Unilateral inguinofemoral lymphadenectomy in patients with early-stage vulvar squamous cell carcinoma and a unilateral metastatic sentinel lymph node is safe.

OBJECTIVE: Optimal management of the contralateral groin in patients with early-stage vulvar squamous cell carcinoma (VSCC) and a metastatic unilateral inguinal sentinel lymph node (SN) is unclear. We analyzed patients who participated in GROINSS-V I or II to determine whether treatment of the contralateral groin can safely be omitted in patients with a unilateral metastatic SN. METHODS: We selected the patients with a unilateral metastatic SN from the GROINSS-V I and II databases. We determined the incidence of contralateral additional non-SN metastases in patients with unilateral SN-metastasis who underwent bilateral inguinofemoral lymphadenectomy (IFL). In those who underwent only ipsilateral groin treatment or no further treatment, we determined the incidence of contralateral groin recurrences during follow-up. RESULTS: Of 1912 patients with early-stage VSCC, 366 had a unilateral metastatic SN. Subsequently, 244 had an IFL or no treatment of the contralateral groin. In seven patients (7/244; 2.9% [95% CI: 1.4%-5.8%]) disease was diagnosed in the contralateral groin: five had contralateral non-SN metastasis at IFL and two developed an isolated contralateral groin recurrence after no further treatment. Five of them had a primary tumor ≥30 mm. Bilateral radiotherapy was administered in 122 patients, of whom one (1/122; 0.8% [95% CI: 0.1%-4.5%]) had a contralateral groin recurrence. CONCLUSION: The risk of contralateral lymph node metastases in patients with early-stage VSCC and a unilateral metastatic SN is low. It appears safe to limit groin treatment to unilateral IFL or inguinofemoral radiotherapy in these cases.

Mainstream germline genetic testing for patients with epithelial ovarian cancer leads to higher testing rates and a reduction in genetics-related healthcare costs from a healthcare payer perspective.

OBJECTIVE: Germline genetic testing is increasingly offered to patients with epithelial ovarian cancer by non-genetic healthcare professionals, so called mainstream genetic testing. The aim of this study was to evaluate the effect of implementing a mainstream genetic testing pathway on the percentage of newly diagnosed patients with epithelial ovarian cancer to whom genetic testing was offered and the genetics-related healthcare costs. METHODS: The possible care pathways for genetic counseling and testing and their associated costs were mapped. Patient files from all newly diagnosed patients with epithelial ovarian cancer before (March 2016 - September 2017) and after (April 2018 - December 2019) implementing our mainstream genetic testing pathway were analyzed. Based on this analysis, the percentage of newly diagnosed patients to whom genetic testing was offered was assessed and genetics-related healthcare costs were calculated using a healthcare payer perspective based on a Diagnosis-Related Group financing approach. RESULTS: Within six months after diagnosis, genetic testing was offered to 56% of patients before and to 70% of patients after implementation of our mainstream genetic testing pathway (p = 0.005). Genetics-related healthcare costs decreased from €3.511,29 per patient before implementation to €2.418,41 per patient after implementation of our mainstream genetic testing pathway (31% reduction, p = 0.000). CONCLUSION: This study shows that mainstream genetic testing leads to a significantly higher proportion of newly diagnosed patients with epithelial ovarian cancer being offered germline genetic testing. In addition, it significantly reduces genetics-related healthcare costs per patient.

Effects of structured involvement of the primary care team versus standard care after a cancer diagnosis on patient satisfaction and healthcare use: the GRIP randomised controlled trial.

BACKGROUND: The growing number of cancer survivors and treatment possibilities call for more personalised and integrated cancer care. Primary care seems well positioned to support this. We aimed to assess the effects of structured follow-up of a primary care team after a cancer diagnosis. METHODS: We performed a multicentre randomised controlled trial enrolling patients curatively treated for breast, lung, colorectal, gynaecologic cancer or melanoma. In addition to usual cancer care in the control group, patients randomized to intervention were offered a "Time Out consultation" (TOC) with the general practitioner (GP) after diagnosis, and subsequent follow-up during and after treatment by a home care oncology nurse (HON). Primary outcomes were patient satisfaction with care (questionnaire: EORTC-INPATSAT-32) and healthcare utilisation. Intention-to-treat linear mixed regression analyses were used for satisfaction with care and other continuous outcome variables. The difference in healthcare utilisation for categorical data was calculated with a Pearson Chi-Square or a Fisher exact test and count data (none versus any) with a log-binomial regression. RESULTS: We included 154 patients (control n = 77, intervention n = 77) who were mostly female (75%), mainly diagnosed with breast cancer (51%), and had a mean age of 61 (SD ± 11.9) years. 81% of the intervention patients had a TOC and 68% had HON contact. Satisfaction with care was high (8 out of 10) in both study groups. At 3 months after treatment, GP satisfaction was significantly lower in the intervention group on 3 of 6 subscales, i.e., quality (- 14.2 (95%CI -27.0;-1.3)), availability (- 15,9 (- 29.1;-2.6)) and information provision (- 15.2 (- 29.1;-1.4)). Patients in the intervention group visited the GP practice and the emergency department more often ((RR 1.3 (1.0;1.7) and 1.70 (1.0;2.8)), respectively). CONCLUSIONS: In conclusion, the GRIP intervention, which was designed to involve the primary care team during and after cancer treatment, increased the number of primary healthcare contacts. However, it did not improve patient satisfaction with care and it increased emergency department visits. As the high uptake of the intervention suggests a need of patients, future research should focus on optimizing the design and implementation of the intervention. TRIAL REGISTRATION: GRIP is retrospectively (21/06/2016) registered in the 'Netherlands Trial Register' (NTR5909).

Age, pathology and CA-125 are prognostic factors for survival in patients with brain metastases from gynaecological tumours.

BACKGROUND AND PURPOSE: Brain metastases originating from gynaecological tumours are a rare phenomenon, but have an increasing incidence due to better targeted therapies. This study aimed to identify factors that predict survival in these patients, which can be used in creating a robust prognostic tool for shared decision making. MATERIALS AND METHODS: We identified a consecutive cohort of 73 patients treated for gynaecological brain metastases in two tertiary institutions. Baseline demographics, pathology and serum CA-125 were included in a multivariable Cox proportional hazards model. RESULTS: Median overall survival in our cohort was 14.4 months, with a one-year survival of 56.4% and a two-year survival of 39.1%. Thirty-eight patients (52.1%) had ovarian carcinoma as the primary malignancy. The following factors were significantly associated with survival: age (HR 1.05 per year), CA-125 (HR 1.02 par 50 U/ml), and uterine and vulvar primary tumours (when compared to ovarian carcinoma, with HRs 3.07 and 8.70). A post-hoc analysis with primary tumour site reclassified into ovary versus non-ovary showed a HR of 0.50 for ovarian primary tumour type. CONCLUSION: We have found that age, pathology and CA-125 are prognostic factors for survival in patients with brain metastases from gynaecological tumours. Our findings may provide a foundation for future development of prediction models, for the benefit of both patients and physicians.

Sentinel nodes in vulvar cancer: Long-term follow-up of the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V) I.

OBJECTIVE: In 2008 GROINSS-V-I, the largest validation trial on the sentinel node (SN) procedure in vulvar cancer, showed that application of the SN-procedure in patients with early-stage vulvar cancer is safe. The current study aimed to evaluate long-term follow-up of these patients regarding recurrences and survival. METHODS: From 2000 until 2006 GROINSS-V-I included 377 patients with unifocal squamous cell carcinoma of the vulva (T1, <4 cm), who underwent the SN-procedure. Only in case of SN metastases an inguinofemoral lymphadenectomy was performed. For the present study follow-up was completed until March 2015. RESULTS: Themedian follow-up was 105 months (range 0­179). The overall local recurrence ratewas 27.2% at 5 years and 39.5% at 10 years after primary treatment, while for SN-negative patients 24.6% and 36.4%, and for SN-positive patients 33.2% and 46.4% respectively (p = 0.03). In 39/253 SN-negative patients (15.4%) an inguinofemoral lymphadenectomy was performed, because of a local recurrence. Isolated groin recurrence rate was 2.5% for SN-negative patients and 8.0% for SN-positive patients at 5 years. Disease-specific 10-year survival was 91% for SN-negative patients compared to 65% for SN-positive patients (p b .0001). For all patients, 10-year disease-specific survival decreased from 90% for patients without to 69% for patients with a local recurrence (p b .0001).

Lymph node detection by MRI before and after a systematic pelvic lymphadenectomy.

OBJECTIVE: Pelvic lymphadenectomy is considered the gold standard to diagnose and possibly treat lymphatic metastases in gynaecological cancer patients. The aim of this study is to evaluate whether all presurgical MRI detected lymph nodes were removed during the systematic pelvic lymph node dissection (PLND) in cervical cancer patients. METHODS: 21 consecutive cervical cancer patients who were scheduled to undergo a PLND were evaluated by a MRI scan prior to surgery and 6 weeks afterwards. All patients had tumour metastasis negative lymph nodes at histopathological examination. RESULTS: On average, 10 pelvic lymph nodes (range 5-17) per patient were detected by presurgical MRI. Postsurgical MRI scans showed that on average 1 (range 0-3) pelvic node per patient was not removed by surgery. In total, 14% of the presurgical MR detected nodes were not removed by surgery (31/225). Approximately half of all lymph nodes that remained after surgery were located in the obturator region. In spite of the remaining nodes, surgery and histopathological examination did detect more nodes than MRI: on average 21 lymph nodes per patient (range 9-59) were removed. Another 2 lymph nodes (range 0-6 per patient) were judged to be newly developed after surgery. CONCLUSION: Although surgery was able to remove many more lymph nodes than those detected by presurgical MRI, 14% of presurgical MRI detected lymph nodes were not removed by PLND. The value of MRI prior to surgery for the detection of pathological lymph nodes is a subject of further research.

Superior performance of liquid-based versus conventional cytology in a population-based cervical cancer screening program.

OBJECTIVE: Liquid-based cytology may offer improvements over conventional cytology for cervical cancer screening. The two cytology techniques were compared in a group of 86,469 women who participated in a population-based screening program. Using a nation-wide pathology database containing both cervical cytology and histology records for all patients, we compared the outcome of the two screenings methods with regard to the detection rate of histological proven abnormalities and the determination of the true false-negative rates for both methods. METHODS: Two cohorts of women living in the same geographical region were used. Cohort 1 (n=51,154 women) was analysed using conventional cytology (conventional cohort) and cohort 2 (liquid cohort) (n=35,315 women) was analysed using liquid-based cytology (SurePath). The samples were processed in one laboratory. The results of histological follow up were available via a central database. RESULTS: The rate of unsatisfactory slides was significantly lower using liquid-based cytology (0.13% vs. 0.89%, p<0.0001). Detection of ASCUS+ (Atypical squamous cells of unknown significance or higher abnormalities) was significantly higher using liquid-based cytology (2.97% vs. 1.64%, p<0.0001), mainly due to the increase in the ASCUS category. The percentage of histological abnormalities within the ASCUS samples was approximately equal in both cohorts, indicating that more true abnormal cases were detected using liquid-based cytology. The sensitivity for detection of a histological proven lesion is significantly higher in the liquid cohort compared to the conventional cohort (96.2% vs. 92.0%), with only a slight difference in specificity (97.8% vs. 98.2%). CONCLUSION: This population study confirmed previous institution-based reports of decreased numbers of unsatisfactory samples based on liquid-based cytology and showed an increased sensitivity for the detection of cytological abnormalities that was validated by subsequent histological investigation.

A leg ulcer as manifestation of metastatic squamous cell vaginal carcinoma.

Cutaneous metastasis of vaginal carcinoma is extremely rare. So far, the total number of reported skin metastasis of vaginal carcinoma is only one. We present another case with an unusual manifestation of vagina carcinoma metastasis: skin metastasis presenting as a leg ulcer on the lower leg.

The limited difference between keratin patterns of squamous cell carcinomas and adenocarcinomas is explicable by both cell lineage and state of differentiation of tumour cells.

AIM: To study the differentiation of epithelial tissues within their histological context, and to identify hypothetically, on the basis of keratin pattern, the putative tissue origin of a (metastatic) carcinoma. METHODS: Using well characterised monoclonal antibodies against individual keratins 7, 8, 18, and 19, which are predominantly found in columnar epithelia, and keratins 4, 10, 13, and 14, predominantly expressed in (non)-keratinising squamous epithelia, the keratin patterns for a series of 45 squamous cell carcinomas and 44 adenocarcinomas originating from various epithelial tissues were characterised. RESULTS: The predominant keratins in all adenocarcinomas proved to be 8, 18, and 19. In addition, these keratins were also abundantly present in squamous cell carcinomas of the lung, cervix, and rectum and, to a lesser extent, of the larynx, oesophagus, and tongue, but not in those of the vulva and skin. Keratins 4, 10, 13, and 14 were present in almost all squamous cell carcinomas, but also focally in some of the adenocarcinomas studied. CONCLUSIONS: There is a limited differential expression of distinctive keratin filaments between squamous cell carcinomas and adenocarcinomas. Apparently, squamous cell carcinomas that originate from columnar epithelium by squamous metaplasia gain the keratins of squamous cells but retain the keratins of columnar epithelial cells. However, the simultaneous expression of two of three squamous keratins (4, 10, and 13) identifies a squamous cell carcinoma, and thus might be useful in solving differential diagnostic problems.

Immunostaining of chain-specific keratins on formalin-fixed, paraffin-embedded tissues: a comparison of various antigen retrieval systems using microwave heating and proteolytic pre-treatments.

The use of chain-specific monoclonal antibodies (MAbs) against keratins in pathology is hampered by their limited staining on formalin-fixed, paraffin-embedded tissue. In the present study, various treatments before immunohistochemistry on paraffin sections were compared, including proteolytic enzymes and microwave antigen retrieval in various solutions. Sections of normal cervical and skin tissue were stained in a three-step immunoperoxidase method, employing a broad panel of MAbs against chain-specific keratins 4, 5, 7, 8, 10, 13, 14, 17, 18, 19 and pankeratin. Using microwave heating, Target Unmasking Fluid (TUF), Antigen Retrieval Solution (ARS), a simple detergent solution (DET), PBS, and distilled water (MiQ) were compared. Microwave heating in PBS or MiQ strongly improved staining results. Moreover, microwave pre-treatment in TUF or DET gave excellent and specific staining with the majority of MAbs tested, comparable with or even better than staining obtained on frozen sections. Using microwave antigen retrieval, tissue morphology remained optimal, and only in a very limited number of MAbs did immunoreactivity on paraffin sections fail to be restored. Proteolytic pre-treatment with trypsin, pepsin, or pronase gave moderate to strong staining with some of the MAbs. Other MAbs, for which microwave pre-treatment was able to restore the loss of immunoreactivity, failed to give appropriate staining with proteolytic pre-treatment. Our results show that microwave heating in either TUF or a simple detergent solution before immunohistochemistry is a reliable method for antigen retrieval of chain-specific keratins in formalin-fixed, paraffin-embedded tissues.

Antigen size influences the type of glomerular pathology in chronic serum sickness.

Chronic serum sickness was induced in four groups of Wistar rats by immunization with BSA, cationized BSA (cBSA), human IgG (HuIgG), or human IgM (HuIgM), followed by repeated intraperitoneal (i.p.) injection of the antigen used, to study the effect of the characteristics of an antigen on renal immunopathology. Renal tissue sampled 2, 4, 7, and 9 weeks after the start of the i.p. injections was examined by light-, immunofluorescence-, and electron-microscopy. Proteinuria was measured in urine collected over 24 h. All animals given BSA, cBSA, or HuIgG developed progressive renal disease characterized by initial deposition of antigen and rat Ig in the mesangium of rats given BSA or HuIgG, and minimal amounts in those given cBSA, followed by the appearance in the first instance of subendothelial deposits in the animals receiving BSA or HuIgG, and later subepithelial deposits in those given BSA, cBSA, or HuIgG. The appearance of immunoglobulin deposits along the glomerular capillary wall was associated with the onset of massive proteinuria reaching average levels of 450 mg/24 h for rats given BSA or cBSA, and 500 mg/24 h for those given HuIgG. Animals injected with HuIgM showed only mesangial deposits of human IgM and rat Ig without the development of proteinuria. Under light-microscopy, rats given BSA, cBSA, or HuIgM showed minimal abnormalities, whereas those receiving HuIgG showed transient but severe influx of granulocytes in glomeruli with the development of diffuse proliferative glomerulonephritis in association with a long-lasting phase characterized by subendothelially localized immune aggregates.(ABSTRACT TRUNCATED AT 250 WORDS)