Ka Yu Tse

Uterine smooth muscle tumors other than the ordinary leiomyomas and leiomyosarcomas: A review of selected variants with emphasis on recent advances and unusual morphology that may cause concern for malignancy

Uterine smooth muscle tumors are classified according to their morphologic features that include architecture, growth pattern, cellular characteristics and constituents of the intercellular stroma. While terminologies used for the pathologic diagnosis of various subtypes may be eloquent and histologically accurate, some of these are confusing for the clinician and may also be open to interpretation by different pathologists: the labeling of atypical leiomyomas epitomizes this intricate system. Clinically, it is probably more useful to classify them as either tumors with or tumors without recurrent and/or metastatic potential. The term “atypical leiomyoma” has been used to label tumors that have a low risk of recurrence and is synonymous with benign tumors. The latter are known variously as leiomyoma with bizarre nuclei, symplastic leiomyoma, or pleomorphic leiomyoma. Variants of benign uterine smooth muscle tumors, such as mitotically active leiomyoma, cellular and highly cellular leiomyoma, epithelioid leiomyoma, and myxoid leiomyoma each have distinctive hallmarks that enable subclassification. Nevertheless, they may occasionally possess one or more unusual features that are cause for alarm. Tumors that have a dissecting growth pattern, with or without extrauterine extension, may mimic malignancy both grossly and microscopically. The current review discusses the pathologic diagnosis of and terminology applied to selected variants of uterine smooth muscle tumors other than the ordinary leiomyomas and leiomyosarcomas with emphasis on unusual reported features that may indicate malignancy. This includes an update on uterine smooth muscle tumor of uncertain malignant potential (STUMP), intravenous leiomyomatosis, benign metastasizing leiomyoma, and diffuse leiomyomatosis. Their clinicopathologic features, differential diagnoses, and management options based on findings in the previously reported cases will also be reviewed.

Relationship between intravoxel incoherent motion diffusion‐weighted MRI and dynamic contrast‐enhanced MRI in tissue perfusion of cervical cancers

To investigate the relationship between intravoxel incoherent motion (IVIM) diffusion‐weighted magnetic resonance imaging (MRI) and dynamic contrast‐enhanced MRI (DCE‐MRI) in cervical cancer perfusion.

Staging of uterine sarcomas.

Uterine sarcomas comprise leiomyosarcoma, endometrial stromal sarcoma, adenosarcoma, undifferentiated endometrial sarcoma, and their variants. Carcinosarcoma is historically classified as sarcoma, but it is now regarded as a metaplastic carcinoma. Uterine sarcomas are rare, and are traditionally staged in the same way as endometrial carcinoma. Because of their different clinical and biological behaviours, the International Federation of Gynecology and Obstetrics introduced a new staging system in 2009 for leiomyosarcoma, endometrial stromal sarcoma and adenosarcoma, and carcinosarcoma, respectively. Following an extensive literature review no good evidence was found to support the modification of the staging system. This is mainly because of the rarity of the sarcomas and the heterogeneity of the reports, the different diagnostic criteria and treatments changing over the decades the retrospective nature and small sample size in most studies, and the lack of uniform pathological review even in large studies. Currently, evidence is still lacking about the use of preoperative imaging for staging purpose, and uterine sarcomas remain to be surgically staged. Total hysterectomy is the cornerstone for both staging and treatment. Newer evidence shows that routine lymphadenectomy and bilateral salpingo-oophorectomy may not be necessary, unless in the presence of extra-uterine spread, suspicious ovaries or lymph nodes, and certain poor histological types, such as undifferentiated endometrial sarcoma and adenosarcoma with sarcomatous overgrowth. More research and data collection are definitely needed in order to verify and further revise the current staging systems.

The role of regular physical examination in the detection of ovarian cancer recurrence

OBJECTIVE To evaluate how ovarian recurrences were first detected and the relative role of Ca 125, symptom enquiry and physical examination in recurrence detection. METHODS In this retrospective study, records from women with ovarian cancer recurrences diagnosed between 1999 and 2004 were reviewed to determine how the recurrences were first detected. Women were routinely followed up by a combination of symptom enquiry, physical examination and Ca 125. When recurrence was suspected, further investigations such as imaging and biopsy of the suspected recurrence would be arranged to confirm the diagnosis. The patients were followed up for a median of 53.5 months. RESULTS Eighty patients were identified to have ovarian cancer recurrences, with median time to recurrence of 12 months. Although 41 (51%) had abnormal physical findings, only three (3.8%) first presented with physical findings and none had positive physical findings alone. Ca 125 taken at the clinic visits in these 3 patients when the signs were detected turned out to be raised. For the remaining 77 patients, 49 (61%) and 28 (35%) first presented with raised Ca 125 level and symptoms respectively. The median survival from the time of recurrence for those first presented with Ca 125, symptoms and physical findings were 25 months, 17 months and 11 months respectively. CONCLUSION Routine physical examination had a very limited additional role and could be possibly omitted as part of the routine follow up strategy.

The use of vaginal antimicrobial after large loop excision of transformation zone: a prospective randomised trial

Objective To investigate whether the use of an antibacterial vaginal pessary containing tetracycline and amphotericin B would reduce complications from large loop excision of the transformation zone (LLETZ).

Epigenetic alteration of the metallothionein 1E gene in human endometrial carcinomas.

Aberrant expression of metallothioneins (MTs) has been observed in several human tumors. In our microarray analysis, MT-1E was found to have much lower expression in endometrial cancer cells as compared with other types of cancer cells generated from the cervix, ovary or prostate. The result was confirmed by quantitative RT-PCR analysis of the MT-1E levels in individual cancer cells. Treatment of endometrial cancer cells with 5-azacytidine could reactivate MT-1E expression. We further analyzed the DNA methylation status of the promoter region of MT-1E using methylation-sensitive restriction enzymes HhaI and HpaII, followed by PCR. Promoter hypermethylation was detected in 42.4% (53/125) of the endometrial carcinoma samples, whilst none of the 38 normal tissues or hyperplasia samples were methylated. The mRNA levels of MT-1E were significantly lower in the methylation-positive than in the methylation-negative samples. Endometrial carcinoma samples with low MT-1E expression coincidently had low levels of estrogen receptor-α expression and vice versa. This phenomenon was not observed in the expression pattern between estrogen receptor-β and MT-1E. There was no significant correlation between MT-1E methylation and any clinical parameters. In conclusion, a high frequency of cancer-specific hypermethylation of MT-1E was found in endometrial carcinomas. Its functional consequence in the development of endometrial cancer warrants further investigation.

Differentiation of aggressive and indolent subtypes of uterine sarcoma using maximum standardized uptake value

ObjectiveThe aim of the study was to elucidate the differential metabolic activities in aggressive and indolent subtypes of uterine sarcomas, which may aid in managing these heterogeneous tumours. MethodsWe retrospectively analysed the PET/computed tomography scans of consecutive patients (N=18) diagnosed with uterine sarcoma at our unit. The patients were divided into indolent (N=4) and aggressive (N=14) tumour groups, and the maximum standardized uptake values (SUVmax) of all lesions (n=134) were measured. The SUVmax of the lesions were compared between the two tumour groups using the Mann–Whitney U-test. We calculated the optimal cutoff value as determined by receiver operating characteristic analysis. A P-value less than 0.05 was considered statistically significant. ResultsThe mean SUVmax of aggressive (n=104) and indolent tumours (n=30) were significantly different (8.0±7.3 vs. 1.9±0.9 respectively; P<0.001). A cutoff of SUVmax greater than 4.0 was able to exclude indolent tumours, with 100% specificity and positive predictive value (sensitivity 72%, negative predictive value 50% and accuracy 78%; area under the curve 97%). By applying this same cutoff value on the most metabolic active lesion in each patient, we were able to correctly classify all but one patient into either the aggressive or indolent tumour group with 100% specificity and positive predictive value (sensitivity 93%, negative predictive value 80% and accuracy 94%). ConclusionAggressive and indolent uterine sarcoma subtypes have differential metabolic activities that can be used to classify them and this can aid in patient management for preoperative surgical planning and treatment stratification.

ReviewGestational trophoblastic disease

Gestational trophoblastic disease is a rare pregnancy-related disorder and its incidence is about 1 in 1000 livebirths in the West. It comprises of partial mole, complete mole, invasive and metastatic mole, choriocarcinoma, placental site trophoblastic tumour and epithelioid trophoblastic tumour. Novel immunohistochemical technologies have helped in the diagnosis of the disease and some of the genes may also serve as prognostic markers. Partial and complete moles can be treated by suction evacuation and most patients do not require further treatment. However, 10–20% of them may develop gestational trophoblastic neoplasia. The Gynecological Oncology Committee has adopted a staging system with incorporation of the modified World Health Organization scoring system. Low-risk disease is treated by single-agent chemotherapy while high-risk disease is treated by multi-agent chemotherapy. The overall cure rate is more than 90% and most patients can preserve fertility and anticipate normal pregnancy outcomes. Nevertheless, the disease can recur. Referral to a specialist centre is important to ensure proper monitoring and management.

The mitosis-specific marker phosphohistone-H3 (PHH3) is an independent prognosticator in uterine smooth muscle tumours: an outcome-based study

Accurate mitosis counting, which is important in the diagnosis of uterine smooth muscle tumours (USMTs), is often difficult and subjective. The mitosis‐specific immunohistochemical marker phosphohistone‐H3 (PHH3) has been shown to be diagnostically useful, but its expression, in relation to outcome, has not been thoroughly investigated. The aim of this study is to evaluate PHH3 as a diagnostic and prognostic marker in USMTs.

Cyclophosphamide, hydroxyurea, actinomycin D, methotrexate, and vincristine in the treatment of gestational trophoblastic neoplasia.

Objective The aim of this study was to evaluate the efficacy and toxicity profile of the cyclophosphamide, hydroxyurea, actinomycin D, methotrexate, and vincristine (CHAMOC) regimen in the treatment of high-risk gestational trophoblastic neoplasia (GTN). Methods We conducted a retrospective study of all patients with GTN treated with the CHAMOC regimen between 1985 and 2012 in a tertiary referral center in Hong Kong. Medical records were reviewed, and data were analyzed. Response rate and toxicity profile were assessed. Results The CHAMOC regimen was given to 79 patients from 1985 to 2012, with a total of 388 cycles administered. Among the 79 patients, CHAMOC was given to 68 as the primary treatment of high-risk GTN, whereas it was used as the salvage chemotherapy in 11 patients for failure with other chemotherapy regimens or recurrent disease. Complete remission was achieved in 58 patients (85.3%) in the primary treatment group and 8 patients (72.7%) in the salvage treatment group. Grade 3 and grade 4 neutropenia were observed in 13.0% and 3.4% of the chemotherapy cycles, respectively. Grade 3 or 4 thrombocytopenia was rare (1.3% of all treatment cycles). No secondary malignancy was observed in our patients with a mean duration of follow-up of 9.7 to 13 years, except 1 patient with advanced colon cancer diagnosed shortly after chemotherapy, which was unlikely to represent a secondary malignancy from the chemotherapy. Conclusions The CHAMOC regimen should be considered as an alternative to other chemotherapy regimens in the primary treatment of high-risk gestational trophoblastic disease, with comparable efficacy, similar short-term side-effects profile, and potentially fewer long-term complications.