Neovascularization in mucinous ductal carcinoma in situ suggests an alternative pathway for invasion.

AIMS: Ductal carcinoma in situ (DCIS) associated with invasive mucinous carcinoma (IMC) has not been well characterized. The aim was to characterize mucinous DCIS (mDCIS) of the breast and to describe, to our knowledge for the first time, neovascularization in mucin. METHODS AND RESULTS: The pathology reports and slides were reviewed from 44 patients treated between 2003 and 2006 at The University of Texas M. D. Anderson Cancer Center, whose diagnosis fulfilled the criteria of IMC or DCIS with mucin production. The patients, all female, had a mean age of 62 years. DCIS was present in 93% of cases and the predominant histological types were solid, cribriform and micropapillary. The DCIS was grade 1 in 12 of 41 cases (29.3%), grade 2 in 25 of 41 cases (61%) and grade 3 in four of 41 cases (9.8%). Mucin was seen in the lumen of the ducts involved by DCIS in 88% of cases, mucin and vessels in 63.4% of cases and neither mucin nor vessels in 12.2%. The DCIS was vascular endothelial growth factor-positive, platelet-derived growth factor receptor-beta-positive and CDX-2-negative (100%). Occasional luminal cells within the DCIS were immunopositive for CD68. CONCLUSIONS: A significant number of mDCIS showed neovascularization in intraluminal mucin. When identified on core needle biopsy, the presence of vascularized mucin should not be used alone to discriminate between invasive and in situ carcinoma. A hypothesis proposed for the source of recruitment of vessels in the mucin is that mucin can promote neovascularization and that tumour cells invade not into the adjacent fibroconnective tissue, but rather into the mucinous, richly vascularized stroma that they have induced. Alternatively, it is possible that both cells and their secretory product invade together. To our knowledge, this is the first study to characterize neovascularization within the mucinous component of DCIS associated with and without IMC.

Ovarian endometriosis associated with carcinoma and sarcoma: case report.

Endometriosis is a common clinical disorder that shares certain characteristics, metastasis and recurrence, with malignant neoplasms. Most malignant ovarian tumors arising from endometriosis are clear cell carcinoma or endometrioid adenocarcinoma. Few reports exist of sarcoma associated with endometriosis, and even fewer exist of multiple types of malignancies occurring simultaneously. Here, we report the case of a 32-year-old woman who presented with infertility and a pelvic mass. She underwent exploratory laparotomy and bilateral salpingo-oophorectomy. She was then referred to our institution for treatment recommendation. The pathologic findings revealed bilateral endometrioid adenofibroma of low malignant potential, which was associated with endometrioid intraepithelial carcinoma in the left ovary and high-grade sarcoma in the right ovary. Both tumors seemed to have arisen from endometriosis. She was treated with 75 mg/m2 of doxorubicin and 10 g/m2 of ifosfamide every three weeks for eight courses. She was later found to have bilateral brain metastases, which were resected and treated by whole-brain irradiation. She was again treated with doxorubicin and ifosfamide. The optimal treatment for endometriosis-associated ovarian cancer depends on the type of malignancy; simultaneously occurring multiple tumor types should be treated individually.

Identical genetic changes in different histologic components of Wilms' tumors.

BACKGROUND: In young children and infants, Wilms' tumor is the most common cancer of the kidney. Wilms' tumor exhibits heterogeneous histopathologic features, consisting of rapidly proliferating blastemal and epithelial cells and a stromal component that has heterologous elements (e.g., cartilage, bone, and striated muscle). It is unclear whether the stromal and heterologous components of sporadic Wilms' tumor are neoplastic or should be considered non-neoplastic. PURPOSE: Our purpose was twofold: 1) to selectively analyze the different histologic tissue components of sporadic Wilms' tumors, including blastemal, epithelial, stromal, and heterologous elements, for loss of heterozygosity (LOH) of the WT1 gene and for expression of the WT1 gene and 2) to determine the role of WT1 gene expression in the development of these tissues. METHODS: By use of tissue microdissection techniques, various histologic elements (blastema, stroma, epithelium, and striated muscle) of sporadic Wilms' tumor were obtained from specimens taken from 18 patients. DNA was extracted from the dissected tissue fragments, and DNA solutions were amplified by use of the polymerase chain reaction and the polymorphic genomic markers D11S1392 and D11S904 to detect LOH at the WT1 gene locus (11p13). Three selected specimens with heterologous elements and LOH at 11p13 were analyzed for expression of the WT1 gene by means of the in situ reverse transcription-polymerase chain reaction. RESULTS: Nine (50%) of the 18 specimens showed LOH at the WT1 locus. Although identical WT1 gene deletion was consistently observed in all of the various histologic components of these nine specimens, WT1 gene expression was high in the blastemal and epithelial elements and low in the stromal and heterologous elements. CONCLUSIONS AND IMPLICATIONS: Identical allelic deletion at 11p13 in all components of the sporadic Wilms' tumors examined suggests that the stromal tissue components are neoplastic rather than non-neoplastic. In conjunction with variable WT1 gene expression in the different histologic components, the results raise the possibility that undifferentiated blastemal cells are the precursors of the stromal and heterologous elements. Morphologically benign stromal and heterologous elements may therefore be derived from neoplastic cells. The developmental state of the various tissue components of Wilms' tumor may be attributed to an altered residual WT1 gene that is required for the maturation of blastemal and epithelial cells but that is not required for the maturation of stromal and heterologous elements.

Ciliated hepatic foregut cyst: a study of six cases and review of the literature.

Ciliated hepatic foregut cyst (CHFC) is a rare, benign, solitary cyst consisting of ciliated pseudostratified columnar epithelium, subepithelial connective tissue, a smooth muscle layer, and an outer fibrous capsule. We studied six previously unreported cases of CHFC and 50 cases from the literature. The literature search revealed that Friedreich first described the lesion in 1857 and hypothesized its congenital origin. The cyst generally is found incidentally on radiologic imaging or during surgical exploration, although one case presented with portal vein compression. It occurs more frequently in men and is found most commonly in the medial segment of the left hepatic lobe, unlike most other solitary cysts that show a female predominance and greater occurrence in the right hepatic lobe. Two of the 56 cases were multilocular. There has been an increase in the number of reports of CHFC during the past 15 years. This may reflect the increased availability and use of various radiologic imaging modalities. A large number of cases have been reported in the Japanese population, but the significance of this is unclear. CHFC should be considered in the differential diagnosis of other solitary liver cysts, including simple cysts, hepatobiliary cystadenomas, and parasitic cysts.

Serous tumors involving extra-abdominal/extra-pelvic sites after the diagnosis of an ovarian serous neoplasm of low malignant potential.

The involvement of extra-abdominal/extra-pelvic sites by serous tumors after the diagnosis of an ovarian serous neoplasm of low malignant potential is extremely rare. In this study we present the clinicopathologic features of 12 such cases seen at our institution during a period of 19 years (1980-1999). The patients' age ranged from 19 to 50 years (mean 33 years). By FIGO staging the original ovarian tumors were distributed as follows: stage I, 4; stage II, 2; stage III, 5; unknown stage, 1. All patients were treated surgically. Ten patients also received adjuvant therapy (radiotherapy, 2; chemotherapy and radiotherapy, 4; chemotherapy, 3; intraperitoneal 32P, 1). The interval between the diagnosis of the ovarian neoplasm and the subsequent tumor involving an extra-abdominal/extra-pelvic site ranged from 4 to 240 months (mean 124 months). Sites of extra-abdominal/extra-pelvic involvement and the number of cases were as follows: left neck lymph nodes (LNs), 4; left and right neck LNs, 1; pleura, 2; lung, 1; mediastinum, 1; chest wall, 1; axillary and chest LNs, 1; and vertebral body, 1. Eight patients were treated with chemotherapy, 1 with radiotherapy, 2 with chemotherapy and radiotherapy, and 1 with surgery alone. Follow-up ranging from 5 months to 18 years was available in 11 patients. Six patients died of disease and 5 patients were alive with no evidence of disease. In this small series of cases, no definitive clinical or pathologic feature related to the occurrence of extra-abdominal/extra-pelvic serous tumors was found. Based on the LN involvement and the endosalpingiosis seen in some cases, these tumors might develop from circulating neoplastic serous cells or from areas of endosalpingiosis involving extra-abdominal/extra-pelvic sites.

Vessels within vessels in the myometrium.

We have encountered a peculiar vascular architecture in the myometrium wherein arteries are found free-floating within cleft-like spaces. Using different colored dye injections in the uterine arteries and veins, we demonstrated that these spaces are venous channels. This was confirmed by immunoperoxidase staining for CD34, which enhanced the cells lining these spaces. A review of 81 hysterectomy specimens showed that this vascular architecture was present in 42 cases (52%), while it was identified in the parenchyma of only two mastectomy specimens among the 45 specimens from different organs studied. A strong association existed between the presence of this architecture and history of menorrhagia (p = 0.0116). This peculiar vascular architecture might be important in the pathogenesis of menorrhagia and the development of intravenous leiomyomatosis. Pathologists should also be able to recognize these spaces as vascular channels in the event that malignant cells are identified within them.

Desmoplastic small round cell tumor: report of a case presenting as a primary ovarian neoplasm.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is an intra-abdominal malignancy that typically has extensive peritoneal spread at the time of diagnosis. We report a case of DSRCT with involvement of the ovary and omentum as well as an elevated CA-125 level at presentation. CASE: A 23-year-old female presented to another institution with a pelvic mass and a CA-125 level of 140 U/ml. During tumor reductive surgery the right ovary, omentum, and liver were found to be involved. Initial histologic examination favored an undifferentiated small cell carcinoma of the ovary. The patient received two cycles of Taxol and cisplatin chemotherapy and was referred to the University of Texas M. D. Anderson Cancer Center. Upon review of the pathology material at the time of the referral, a diagnosis of DSRCT was made. Despite two additional cycles of chemotherapy, the tumor progressed, and the patient returned home. CONCLUSION: DSRCT may mimic an ovarian primary tumor by presenting with involvement of the ovary and an elevated CA-125 level, and should be included in the differential diagnosis of ovarian neoplasms in young patients.

High-grade ovarian serous carcinoma exhibits significantly higher p16 expression than low-grade serous carcinoma and serous borderline tumour.

AIMS: A dualistic pathway of ovarian serous carcinogenesis is now well established whereby high-grade serous carcinoma and low-grade serous carcinoma represent two distinct tumour types with a different underlying pathogenesis. The aim of this study was to compare expression of p16 INK4A (p16) in these two tumour types. We also included cases of serous borderline tumour, since these are considered to represent a precursor lesion of low-grade serous carcinoma. METHODS AND RESULTS: Cases of serous borderline tumour (n = 18), low-grade ovarian serous carcinoma (n = 22) and high-grade ovarian serous carcinoma (n = 24) were stained with a monoclonal antibody against p16. Cases were scored both with respect to intensity of immunoreactivity (weak, 1+; moderate, 2+; or strong, 3+) and distribution (0, negative or occasional positive cells; 1+, < 10% cells positive; 2+, 10-25% cells positive; 3+, 26-50% cells positive; 4+, 51-75% cells positive; or 5+, 76-100% cells positive). An immunohistochemical composite score was also calculated (0-15) by multiplying the intensity and distribution scores. There was a statistically significant difference in p16 immunoreactivity with respect to intensity, distribution and composite score between high-grade serous carcinoma and each of the other two groups, with the high-grade neoplasms exhibiting stronger and more diffuse positivity. Most high-grade serous carcinomas exhibited positivity of close to 100% of tumour cells. There was no significant difference in p16 expression between the borderline tumours and low-grade serous carcinomas. CONCLUSIONS: The increased expression of p16 in high-grade serous carcinoma compared with low-grade serous carcinoma and serous borderline tumour is in keeping with a different underlying pathogenesis. p16 may be implicated in the development of high-grade serous neoplasia within the ovary and elsewhere within the female genital tract.

Metastasis to sigmoid colon mucosa and submucosa from serous borderline ovarian tumor: response to hormone therapy.

Distant metastasis to sites other than lymph nodes of borderline ovarian tumor is rare. We describe a case metastasized to sigmoid colon mucosa and submucosa. The metastatic lesion was detected incidentally by screening colonoscopy 7 years after the patient was treated for the primary tumor. The metastatic lesion responded well to treatment with oral Arimidex 1 mg/day. A follow-up colonoscopy with biopsy and imaging studies after 3 months of treatment revealed no evidence of disease in the sigmoid colon. This case showed that the sigmoid colon mucosa and submucosa should be considered as one of distant metastatic sites of a serous borderline ovarian tumor and the favorable response to Arimidex provides support the use of hormone therapy in women with serous borderline ovarian tumor.

Discordant genetic changes in ovarian and endometrial endometrioid carcinomas: a potential pitfall in molecular diagnosis.

Endometrioid carcinoma simultaneously involving ovaries as well as the uterine corpus may present a diagnostic dilemma because of the difficulty in determining whether the lesions are separate primary tumors or metastases. It has been reported that the detection of clonality using microsatellite markers may be useful in solving this dilemma. To determine the usefulness of this technique, we compared the genetic alterations in microsatellite markers present in matched pairs of ovarian tumors from 12 patients. The study includes four ovarian cancer FIGO stage I and eight stage III/IV patients, and four patients also with independent endometrial carcinoma of the uterus. DNA from paraffin-embedded tissue was extracted and amplified using a multiplex polymerase chain reaction, after which the status of microsatellite instability and loss of heterozygosity in four microsatellite loci (BAT25, BAT26, D17S250, and D5S346) were determined. In the four patients with stage I ovarian cancer, four microsatellite markers were identical in one patient and three were identical in the remaining three patients. In high-stage patients, three markers were identical in at least 4/8 cases. In three of four patients with uterine involvement, three of the four markers were identical in the uterine tumor and one of the corresponding ovarian tumors. These results suggest that genetic discordance does not indicate independent origin or metastasis of the tumor but instead a progression of genetic changes at separate sites probably due to the marked genetic instability existing in these tumors. Because of these discordant genetic changes, great caution should be taken when distinguishing between primary and metastatic tumors on the basis of microsatellite markers.

Expression of HER-2/neu, epidermal growth factor receptor, vascular endothelial growth factor, cyclooxygenase-2, estrogen receptor, and progesterone receptor in small cell and large cell neuroendocrine carcinoma of the uterine cervix: a clinicopathologic and prognostic study.

We studied the immunohistochemical expression of HER-2/neu, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), estrogen receptor (ER), and progesterone receptor (PR) in uterine cervical small cell and large cell neuroendocrine carcinomas (SCNECs and LCNECs) from 24 patients seen at The University of Texas M.D. Anderson Cancer Center. The objectives were to determine their expression and prognostic role in survival. Twenty-three cases (95.8%) expressed VEGF. The tumors expressing EGFR, HER-2/neu, and COX-2 were modest in numbers: eight (33.3%), 10 (41.7%), and seven (29.2%), respectively. Only one tumor (4.2%) expressed ER, and only two tumors (8.3%) expressed PR. No significant differences in the expression of these factors were found between SCNECs and LCNECs or between stage I and stage II-III tumors. The median overall survival was 21.1 months (95% confidence interval [CI], 17.2-25.0 months). Only HER-2/neu expression was significantly associated with survival. Patients with negative HER-2/neu expression tumors had significantly shorter survival than those whose tumors were positive, 14.2 months (95% CI, 10.6-17.7 months) versus 33.1 months (95% CI, 0-76.92 months) (P = 0.03). There was a trend toward worse survival in patients with EGFR expression, but this finding was not significant. The combination of negative HER-2/neu expression and positive EGFR expression had the worst impact on survival.

Immunohistochemistry in gynecological pathology.

Although the majority of diagnoses in gynecological pathology are established on examination of routine hematoxylin and eosin stained sections, additional tests are occasionally required. Immunohistochemistry is widely used to provide additional diagnostic information in problematic cases. This review touches on some of the basics of the procedure, presents an example immunohistochemical panel, and discusses some of the most common immunohistochemical markers used in diagnostic gynecological pathology. Differential diagnostic problems and relevant immunohistochemical stains for the vulva, vagina, cervix, uterus, and ovary are also addressed.

Ovarian non-Hodgkin's lymphoma: a clinicopathologic study of eight primary cases.

Primary (localized) non-Hodgkin's lymphoma (NHL) of the ovary is rare. We studied eight cases of primary ovarian NHL to better understand the clinicopathologic and immunophenotypic features of these tumors. The patients ranged in age from 29 to 62 years (mean 47 years). Pelvic complaints were the most common symptoms; however, three of eight neoplasms were discovered incidentally. All tumors were unilateral and Ann Arbor stage I(E). The three incidental NHL were microscopic (largest 1.2 cm), whereas the grossly evident lesions ranged from 7.5 to 20 cm (mean 13.3). Each tumor was classified according to the World Health Organization Classification as follows: diffuse large B-cell lymphoma (three cases), follicular lymphoma (two cases), Burkitt lymphoma (one case), T-cell anaplastic large cell lymphoma (one case), and precursor T-lymphoblastic lymphoma (one case). Six tumors were of B-cell lineage, and two tumors were of T-cell lineage. All three diffuse large B-cell lymphomas were positive for BCL-6, two were positive for CD10, and two were positive for BCL-2. Estrogen and progesterone receptors were negative in all NHLs assessed. Patients were treated by various combinations of surgery, chemotherapy, and radiotherapy. Clinical follow-up ranged from 1.3 to 11.7 years (mean 5.2) and all patients were alive without disease at last follow-up. We conclude that most patients with primary ovarian NHL present with symptoms attributable to an ovarian mass, but in a subset of patients ovarian NHL may be detected incidentally. With appropriate therapy, patients appear to have a favorable prognosis although follow-up is short for some patients in this study.

Uterine leiomyomas with Eosinophils: a clinicopathologic study of 3 cases.

Although leiomyomas (LMs) of the uterus are common, hematopoietic components within these tumors are not. Lymphoid and other hematopoietic elements have been previously recognized, but eosinophilic infiltrates in LMs have received little attention in the literature. The clinical and pathologic features of 3 cases of uterine LM with eosinophilic infiltration were studied. The patients ranged in age from 35 to 62 years and presented with abdominal and/or pelvic pain and abnormal uterine bleeding. None had peripheral blood eosinophilia or clinical evidence of allergy or parasitic infection. One patient had a benign LM, and the other 2 patients had smooth muscle tumors of uncertain malignant potential. The tumors contained variable numbers of eosinophils and Giemsa stains showed variable numbers of mast cells in addition to the eosinophils. We also performed immunohistochemical and in situ hybridization studies to assess for interleukin-5 (IL-5) and eotaxin in these LMs. There was no consistent association between the presence of eosinophils and either IL-5 or eotaxin in smooth muscle cells, suggesting that mechanisms other than IL-5 or eotaxin production may account for the eosinophilia. Because eosinophils are believed to be involved in wound healing, tissue remodeling, and fibrosis, their presence within LMs may reflect a response to tissue injury produced by the neoplasm rather than intrinsic recruitment by chemotactic factors produced by the smooth muscle cells. Their presence, however, does not appear to have any clinical significance.

Ovarian mixed-epithelial carcinomas with a microcystic pattern and signet-ring cells.

Primary ovarian carcinomas with unusual histologic patterns can be difficult to differentiate from metastases. In this study, we reviewed 15 cases of mixed-epithelial carcinoma (12 serous, 1 serous and endometrioid, 1 endometrioid, 1 undifferentiated) with a predominant microcystic pattern and signet-ring cells. The patients' ages ranged from 31 to 78 (mean 58) years. The microcystic component in 11 patients had features of high-grade carcinoma and in 4 patients had features of low-grade carcinoma associated with areas of borderline tumor. The tumors in all 15 patients showed a predominant microcystic growth pattern composed of small cysts that were variable in size and shape. Signet-ring cells were also present in all cases (diffusely in nine cases, focally in six cases) within the neoplastic epithelial proliferation. Mucin was present in the lumina of some of the microcysts and in the cytoplasm of most of the signet-ring cells. A microcystic pattern and mucin-containing signet-ring cells can be seen as small foci or as a predominant component in primary epithelial nonmucinous ovarian carcinomas. It is important for pathologists to recognize these unusual findings in ovarian neoplasms, because they may produce a confusing apperance, even potentially suggesting a metastasis.

Immunohistochemical analysis of clear cell carcinoma of the gynecologic tract.

Clear cell carcinoma of the gynecologic tract has been defined in terms of its clinical and histologic features; however, its immunophenotypic profile has not been fully characterized. Seventeen cases of primary clear cell carcinoma from various sites within the female genital tract (11 ovary, 5 uterus, 1 vagina) were analyzed by immunohistochemistry. These tumors were assessed for the expression of cytokeratin 7 (CK7), cytokeratin 20 (CK20), low and high molecular weight cytokeratin, (CAM5.2 and 34 beta E12, respectively), carcinoembryonic antigen (CEA), Leu-M1, vimentin, estrogen receptor (ER), progesterone receptor (PR), bcl-2, p53, HER-2/neu, and CA-125. The characteristic immunoprofile for all sites was positivity for CK7, CAM5.2, 34 beta E12, CEA, Leu-M1, vimentin, bcl-2, p53, and CA-125; variably positivity for ER and HER-2/neu; and negativity for CK20 and PR. For comparison, two cases of urologic clear cell carcinoma (1 bladder, 1 urethra) were also studied, and their profile was found to be similar to the gynecologic cases. Aside from minor differences, clear cell carcinoma appears to have the same immunophenotype regardless of whether it originates in the endometrium, ovary, or genitourinary tract. Much of its profile is similar to other gynecologic adenocarcinomas, but some of the markers studied may be useful in the differential diagnosis of this tumor.

In vivo expression of the novel CXC chemokine BRAK in normal and cancerous human tissue.

Using differential display, we cloned a gene with reduced expression in short-term explants of head and neck squamous cell carcinoma (HNSCC) tumors compared to cultured normal oral epithelial cells. The differentially expressed gene was identical to the recently cloned CXC chemokine BRAK, which is ubiquitously expressed in normal tissue extracts but is absent from many tumor cell lines in vitro. To define the cell populations expressing BRAK in vivo, in situ mRNA hybridization was performed on normal and cancerous tissues from six different histological sites. The predominant normal cell type constitutively expressing BRAK in vivo was squamous epithelium. Expression in tumors was heterogeneous, with the majority of HNSCCs and some cervical squamous cell carcinomas (SCCs) showing loss of BRAK mRNA. Although absent in unstimulated peripheral blood mononuclear cells, high levels of BRAK were consistently found in infiltrating inflammatory cells (with lymphocyte morphology) in nearly all cancers examined. Furthermore, BRAK expression was demonstrated in B cells and monocytes, after stimulation of peripheral blood mononuclear cells with lipopolysaccharide. This study demonstrates for the first time up-regulation of BRAK mRNA by inflammatory cells in the tumor microenvironment and lost expression from certain cancers in vivo. The data suggest that BRAK may have a role in host-tumor interactions.