Cunxian Zhang

Overexpression of p53 is correlated with stromal invasion in extramammary Paget’s disease of the vulva

Molecular alterations that are associated with clinicopathological features of extramammary Pagets disease of the vulva (PDV) are poorly understood. Consequently, we have investigated whether a correlation exists between overexpression of p53 protein and various clinicopathologic features of PDV. Our study group comprises 10 primary noninvasive PDVs, 3 primary PDVs with minimal invasion, and 1 primary PDV with frank invasion. Recurrence in the form of noninvasive PDV was seen in 4 patients with previously noninvasive PDVs and in 1 patient who previously had PDV with minimal invasion. Metastases to the inguinal lymph nodes were associated with the 1 PDV with frank invasion and 1 of the PDVs with minimal invasion. An immunohistochemical study of p53 expression was performed on paraffin-embedded tissue. Negative p53 immunostaining was seen in all of the primary noninvasive PDVs as well as their recurrences. Positive p53 immunostaining was observed in the invasive as well as the intraepidermal components of all of the primary PDVs with invasion, the metastatic tumors in the inguinal lymph nodes, and the recurrent PDV associated with prior invasion, indicating a possible role of p53 in the progression of PDV. To our knowledge, our observation of p53 overexpression in the intraepidermal component of PDVs associated with invasion is the first to be reported in the literature. This observation may prove helpful in identifying stromal invasion in small biopsies. We also report for the first time an association between high nuclear grade in PDV and the propensity for inguinal lymph node metastasis.

Simplex (differentiated) type VIN: absence of p16INK4 supports its weak association with HPV and its probable precursor role in non-HPV related vulvar squamous cancers

any histological resemblance to tumours of Müllerian origin support such a diagnosis. The most effective therapy is complete surgical excision, while the role of adjuvant radiotherapy and chemotherapy remains controversial. The FATWO should be distinguished from granulosa cell tumours, mainly of the diffuse or the infantile type, Sertoli-Leydig cell tumours and adenomatoid tumours and endometrioid carcinomas of the Fallopian tubes. The resemblance to these tumours, however, is only superficial and, if sufficient tissue is examined, the Wolffian origin of the tumour becomes apparent. Endometrioid carcinoma of the Fallopian tube usually occurs as an intralumenal mass and has abnormal hyperchromatic nuclei and high mitotic activity. Intralumenal mucin is common, and reticulin is arranged around groups of neoplastic glands that are EMA-positive. Sertoli-Leydig cell tumours more commonly occur in young females, aged 20–30 years, and develop in the ovaries, rather than the broad ligaments or the mesosalpinx. More importantly, they contain typical Leydig cells with abundant eosinophilic granular cytoplasm, and may be associated with endocrine manifestations due to androgen secretion. In addition, Sertoli-Leydig cell tumours often express a-inhibin. Granulosa cell tumours are composed of typical cells exhibiting longitudinal nuclear grooving and a strong diffuse inhibin positivity. Adenomatoid tumours also contain cyst-like spaces, but these are set in a connective tissue stroma that is often hyalinized and contains smooth muscle fibres. Nonetheless, it has been reported that among 25 FATWO seen in consultation, the correct diagnosis was considered by the referring pathologist in only 17%. The biological behaviour of these tumours is unpredictable but is, in general, benign. This is only the seventh malignant tumour described thus far, with distinctive morphological features being the large size of the tumour, larger than 100 mm, apparent hypercellularity, capsular invasion, and rupture of the capsule with demonstrable tumour implants and metastases. This report serves to remind us of the existence of female adnexal tumours of probable Wolffian origin and, in particular, their malignant potential.

Maspin expression in CIN 3, microinvasive squamous cell carcinoma, and invasive squamous cell carcinoma of the uterine cervix

Maspin is a serine protease inhibitor with tumor suppression activity. It is expressed in normal breast and prostate tissue but is downregulated or absent in breast and prostate tumors. Recent reports have shown that decreased expression is associated with a greater propensity for metastasis in oral squamous cell carcinomas. We know that some high-grade cervical intraepithelial neoplasia progress to invasive carcinomas while others either persist at the same degree of atypia or regress. The pattern of maspin expression in cervical intraepithelial neoplasia-grade 3, microinvasive squamous carcinomas and overtly invasive squamous cell carcinomas of the uterine cervix was studied to determine the relationship between the extent of maspin expression and the progression of cervical intraepithelial neoplasia to squamous cell carcinoma. In total, 36 cases were evaluated: 18 cases of cervical intraepithelial neoplasia-grade 3, seven cases of microinvasive squamous cell carcinoma and 11 cases of invasive squamous cell carcinoma. A monoclonal antibody was used on paraffin-embedded tissues. Immunoreactivity was scored semiquantitatively using a scale of 0–3. The sums of the scores of the different groups were compared using the Mann–Whitney U-test. A significant decrease in maspin scores was noted between cervical intraepithelial neoplasia-grade 3 vs invasive squamous cell carcinoma (P<0.005), microinvasive squamous cell carcinoma vs invasive squamous cell carcinoma (P<0.05), and cervical intraepithelial neoplasia-grade 3 vs tumor emboli (P<0.005). Although not statistically significant, scores of cervical intraepithelial neoplasia-grade 3 associated with invasive squamous cell carcinoma were lower compared to that cervical intraepithelial neoplasia-grade 3 without invasive squamous cell carcinoma. These findings suggest that maspin likely plays a role in disease progression from in situ to invasive carcinoma. Virtual absence of maspin immunopositivity in tumor emboli indicates that maspin may also play a role in metastasis.

High Nuclear Grade, Frequent Mitotic Activity, Cyclin D1 and p53 Overexpression Are Associated with Stromal Invasion in Mammary Intracystic Papillary Carcinoma

Abstract:  Stromal invasion is identified with difficulty in routine hematoxylin‐eosin‐stained sections of core needle biopsy specimens from mammary intracystic papillary carcinomas. The goal of this study was to determine if nuclear grade, mitotic activity, and immunohistochemical stains for p53 and cyclin D1 would assist in differentiating intracystic papillary carcinomas without stromal invasion (ICPC) from tumors with stromal invasion (ICPC‐INVA). Eight cases of ICPC and 12 cases of ICPC‐INVA were reviewed. Hematoxylin‐eosin slides were examined to determine the histologic features. Immunohistochemistry was performed using monoclonal antibodies to human p53 and cyclin D1. Fishers exact test was used to compare the nuclear grade, mitotic activity, and immunoreactivity between ICPC and ICPC‐INVA. High nuclear grade was more often associated with ICPC‐INVA than with ICPC, although the difference was not statistically significant (p = 0.069). Frequent mitotic activity was associated with ICPC‐INVA more than with ICPC (p = 0.0198). All cases of ICPC were negative for either p53 or cyclin D1, whereas 7 of 12 cases (58.3%) of ICPC‐INVA were positive for either cyclin D1 alone (3 cases), p53 alone (3 cases), or both cyclin D1 and p53 (1 case) (p = 0.0147). Identical nuclear grade, mitotic activity, and immunostaining patterns were seen in the intracystic and the invasive components, and in the core biopsy and the excision of the same tumor. When any one of the positive indicators (high nuclear grade, frequent mitotic activity, or positive immunostains for cyclin D1 and/or p53) was present, the positive predictive value for stromal invasion was 91.7%. When none of the positive indicators was present, the negative predictive value was 87.5%. 

Progressive loss of selenium-binding protein 1 expression correlates with increasing epithelial proliferation and papillary complexity in ovarian serous borderline tumor and low-grade serous carcinoma

Ovarian serous borderline tumor, micropapillary serous borderline tumor, and low-grade serous carcinoma often show a spectrum of histologic components with increasing epithelial proliferation and papillary complexity from flat cyst wall, hierarchical structures (with primary papillae branching into secondary papillae), micropapillae, and invasive carcinoma. Although tremendous research has been carried out to elucidate the causes of these tumors, the pathogenesis remains unclear. Literature has described a relationship between insufficient selenium intake and increased risk of cancer. The anticancer action of selenium has been suggested to be mediated by selenium-binding protein 1 as selenium-binding protein 1 is decreased in several cancers. The aim of the study was to examine by immunohistochemistry the expression of selenium-binding protein 1 in the various histologic components within ovarian serous borderline tumor, micropapillary serous borderline tumor, and low-grade serous carcinoma. Our study consisted of 62 cases of ovarian serous borderline tumor, 11 of micropapillary serous borderline tumor, and 7 of low-grade serous carcinoma. Review of archival slides showed flat cyst wall in 69 cases, primary and secondary papillae of hierarchical structures in 75 cases, micropapillae in 26 cases, microinvasion in 1 case, and frankly invasive carcinoma in 7 cases. The strongest immunoreactivity of selenium-binding protein 1 was seen in epithelial cells of flat cyst wall and primary papillae, followed by secondary papillae of the hierarchical structures. Micropapillae and invasive carcinoma (including microinvasion) exhibited a near complete loss of selenium-binding protein 1 expression. Selenium-binding protein 1 immunoreactivity remained the same regardless of the size of the micropapillae. Similar selenium-binding protein 1 expression was seen in the same histologic components from either ovarian serous borderline tumor or micropapillary serous borderline tumor. The gradual loss of selenium-binding protein 1 associated with increasing epithelial proliferation and papillary complexity indicates that selenium-binding protein 1 is involved in tumorigenesis of ovarian serous borderline tumor, micropapillary serous borderline tumor, and low-grade serous carcinoma. Our findings may provide a basis for future studies concerning the molecular mechanisms of selenium-binding protein 1 in tumorigenesis as well as a possible role of selenium in chemoprevention and treatment of ovarian serous borderline tumor, micropapillary serous borderline tumor, and low-grade serous carcinoma.

Atypical Adenomyoepithelioma of the Breast: Diagnostic Problems and Practical Approaches in Core Needle Biopsy

A lthough adenomyoepithelioma of the breast can be easily recognized in an excised lesion, it is more difficult to make a definitive diagnosis with a core needle biopsy. We present a case of atypical adenomyoepithelioma and discuss the diagnostic problems associated with core needle biopsy. A 76-year-old woman was treated for a moderately differentiated infiltrating ductal carcinoma of the left breast in 1994. She had a local recurrence in 1998. In 2001, she presented with a nodule in the center of her right breast and a core needle biopsy was performed. Microscopically the lesion showed irregular, solid nests, some with a small lumen, composed of atypical polygonal cells with abundant clear cytoplasm and pleomorphic nuclei exhibiting occasional mitoses. The histologic diagnosis was infiltrating ductal carcinoma. The patient subsequently underwent a wide local excision of the lesion. The excised specimen consisted of an 8 cm × 7 cm × 4.5 cm fragment of breast tissue, in the center of which was an 0.8 cm × 0.5 cm × 0.5 cm, well-defined, firm lesion with central hemorrhage. Microscopically this lesion had an invasive border and exhibited a biphasic cellular pattern, forming tubules lined by an inner layer of ductal epithelial cells surrounded by multiple layers of myoepithelial cells that, in some areas, also formed irregular solid nests. The myoepithelial cells contained abundant clear cytoplasm, and nuclei with severe atypia, prominent nucleoli, and a mitotic count of up to 4/10 high power fields (HPF), consistent with an atypical adenomyoepithelioma. The specimen also revealed evidence of the previous biopsy site within the adenomyoepithelioma. Immunohistochemistry confirmed the biphasic cellular nature of the tumor, not only in the excised lesion but also in the previous core needle biopsy. In the excised lesion, the inner cells of the tubules were positive for cytokeratin (AE1/AE3), carcinoembryonic antigen (CEA), and epithelial membrane antigen, but were negative for smooth muscle markers including smooth muscle actin and calponin, consistent with a ductal epithelial origin. The outer cells of the tubules and the cells in the solid nests were strongly positive for smooth muscle actin and calponin, weakly positive for AE1/AE3, but negative for CEA and epithelial membrane antigen, consistent with a myoepithelial origin. Immunohistochemistry of the core needle biopsy demonstrated nests of cells with a small lumen lined by an inner layer of ductal epithelial cells and multiple outer layers of myoepithelial cells that merged with the surrounding solid nests of myoepithelial cells. The surgical margins of the excised specimen were clear, and since no definitive malignancy was demonstrated, no further treatment was recommended. The patient has been closely followed for 2 years and is free of disease. Our case indicates a diagnostic problem associated with adenomyoepithelioma with cytologic atypia, which may be confused with infiltrating ductal carcinoma in a core needle biopsy because of limited tissue sampling. However, abundant clear cytoplasm in the tumor cells may suggest the possibility of a unusual tumor. Abundant clear cytoplasm may be seen in a number of tumors of the breast, including adenomyoepithelioma, clear cell carcinoma (primary versus metastatic), lipid-rich carcinoma, apocrine carcinoma, and occasionally, infiltrating ductal carcinoma of the usual type. In contrast to carcinomas composed of a uniform population of malignant epithelial cells, adenomyoepithelioma exhibits biphasic cellular elements of ductal and myoepithelial cells

The presence and location of epithelial implants and implants with epithelial proliferation may predict a higher risk of recurrence in serous borderline ovarian tumors: a clinicopathologic study of 188 cases.

Serous borderline ovarian tumors have a favorable prognosis, and recurrences are uncommon. The factors influencing recurrence are not fully understood. Epithelial inclusions are identified in serous borderline ovarian tumors and are traditionally referred to as epithelial implants, which often show epithelial proliferation. We investigated whether the presence of epithelial implant and epithelial proliferation portends a higher risk for recurrence of serous borderline ovarian tumors in patients who underwent surgical removal of these tumors. Also examined was whether the anatomical site of epithelial implant and epithelial proliferation was associated with a higher risk of recurrence. One hundred eighty-eight cases of pure serous or predominantly serous borderline ovarian tumors were studied for the presence of epithelial implant and epithelial proliferation, and subsequent recurrences were recorded. The anatomical sites of epithelial implant and epithelial proliferation were compared between serous borderline ovarian tumors with or without recurrence. Statistical analysis was performed using the χ(2) test. Epithelial implant was noted in 106 cases (56%), and epithelial proliferation, in 26 cases (14%). Recurrence was identified in 10.4% cases with epithelial implant and 23% cases with epithelial proliferation. Statistical analyses of patients with recurrence showed significant differences in the following groups: epithelial implant versus no epithelial implant (P < .025) and epithelial proliferation versus no epithelial implant (P < .001). Recurrence rates were higher in the epithelial implant and epithelial proliferation groups as compared with no epithelial implant or epithelial proliferation groups. Epithelial implant and epithelial proliferation appear to pose a statistically significantly higher risk of recurrence in serous borderline ovarian tumors as compared with the absence of epithelial implant. Although the anatomical location of such implants was not significantly associated with a higher risk, the presence of epithelial proliferation at multiple sites was more frequently seen in recurrent serous borderline ovarian tumors.

Squamous inclusion cyst with evidence of focal glandular differentiation in an axillary lymph node

Sir: Epithelial inclusions of the axillary lymph nodes are rare, but may be confused with malignant diseases clinically and pathologically. Some are incidental findings during procedures for other conditions. Others present as enlarged lymph nodes which are often excised because of clinical concerns of malignancy. We describe a benign squamous inclusion cystwith evidence of focal glandular differentiation in an axillary lymph node which was clinically thought to be lymphoma. A 50-year-old female patient presented with intermittent anaemia for 2 years, increased fatigue for several months, and occasional night sweat for 6 weeks. Her past medical history included Hashimoto’s thyroiditis, haemorrhoids, and benign breast biopsies many years ago; she received Synthroid and occasional iron therapy. Two recent gastrointestinal workups and a mammography were negative. Physical examination, computed tomographic scan and ultrasound evaluation revealed an enlarged, mobile and non-tender right axillary lymph node, as well as multiple smaller lymph nodes in the left axilla and the inguinal regions. Because of a clinical suspicion of lymphoma, the enlarged right axillary lymph node was excised for pathological examination. Gross examination of the specimen revealed a 15 · 10 · 10 mm, cystic nodule filled with caseous material. Microscopic examination showed a lymph node with a centrally located cyst containing keratin debris (Figure 1). Parts of the cyst were lined by keratinized squamous epithelium with prominent granular cell layers, mimicking the lining of an epidermal inclusion cyst of the skin (Figure 2). Other parts were lined by multiple layers of polygonal cells, morphologically consistent with immature squamous metaplasia. The cells toward the cyst lumen in these areas exhibited intracytoplasmic mucin vacuoles, as confirmed by a positive mucicarmine stain (Figure 3). These cells were also immunopositive for carcinoembryonic antigen (CEA), a marker of glandular differentiation; however, no apparent glandular structureswere seen in the lesion. All cyst-lining cells were positive for both AE1 and AE3, althoughAE3was stronger in the keratinized than in the non-keratinized epithelium. All the cells were immunonegative for oestrogen receptors, progesterone receptors, and gross cystic disease fluid protein-15. Focal rupture of the cyst was associated with reactive fibrosis. Surrounding the cyst was residual lymphoid tissue showing follicular hyperplasia and a well-formed fibrous capsule. About 20 cases of epithelial inclusions of the axillary lymph nodes have been reported in the literature. Most describe aggregates of mammary duct-like structures alone, or associated with cysts lined by apocrine or squamous epithelium. Four other reports, similar to ours, showed cysts lined by apparently pure stratified squamous epithelium. The subcapsular location of the cysts in some cases and documentation of prior biopsy of the breast in others suggest a mechanism of benign implantation of breast tissue via lymphatic channels. Although our patient had a previous breast procedure, the more central, in contrast to the subcapsular, location of the cyst in the axillary lymph node is difficult to explain by means of benign implantation. Embryological displacement may serve Figure 1. Squamous epithelial inclusion cyst with residual lymphoid tissue showing follicular hyperplasia.

Vulvar encapsulated solid papillary carcinoma with neuroendocrine differentiation: a case report.

A 40-year-old woman underwent excision of a painless left vulvar mass. The specimen showed a well-circumscribed mass measuring 3.5 × 2.7 × 2.5 cm. Microscopic examination exhibited an encapsulated neoplasm with a solid and papillary growth pattern. The tumor cells were oval to columnar and showed moderate nuclear atypia. No capsular invasion was identified. Immunonegativity for calponin and p63 confirmed the absence of myoepithelial cells either within or at the periphery of the tumor. The tumor was immunopositive for gross cystic disease fluid protein 15, synaptophysin, and chromogranin. The histologic and immunohistochemical characteristics were consistent with an encapsulated solid papillary carcinoma with neuroendocrine differentiation. The patient has been free of disease for 4 years after surgery. This is the first report of a vulvar encapsulated solid papillary carcinoma with neuroendocrine differentiation. Correct diagnosis is imperative because of the distinct biologic behavior of the tumor.