they are small and can be confidently removed in their entirety using VAB.

Skin squamous cell carcinoma propagating cells increase with tumour progression and invasiveness

Cancer stem cells have been described in various cancers including squamous tumours of the skin by their ability to reform secondary tumours upon transplantation into immunodeficient mice. Here, we used transplantation of limiting dilution of different populations of FACS-isolated tumour cells from four distinct mouse models of squamous skin tumours to investigate the frequency of tumour propagating cells (TPCs) at different stages of tumour progression. We found that benign papillomas, despite growing rapidly in vivo and being clonogenic in vitro, reformed secondary tumours upon transplantation at very low frequency and only when tumour cells were co-transplanted together with tumour-associated fibroblasts or endothelial cells. In two models of skin squamous cell carcinoma (SCC), TPCs increased with tumour invasiveness. Interestingly, the frequency of TPCs increased in CD34(HI) but not in CD34(LO) SCC cells with serial transplantations, while the two populations initially gave rise to secondary tumours with the same frequency. Our results illustrate the progressive increase of squamous skin TPCs with tumour progression and invasiveness and reveal that serial transplantation may be required to define the long-term renewal potential of TPCs.

Activation of K-Ras in Arf-Null Mice Is Not Sufficient for Malignant Transformation of Post-Germinal Center B-Cells

Abstract 5016Activating mutations in Ras (N- and K-) are the most common mutations in multiple myeloma (MM), and are associated with advanced clinical stage and poor outcomes. As previously reported, we re-sequenced coding regions of highly expressed cytokine signaling candidate genes from MM patient samples and found the most common mutations to affect Ras oncogenes (N and K-). To test the role of Ras activation in MM pathogenesis directly, we generated mice harboring a mutant K-ras allele, Lox-stop-lox(LSL)- K-ras G12D (K-ras+/G12D) with Cγ1-Cre knock-in mice (Cγ1+/Cre), activated specifically in germinal center (GC) cells. K-ras+/+/Cγ1+/Cre mice served as negative controls. We found 58% of unstimulated K-ras+/G12D/Cγ1+/Cre mice developed fatal double-positive CD4/8 T-cell lymphomas (n=12) and 42% developed lung adenocarcinomas (n=12), phenotypes that have previously been reported for K-ras+/G12D mice. Tumor cells demonstrated successful recombination of the K-Ras locus. We showed recombination in splenic germinal center cells (B220+, GL7+ and IgG1+), as well as in post-germinal center cells (B220-, CD138+). No evidence of plasma cell proliferation was seen by serum ELISA, SPEP, flow cytometry or histological examination. We confirmed these results by crossing the K-ras+/G12D mice to a second strain, AID-Cre, which expresses the recombinase earlier and more specifically in the GC. We found 100% (n=20) of K-ras+/G12D/AID-Cre-YFP mice possessed visible, small benign papillomas on the ventral neck, as early as 3 weeks of age. To stimulate malignant transformation, vitamin D deficient chow and/or sub-lethal radiation was given to K-ras+/G12D/AID-Cre-YFP and negative control, K-ras+/G12D mice. Dual treatment increased the size and number of papillomas, giving a median survival of 26 weeks, compared to 52 weeks with control. However, no evidence of MM was detected by serum ELISA, SPEP, flow cytometry or histological examination. Finally, we generated AID-Cre-K-ras+/G12D triple transgenic mice in a tumor prone Arf-null background. After 13 wks, we found sarcomas in 66% (n=3) of K-ras+/G12D/AID-Cre-YFP/Arf−/− mice. Additionally, 100% (n=3) of these mice had rapid growing benign papillomas and only a minimal increase in the plasma cell compartment, compared to K-ras+/G12D/AID-Cre/Arf +/− control. Together, these data demonstrate that Ras activation is not sufficient to transform primary germinal center or plasma cells, even in an Arf-null context, and suggests that specific myeloma events, yet to be identified, are required for malignant transformation. Disclosures:No relevant conflicts of interest to declare.

Benign Mullerian Papilloma of the Cervix at Vaginoscopy

This video demonstrates benign mullerian papilloma of the cervix in a 4 year old girl with spotting per vaginum who was referred for vaginoscopy. The hysteroscope was introduced through the intact hymen opening. The vaginal walls were unremarkable, and there was no evidence of any foreign body. The cervix had a rough surface with irregular contours.

Intraductal Papillary Lesions of the Breast: Clinical and Pathological Correlation

Papillary lesions of the breast range from a spectrum of benign intraductal papillomas with and without atypia to papillary carcinoma. Distinction between benign and malignant lesions on core needle biopsy (CNB) is difficult without surgical excision. We examined if clinical findings in patients with benign intraductal papillomas (IP) on CNB correlate with pathology at surgical excision. Between 1998 and 2011, 103 patients were identified with a papillary lesion on CNB. Clinical variables were studied to determine if there was clinical correlation with pathological outcomes at final surgical excision. Of the 103 patients, 59 (57%) patients had IP on initial CNB and were included in our analysis. On final pathology, 17 (29%) of these were upstaged to intraductal papilloma with atypia and six (10%) were found to have carcinoma. A clinically palpable mass was the only significant predictor of upstaging to malignancy (P<0.05). No radiographic findings were found to be significant predictors of pathological upstaging. In conclusion, surgical excision is still recommended for benign papillary lesions diagnosed on CNB because the correlation with clinical and radiological findings does not assure benign pathology.

Papillary lesions of the breast: Can larger core needle biopsy samples identify patients who may avoid surgical excision?

44 Background: Papillary lesions of the breast are frequently diagnosed on core needle biopsy (CNB). The ability to distinguish benign from atypical/malignant papillary lesions is limited by the representative nature of the biopsy method; thus follow-up excision is usually recommended. We aimed to determine if larger CNB samples can more reliably predict the true benign nature of a papillary lesion, thereby sparing certain patients a formal surgical excision. Methods: We reviewed medical records of 53 female patients diagnosed with histologically benign papillary lesions on CNB from 2000 to 2010, who subsequently underwent surgical excision. Pathology slides of the CNB were reviewed to document the benign histologic features of the papilloma, the number of cores sampled and the area of tissue biopsied (mm2). Statistical analysis was performed to identify the characteristics of the CNB that were associated with retention of benign histology on excision. Results: Atypical ductal hyperplasia (ADH) and carcinoma were identified in 6% (3/53) and 8% (4/53) of papillary lesions, respectively, when excised. Clinical and radiographic characteristics did not distinguish the ADH/malignant lesions from benign papillomas. The CNB needle sizes ranged from 9- to 18-gauge (median 14). The number of cores sampled ranged from 3-16 (mean 4.5). Patients with benign excisions had a significantly larger area of tissue sampled by CNB than those found to have ADH/malignant lesions on excision (mean ± SD: 95.6 ± 101.2 vs. 41.7 ± 21.9, respectively, p=0.003). By logistic regression, CNB tissue samples consisting of ≥7 cores, or measuring &gt;96 mm2 in aggregate, had a negative predictive value for ADH/malignancy of 100% (AUC of 0.69 and 0.68, respectively). Conclusions: Although no clinical or radiologic features distinguished benign from pathologically significant papillary lesions, larger sample sizes significantly improved the predictive value of benign histology on CNB. A papilloma sampled by ≥ 7 cores or &gt; 96 mm2 showing benign histology at CNB, retained benign features upon excision. Close surveillance may be a reasonable option for patients whose benign papillomas are generously sampled at the time of CNB.