Intraepithelial Spread Research Articles

Novel insights into the intraepithelial spread of extrahepatic cholangiocarcinoma: clinicopathological study of 382 cases on extrahepatic cholangiocarcinoma.

Extrahepatic cholangiocarcinoma (eCCA) is a rare and aggressive disease and consisted of conventional eCCA and intraductal papillary neoplasm of the bile duct (IPNB). Intraepithelial spread (IES) of cancer cells beyond the invasive area is often observed in IPNBs; however, the prevalence of IES remains to be examined in conventional eCCAs. Here, we evaluated the clinicopathological features of eCCAs according to tumor location, with a focus on the presence of IES. The IES extension was also compared among biliary tract cancers (BTCs). We examined the prevalence and clinicopathological significance of IES in eCCAs (n=382) and the IES extension of BTCs, including gallbladder (n=172), cystic duct (n=20), and ampullary cancers (n=102). Among the invasive eCCAs, IPNB had a higher rate of IES (89.2%) than conventional eCCAs (57.0%). Among conventional eCCAs, distal eCCAs (75.4%) had a significantly higher prevalence of IES than perihilar eCCAs (41.3%). The presence of IES was associated with a significantly higher survival rate in patients with distal eCCAs (P=0.030). Extension of the IES into the cystic duct (CyD) in distal eCCAs that cancer cells reached the junction of the CyD was a favorable prognostic factor (P<0.001). The association of survival with IES, either on the extrahepatic bile duct or on the CyD, differed depending on the tumor location and type of eCCA. The extension properties of IES were also dependent on different types of tumors among BTCs; usually, the IES incidence became higher than 50% in the tissues that the tumor developed, whereas IES extension to other tissues decreased the incidence. Thus, eCCAs have different clinicopathological characteristics depending on the tumor location and type.

The Paget Trial: topical 5% imiquimod cream for noninvasive vulvar Paget disease

Vulvar Paget disease is an extremely rare skin disorder, which is most common in postmenopausal women. Most vulvar Paget disease cases are noninvasive; however, it may be invasive or associated with an underlying vulvar or distant adenocarcinoma. The current treatment of choice for noninvasive vulvar Paget disease is wide local excision, which is challenging because of extensive intraepithelial spread and may cause severe morbidity. Recurrence rates are high, ranging from 15% to 70%, which emphasizes the need for new treatment options. Imiquimod, a topical immune response modifier, has been shown to be effective in a few studies and case reports, and is a promising new treatment modality. To prospectively investigate the efficacy, safety, and effect on quality of life of a standardized treatment schedule with 5% imiquimod cream in patients with noninvasive vulvar Paget disease. The Paget Trial is a multicenter prospective observational clinical study including 7 tertiary referral hospitals in the Netherlands. A total of 24 patients with noninvasive vulvar Paget disease were treated with topical 5% imiquimod cream 3 times a week for 16 weeks. The primary efficacy outcome was the reduction in lesion size at 12 weeks after the end of treatment. Secondary outcomes were safety, clinical response after 1 year, and quality of life. Safety was assessed by evaluation of adverse events and tolerability of treatment. Quality of life was investigated with 3 questionnaires taken before, during, and after treatment. Data were available for 23 patients, 82.6% of whom responded to therapy. A complete response was reported in 12 patients (52.2%), and 7 patients (30.4%) had a partial response. A histologic complete response was observed in 10 of the 12 patients with a completeresponse. Patients experienced side effects such as fatigue (66.7%-70.9%) and headaches (16.7%-45.8%), and almost 80% needed painkillers during treatment. Eight patients (34.8%) adjusted the treatment protocol to 2 applications a week, and 3 patients (13.0%) stopped treatment because of side effects after 4 to 11 weeks. Treatment improved quality of life, whereas a slight, temporary negative impact was observed during treatment. Two patients with a complete response developed a recurrence within 1 year after treatment. Follow-up showed 6 patients with a noninvasive recurrence after a median of 31 months (14-46 months) after the end of treatment. Topical 5% imiquimod cream can be an effective and safe treatment alternative for noninvasive vulvar Paget disease, particularly when compared with treatment with surgical excision.

Intraepithelial growth pattern for eyelid sebaceous carcinoma: a cohort of 214 patients from a single institution

AimsTo determine the distribution of three different intraepithelial growth patterns (pagetoid, bowenoid and papillary) in eyelid sebaceous carcinoma (SC) and correlate them with the clinical characteristics and prognosis.MethodsA retrospective cohort...

High-risk human papillomavirus and ZEB1 in ocular adnexal sebaceous carcinoma.

Ocular adnexal (OA) sebaceous carcinoma is an aggressive malignancy. Oncologic drivers of ocular sebaceous carcinoma are incompletely understood. A retrospective search of our pathology archives for OA sebaceous carcinoma identified 18 primary resection specimens. Immunohistochemistry for p16 and ZEB1 and RNA in situ hybridization for high-risk human papillomavirus (HPV) subtypes were performed. High-risk HPV was demonstrated in 2/11 (18%) cases. p16 overexpression was observed in 10/11 (91%). No association between gender, age at presentation, tumor location, intraepithelial spread, tumor size, and T stage was observed between HPV-driven and nonviral cases. High expression of ZEB1 was observed in the intraepithelial component of 4/14 (28%) cases and in the subepithelial component of 1/13 (7%) cases. ZEB1 overexpression was not associated with HPV status, T stage, or tumor size. As previously described by others, our findings suggest that a subset of OA sebaceous carcinomas may arise via an HPV-dependent pathway. However, unlike high-risk HPV-driven carcinomas of the oropharynx, we did not identify an association between HPV-status and prognostic features. Furthermore, p16 expression was not a useful surrogate marker for HPV-driven disease. ZEB1 overexpression is not associated with HPV in our cohort of ocular sebaceous carcinoma.

Clinicopathological Characteristics of Microscopic Tubal Intraepithelial Metastases from Adenocarcinoma and Small Cell Neuroendocrine Carcinoma of the Uterine Cervix.

Some metastatic tumors that involve the fallopian tube show intraepithelial spread, mimicking primary tubal neoplasm and representing a potential diagnostic pitfall. In this study, we aimed to investigate the clinicopathological characteristics of tubal intraepithelial metastasis (IEM) from cervical carcinoma. We analyzed the clinical features, histological features, and immunophenotypes of IEMs in five patients with cervical carcinoma. This study included usual-type (1/5), mucinous-type (1/5), and gastric-type (2/5) endocervical adenocarcinomas and small cell neuroendocrine carcinoma (1/5) cases. None of the patients had ovarian metastasis, but metastatic tumor cells spread along the tubal mucosal surface and partially replaced the lining epithelium. Histological features of metastatic tumors closely resembled those of the primary tumors in all cases. Tubal IEM can mimic various tubal lesions including serous tubal intraepithelial carcinoma. Morphological consistency between the primary and metastatic tumors and immunostaining help guide the differential diagnosis of challenging intraepithelial lesions of the fallopian tube.

Penile Paget's Disease: A Case Report and Review of the Literature.

Extramammary Paget's Disease (EMPD) is a rare cutaneous, slow growing, intraepithelial adenocarcinoma that can be either primary (intraepithelial arising within the epidermis) or secondary (intraepithelial spread of a visceral carcinoma). Here we present the case of a 63-year-old male with EMPD of the glans penis stemming from underlying urothelial carcinoma. Our treatment decision elected for management with chemotherapy and local treatment with radiation therapy. Subsequent, review of the literature demonstrated a rare disease with a variety of underlying malignancies causing this secondary pathology. Caregivers should be aware of the association of Paget's disease and urothelial cancer and should have a high index of suspicion that erythematous penile lesions may represent Paget's disease and that penile biopsies should be performed early in this setting.

2747 A Rare Case of Esophageal Squamous Cell Carcinoma With Intramural Gastric Metastasis

INTRODUCTION: Esophageal cancer makes up about 1% of all cancers diagnosed in the United States . Gastric metastasis from esophageal cancer is relatively rare. Four different types of metastatic mechanisms were reported: 1) via peri-gastric lymph nodes; 2) gastric intramural metastasis; 3) direct invasion of the gastric wall, and 4) intra-epithelial spread to the gastric epithelium . Here we present a case with intramural gastric metastasis in a patient with esophageal squamous cell carcinoma. CASE DESCRIPTION/METHODS: A 76-year-old Indian male with past medical history significant for idiopathic pulmonary fibrosis and coronary artery disease, recently started on aspirin and clopidogrel, presented with new onset fatigue and five days of black tarry stools. Hemoglobin (Hgb) on admission was 7.1 g/dL. Despite transfusion of one unit of packed red blood cells, repeat Hgb dropped to 6.6 g/dL. Emergent upper endoscopy was performed for suspected active gastrointestinal bleeding in the setting of blood thinner use. Endoscopy showed a 3 cm, non-bleeding, fungating and ulcerated mass in the middle third of the esophagus, as well as a 4-5 cm fungating, infiltrative and ulcerated gastric mass in the cardia with stigmata of recent bleeding (adherent clot) (see Figure 1). Removal of the clot revealed underlying oozing from the ulcer bed which was treated successfully with dilute epinephrine injection followed by hemostatic clip placement. Forceps biopsies of both the esophageal and cardia masses were obtained. Histopathology of both lesions revealed keratinized squamous cell carcinoma. CT of the chest, abdomen and pelvis showed no evidence of other metastatic disease. Oncology consultation was scheduled to discuss potential chemotherapy, radiation, and endoscopic interventions. DISCUSSION: Esophageal cancer with intramural gastric metastasis is very rare compared to other mechanisms of tumor spread. The prognosis is very poor with the mean survival time reported to be 8.6 months . Conventional chemotherapy or radiotherapy after surgery were ineffective in improving prognosis in current report, suggesting other techniques could provide a benefit when used adjunctively or in combination with more traditional approaches.

Predictors of Local Recurrence for Eyelid Sebaceous Carcinoma: Questionable Value of Routine Conjunctival Map Biopsies for Detection of Pagetoid Spread.

To identify clinicopathologic factors associated with local recurrence of eyelid sebaceous carcinoma and determine whether routine conjunctival map biopsies are necessary to detect pagetoid spread. The authors searched PubMed for articles on eyelid sebaceous carcinoma and pagetoid spread published in English during 1982 to 2018, and they reviewed 99 consecutive patients with eyelid sebaceous carcinoma who underwent surgical excision with frozen section control of margins performed by 1 author (BE) during 1999 to 2017. Local recurrence rates after surgery were 5% to 25% in the literature and 6% in the authors' cohort. Risk factors for local recurrence included T3b (>20 mm) or worse disease according to the AJCC Cancer Staging Manual, eighth edition, pagetoid spread, diffuse growth pattern, and multicentric origin. Pagetoid spread was observed in 8.3% to 70% of patients in the literature and 31% of patients in the authors' cohort. The literature review showed that surgical excision with frozen section control is the mainstay of management of eyelid sebaceous carcinoma, with topical chemotherapy and cryotherapy used in cases with pagetoid spread. The authors found no solid evidence for added value from routine 4-quadrant conjunctival map biopsies, and some studies called into question their accuracy and yield. In patients with eyelid sebaceous carcinoma, meticulous microscopic margin control is appropriate in all cases and particularly for tumors >20 mm and adjuvant topical chemotherapy should be considered for tumors with conjunctival pagetoid spread. Routine conjunctival map biopsies are not essential, but targeted map biopsies of areas with signs suggestive of pagetoid intraepithelial spread may be appropriate to guide future closer observation or adjuvant treatments.

Differentiated Vulvar Intraepithelial Neoplasia Associated with Intraepithelial Neoplastic Spread

Differentiated vulvar intraepithelial neoplasia (dVIN) associated with intraepithelial neoplastic spread and with usual vulvar intraepithelial neoplasia (uVIN) has not been studied...

Rectal malignant melanoma with extensive intraepithelial spread resulting in incomplete resection by EMR: a case report

Rectal malignant melanoma with extensive intraepithelial spread resulting in incomplete resection by EMR: a case report

Metastatic Adenocarcinoma to the Uterine Cervix Versus Primary Cervical Adenocarcinoma

Abstract Adenocarcinoma metastases to the cervix can originate from the endometrium, the upper müllerian tract, or from extramüllerian sites such as the gastrointestinal and pancreatobiliary tract, bladder, breast, lung, or even the salivary gland. In some cases, the metastatic lesions have signet-ring morphology, infiltrative pattern, and/or extensive lymphovascular spread. In others, however, the distinction between a primary cervical lesion and a metastasis to the cervix is more challenging because metastases may mimic endocervical adenocarcinoma in situ by colonizing the native endocervical mucosa through intraepithelial spread. Careful morphologic interpretation, combined with immunohistochemistry, human papillomavirus molecular testing, and clinical correlation, is required in order to arrive at the correct diagnosis.

Perforin expression in eyelid sebaceous carcinomas: a useful and specific immunomarker for the differential diagnosis of eyelid carcinomas.

Eyelid sebaceous carcinoma (SC) remains a common diagnostic pitfall for both the clinician and histopathologist. The aim of this study was to describe perforin as a new marker in the immunohistochemistry panel for SC. A total of 29 cases were retrieved from the Pathology archives, including 11 sebaceous neoplasms (nine SC; two sebaceomas), 10 squamous cell carcinomas (SCC) and eight basal cell carcinomas (BCC). These were stained using the monoclonal antibody for perforin, epithelial membrane antigen (EMA), Ber-EP4 and adipophilin (ADP). Sensitivity and specificity of perforin as an immunohistologic marker for sebaceous tumours were compared to EMA, ADP and Ber-EP4. Perforin stained strongly 9/11 (81%) of the sebaceous neoplasms (SN), 7/9 SC and 2/2 of sebaceomas (2/2), similar to ADP. Epithelial membrane antigen (EMA) stained 8/9 SC and was negative (1/2) or only very weakly expressed (1/2) in sebaceomas. The specificity of perforin in identifying SN versus SCC and BCC was 100% (95% CI 69-100), while EMA specificity in identifying SN varied according the comparison group (SCC: 50%, 95% CI 18-81, 100% (95% CI 63-100). Perforin better highlighted the intraepithelial spread of SC than EMA. Ber-EP4 was strongly expressed in six of nine SC, but was consistently negative in sebaceomas. The expression pattern of perforin in sebaceous neoplasms enables us to recommend the use of perforin as a new immunohistochemical marker for sebaceous neoplasms.

Renal cell carcinoma metastatic to the ovary or fallopian tube: a clinicopathological study of 9 cases

Renal cell carcinoma (RCC), the most common type of kidney cancer in adult, rarely metastasizes to the ovary or fallopian tube, and most cases published in the literature were case reports. Herein, we describe the clinicopathological features of 9 cases of RCC metastatic to the ovary (n = 8) or the fallopian tube (n = 1). The patients' age at the onset of primary renal tumor was available in 8 patients, ranging from 37 to 73 years (mean, 51 years; median, 50 years). Ovarian metastasis was detected prior to or concurrently with the primary renal tumors in 3 patients, and after the diagnosis of renal tumors in 6 patients. The histotypes of the RCCs were clear cell (n = 7), chromophobe (n = 1), and unclassified (n = 1). Immunohistochemical stainings were performed on the sections containing metastatic tumors in 4 cases. Interestingly, pagetoid intraepithelial spread in the tubal mucosa was observed in the case of RCC metastatic to the fallopian tube. Among the 8 patients with follow-up data, 5 died of disease and 3 were alive with disease, with a follow-up period ranging from 3.7 months to 17 years (mean, 77 months; median, 53 months) after the diagnosis of primary kidney tumors. Diagnostically, metastatic RCC may mimic primary ovarian tumors clinically, morphologically, or immunophenotypically. Pathologists should also keep in mind that both ovarian and kidney tumors express PAX8 and PAX2, the markers commonly used to diagnose metastatic RCC. In addition, chromophobe RCC only rarely metastasizes, but it can be a diagnostic challenge when it metastasizes to the ovary.

気管支上皮内進展を来しポリープ様に認められた大細胞神経内分泌癌の1例

症例は80歳男性，現喫煙者．気管支喘息で加療中に呼吸困難，咳嗽を自覚した．胸部CTで右主気管支内腔に軟部陰影を認め，気管支鏡検査で右主気管支入口部に有茎性ポリープを認めた．Polypectomy標本の病理像から大細胞神経内分泌癌が考えられた．化学療法CBDCA＋VP-16を先行後，右上葉切除を行い，術後化学療法を施行した．中枢気管支発症の大細胞神経内分泌癌は極めて稀であり，発育機序も含め考察する．

High-Grade Neuroendocrine Carcinoma with Bronchial Intraepithelial Tumor Spread: Possibly a New Histologic Feature of Large-Cell Neuroendocrine Carcinoma

During surgical resection of a peripherally located high-grade neuroendocrine carcinoma (HGNEC), we unexpectedly discovered prominent bronchial intraepithelial tumor spread up to the surgical end of the bronchus. Because bronchial intraepithelial tumor spread of peripherally located HGNEC has been rarely reported, we conducted a retrospective analysis at our hospital. We histologically reviewed surgically resected HGNEC cases to assess bronchial intraepithelial spread of tumor cells. HGNECs with bronchial intraepithelial tumor spread were further studied by immunohistochemistry for neuroendocrine markers, and their clinicopathological characteristics were evaluated. Of 1778 cases of surgically resected lung cancer in our hospital, 47 cases of HGNEC were evaluated. Bronchial intraepithelial tumor spread was observed in nine cases (19.1%); eight of these cases were large-cell neuroendocrine carcinoma (LCNEC) or small-cell lung carcinoma with an LCNEC component. Moreover, bronchial intraepithelial tumor spread was continuous from the primary tumor to the resected end of the bronchus in four cases, and all these cases had an LCNEC component. Furthermore, HGNEC with bronchial intraepithelial tumor spread was associated with a higher recurrence rate than no bronchial intraepithelial tumor spread. The results of this study suggest that bronchial intraepithelial tumor spread is commonly observed in cases of peripherally located HGNEC and may be a unique form of tumor invasion, especially tumors with LCNEC morphology. Therefore, surgeons and pathologists should be cognizant of bronchial intraepithelial tumor spread in peripherally located HGNEC, as well as its potential role as an indicator of HGNEC aggressiveness.

Recurrent sebaceous carcinoma with wide intraepithelial spread to the nasal cavity: Report of two cases

Background: Sebaceous carcinoma (SC) is a relatively rare tumor that usually arises from the eyelid. Local extension down the nasolacrimal duct is relatively rare event for SC. Method: We herein report two cases of recurrent SC in the nasal cavity. Both patients had previously received primary treatment for SC of the eyelid. Seven years after the initial treatment, the first patient presented with a mass on the left medial canthus of the eyelid. Sixteen months after the initial treatment, the second patient presented with a large mass in the right nasal cavity. Results: The wide intraepithelial spread of SC over 30 mm from the initial surgical margin was beyond our expectations. The first patient is currently alive with local recurrence following the administration of chemoradiotherapy 46 months after treatment, while the second patient died of distant metastasis. Conclusion: This report focuses on the unique clinical features of intranasal recurrence of SC after treatment. ACTA MEDICA NAGASAKIENSIA 59: 107−110, 2014

Sebaceous carcinoma of the eyelid: Recognition of intraepithelial pagetoid spread

Sebaceous carcinoma of the eyelid: Recognition of intraepithelial pagetoid spread

Clinicopathological Characteristics in Oesophageal Squamous Cell Carcinoma

Oesophageal cancer is an aggressive disease with a generally poor prognosis. Frequently, patients present late with obstructive symptoms indicating advanced tumours. Therefore, serial histopathological investigations of oesophageal cancer are now being performed more extensively, and several distinctive clinicopathological features have been demonstrated. In this review, we present some of the distinctive features of oesophageal cancer and discuss their clinicopathological significance. These characteristics include: (1) the frequent presence of lymph node metastasis, (2) the morphological features and depth of tumour invasion, (3) the synchronous and metachronous occurrence of carcinoma of other organs, (4) the frequent coexistence of squamous epithelial dysplasia, (5) the frequent coexistence of intraepithelial spread, blood vessel, and lymphatic permeation, (6) the occasional existence of intramural metastasis, (7) the frequent coexistence of multiple primary carcinomas and (8) the occasional coexistence of glandular differentiation with squamous cell carcinoma (SCC).

Pulmonary large cell neuroendocrine carcinoma exhibiting extensive pagetoid spread in the bronchial epithelium: A case report.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive malignant tumor, which was proposed as a novel type of neuroendocrine tumor in 1991. Although it is categorized as a non-small cell lung carcinoma, the precise pathological condition is unknown due to its rare occurrence. The present study outlines the case of a patient presenting with an LCNEC that exhibited pagetoid spread from the region of the primary tumor to the bronchial epithelium (distance, >30 mm). The pagetoid spread was unconfirmed preoperatively, however, was identified by intraoperative rapid diagnosis. This caused us to suffer the perioperative decision of additional resection and resulted in an incomplete resection, as suture of the bronchus was not possible. Pagetoid spread, which is often apparent in the breast, presents as a rare pattern of infiltration of cancer cells when a massive carcinoma is identified beneath the intraepithelial spread. Although preoperative diagnosis of pagetoid spread is difficult due to its rarity and undefined clinical features, it is important for surgeons and pathologists treating lung cancer patients to be aware of potential pagetoid spread in the thoracic region.

Sebaceous carcinoma: clinicopathologic features and diagnostic role of immunohistochemistry (including androgen receptor)

ObjectiveTo explicate the clinicopathologic features of periocular sebaceous carcinoma (SC) and emphasize the importance of immunohistochemical staining that includes androgen receptor (AR) in their diagnosis. DesignRetrospective study. MethodsClinical and histopathologic features in 56 patients with periocular SC were analyzed. Immunohistochemical staining for pan-cytokeratin (CK), epithelial membrane antigen (EMA), Ber-EP4, adipophilin (ADP), and AR was performed on all cases. Immunostaining in SC was compared with that of squamous cell carcinoma (SCC; n = 25) and basal cell carcinoma (BCC; n = 18) for all antibodies. ResultsSGC was more frequent in females, most commonly presenting as a discrete and nodular mass. Four patients had regional lymph node metastases, whereas in 2, the tumour metastasized to the liver. Eight patients had a locoregional recurrence between the 3rd and 45th months of follow-up. Fifty patients had a moderately differentiated tumour. In 3 patients, the resected margins displayed intraepithelial tumour spread, and 2 patients died of the disease. In general, the staining pattern in SGC was CK+, EMA+, BerEP4–, ADP+, and AR+. SCCs were CK+, EMA+, Ber-EP4–, ADP–/+, and AR–, whereas BCC were CK+, EMA–, Ber-EP4+, ADP–, and AR–/+. p53 expression and Ki-67 index were higher in SC than SCC or BCC. ConclusionsImmunostaining using a panel of antibodies comprising BerEP4, ADP, EMA, and AR is useful in diagnosing sebaceous carcinoma and differentiating it from SCC and BCC, which are common to the periocular location and sometimes are morphologically identical to SC.