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Increasingly radical surgery combined with neo-adjuvant radiotherapy present a challenge for the reconstructive surgeon. The study objective was to review outcomes of Vertical Rectus Abdominis Myocutaneous (VRAM) flap-based perineal reconstruction following resectional surgery for pelvic malignancies. Single-centre retrospective analysis of patients undergoing immediate VRAM flap reconstruction of a perineal/pelvic defect for pelvic malignancy between July 2009 and November 2017. Primary outcome was perineal morbidity (surgical site infection (SSI), flap loss or dehiscence and perineal hernia). Secondary outcomes were length of stay and donor site morbidity (SSI, full-thickness dehiscence and incisional hernia). A total of 178 patients (96 females) were included. Median age was 67 years (range 28–88). The majority were performed for locally advanced rectal adenocarcinoma (n = 122; 68.5%) and 136 (76.4%) patients had received neoadjuvant radiotherapy. Four patients had complete flap loss (2.3%), and 40 had perineal dehiscence (22.5%); however, only, 18 patients required a return to theatre during the admission for perineal-related complications (10.1%). Abdominal dehiscence occurred in six patients (3.4%). Median length of post-operative stay was 15 days (6–131). Sixty-day mortality rate was 1.1%. SSI at the midline and perineum occurred in 34 (19.1%) and 38 patients (21.3%), respectively. At 90-day post-operatively, 75.6% of perineal wounds were healed. During a median follow-up of 44.5 months, twelve, eleven and 39 patients were diagnosed with perineal, midline and parastomal hernias, respectively (6.9%, 6.2% and 21.9%). It is important to have accurate knowledge of perineal and donor-site morbidity rates to allow an informed consent process.

Summary Background The vertical rectus abdominis myocutaneous (VRAM) flap is an established technique employed to reconstruct pelvic and perineal defects not amenable to primary closure. The aim of this study was to systematically review the morbidity of VRAM flap reconstruction following exenterative pelvic surgery. Materials and methods A systematic literature search was conducted by using Medline, EMBASE, and Cochrane databases. Abstracts of all studies published from inception to November 2019 were identified. Search terms used included ‘vertical rectus abdominis myocutaneous’, ‘vertical rectus abdominis musculocutaneous’ and ‘VRAM’. Only studies that described outcomes when a VRAM flap was used during exenterative pelvic surgery were included; case reports were excluded. The primary outcome measure was VRAM flap morbidity. Secondary outcome measures included donor site morbidity and hospital length of stay. Results Sixty-five studies with a total of 1827 patients were identified and included. Perineal reconstruction was most commonly performed following abdominal perineal excision of the rectum (APER) (n = 636 and 34.8%). Median patient age at surgery ranged from 38 to 78 years. Mean perineal flap morbidity was 27%, with a complete flap loss rate of 1.8% and a perineal hernia rate of 0.2%. Mean donor site morbidity was 15%, with an abdominal dehiscence rate of 5.5% and an incisional hernia rate of 3.3%. Conclusions While overall morbidity after VRAM flap reconstruction in pelvic visceral surgery is high; the risk of major complications remains low. These data are important when counselling patients for surgery.

Secretory carcinoma (SC) is an uncommon salivary gland neoplasm of the oral cavity that microscopically may mimic acinic cell carcinoma (ACC) and mucoepidermoid carcinoma (MEC). This study describes a series of SC in minor glands with a literature review. We performed a retrospective search for oral SC, within the archives of the University of Florida, Oral Pathology and Surgical Pathology Biopsy services from 2010 to 2018. A total of 10 SCs were identified in the oral and maxillofacial region, four of which were in the minor salivary glands. The demographic, clinical, histological, and molecular findings were aggregated for all 4 cases. Patient age varied from 30 to 60 years, with an average of 45 years. Two cases each were in female and male patients. Two cases presented on the labial mucosa, and one each on the hard and soft palate. Immunohistochemical (IHC) staining showed mammaglobin positivity in all cases, GATA3 positivity in two cases, S100 positivity in three cases, and SOX10 positivity in only one case. Fluorescence in situ hybridization demonstrated positivity for ETV6-NTRK3 fusion in 4 cases. Although oral SC is rare, pathologists should be aware of the histologic overlap between the SC and other salivary gland neoplasms such as ACC and MEC. A judicious application of IHC staining would aid in diagnosis. SC should be considered in the differential diagnosis for intraoral salivary gland tumors.

Calciphylaxis is a rare systemic condition usually seen in patients with end-stage renal disease. It is characterised by pathological calcification of dermal blood vessels, causing ischaemia and necrosis in the skin and subcutaneous fat. The lesions are usually small but, in extreme cases, may be very extensive and may mimic necrotising fasciitis, prompting extensive surgical debridement. We describe the challenges faced in managing such a case. A 38-year-old female patient was admitted to another hospital with widespread progressive truncal skin necrosis. A provisional diagnosis of necrotising fasciitis was made, and she underwent debridement of 32% of her total body surface area (TBSA). However, her condition rapidly deteriorated and she was transferred to our burn centre for further management. Diagnosis of calciphylaxis was based on clinical features and confirmed by tissue biopsy. Characteristic findings of progressive skin and fat necrosis at the wound margins with healthy underlying fascia and muscle were recognised from previously treated cases of calciphylaxis; however, the absence of renal disease proved misleading. Non-uraemic calciphylaxis is very rare but can, as in this case, be associated with alcoholic liver disease. At our centre, the patient required prolonged ventilation and supportive treatment in burns critical care, combined with intensive wound management, repeated episodes of debridement, temporary wound cover using human skin allografts and reconstruction using split-thickness autograft. We report this case to alert others to this rare condition as a possible diagnosis in patients presenting with extensive panniculitis. We discuss associations, diagnostic difficulties, novel therapies and the importance of multidisciplinary care in managing these complex cases. Level of evidence: Level V, diagnostic study.

There is controversy about the prognosis of Hurthle cell carcinoma of the thyroid. The purpose of this project is to report the outcome of a well-defined group of patients treated at a single institution in the modern era.Sixteen patients met the following inclusion criteria: Treatment with curative intent at our institution between January 1, 1997, and December 31, 2010. Primary treatment with total thyroidectomy with or without neck dissection. Age18 years at the time of thyroidectomy. Confirmation by a pathologist of the diagnosis of a primary Hurthle cell carcinoma of the thyroid based on ≥75% Hurthle cells with extension through the tumor capsule. No areas of poorly differentiated (insular) or undifferentiated (anaplastic) carcinoma. Stage T1-3, NX-1b, M0. All patients received radioiodine immediately after thyroidectomy (remnant ablation, n=14) or as adjuvant for a recurrence (n=2). External-beam radiotherapy to the neck as adjuvant therapy after thyroidectomy was used in 2 patients and after resection of a neck recurrence in 1 patient.Five-year actuarial rates with a median 6 years of follow up on surviving patients were as follows:Overall and cancer-specific survival: 92% (1 death from Hurthle cell carcinoma). Relapse-free survival (no visible tumor and unstimulated thyroglobulin ≤1.0): 65%.Our experience suggests that the outcome of Hurthle cell carcinoma of the thyroid is favorable in adults with stage T1-3 NX-1b M0 disease who are managed with total thyroidectomy, radioiodine, and-in selected cases-external-beam radiotherapy. We do not have the ability to compare our results to other management strategies.

Patient: Male, 72-year-old Final Diagnosis: Sarcomatoid carcinoma arising from inverted papilloma Symptoms: Nasal mass • nasal obstruction Medication: — Clinical Procedure: Excsion Specialty: Pathology Objective: Challenging differential diagnosis Background: Carcinosarcoma of the sinonasal tract is an extremely rare malignant neoplasm; it is often designated as carcinoma with spindle cell or sarcomatoid features. We report a case of carcinosarcoma arising in a pre-existing inverted Schneiderian papilloma in the left maxillary antrum and nasal cavity of a 72-year old male patient. Case Report: The patient had a significant history of radiotherapy for squamous cell carcinoma in the sinonasal area, 3 decades ago. The patient presented with chief complaints of left nasal blockage, nasal discharge, anosmia, and occasional epistaxis. Computed tomography scan displayed a lobular soft tissue mass resulting in narrowing of the nasopharyngeal airway with massive destruction of palatal tissue. The lesion was resected via endoscopic surgery. Macroscopically, a white fleshy appearance with necrosis was noted in the submitted specimen. Microscopically, the tumor was composed of pleomorphic epithelial and spindle cells with numerous mitoses and remarkable tissue necrosis. Residual inverted papilloma (IP) with high-grade dysplasia, and minimal foci of moderately differentiated squamous cell carcinoma (SCC) component was present at the tumor margin. A distinct zone of transition of SCC to spindle cell carcinoma (SpSCC) was noted and confirmed by focal positivity of p63 in epithelial and sacromatoid components. The pleomorphic sarcomatoid tumor was positive for vimentin with Ki67 highlighting 70% of tumor cells. A final diagnosis of sinonasal spindle cell carcinoma associated with residual inverted papilloma was rendered. Conclusions: Due to the rarity of such cases, the prognosis and response to treatment is unclear. No effective directed treatment has been developed. Unfortunately, the patient refused any further treatment and died of persistent disease. To the best of our knowledge, only one case of sinonasal carcinosarcoma arising from dysplastic inverted papilloma has been reported. The distinct possibility of previous radiotherapy contributing to development of sarcomatoid features in this neoplasm should also be considered.

Merkel cell carcinoma (MCC) is an uncommon but highly malignant neuroendocrine tumor of the skin. Merkel cell carcinoma can metastasize, but involvement of the central nervous system is rare. Here we report a case of rapidly progressing metastatic MCC to the clivus and bilateral cavernous sinus in an immunocompromised patient. This case is unique in that it is the first case report showing MCC metastasis to the clivus from a distal site. It also demonstrates that a MCC metastasis can masquerade with symptoms of Tolosa-Hunt syndrome. A literature review on MCC with CNS metastasis is presented.

Carcinosarcoma or carcinoma with spindle cell/sarcomatoid features of the nasal cavity and paranasal sinuses is an exceedingly rare malignancy. We report a case of carcinosarcoma with synchronous inverted papilloma developing in the left nasal cavity and maxillary sinus, in a 72-year-old male with a history of radiation therapy for sinonasal squamous cell carcinoma, 30 years ago. The patient's chief complaint was left nasal obstruction. He also reported purulent nasal drainage, impaired sense of smell and occasional epistaxis. CT imaging showed lobular growth of soft tissue narrowing nasopharyngeal airway with extensive palatal erosion. Endoscopic sinonasal surgery was performed to remove the sinonasal mass. Grossly, the tumor had a white fleshy appearance with tumor necrosis. Microscopically, the tumor was composed of pleomorphic epithelial and spindle cells with frequent mitoses and tumor necrosis. Residual inverted papilloma (IP) with high-grade dysplasia, and foci of keratinizing squamous cell carcinoma (SCC) component (2%) was present at the edge of the main tumor. A transition of SCC to spindle cell carcinoma was present confirmed by focal p63 positivity in both components. The pleomorphic sarcomatoid tumor was positive for vimentin and negative for P40, CK5/6, AE1/AE3, p16, S-100, CD34, CD31, ERG1, SMA, desmin, Sox10, and myogenin with Ki67 highlighting 70% of tumor cells. A final diagnosis of sinonasal sarcomatoid carcinoma associated with residual transformation from IP to SCC was rendered. Due to rarity of such a case, the prognosis and response of treatment is uncertain. So far, no effective targeted therapy has been reported. The patient is currently being treated with aggressive chemotherapy. To the best of our knowledge, this is only the second case of sinonasal carcinosarcoma arising from inverted papilloma with high-grade dysplasia and transition to sarcomaitoid SCC. Perhaps the previous radiation therapy played a role in the development of the sarcomatoid variant of SCC.

Bovio I M, Al-Quran S Z, Rosser C J, Algood C B, Drew P A & Allan R W (2010) Histopathology 56, 951–956 Smoothelin immunohistochemistry is a useful adjunct for assessing muscularis propria invasion in bladder carcinoma Aims: To prospectively evaluate the utility of smoothelin immunohistochemical expression for the evaluation of muscularis propria (MP) in diagnostic transurethral resection of bladder tumour (TURBT) specimens and cystectomies. Methods and results: Smoothelin immunohistochemistry was performed on a total of 26 TURBT and cystectomy specimens. All but two cases (24/26) demonstrated strong (3+) or moderate (2+) immunoreactivity of the MP with smoothelin. Muscularis mucosae (MM) never displayed strong (3+) reactivity, and in only one case did the MM have moderate (2+) reactivity; in this case the MP had strong (3+) reactivity. MM intensity mirrored the intensity of reactivity of blood vessels in all cases (26/26). Using moderate or strong immunoreactivity as a cut-off, smoothelin had a sensitivity of 92% for detecting MP and a specificity of 97% for distinguishing between MP and MM. In all unequivocal MP-invasive and lamina proporia-invasive cases by haematoxylin and eosin (H&E), smoothelin immunohistochemistry confirmed the original light microscopic diagnosis. In four cases in which there was equivocal MP involvement by H&E, smoothelin helped establish MP invasion. Conclusions: Smoothelin immunohistochemistry has diagnostic utility in the evaluation of MP invasion in urothelial carcinoma. Smoothelin could be used as an adjunct to traditional H&E-stained light microscopy and may help reduce the number of equivocal diagnoses.

OBJECTIVES We set out to examine our use of the squamous intraepithelial lesion (SIL) category, compare our SIL rate to rates reported by others, and determine the corre-lation between SIL and histologically proven cervical intraepithelial neoplasia (CIN) in our population. MATERIALS AND METHODS Reports from all Papanicolaou smears and associated histological specimens interpreted by the University of Florida Department of Pathology between 1992 and 1996 were reviewed. RESULTS Of 39,484 Papanicolaou smears, 2,101 (5.3%) were classified as low-grade squamous intraepithelial lesion (LGSIL) and 1,366 (3.5%) were classified as high-grade (HGSIL). Of the LGSIL cases, 972 (46.3%) underwent timely biopsy: Findings were benign in 29.9%; 41.7% had CIN1,20.9% had CIN2, and 7.5% had CIN3. Of the HGSIL cases, 932 (68.2%) underwent timely biopsy: Findings were benign in 12.3%; 17.1% had CIN1, 26.7% had CIN2, 42.2% had CIN3, and 1.6% showed squamous cell carcinoma. Condusions. Our LGSIL rate is similar to reported rates, but our HGSIL rate of 3.5% is higher. We found good correlation between SIL on Papanicolaou smear and CIN on biopsy (70.1% for LGSIL and 86% for HGSIL).

Hemangioblastoma primarily occurs in the CNS, most commonly in the posterior fossa. Extracranial locations are less common, and metastatic tumor involving the lung is exceedingly rare with only three cases previously reported. Two were autopsy studies in patients who died of complications of the CNS hemangioblastomas in 1943 and 1981, and the third was mentioned in a case report addendum providing follow-up information on hepatic hemangioblastoma in 1991. We report a case of a 48-year-old man who presented with multiple lung nodules treated by surgical excision. Pathological study revealed features classic for hemangioblastoma. The patient had a remote history of hemangioblastomas having been excised from the posterior fossa 7 and 20 years previously. This report details a fourth case of metastatic pulmonary hemangioblastoma. It is the first report on surgically resected hemangioblastomas from the lung of a living patient with histological and immunohistochemical characterization.

Purpose: Androgen deprivation therapy with analogues of luteinizing hormone-releasing hormone produces distinctive histological changes in neoplastic and nonneoplastic prostate tissue. Others have described these features in cases in which treatment status was known. To our knowledge the specificity and sensitivity of luteinizing hormone-releasing hormone effects based only on histology and possible reasons for interobserver variation have not been addressed previously.Materials and Methods: Slides from 97 prostatectomies performed in a 3-year period were reviewed by 2 observers blinded to knowledge of previous hormonal treatment. The observers evaluated each case, recording the presence or absence of 14 features associated with androgen deprivation therapy, and then made an overall assessment regarding treatment status.Results: Of the 97 patients 31 had received androgen deprivation therapy with the luteinizing hormone-releasing hormone agonist leuprolide. A luteinizing hormone-releasing hormone ...

Clear cell adenocarcinoma of the lower urinary tract is a rare neoplasm whose histogenesis has not been thoroughly investigated. We have examined six specimens of clear cell adenocarcinomas collected from three institutions using histological, histochemical, and immunohistochemical techniques. Results indicate that almost all clear cell adenocarcinomas of this region express morphological and antigenic features, suggesting müllerian differentiation, and that müllerian differentiation is not a feature of either nonclear cell adenocarcinomas or normal female paraurethral glands. Including the authors' six specimens, 46 specimens have been reported in the available English literature. The accumulated experience confirms the initial impression that these tumors develop predominantly in the urethras of women and occur over a wide age range. Despite high stage at diagnosis, most patients have been alive with no evidence of disease when reported, a prognosis that seems to apply regardless of length of follow-up.

Background. Leuprolide, an agonist of luteinizing hormone-releasing hormone (LH-RH), and flutamide, an antiandrogen, increasingly are being used in the treatment of clinically localized prostate cancer. Only two small series (of 23 and 12 patients) have been published on the distinctive pathologic changes induced in the prostate by androgen deprivation therapy with discrepancies on the presence of squamous metaplasia, necrosis, and possible tumor destruction by combined androgen deprivation therapy. Methods. One hundred and thirteen radical prostatectomy specimens obtained after at least 3 months of leuprolide-flutamide androgen inhibition therapy and 60 nonhormonally treated prostates in randomly selected clinical Stage T2 prostate adenocarcinoma patients were entirely sectioned. Distinctive histologic findings were tabulated and their statistical value determined. Results. Resection margins of excision were involved by tumor in 43% of untreated and in 19% of androgen-deprived patients. Characteristic changes in androgen-inhibited nontumor glands included atrophy, basal cell prominence, vacuolated luminal cell layer, and squamous and transitional cell metaplasia. Prostatic intraepithelial neoplasia (PIN) was observed in 35% of treated patients. The presence of small tumor glands separated by stroma was the most frequently noted effect of androgen deprivation on prostate adenocarcinoma; pyknosis and branching empty spaces were less frequent. Large clear tumor cells within an inflammatory response was a third histologic pattern. Apparently unaltered tumor areas were observed in 43% of prostates exposed to androgen deprivation therapy. Conclusions. Androgen deprivation therapy result in histologically distinctive changes that can be recognized in both nonneoplastic and neoplastic prostate tissue. Residual tumor was present in all 113 treated radical prostatectomy specimens. In addition to glandular shrinkage, therapy was associated with statistically significant reductions in the frequency of high grade PIN and extension of cancer to prostate specimen margins of excisions. Cancer 1995;75:1634-41.

The proliferative activity of invasive squamous cell carcinoma of the vulva was examined using a Ki-67 equivalent monoclonal antibody (MIB1), which gives a strong immunoreaction in paraffin-embedded tissue. Quantitation of Ki-67 immunostaining was accomplished by image analysis. Ki-67 immunostaining revealed two general patterns of reactivity in vulvar tumors: (a) a diffuse distribution of Ki-67 positive nuclei within the tumor mass and (b) a localized distribution of Ki-67 positive nuclei staining predominantly basilar components of tumor aggregates. The distribution of localized and diffuse patterns did not differ significantly between various clinicopathologic categories (age, histologic type and grade, FIGO stage, and lymph node status). However, the survival times for patients with a diffuse Ki-67 labelling pattern tended to be shorter than those for patients with a localized pattern. Survival curves based on the median positive nuclear area (PNA) calculated by image analysis did not differ significantly. Thus, the pattern of Ki-67 immunostaining, rather than the percentage of PNA, may have prognostic significance in vulvar squamous cell carcinoma.

Paragangliomas, also known as extra‐adrenal pheochromocytomas, arise from chromaffin cells within the autonomonic ganglia. Catecholamine secreting paragangliomas have been described in the mediastinum, but rarely invade the heart. This case describes the use of a novel bioabsorbable matrix that was used to replace a tumor invading the posterior left atrium. Copyright © 2009 Wiley Periodicals, Inc.

Objectives The accuracy and diagnostic benefits of the labial salivary gland (LSG) biopsy for Sjogren's syndrome (SS) have received mixed reviews. This study was conducted to assess (1) the inter-rater agreement among 5 pathologists, and (2) the relationship between biopsy findings and clinical disease parameters. Study design Three oral pathologists (OP) and two surgical pathologists (SP) provided independent diagnoses, focus scores, and plasma cell characterizations for 37 LSG biopsies. Inter-rater reliability was assessed using percentage of overall agreement and intraclass correlation coefficients. Relationships between diagnoses and clinical parameters were assessed by nonparametric correlations. Results Overall agreement among the pathologists was poor, although the intra-specialty agreement was good. The ratings of OP were most highly correlated with serological measures, while those of SP were correlated with salivary flow rate and disease damage. Conclusion Since the LSG biopsy can be the determining factor in SS diagnoses, these demonstrated inconsistencies merit further consideration.

Pulmonary cryptococcosis was diagnosed by examining smears obtained by fine-needle aspiration (FNA) in a patient with pituitary Cushing's disease. FNA allowed for rapid diagnosis and prompt treatment of a potentially serious infection. The patient fully recovered from her pulmonary disease. Although opportunistic infections may occur in patients with endogenous Cushing's syndrome, it is rare to see such infections in the subset of patients with pituitary Cushing's disease. Hypercortisolism associated with Cushing's syndrome appears to induce a transitory immune deficiency state and opens a window of opportunity for certain infectious agents such as Cryptococcus neoformans to exploit. To our knowledge, this is the third such case reported in this clinical setting, and the first diagnosed by FNA.

Burns due to hot beverages are a well known public health hazard, both at home and in the work place. Although, such injuries are often minor, they can be severely debilitating, and on certain occasions, fatal. Burns due to hot liquids most commonly affect children but in certain circumstances, the adult population is at risk. Scald burns to the perineum from hot liquids served at drive through restaurants have not previously been reported. Perineal scalds are associated with both physical and psychological morbidity. The scalds sustained in these cases were embarrassing and upsetting for the patient. They were associated with prolonged periods away from work, and several visits to the hospital for dressing changes and wound assessment. Most importantly, they were preventable injuries. If certain health and safety measures relating to the dispensing of hot liquids at drive through restaurants were observed, these injuries would greatly reduce in incidence. Â Â [Abstract unavailable] Language: en

OBJECTIVE Does papillary squamotransitional cell carcinoma (PSTCC) behave differently from conventional squamous cell carcinoma of the cervix and does PSTCC have true transitional cell differentiation? MATERIALS AND METHODS Twenty cases of PSTCC were identified from archival files. Clinical data were compiled. Immunoperoxidase stains for uroplakin III, p63 and p16 were performed on available tissue blocks. RESULTS Patients ranged in age from 27 to 85 years. Twelve patients were FIGO Stage I, 4 were Stage II, and 2 were Stage III. Thirteen patients had clinical follow-up ranging from 5 to 132 months. Three patients subsequently had more extensive disease than initial clinical staging indicated. Nine patients had no tumor progression, three had local recurrence and one had metastatic disease. Eight cases were strongly immunoreactive for p63 and p16 and 14 were negative for uroplakin III. CONCLUSIONS PSTCC lacks true transitional cell differentiation and probably shares similar clinicopathologic features with conventional cervical squamous cell carcinoma.

Transplant-related lung fibrosis is characterized by excessive fibro-collagenous deposition. Induction of arginase, an enzyme that metabolizes L-arginine to urea and L-ornithine, is vital for collagen synthesis. Pirfenidone is an investigational anti-fibrotic agent shown to be effective in blocking pulmonary fibrosis. The purpose of this study was to determine if pirfenidone was protective against the development of fibro-collagenous injury in rat lung orthotopic transplants through altering L-arginine-arginase metabolic pathways. Lung transplants were performed using Lewis donors and Sprague-Dawley recipients (allografts) or the same strain (isografts). Recipients were given pirfenidone (0.5% chow) 1-21-day post-transplantation. A significantly increased peak airway pressure (PawP) with excessive collagen deposition was found in untreated lung allografts. Pirfenidone treatment decreased PawP and collagen content in lung allografts. The beneficial effects were associated with downregulation of arginase protein expression and activity. In addition, pirfenidone decreased endogenous transforming growth factor (TGF)-beta level in lung allografts, and TGF-beta stimulated arginase activity in a dose-dependent manner in both lung tissue and fibroblasts. These results suggest that pirfenidone inhibits local arginase activity possibly through suppression of endogenous TGF-beta, hence, limiting the development of fibrosis in lung allografts.

The clinical staging of carcinoma of the vulva is a predictor of patient survival; however, the significance of other prognostic factors remains somewhat controversial. Length of survival after diagnosis of invasive squamous cell carcinoma was determined for 39 clinically staged and surgically treated patients who were followed at our institution. Clinical stage, tumor type, use of radiotherapy (RT), histopathologic features (invasive pattern, depth of invasion, lymph node status, nuclear grade, adjacent dysplasia, desmoplasia, inflammation) and DNA ploidy (determined by flow cytometry from paraffin-embedded tissue) were evaluated as predictors of survival. Kaplan-Meier survival curves were generated for strata defined by each of the various predictors and compared using the log-rank test. Advanced stage (p = 0.0002), RT use (p = 0.0004), "spray" invasive pattern (p = 0.005), positive lymph node status (p = 0.001), increased positive lymph node number (p = 0.016), and greater depth of invasion (p = 0.039) were associated univariantly with decreased survival time. Spray invasive pattern (p = 0.018), positive lymph node status (p = 0.030), positive lymph node number (p = 0.040), and RT use (p = 0.045) continued to be associated with decreased survival time after controlling for stage. Of the significant factors, invasive pattern stands out as a qualitative feature that may have potential benefit in predicting survival independent of clinical stage in patients with vulvar carcinoma.

Citrulline generation in isolated rat liver mitochondria is markedly inhibited by the carbonic anhydrase inhibitor acetazolamide (Dodgson et al., 1983). This finding suggests that hepatic mitochondrial-matrix carbonic anhydrase may exert an important controlling effect on ureogenesis by supplying bicarbonate for carbamoyl phosphate synthesis. Three different carbonic anhydrase isoenzymes have been identified in mammals and designated CAI, CAII and CAIII. In liver CAII is uniquely sensitive to inhibition by acetazolamide and is present in a 4-fold higher concentration in the hepatocyte cytosol of female rats than in males (Jeffrey et al., 1984). with higher cytosol concentration of CAIII being found in males (Shiels et al., 1984). Sex differences in mitochondrial carbonic anhydrase have not been reported. We have extended these findings by examining the effect of acetazolamide on rates or ureogenesis and gluconeogenesis in isolated rat hepatocytes from male and female rats. Isolated rat hepatocytes were prepared from 48 h-starved male and female SpragueDawley rats by collagenase perfusion and suspended in Krebs bicarbonate buffer (Krebs & Henseleit, 1932) gassed with O-,/CO, (19 : 1). Samples (2ml) of cell suspension (30-60mg wet wt.) were incubated with I .8mM-NH4CI. SmM-L-( +)-lactate and 0.2mM-ornithine in the presence or absence of different concentrations of acetazolamide. Incubations were terminated after either 10 or 20min by the additions of 4.5ml of 0.6M-HCI0,. Urea and glucose were determined in the deproteinized supernatant by standard spectrophotometric methods. Rates of ureogenesis and gluconeogenesis were determined between the 10 and 20min time points. Ureogenesis and gluconeogenesis in male rat hepatocytes were markedly inhibited by acetazolamide (Fig. 1 ) . Maximum inhibition of ureogenesis (7506) occurred at acetazolamide concentrations between 0.5 and I .OmM, with 25% inhibition evident at 0.005 mM. Gluconeogenesis was inhibited by a maximum of 400; at I.0rnM-acetazolamide. with l2:$ inhibition at 0.05mM. An identical degree of inhibition of ureogenesis was obtained with hepatocytes from female rats. These data suggest that inhibition of ciirbonic anhydrase by acetazolamide may decrease the supply of intramitochondrial bicarbonate for both the carbamoyl-phosphate synthetase and pyruvate carboxylase reactions. I t is thus possible that bicarbonate availability may be a limiting factor in both urea and glucose production. This conclusion is supported by the demonstrations of inhibition of ureogenesis by metabolic acidosis at a site proximal to citrulline synthesis (Monson r t ul.. 1984). The observed similarity between acetarolamide inhibition of urea production in hepatocytes from mule and female rats suggests the presence of similar mitochondria1 concentrations in males and females of one or more susceptible carbonic anhydrase isozymes. The possibility of mechanisms other than carbonic anhydrase inhibition being responsible for the effects of acetazolc 20