Late presentation of metastatic smooth muscle neoplasm of the uterus with low malignant potential

A 48-year-old woman underwent total abdominal hysterectomy with conservation of the ovaries and tubes. Histology showed a well-circumscribed smooth muscle tumor with foci of degeneration (including infarct-type necrosis) but no coagulative tumor cell necrosis and only mild focal cytological atypia. She presented, 24 years later with shortness of breath and abdominal distension and underwent bilateral salpingo-oophorectomy, appendectomy, omental biopsy and para-aortic lymph node sampling. Histology showed bilateral ovarian smooth muscle tumors with no coagulative tumor cell necrosis or significant cellular atypia. The cells were mitotically active. The tumors in both ovaries were most likely secondary to the previous uterine smooth muscle neoplasm. To our knowledge, this case is the first in the literature to describe a benign cellular leiomyoma that subsequently behaved as a smooth muscle tumor of uncertain malignant potential, which recurred 24 years after the initial diagnosis.     

Dynamic alterations of the extracellular environment of ovarian surface epithelial cells in premalignant transformation,tumorigenicity, and metastasis

BACKGROUND: Ovarian surface epithelial cells are positionally organized as a single cell layer by a sheet of basement membrane. It is believed that the contact of the ovarian surface epithelial cells with the basement membrane regulates cell growth and ensures the organization of the epithelium. Disabled-2 (Dab2), a signal transduction protein and a candidate tumor suppressor of ovarian carcinoma, functions in positional organization of ovarian surface epithelial cells. In ovarian carcinomas, genetic and epigenetic changes enable the tumor cells to escape positional control and proliferate in a disorganized fashion. Alterations in the extracellular environment may also be critical for tumor initiation and progression. METHODS: We analyzed and compared the presence of collagen IV and laminin, the scaffold proteins of the basement membrane, and Dab2 in 50 ovarian tumors that are restricted to the ovaries and in 50 metastases of ovarian tumors by immunohistochemistry. Expression of collagen IV, laminin, and Dab2 was also analyzed by Northern blotting in a panel of human ovarian surface epithelial and cancer cell lines. RESULTS: The basement membrane is often absent in morphologically benign ovarian surface and cyst epithelium and low-grade tumors and collagen IV and laminin are absent in the extracellular matrix of most of the primary tumors tested. Of the 50 ovarian tumors confined to the ovaries, 6% (3 of 50) were collagen IV positive and 24% (12 of 50) were laminin positive tumors. Of the 50 metastatic tumors, 16% (8 of 50) are collagen IV positive and 86% (43 of 50) are laminin positive. In addition, even in the metastatic ovarian tumors that are largely collagen IV negative, there are pockets of local areas in which the tumor cells are surrounded by collagen IV-positive staining. Dab2 is absent in the majority of ovarian tumors found in both ovaries and metastatic sites. In both nontumorigenic human ovarian surface epithelial and cancer cell lines, collagen IV, laminin, and Dab2 are expressed aberrantly. CONCLUSIONS: Loss of the basement membrane may be an early event in the preneoplastic transformation of ovarian surface epithelium and in the early stages of tumorigenesis before tumor invasion and metastasis. The majority of primary ovarian tumors examined lack collagen IV and laminin in their extracellular matrix. However, expression of laminin is restored in the majority of metastatic tumors. Reexpression of collagen IV may also contribute to tumor metastasis. The ability of tumor cells to dynamically alter the expression of collagen IV and laminin may facilitate the shedding of cancer cells into the peritoneal spaces and subsequent attachment to the metastatic sites. We propose that loss of collagen IV and laminin may be an initial event in ovarian tumorigenicity and that restoration of collagen IV and laminin expression in the later stages of tumor development may promote metastasis of ovarian tumors.     

Expression of heparanase, Mdm2, and erbB2 in ovarian cancer

Ovarian cancer is the most lethal of gynecological malignancies. Yet early diagnosis and prognosis are far from being satisfactory. Degradation of heparan sulfate proteoglycans by heparanase appears to play an important role in the invasiveness of tumor cells through the basement membrane and into the extracellular matrix. Recent cloning of the heparanase gene and generation of monoclonal antibodies against the enzyme permit to examine tumor cell expression of the enzyme. The aim of the present study was to assess heparanase activity and localization in various subtypes of epithelial ovarian cancer in correlation with oncogene expression. Histologically confirmed malignant ovarian tissue from ten women and tissue from 2 benign ovarian tumors and 4 normal ovaries were assessed for heparanase presence, activity and localization, incidence of apoptosis and expression of the oncogenes erbB2 and Mdm2. Heparanase immunohistostaining and activity were present in mucinous carcinomas and were more intense than in endometrioid and in serous carcinomas. The lowest activity was observed in benign ovarian tumors and normal ovaries. In ovarian carcinomas the enzyme was intensely concentrated in the cytoplasm of the cancerous cells. In contrast, in normal ovaries and benign tumors the enzyme was predominantly localized in endothelial cells lining blood capillaries. The rate of apoptosis was considerably higher in mucinous and endometrioid carcinomas, and was lower in serous and primary peritoneal carcinomas. Extremely high concentration of heparanase was often demonstrated in apoptotic cells. Endometrioid and serous carcinomas showed high expression of Mdm2 and erbB2 while mucinous carcinomas showed low expression. In benign ovarian tumors and normal ovaries the expression of both oncoproteins was extremely low. In conclusion ovarian carcinomas demonstrate higher levels of heparanase than benign tumors and normal ovaries suggesting that the enzyme may play an important role in metastatic spread of the cancerous cells. Apoptosis may be a significant part of the mechanism of the enzyme release into the extracellular space. Although heparanase activity seems to play an essential role in tumor progression, expression of oncogenes, such as erbB2 and Mdm2 seems to play the dominant role in the development of ovarian cancer.     

A case of ovarian cancer in which a remarkable effect was seen with low-dose CDDP intratumoral injection of CPT-11

We treated an ovarian cancer patient in whom low-dose CDDP intratumoral injection with CPT-11 therapy was very effective. The patient was a 63-year-old woman. She showed symptoms of peritonitis. Carcinomatous peritonitis was suspected on abdominal CT scan and tumor markers were at high levels (CA125 10,827 U/ml, SLX 82 U/ml). At laparotomy, massive ascites (3,000 ml), omental cakes and disseminated peritoneal tumors were revealed. Her uterus and adnexa were not enlarged. The omental tumor and ovaries were biopsied and revealed serous adenocarcinoma. The patient was treated with combined chemotherapy of CDDP and CPT-11. CDDP (20 mg/day) was administered by intraperitoneally for 3 days, and CDDP (10 mg/day) was administered by intratumoral injection (percutaneous for omental tumor) for 5 days. CPT-11 (40 mg/day) was administered twice a week. As a result, marked shrinkage of the tumors was confirmed. This low-dose CDDP intratumoral injection with CPT-11 may be effective for such omental tumors with carcinomatous peritonitis.     

Molecular analysis of an immature ovarian teratoma with gliomatosis peritonei and recurrence suggests genetic independence of multiple tumors

Immature ovarian teratoma is a common germ cell tumor of young women. Patients with immature teratoma often exhibit multiple neoplasms, including tumors outside the ovaries, and occasionally a rare benign condition termed gliomatosis peritonei (GP). These multiple neoplasms are generally believed genetically-linked progeny of the ovarian tumor resulting from local recurrence/spread. In this study, we performed a molecular analysis of a single patient clinically diagnosed with immature ovarian teratoma, GP, and recurrent pelvic mucinous teratoma. Microsatellite PCR and amplicon analysis was performed to genetically characterize tissue samples from omental glial implants and multiple peritoneal tumors. PCR-based amplification of microsatellite markers identifies unique genetic differences (allelic variation) between tumors resulting from divergent natural histories among multiple tumor nodules in a single patient. A total of 21 different microsatellite markers were employed, and seven provided informative results (D3S1744, D6S1056, D7S2846, D14S306, D16S764, D18S858, D22S420). These markers demonstrated mutually exclusive genetic differences among the tumors from this patient, establishing the neoplasms as genetically distinct from each other (non-identical), and that no lineage relationship exists among them. This observation suggests that the multiple tumors arising in this patient with immature ovarian teratoma, GP, and recurrent pelvic mucinous neoplasm represent multiple independent tumors rather than true tumor recurrence/spread. The results of this study suggest strongly that patients with recurrent teratoma may be afflicted with a tumor-prone syndrome where one or more peritoneal cell types or populations are predisposed to neoplastic conversion and formation of tumors as a result of an endogenous or exogenous neoplastic stimuli.     

卵巢转移癌

报告50例卵巢转移癌,13例与原发癌作对比病理观察。患者19—65岁,31—50岁占64％。80％原发癌在胃肠道。多累犯双侧卵巢。间质网格状水肿,亦有助于与卵巢原发癌区别。转移癌呈6种不同组织学类型,仅35例见印戒状癌细胞。后者,只见于所有胃肠源性之卵巢转移癌,而不管原发癌中有无此种细胞。组织学分化程度,转移癌比原发癌多明显提高,尤其印戒状癌细胞的体积常特大,更有意义。为澄清对Krukenberg瘤含意的不同理解,建议仅将符合Krukenberg描述的卵巢原发瘤,称为Krukenberg瘤,一切转移到卵巢的癌瘤,不管其形态如何,统称为卵巢转移癌较为合理。     

Factors affecting the incidence of metastasis of malignant epithelial tumors of the ovaries

Clinico-morphological data on 714 cases of epithelial ovarian malignancy were evaluated. 558 patients (78.2%) revealed metastases at various sites in the course of primary treatment. Frequency of dissemination was significantly higher in patients over 40 years, postmenopausal ones and those with a shorter history of disease (duration of symptoms). A significantly higher frequency of metastatic spread was also observed in cases of bilateral involvement of the ovaries, invasion through the tumor capsule and into adjacent tissues and organs, adhesions, ascitis, hydrothorax, cystic-solid, solid and papillary growth patterns (vs relatively lower frequency for cystic tumors). Histologic type of tumor was of major importance, too.     

Analysis of tumor heterogeneity in a patient with synchronously occurring female genital tract malignancies by DNA flow cytometry, DNA fingerprinting, and immunohistochemistry

A case of a patient with bilateral ovarian cancer and a uterine malignant mesodermal mixed tumor with ascites and metastatic disease is presented. Flow cytometry, DNA fingerprinting, and immunohistochemistry were performed to assess the origin of these malignancies. Ploidy analysis showed that both ovarian tumors had different aneuploid stemlines (DNA index [DI] = 1.64, 1.85, right ovary and DI = 1.73, left ovary) indicating independent origins. One of the stemlines in the right ovary (DI = 1.64) was also present in the ascites cells, whereas omentum metastases showed the same stemline (DI = 1.73) as the left ovarian tumor. The uterine malignancy contained three aneuploid stemlines. The highest stemline was associated with epithelial differentiation, but a metastatic origin from the left ovarian tumor seems unlikely. DNA fingerprinting analysis revealed a common change in restriction fragment length pattern in the DNA from all tumor localizations as compared with the patient's constitutional DNA. These results indicate that DNA flow cytometry can be helpful in discriminating intragenital metastatic disease from multiple primary tumors.     

以转移性卵巢癌为首发表现的胃癌25例临床分析

目的探讨胃癌伴卵巢转移（krukenberg瘤）的临床特点、诊断及治疗经验,以减少误诊。方法回顾性分析经手术和病理证实的25例胃癌伴卵巢转移患者的临床资料。结果25例患者年龄27～56岁,平均37．5岁,绝经前21例,占84．0％。首发的主要临床症状为腹胀、腹痛及下腹部包块。病理类型以印戒细胞癌为主,共14例,占56．0％。侵及双侧卵巢者15例,占60．0％。术前误诊为卵巢原发肿瘤者9例,占36．0％。la生存率为51．9％,2a生存率为21．3％。结论胃癌伴卵巢转移常以转移性卵巢癌为首发表现,好发于绝经前中青年妇女,易误诊,预后差;发现卵巢肿瘤的患者,应常规行胃肠道检查以排除转移瘤的可能。     

May increased CA125 in borderline ovarian tumor be indicative of a poor prognosis? A case report

We present a case of a 58-year-old menopausal woman referred to our hospital for the presence of large pelvic masses diagnosed by clinical examination and pelvic ultrasound. MRI examination showed voluminous bilateral capsulated multilocular ovarian cysts slightly hyperintense on T1-weighted images with thick septa and small papillary projections. CT scan confirmed the MRI findings. Among the ovarian tumor markers analyzed (CA125, HE4, and CA72.4), only Ca125 was slightly increased (48 U/ml). These data were suggestive of mucinous ovarian tumor. The patient underwent total hysterectomy with bilateral salpingo-oophorectomy, appendectomy, and multiple peritoneal biopsies. Pathological examination revealed bilateral borderline mucinous ovarian tumor with superficial atypical implants. Nine months later, the patient complained of left coxofemoral pain and underwent a PET/TC total body that suggested pubic bone metastases. Ovarian tumor markers were analyzed, and a second PET/TC was performed. CA125 was 252 U/ml, HE4 62 pM/L, and CA72.4?>?100 U/Ml. PET/TC was suggestive of peritoneal carcinosis. The patient was readmitted to the hospital. Clinical examination revealed small vaginal nodules. All nodules were excised. Microscopic analysis of all specimens revealed metastatic mucinous adenocarcinoma of intestinal type. The case shows that even a slight CA125 increase in the presence of a borderline ovarian tumor should not be overlooked since it can be indicative of a progressive disease. This case also highlights its additional diagnostic value when serum CA125 analysis is used in conjunction with MRI and CT imaging for the prognosis of mucinous borderline ovarian tumors (mBOTs).     

Krukenberg tumor in pregnancy. The lethal outcome

Krukenberg tumor refers to gastrointestinal cancer metastatic to the ovaries and its prognosis is uniformly poor. This case report concerns a 38-year-old pregnant woman suffering from abdominal pain and iterative vomiting episodes. She presented with a large abdominopelvic tumor. Because of suspected ovarian torsion, we performed urgent surgery. At laparotomy, bilateral ovarian tumors, ascites and gastric cancer located at the cardia and the lesser curvature invading the serosa were identified. We performed right ovariectomy, resection of the left ovary, and gastric biopsy. Histological examination of the specimen yielded diagnosis of Krukenberg tumor. Ten days later the patient underwent an elective Cesarean section in the 25th gestational week because of fetal asphyxia and very poor maternal life prognosis. We performed Cesarean delivery and extracted a vital female newborn of 31 cm, 600 g, Ap score 3, with virilization. Few days later the baby died at the intensive care unit. Two weeks later the mother died because of pulmonary failure.(Pathology Oncology Research Vol 12, No 2, 108–110)     

B16 melanoma metastasis to an "artificial organ" implant.

The mouse B16 melanoma metastasizes in two stages, first to the lungs and then from lung metastases to systemic organs. Despite widespread dissemination, visible metastases generally occur only in the brain, adrenals, kidneys, ovaries, pancreas, and mesentery. As a novel approach to investigate the basis of metastatic patterning in this system, the possibility was explored that an implantable "artificial organ" could serve as a site for the occurrence and experimental modulation of secondary-stage metastasis. Each implant consisted of a cellulose disc 4 mm in diameter, with a central 1-mm polymer pellet to effect local sustained release of angiogenic or growth factors in a s.c. environment. During the secondary spread of tumors initiated with the B16 melanoma clone G3.12 and with the more metastatic variant G3.12/BM2, metastatic involvement of implants containing angiogenic factors was mainly as invisible micrometastases demonstrable by bioassay; visible metastases were rare and were located in implant blood vessels. Metastasis occurred in about 30% (G3.12) and 50% (G3.12/BM2) of implants with vasculature induced by ethylene-vinyl acetate copolymer alone. Endothelial cell growth factor and heparin promoted greater vascularization but did not significantly alter metastatic involvement of implants. Release of tumor cell mitogenic activity from pellets containing a crude extract of mouse lungs increased the incidence of G3.12/BM2 metastasis in implants to over 70% and stimulated growth of visible metastases within the cellulose matrix. In contrast, liver extract inhibited metastasis growth. Colonization of implants following intracardiac injection of G3.12/BM2 cells was generally similar to metastasis, but visible colonies formed more readily and were less dependent on the influence of lung extract. These results indicate that metastasis and colonization can occur regularly in implants and that the relative favorability of the implant environment for secondary tumor growth can be altered by incorporation of tumor cell growth modulators.     

Collision Metastasis of Breast and Ovarian Adenocarcinoma in Axillary Lymph Nodes: A Case Report and Review of the Literature

Despite their accepted clinical and genetic association, the incidence of synchronous breast and ovarian carcinoma is rare. Moreover, collision metastasis from both breast and ovarian carcinomas to the same lymph node, to our knowledge has never been reported. Review of the literature revealed eleven cases of metastatic malignant tumors colliding in the same lymph node, none of which had both ovarian and breast carcinoma. Our case was that of a 63 year old woman presenting with a breast lump that was diagnosed as infiltrating ductal carcinoma after a needle biopsy. One month later the patient was found to have malignant ascites, omental carcinomatosis and an ovarian mass. Histology and immunohistochemistry revealed high grade serous papillary adenocarcinoma. When surgery was done to treat the breast tumor some of the axillary lymph nodes revealed metastases from the breast primary, others metastases from the ovarian primary and one had both tumors in a collision phenomenon. Immunohistochemistry was used to confirm this finding.     

Urinary cholesterol. VIII. Its excretion in women with ovarian neoplasms.

The urinary excretion of nonesterified cholesterol (NEC) has been investigated in 57 women with ovarian neoplasms and/or related nonneoplastic diseases. Twelve patients had benign tumors or lesions and 45 had malignant neoplasms of their ovaries. All patients with nonmalignant ovarian tumors or lesions had normal NEC excretion irrespective of the type of tumor or lesion or its degree of extension. In contrast, urinary NEC hyperexcretion occurred with the following frequencies in patients with active malignant ovarian neoplasms: 18 of 19 cystadenocarcinomas of the serous and/or mucinous types; one of one endometrioid carcinoma; four of four malignant granulosa cell tumors; two of two mixed malignant germ cell tumors; and one of one malignant mixed müllerian tumor. Single cases of clear cell carcinoma and of rhabdomyosarcoma had a normal NEC excretion. Urinary hyperexcretion of NEC was also found after surgery in two of seven surviving patients with apparently localized resectable disease according to their staging. It is possible that in these two patients NEC hyperexcretion was due to undetected foci of cancer (wrong staging), since neither omental and peritoneal biopsies, nor cytologic examination of peritoneal washings or free fluid were performed. A normal excretion of urinary NEC has been characteristic of 19 of 21 surviving patients treated by surgery and adjunctive therapy in whom we have performed follow-up NEC determinations. They were 16 of 18 cystadenocarcinomas malignant germ cell tumor. The 94% correlation between the presence of proven active ovarian carcinomas and urinary NEC hyperexcretion is significant. The clinical significance of this investigation is even greater when one considers that cystadenocarcinomas constitute more than 75% of all primary malignant ovarian tumors.     

Elevated Expression of Ferritin H-Chain mRNA in Metastatic Ovarian Tumor

To identify genes associated with tumor metastasis, we prepared 5 cDNA libraries using mRNA from normal ovaries, paired primary and metastatic ovarian tumors, as well as paired cultured ovarian tumor cells. By differential screening, we identified 12 clones, which can be divided into 3 classes based on hybridization to various probes. Class 1 clones showed no reaction with the normal probe, slight or no reaction with the primary probe, but high reaction with the metastatic probe. Class 2 clones showed some reaction with normal and primary probes, but showed stronger reaction with the metastatic probe. Class 3 clones showed strong hybridization to the normal probe, slight or no reaction with the primary probe, and did not hybridize with the metastatic clone. These clones were further analyzed by determination of DNA sequence. One of the class 1 clones (clone I) was identified as ferritin heavy chain. Northern blot analysis showed higher expression of ferritin H-chain in metastatic samples compared to primary tumor in 16/23 pairs of samples analyzed so far.     

A curious discourse of Krukenberg tumor: a case report

Krukenberg tumor is usually but not always a bilateral involvement of ovaries from metastatic deposit from adenocarcinoma of stomach and rarely from other gastrointestinal (GI) and non GI organs. The route of metastatsis of this rare condition is still not proven. It is still uncertain whether surgical resection of ovarian metastases and/or primary tumor could improve the outcome. We report even a rare presentation of this rare disease entity.     

Induction of matric metalloprotease-7 is common in mucinous ovarian tumors including early stage disease

Matrix metalloproteases are known to play an important role in tumor invasion by mediating degradation of the extracellular matrix. In this study, we have investigated the immunohistochemical expression of matrix metalloprotease-7 (MMP-7) in 44 mucinous ovarian tumors (9 adenomas, 13 low malignant potential tumors, 22 adenocarcinomas) and 6 normal ovaries. Positive staining of MMP-7 is observed in all mucinous ovarian tumors, whereas little or no staining was observed in surface epithelium as well as the epithelial cells of germinal inclusion cyst of the normal ovary. Positive immunostaining of MMP-7 is also observed in the secreted mucin in the tumor glands, which suggests the secretion of the MMP-7 protein from tumor cells. mRNA expression of MMP-7 was confirmed using RT-PCR. The MMP-7 gene was amplified in parallel with an internal control gene β-tubulin using a thermal cycler. mRNA expression levels of MMP-7 were significantly elevated in mucinous tumor samples compared with that in normal ovaries. Our results suggest that MMP-7 is frequently overexpressed in mucinous ovarian tumors and secreted with the mucin which is produced from the tumor cells. MMP-7 may therefore contribute to mucinous ovarian tumor development or enhanced growth capacity of mucinous ovarian tumors. MMP-7 may also serve as a target for therapeutic intervention in the down regulation of tumor progression.     

Pathology of ovarian carcinoma

Serous carcinoma is the most common type of ovarian cancer and usually is associated with peritoneal metastases and poor survival except for meticulously staged patients with tumors confined to the ovaries. Endometrioid and clear cell carcinomas account for most nonserous carcinomas and more often present with low-stage disease; survival for the various cell types is similar when stratified by stage. Borderline ovarian tumors can be subdivided into benign and malignant neoplasms, and in the view of some experts, this renders the borderline category obsolete. Women with typical serous borderline tumors (atypical proliferative serous tumors) constitute most of these patients and have virtually 100% survival, unless invasive peritoneal implants are present. Micropapillary serous carcinomas (a less common variant, also called serous borderline tumor with a micropapillary pattern) and tumors with invasive implants behave similar to low-grade invasive carcinomas.