Renal Allograft Failure After Ipilimumab Therapy for Metastatic Melanoma: A Case Report and Review of the Literature.

Transplant recipients are at an increased risk of malignant melanoma, a result of chronic immunosuppression. Ipilimumab is a newer biological agent targeting T lymphocytes to potentiate an immune response against melanoma, and the use of this agent results in a new adverse effect profile that the clinician must be aware of while a patient is on therapy. We report the case of a male renal transplant recipient who developed graft failure while treated with ipilimumab and minimal immunosuppressive therapy for metastatic ocular melanoma, with biopsy evidence of glomerulonephritis and acute rejection. We highlight the immunological side effects that can manifest from ipilimumab therapy and conclude that it did influence graft function in this patient. Our case illustrates the importance of weighing the risks and benefits to graft function and long-term survival as well as the importance of considering other treatment modalities in this specific group of melanoma patients.

Expression of miR-210 in relation to other measures of hypoxia and prediction of benefit from hypoxia modification in patients with bladder cancer.

BACKGROUND: The addition of hypoxia modifiers carbogen and nicotinamide (CON) to radiotherapy (RT) improved overall survival (OS) in bladder cancer patients in the BCON phase III clinical trial. We investigate whether expression of hsa-miR-210 in BCON patient samples reflects hypoxia and predicts benefit from hypoxia modification. METHODS: In all, 183 T1-T4a bladder cancer samples were available for miR-210 analysis. A total of 86 received RT+CON and 97 received RT alone. TaqMan qPCR plates were used to assess miR-210 expression. Patients were classified as low (

Expression of hypoxia-inducible factor-1α predicts benefit from hypoxia modification in invasive bladder cancer.

BACKGROUND: The addition of carbogen and nicotinamide (CON) to radiotherapy (RT) improves overall survival in invasive bladder cancer. We explored whether expression of the hypoxia marker hypoxia-inducible factor-1α (HIF-1α) alone or in combination with other markers predicted benefit from CON. METHODS: A retrospective study was carried out using material from patients with high-grade invasive bladder carcinoma enrolled in the BCON phase III trial of RT alone or with CON (RT+CON). HIF-1α expression was studied in 137 tumours using tissue microarrays and immunohistochemistry. Data were available from other studies for carbonic anhydrase IX and glucose transporter 1 protein and gene expression and tumour necrosis. RESULTS: Patients with high HIF-1α expression had improved 5-year local relapse-free survival with RT+CON (47%) compared with RT alone (21%; hazard ratio (HR) 0.48, 95% CI 0.26-0.8, P=0.02), no benefit was seen with low HIF-1α expression (HR 0.81, 95% CI 0.43-1.50, P=0.5). Combinations of markers including necrosis also predicted benefit but did not improve on prediction using necrosis alone. CONCLUSIONS: HIF-1α may be used to predict benefit from CON in patients with bladder cancer but does not improve on use of necrosis.

Phenotypic similarities in bilateral breast cancer.

Bilateral breast cancers that develop at similar times in an individual are likely to have been subjected to similar hormonal, environmental and genetic influences during tumourogenesis compared with metachronous tumours. As such, it is possible that tumour phenotype in synchronous bilateral breast cancer may display similar biological characteristics. The aim of this study was to identify phenotypic similarities between synchronous and metachronous bilateral breast cancers which may suggest a common origin. Thirty-three cases of synchronous and 46 cases of metachronous bilateral breast cancer that displayed similar tumour type were analysed for concordance in relation to various histological and immunohistochemical parameters. A higher level of concordance was demonstrated for synchronous cases with the highest level seen for oestrogen receptor. It is likely that this is related to similar tumourogenic pathways occurring at equivalent exposure times to various environmental and hormonal influences, although, in a proportion of cases, inherited genetic factors may play a role.

Are medullary breast cancers an indication for BRCA1 mutation screening? A mutation analysis of 42 cases of medullary breast cancer.

Recommended guidelines have limited breast cancer gene ( BRCA1 ) mutation testing to individuals with a personal or family history of early onset breast and/or ovarian cancer, and those with multiple affected close relatives. Such large breast cancer families are rare in the general population, limiting the clinical application of the BRCA1 discovery. Previous reports have suggested an association between medullary breast cancer and BRCA1 mutation carriers. To test the feasibility of using these rare histological subtypes as an alternative to epidemiological factors, 42 cases of medullary cancer unselected for family history were screened for BRCA1 point mutations and large exon rearrangements. The large majority (83%) of these patients did not have significant family of breast or ovarian cancer. Two deleterious mutations resulting in a premature stop codon, and one exon 13 duplication were found. All mutations were detected in patients with typical medullary cancer, who had family history of multiple breast and ovarian cancers. Our findings suggest that medullary breast cancers are not an indication for BRCA1 mutation screening in the absence of significant family risk factors.

Excision biopsy findings of patients with breast needle core biopsies reported as suspicious of malignancy (B4) or lesion of uncertain malignant potential (B3).

AIMS: The UK National Health Service Breast Screening Programme has proposed five categories for reporting breast needle core biopsies. The majority of cores are reported as benign (B1), normal (B2) or malignant (B5). The predictive value of the two borderline categories suspicious of malignancy (B4) and lesion of uncertain malignant potential (B3) was studied. METHODS AND RESULTS: Over a 2-year period a total of 3822 breast needle core biopsies were performed, with 2997 from symptomatic patients and 825 from women undergoing mammographic screening, including 43 B4 reports (40 patients) and 120 B3 reports (116 lesions in 115 patients). The frequencies of B4 (2.5% versus 0.7%) and B3 cores (7.3% versus 2.0%) were both higher in screening than in symptomatic patients. B4 was most commonly used for small fragments of atypical cells separate from the main core or focal atypical intraductal proliferations. The criteria for calling a core B3 were: atypical intraductal epithelial proliferations (including foci that in excision specimens would be classified as atypical ductal hyperplasia), lobular neoplasia, radial scar, papillary lesion, fibroepithelial lesion with cellular stroma and spindle cell proliferations. Excision biopsies were performed in 39 patients with B4 core and 96 with B3 core. Invasive carcinoma or ductal carcinoma in situ was seen in 33 of the patients with B4 (85%) and in 29 of those with B3 cores (25%). Some categories of B3 core were associated with a higher rate of malignancy (40% for atypical intraductal epithelial proliferations and 46% for lobular neoplasia). CONCLUSIONS: The positive predictive value for carcinoma is high following a B4 core (86%). The lesion should be excised, but definitive cancer treatment is not appropriate. In some cases a definite diagnosis of malignancy can be made on repeat core. The B3 group is more heterogeneous and has a lower rate of malignancy on further biopsy (25%). The majority of B3 lesions require excision. All these patients should be discussed at multidisciplinary meetings.

Inter-observer variation between general and specialist gastrointestinal pathologists when grading dysplasia in ulcerative colitis.

Histological dysplasia is the cornerstone of colorectal cancer surveillance in ulcerative colitis (UC). Recently, pathologists have received unfavourable media attention concerning other cancer screening programmes. The aim of this study was to determine whether colonic biopsy specimens should be examined by gastrointestinal pathologists as opposed to generalists, by examining inter-observer variation between the two groups. Fifty-one coded slides showing varying degrees of dysplasia were mailed to seven gastrointestinal and six general histopathologists. Pathologists allocated each biopsy into one of four categories without the benefit of a clinical history or an opportunity to use the 'indefinite' category that is included in the Riddell classification. The responses were analysed using kappa statistics. The overall kappa statistic for gastrointestinal pathologists was 0.30 [95% confidence interval (CI)=0.26-0.34] and for general pathologists 0.28 (95% CI=0.23-0.32). Agreement was best for high-grade dysplasia (kappa of 0.54 and 0.61 for GI and general pathologists, respectively). There was total concordance of the 13 pathologists in only four of the 51 slides (7.8%) (95% CI=0.4-15.2%). It is concluded from these results that gastrointestinal pathologists are no better than generalists when grading dysplasia in UC and that agreement is poor in both groups. There is therefore no evidence that there would be any benefit in having specialist histopathology centres concentrating specifically on the interpretation of all surveillance colonoscopy biopsies from around the UK. It must be made clear to the public that surveillance and screening programmes carry a significant rate of histological error and that perfection cannot be expected or achieved with present methods.

Preoperative assessment of prognostic factors in breast cancer.

The adoption of preoperative diagnostic strategies involving fine needle aspiration cytology (FNAC) or core biopsy is well established, allowing the planning of operating lists and bed occupancy and patient involvement in therapeutic management. In addition to diagnosis, however, pathologists are increasingly being asked to provide pathological prognostic information from preoperative samples. This leader describes techniques for predicting prognosis and response to treatment on these specimens and some of the problems inherent in the determination of prognosis on small samples. For example, although histological grade can be assessed relatively reliably on either core or FNAC samples, the evaluation of tumour type (which includes an overall assessment of the architecture of a given tumour) may be less reliable on small preoperative samples. Other well recognised histological prognostic factors, such as vascular channel invasion or tumour size, cannot be determined accurately on small preoperative samples. For those patients who might benefit from neoadjuvant treatment, predicting the response to such treatments--for example, by the assessment of oestrogen receptor status--can readily be performed on either core biopsy or FNAC. In the future, other molecular markers such as C-erbB-2 might also prove beneficial in predicting response to newly developed treatments.

Imaging for staging bladder cancer: a clinical study of intravenous 111indium-labelled anti-MUC1 mucin monoclonal antibody C595.

OBJECTIVE: To investigate the clinical application of an 111In-labelled anti-MUC1 mucin monoclonal antibody (mAb) imaging for staging invasive bladder cancer. PATIENTS AND METHODS: Indirect immunohistochemistry was used to confirm the expression of the MUC1 target antigen by metastatic tumours. Twelve patients with bladder cancer (two with superficial and 10 with locally invasive/metastatic disease) underwent planar gamma-scintigraphy 48 h after an intravenous injection with 111In-labelled anti-MUC1 mucin mAb C595. RESULTS: No bladder uptake was detected in the two patients with superficial disease, but scintigraphy showed primary and recurrent bladder tumours and metastases in nine of the remaining 10 patients with invasive disease. In three patients additional staging information was obtained from the mAb imaging which would have altered patient management. There were no reported side-effects. CONCLUSION: This study confirmed the ability of the mAb technique to detect both primary and recurrent invasive bladder tumours and distant metastases. Some lesions shown by mAb imaging were not detected by other methods. The use of mAb imaging has the potential to improve clinical staging and assist in selecting those patients most likely to benefit from radical therapy.

Predicting invasion in mammographically detected microcalcification.

AIM: To identify pre-operative factors which predict presence of invasive disease within mammographically detected malignant microcalcification. MATERIALS AND METHODS: A retrospective analysis was undertaken of 116 serial stereotactic core needle biopsies (SCNBs) performed on malignant mammographic calcification. Final surgical pathology was correlated with pre-operative features (clinical, radiological and core histology) in an attempt to predict the presence of an invasive component. RESULTS: Thirty-eight clusters contained invasive carcinoma. The sensitivity of SCNB for invasion was 55%. Clinical features, calcium morphology and cluster size were not shown to be predictive of invasive disease. Ductal carcinoma in situ (DCIS) of high grade on core histology and increasing number of calcifications were predictive of increased risk of invasion (high grade core biopsy DCIS and > 40 calcifications 48% invasive at surgical histology; high grade core biopsy DCIS and < 40 calcifications 15% invasive; non-high grade core biopsy DCIS 0% invasive). CONCLUSIONS: Identification of those clusters diagnosed as DCIS by percutaneous biopsy which are likely to harbour an invasive component is possible. It would seem reasonable to consider staging the axilla at therapeutic surgery in these patients.

c-erbB-4 protein expression in human breast cancer.

The Type 1 family of growth factor receptors includes epidermal growth factor receptor (EGFR), c-erbB-2, c-erbB-3 and c-erbB-4. Overexpression of the first two members is associated with poorer prognosis in patients with breast carcinoma. In this study we examined the expression of c-erbB-4 protein using the monoclonal antibody HFR-1. A total of 127 consecutive cases of primary operable invasive breast carcinoma presenting between 1975 and 1977 were studied. All patients were managed by simple mastectomy or conservation surgery with radiotherapy and no adjuvant therapy given. Long-term follow-up was maintained. Routine, formalin-fixed, paraffin-embedded tumour samples were used and sections were stained immunohistochemically using the Duet StreptABC method. Immunoreactivity was classified using a simple semi-quantitative scoring method. Protein expression was generally low but definite positive cytoplasmic, membranous and nuclear reactivity was identified in 58%, 41% and 25% of cases respectively. Expression at all three sites demonstrated significant inverse associations were histological grade. In addition, membrane accentuation correlated inversely with the Nottingham Prognostic Index (NPI), while cytoplasmic reactivity showed a positive association with c-erbB-3 expression. No significant associations were found with disease-free interval or survival. The results of this study demonstrate that higher levels of c-erbB-4 protein expression are associated with a more differentiated histological phenotype in contrast to the other members of the Type 1 family. Larger series with extended follow-up will be required to ascertain definitively the prognostic value of c-erbB-4 expression in breast carcinoma.

Metaplastic carcinoma of the breast arising within complex sclerosing lesion: a report of five cases.

AIMS: This study presents a series of five cases in which metaplastic carcinoma, predominantly low-grade adenosquamous carcinoma, of the breast is seen arising within a background of a complex sclerosing lesion. This association has been recognized previously but has not been documented in detail. This study describes the characteristics of the components present in each case and discusses the existing literature. This observation adds further evidence to support an association between some types of invasive breast carcinoma and sclerosing lesions of the breast. METHODS AND RESULTS: Four of these cases were received as referral cases for opinion. The fifth was received as part of the routine surgical workload within our own institution. Two patients presented following mammographic screening and three symptomatically; their mean age was 62 years (range 49-68). The mean lesion size was 16 mm (range 7-24). All five lesions showed features of a complex sclerosing lesion/radial scar in the form of central sclerosis with elastosis and radiating benign entrapped tubules. One had associated benign papillary structures and two had focal benign squamous metaplasia. Four cases showed coexisting but distinct areas of low-grade adenosquamous carcinoma with glandular and squamous epithelial differentiation in a spindle cell background. One case had associated undifferentiated spindle cell carcinoma. Detailed immunophenotypic characteristics of two cases are presented. CONCLUSIONS: This series illustrates a postulated but previously unconfirmed association between an unusual form of metaplastic breast carcinoma (adenosquamous carcinoma) and complex sclerosing lesions. The mechanisms of induction of breast carcinoma are poorly understood but these observations further emphasize the potential for sclerosing lesion of the breast to be associated with, and possibly give rise to, invasive carcinoma of different types. The precise nature of the interaction between the pathological processes remains unclear.

Targeting superficial bladder cancer by the intravesical administration of copper-67-labeled anti-MUC1 mucin monoclonal antibody C595.

PURPOSE: More effective intravesical agents are required to limit the recurrence and progression of superficial bladder cancer. This study assessed the ability of copper-67 ((67)Cu)-C595 murine antimucin monoclonal antibody to bind selectively to superficial bladder tumors when administered intravesically, with a view to its development for therapy. PATIENTS AND METHODS: Approximately 20 MBq of (67)Cu-C595 monoclonal antibody was administered intravesically to 16 patients with a clinical indication of superficial bladder cancer. After 1 hour, the bladder was drained and irrigated. Tissue uptake was assessed by imaging and by the assay of tumor and normal tissues obtained by endoscopic resection. RESULTS: Tumor was correctly identified in the images of 12 of 15 patients who were subsequently found to have tumors. Assay of biopsy samples at 2 hours showed a mean tumor uptake of 59.4% of the injected dose per kilogram (SD = 48.0), with a tumor-to-normal tissue ratio of 14.6:1 (SD = 20). After 24 hours (n = 5), this decreased to 4.3% of the injected dose per kilogram (SD = 2.9), with a tumor-to-normal tissue ratio of 1.8:1 (SD = 0.8). CONCLUSION: This study indicates a promising method for the treatment of superficial bladder cancer. Although the mean initial tumor uptake was high, effective therapy of bladder tumors will require an increased retention of the cytotoxic radionuclide in tumor tissue.

Bilateral breast carcinomas: do they have similar mammographic features?

AIMS: This study compared the mammographic appearance, site and histological features of synchronous and metachronous bilateral breast carcinomas. METHODS: Site, type of abnormality and background pattern seen on the diagnostic mammograms of 63 women with bilateral breast carcinoma were compared. The histological type and grade of all the carcinomas were verified by histological review. RESULTS: There was a tendency for the contralateral tumour to have similar mammographic features to those of the initial tumour. In patients in whom the first carcinoma was visible purely as a mass, the contralateral carcinoma had a similar appearance in 82% (P < 0.001). When the original tumour showed mammographic calcification the contralateral tumour did so in 65% (P< 0.001). Normal mammography or calcification alone were seen almost exclusively in women with a dense background pattern (100% and 92% respectively) while masses and calcification with masses were seen in women with dense and fatty patterns (58% and 35% dense respectively). When the mammographic site of the contralateral tumour was compared with that of the first tumour no significant correlation could be demonstrated. There was a significant trend for contralateral carcinomas to be of the same histological grade (P < 0.005) but not histological type. CONCLUSIONS: Contralateral carcinomas often have a similar mammographic appearance to the first tumours. Two factors may be responsible: (i) the tendency for contralateral carcinomas to be of the same histological grade and (ii) the influence of mammographic background pattern on the radiological appearance of breast carcinoma. This knowledge may assist in the interpretation of follow-up mammography in patients with a previous breast carcinoma.

Is mammography of value in women with disseminated cancer of unknown origin?

Mammography is often requested to try to identify occult primary breast carcinoma in women with metastatic cancer of unknown primary site. This study aimed to investigate whether mammography is of use in these patients in identifying the breast as the origin of the metastatic disease. Thirty-one women with a working diagnosis of metastatic cancer underwent mammography in an attempt to determine the primary site. None of these women had a palpable breast mass. The site of presentation, pathological type of tumour, site of origin, and benefit of mammography and mammography-provoked biopsy were clarified for each patient. The patients were also followed up to determine survival. The commonest sites of presentation were lung (45%), lymph nodes (19%) and abdomen (16%). The primary sites of these cancers were identified with confidence in 27 patients (87%). The commonest known primary tumour sites were lung (45%), breast (16%) and ovary (16%). Abnormal mammograms were detected in four patients (13%), but three of these did not have breast cancer. In one, the site of origin remained indeterminate, as either breast or lung. Five (16%) had a confident diagnosis of breast carcinoma; all of these women had normal mammograms. We conclude that mammography in women presenting with metastatic disease from an unknown primary site is unhelpful and is not recommended. Furthermore, we could not demonstrate its value in women presenting with axillary lymphadenopathy.

Sustentacular cells in pulmonary neuroendocrine tumours.

AIMS: To determine the prevalence of sustentacular cells across the range of pulmonary neuroendocrine tumours: typical and atypical carcinoid tumours and large cell and small cell neuroendocrine carcinomas. METHODS AND RESULTS: Sustentacular cells were sought in 80 pulmonary neuroendocrine tumours by immunolabelling for S100 protein, nerve growth factor receptor and glial fibrillary acidic protein. Intratumoural macrophages and Langerhans cells were identified with the KP 1 (CD68) and CD1A antibodies. S100-positive sustentacular cells were present in 25 of 30 typical carcinoids, 200 of 25 atypical tumours, six of 10 large cell carcinomas and six of 15 small cell lesions. They were most numerous in the typical carcinoids but very few in the small cell carcinomas, their prevalance being clearly related to grade of differentiation and, in particular, to the degree of architectural organization. CONCLUSIONS: Sustentacular cells are often found in pulmonary neuroendocrine tumours, especially better-differentiated lesions with a well-developed architecture. their prevalence clearly reflecting the degree of structural organization. Whether their prevalence is a useful prognostic indicator within a particular group of such tumours, such as the atypical carcinoids or the large cell carcinomas, as appears to be the case with paragangliomas, is unclear.

Fibroadenomatoid hyperplasia: a cause of suspicious microcalcification on mammographic screening.

OBJECTIVE: Fibroadenomatoid hyperplasia is a well-described but rare benign breast lesion with composite features of fibroadenoma and fibrocystic change. Because fibroadenomatoid hyperplasia has not to our knowledge been reported as a cause of suspicious microcalcifications and because several pathology reports of biopsies of mammographically detected microcalcification at our institution included fibroadenomatoid hyperplasia, we undertook this study to describe the features of mammographically detected microcalcification seen in patients with fibroadenomatoid hyperplasia. MATERIALS AND METHODS: Two breast pathologists reviewed the records of 54 mammographically detected lesions that were compatible with a diagnosis of fibroadenomatoid hyperplasia and that provoked subsequent core biopsy or surgical excision of microcalcifications. Eleven cases (20%) fulfilled the diagnostic criteria for fibroadenomatoid hyperplasia. The sites of all calcifications found at histology were documented, and the mammographic features were described. RESULTS: Eleven cases of fibroadenomatoid hyperplasia were identified in nine core biopsy samples and two surgical specimens. Calcification was present in all 11 pathologic specimens. Calcification was stromal in nine, subepithelial in two, and epithelial in none. The mammographic features of fibroadenomatoid hyperplasia in all 11 cases were granular microcalcifications that varied in shape, size, and density and had no associated mass; of these calcifications, 91% were in a localized, irregularly shaped cluster. Rod-shaped calcifications were also seen in 64% of cases. CONCLUSION: Fibroadenomatoid hyperplasia is a cause of suspicious, granular, clustered microcalcifications on screening mammography. Fibroadenomatoid hyperplasia can be confirmed using 14-gauge core biopsy in most cases.

Transthoracic fine needle aspiration cytology of lung for suspected malignancy: an audit of cytological findings with histopathological correlation.

Transthoracic fine needle aspiration cytology (TFNAC) is an invasive procedure and should therefore be subject to regular review. We report an audit of TFNAC from 146 patients. One hundred and thirty-six samples (93%) were adequate and 86 were malignant, 16 suspicious and 34 contained no malignant cells. TFNAC was the sole means of diagnosis of malignancy in 55 patients. However, further pathological data were available in 58 of the adequate samples; TFNAC was malignant in 31, suspicious in eight and contained no malignant cells in 19. All malignant TFNAC were confirmed (absolute sensitivity = 85%; positive predictive value = 100%); as were five of eight with suspicious cytology. Of 19 patients with negative TFNAC, nine were subsequently found to have a malignancy (specificity = 68%).

Production and characterization of a recombinant anti-MUC1 scFv reactive with human carcinomas.

Recombinant single-chain fragments (scFv) of the murine anti-MUC1 monoclonal antibody C595 have been produced using the original hybridoma cells as a source of variable heavy (V(H))- and variable light (V(L))-chain-encoding antibody genes. The use of the polymerase chain reaction (PCR), bacteriophage (phage) display technology and gene expression systems in E. coli has led to the production of soluble C595 scFv. The scFv has been purified from the bacterial supernatant by peptide epitope affinity chromatography, leading to the recovery of immunoreactive C595 scFv, which was similar in activity to the C595 parent antibody. Analysis by DNA sequencing, SDS-PAGE and Western blotting has demonstrated the integrity of the scFv, while ELISA, FACScan analysis, fluorescence quenching, quantitative immunoreactivity experiments and immunohistochemistry confirm that the activity of the scFv compares favourably with that of the parent antibody. The retention of binding activity to MUC1 antigen on human bladder and breast carcinoma tissue specimens illustrates the potential application of this novel product as an immunodiagnostic and immunotherapeutic reagent.