Micropapillary Differentiation Research Articles

Predicting individual outcomes after radical cystectomy in urothelial variants with Cancer of the Bladder Risk Assessment (COBRA) score.

To validate the Cancer of the Bladder Risk Assessment (COBRA) score in patients with urothelial variants. Epidemiological, clinical, radiological, and anatomopathological data were collected from patients with urothelial carcinoma who underwent radical cystectomy at the Institute of Cancer of São Paulo between May 2008 and December 2022. Patients with the presence of at least 10% of any urothelial variants in the radical cystectomy specimens' anatomopathological exam were included in the study. The COBRA score and derivatives were applied and correlated with oncological outcomes. A total of 680 patients [482 men (70.9%) and 198 women (29.1%)]; 66years (IQR 59-73) underwent radical cystectomy for bladder tumor, and of these patients, a total of 167 patients presented any type of urothelial variant. The median follow-up time was 28.77months (IQR 12-85). The three most prevalent UV were squamous differentiation (50.8%), glandular differentiation (31.3%), and micropapillary differentiation (11.3%). The subtypes with the worst prognosis were sarcomatoid with a median survival of 8months (HR 1.161; 95% CI 0.555-2.432) and plasmacytoid with 14months (HR 1.466; 95% CI 0.528-4.070). The COBRA score for patients with micropapillary variants demonstrated good predictive accuracy for OS (log-rank P = 0.009; 95% IC 6.78-29.21) and CSS (log-rank P = 0.002; 95% IC 13.06-26.93). In our study, the COBRA score proved an effective risk stratification tool for urothelial histological variants, especially for the micropapillary urothelial variant. It may be helpful in the prognosis evaluation of UV patients after radical cystectomy.

Invasive Micropapillary Urothelial Carcinoma: an Uncommon and Underreported Variant in Cystectomy Specimens.

Conventional urothelial carcinoma is the most common histological type of urinary bladder carcinoma. The latest edition of the WHO classification of tumours of the urothelial tract lays special emphasis on the ability of urothelial tumours to exhibit divergent differentiation with multiple histologic variants and a diverse genomic landscape. The presence of a micropapillary component (MPC) in urothelial carcinoma is associated with high-grade disease and poor response to intravesical chemotherapy. The present study aims to enumerate the clinicohistological features of urothelial carcinomas with micropapillary differentiation. Slides from 144 radical cystectomy specimens received over 6 years were reviewed independently by two pathologists. A predominant histological pattern along with co-existing pathology was noted. Of these, five cases were pure micropapillary carcinomas, four had conventional urothelial carcinoma with a MPC, one had a microscopic tumour at the mucosal surface, and two cases showed micropapillary histology in the lymph node metastasis, following transurethral resection of bladder tumour and Bacillus Calmette-Guerin therapy. The tumours with pure micropapillary carcinoma presented with a higher pathological stage and poor overall survival. Organ and lymph node metastasis was noted in five and eight cases, respectively, of which six showed a micropapillary pattern in the lymph nodes. Micropapillary urothelial carcinoma is a rare and aggressive variant of urothelial carcinoma with unique histologic features. This variant is often missed and underreported in biopsy and surgical resection specimens. Since the presence of MPC confers a poorer prognosis, the identification and reporting of this entity are important.

Mucinous Carcinoma of the breast with micropapillary pattern and psammomatous calcification: A case study.

Mucinous carcinoma with a micropapillary pattern is an unusual form of Invasive breast cancer exhibiting dual mucinous and micropapillary differentiation. The present case is of a 47-year-old nulliparous female who presented with an incidental finding of a hard lump in her left breast. Mammography revealed a BIRADS 4 lesion. Modified radical mastectomy was done and the specimen was grossed, revealing a tumor of 3x2.6x2.6 cm in the outer quadrant. Microscopy revealed the tumor having extracellular mucin pools with floating psammoma bodies and focal micropapillary pattern. Four of the twenty-six lymph nodes sampled were found to have tumor deposits. The micropapillary pattern was maintained in the metastatic deposits. Immunohistochemistry revealed ER and PR positivity and Her2Neu negativity. EMA corroborated the findings. It is important to recognize the micropapillary pattern in mucinous carcinomas of the breast as these tumors tend to be more aggressive than pure mucinous breast lesions.

Histology of variants of urothelial carcinoma of the bladder: a Moroccan series of 39 cases

BackgroundThe variant of urothelial carcinoma (UCV) is a rare and aggressive histological entity; its therapeutic management remains debated.MethodsBetween January 2017 and October 2019, 39 patients were diagnosed retrospectively with urothelial carcinoma with a histological variant. The aim of this study was to analyze the clinico-pathological and therapeutic aspects of these variants to better understand this invasive disease.ResultsIn 39 cases, 36 (92%) were men and 3 (8%) were women; the average age was 62 years; 54% of patients had a ≥ cT3 stage with clinical lymph node involvement in 28% and 23% had distant metastases, 36% of patients were treated with RC and 54% by other therapeutic and 10% refused RC. No patient received neoadjuvant chemotherapy. Lymph node involvement was 28.5%. The two predominant histological types were squamous and micropapillary differentiation between the operating piece and bladder biopsy 28.5%, 30% and 21.5% and 13%, respectively. The overall survival at 20 months was 70 and 40% for RC and the other therapeutic (TURB alone or a TURB with an adjuvant), respectively. There was no significant difference in survival between the two groups (p = 0.27).ConclusionUCVs are heterogeneous groups of tumors which are increasingly identified due to their distinct morphological characteristics with variable clinical prognosis. Therapeutic management is not in favor of cystectomy in our study. However, a prospective study using a larger cohort is still necessary to validate our results.

Triple-Positive Breast Carcinoma: Histopathologic Features and Response to Neoadjuvant Chemotherapy.

It is unclear whether HER2+ tumors expressing both estrogen receptor (ER) and progesterone receptor (PR), that is, triple-positive breast carcinomas (TPBCs), show unique morphologic and clinical features and response to neoadjuvant chemotherapy (NAC). To study the morphologic and immunohistochemical features of TPBCs from patients who underwent NAC. We retrospectively reviewed core biopsy and post-NAC slides of 85 TPBCs. H-scores were calculated for ER and PR. HER2 slides and fluorescence in situ hybridization (FISH) reports were reviewed. Residual cancer burden was calculated for post-NAC specimens. Eighty-one of the 85 tumors (95.3%) showed ductal histology, 3 (3.5%) were invasive lobular carcinomas, and 1 (1.2%) showed mixed ductal and lobular features. A subset showed mucinous (n = 7, 8.2%), apocrine (n = 5, 5.9%), and/or micropapillary (n = 4, 4.7%) differentiation. Fifty-four TPBCs (63.5%) showed high ER expression (H-score >200), including 27 (31.8%) with high expression of ER and PR. Fifty-two tumors (61.1%) showed HER2 3+ staining. Mean HER2/CEP17 ratio by FISH was 3.6 (range, 2-12.2) and mean HER2 signals per cell was 8 (range, 3.7-30.4). Pathologic complete response (pCR) rate was 35.3% (30 of 85). HER2 3+ staining was the only significant predictor of pCR on multivariate analysis (odds ratio = 9.215; 95% CI, 2.401-35.371; P < .001). The ER/PR expression did not correlate with response to therapy. TPBCs are heterogeneous with some showing mucinous, lobular, or micropapillary differentiation. The pCR rate of TPBCs is similar to that reported for ER+/PR-/HER2+ tumors. HER2 overexpression by IHC was associated with significantly better response to therapy and may help select patients for treatment in the neoadjuvant setting.

265 BK-Virus Positive Invasive High-Grade Urothelial Carcinoma in an 8-Year-Old Renal Transplant Recipient With BK Virus Nephropathy

Urothelial carcinoma is extremely rare in children and may be fundamentally different than in adults. Fewer than 30 cases have been reported in patients under 10 years old. BK polyomavirus infection is a major problem in transplantation, especially in renal transplant recipients. According to literature, 1%-10% of renal transplant recipients develop polyomavirus-associated nephropathy. The possibility that BK polyomavirus may be carcinogenic in humans is controversial, but SV40 large T antigen is known to inhibit tumor suppressors pRB and p53, and to transform some cell lines in culture. Adult renal transplant recipients have a 3-5x increased risk of urothelial carcinoma. The cystoprostatectomy specimen from an 8-year-old boy with a history of renal transplantation was processed according to standard procedure, and evaluated using H&E and immunohistochemical stains (IHC). Additional ancillary testing included molecular studies for BK virus using PCR for VP1 and identity testing using HLA typing. The patient was an 8-year-old ex 32-week gestation twin boy with a history of chronic kidney disease and developmental delay. He had end-stage renal disease of unclear etiology and underwent kidney transplantation five years earlier from a living non-related donor who was a smoker. He had been immunosuppressed since transplantation, and his course was complicated by uncontrolled BK viremia and BK nephropathy despite prolonged treatment. Five years after his renal transplant, he was noted to have gross painless hematuria. Biopsy of a bladder lesion showed high-grade urothelial carcinoma, and ureteroscopy of native and transplant ureters showed no gross malignancy. He underwent cystoprostatectomy and bilateral native nephroureterectomies with cutaneous ureterostomy from the transplant kidney. Histological examination of the bladder revealed invasive high-grade urothelial carcinoma with micropapillary features with invasion into muscularis propria. Lymphovascular invasion was also noted. The bilateral native kidneys were atrophic with simple cysts and chronic inflammation. The prostate, bilateral seminal vesicles, vas deferens, and distal transplant ureter cuff were negative for tumor. Immunohistochemical staining of the tumor for SV40 antigen showed strong and diffuse staining. In contrast, immunohistochemistry for viral protein VP1 was negative. Molecular testing for BK virus by PCR for VP1 was positive. Immunohistochemistry for mismatch repair proteins showed normal, preserved expression. Identity testing confirmed that the tumor cells belonged to the patient and not to the donor. BK virus positivity has been reported in rare cases of urothelial carcinomas, mainly in adult transplant patients. To our knowledge, this is the first reported incidence of BK virus-associated urothelial carcinoma in a pediatric patient. Absence of late VP1 expression by IHC in conjunction with positive SV40 staining and positive BK virus PCR is consistent with a non-productive BK virus infection. Pathologists should be aware that identity testing should be considered in transplant patients with urothelial carcinoma to confirm the genetic origin of the tumor. Micropapillary differentiation may be a feature of BK virus-associated carcinoma.

Cervical carcinomas with a micropapillary component: a clinicopathological study of eight cases.

Micropapillary carcinomas, or carcinomas with a micropapillary component, are well recognised in the breast and other anatomical sites. However, they have seldom been described in the cervix. In this article, we present a clinicopathological analysis of eight cervical tumours that showed at least a focal (≥5%) component of micropapillary carcinoma. The study group comprised eight cervical carcinomas (four adenocarcinomas and four adenosquamous carcinomas) with a micropapillary component. The median patient age was 41.5years (range 27-65years). At presentation, five patients were stage IB, two were stage IIB, and one was stage IV. The micropapillary component accounted for ≤25% of the tumour on initial biopsy or resection specimens in all but one case. Immunohistochemistry showed 'inside-out' (reverse polarity) mucin 1 staining along the cell membrane abutting the stroma. Four patients developed metastasis, all of whom showed a pure micropapillary pattern; this led to a misdiagnosis of an apparently independent peritoneal serous carcinoma in one case. All tumours showed diffuse p16 expression, and all three cases that were tested were positive for human papillomavirus (HPV) 18. Three of the six patients with at least 12months of follow-up died of disease, and one is alive with distant metastasis. Usual-type (HPV-related) cervical carcinomas may show micropapillary differentiation, usually as a focal finding, and the cells show reverse polarity like similar tumours arising in other sites. Micropapillary cervical carcinoma appears to be a clinically aggressive malignancy, although this needs to be confirmed in larger studies.

The Response of Variant Histology Bladder Cancer to Intravesical Immunotherapy Compared to Conventional Cancer.

High-grade urothelial carcinomas (UCs) often show foci of variant differentiation. There is limited information in the literature about the response of these variant urothelial tumors to immunotherapy with bacillus Calmette-Guerin (BCG). We compared the response, to treatment with BCG, of UC containing glandular, squamous, nested, and micropapillary types of differentiation to response of conventional non-muscle invasive high-grade UC. A total of 100 patients were diagnosed with variant histology urothelial cancer between June 1995 and December 2013. Forty-one patients with Ta or T1, confirmed by second look biopsies, received immunotherapy with BCG. Fourteen patients in this group were diagnosed with micropapillary differentiation, 13 patients with squamous differentiation, 9 patients with glandular differentiation, and 7 patients with nested variants. The control group included 140 patients with conventional high-grade UC. Both groups have been treated and followed similarly. Patients with variant tumors had similar clinical features to patients with conventional disease, including age, male to female ratio, stage, the presence of Tis, and median follow-up. Patients with variant tumors had a significantly worse prognosis compared to patients with conventional high-grade UC, including 5-year recurrence-free survival (63.5 Vs. 71.5%, p = 0.05), 5-year progression (≥T2)-free survival (60 Vs. 82.5%, p = 0.002), 5-year disease-specific survival (73 Vs. 92.5%, p = 0.0004), and overall survival (66 Vs. 89.5%, 0.05). A patient with variant bladder cancer treated with intravesical immunotherapy has a 27% chance of dying from this disease within 5 years compared to 7.5% chance for a patient with conventional high-grade UC.

Is Immediate Radical Cystectomy Necessary for All Patients with Non-Muscle-Invasive Micropapillary Bladder Cancer?

Introduction: We aim to review the outcomes of micropapillary urothelial carcinoma (MPUC) of the bladder from a single institution. The hypothesis is that non-muscle-invasive (NMI) MPUC may have a heterogeneous prognosis, and detailed pathological analysis may identify patients that could be managed without immediate cystectomy. Patients and Methods: This is a retrospective analysis of patients presenting with MPUC in a primary transurethral resection specimen (n = 40). The pattern of micropapillary (MP) differentiation [surface/non-invasive (sMP) or invasive (iMP)], extent of MP differentiation and lymphovascular invasion (LVI) were correlated with overall survival (OS), recurrence-free survival and upstaging at re-resection. Results: Sixteen of 40 patients died after a median follow-up of 37 months. Tumour stage was strongly predictive of OS (p < 0.0001). LVI was associated with increased mortality (hazard ratio 12.4, 95% CI: 3.5-44.5, p = 0.0001), higher pathological stage (p = 0.001), lymph node involvement (p = 0.001) and iMP differentiation (p = 0.006). In NMI patients not undergoing cystectomy (n = 17), NMI-sMP compared with NMI-iMP differentiation was associated with an improved OS when compared with iMP (63 vs. 47 months, p = 0.05). Conclusions: MPUC is an aggressive variant of urothelial carcinoma (UC). Similar to conventional UC, LVI associated with MPUC is an adverse prognostic indicator. iMP is a morphological marker for LVI. Histopathological reports should distinguish between sMP and iMP differentiation.

Case report: micropapillary and sebaceous differentiation in a male breast carcinoma

A micropapillary growth pattern is uncommon in male breast carcinomas and is typically associated with an aggressive clinical course. This case report describes a 71-year-old male who presented with a fungating chest wall mass arising in the vicinity of the nipple. The tumour displayed significant micropapillary and sebaceous differentiation within a predominantly nested and solid pattern of invasive carcinoma. The tumour was positive for oestrogen and progesterone receptors on immunohistochemistry. Rare cases of pure micropapillary carcinomas have been reported in males. This case report highlights this unusual presentation and includes a brief review of the literature.

13. Mucinous micropapillary carcinoma of the breast

Introduction Mucinous micropapillary carcinoma of the breast (MUMPC), also described as ‘pure mucinous carcinoma with micropapillary pattern’, is a newly recognised entity with histological features of both mucinous carcinoma and invasive micropapillary carcinoma. It has been observed to behave in a way intermediate between these subtypes. Case summary A 38-year-old woman was found to have a right-sided 8 cm breast lump and axillary lymphadenopathy. Mammography showed a large area of abnormality and microcalcifications. Core biopsies of the breast and axilla showed an infiltrating carcinoma with mucinous and micropapillary differentiation. It had a Ki67 proliferation index in the order of 50% and p53 labelling. It was positive for ER and negative for PR and HER2. High grade comedo-type DCIS was present. The patient underwent neoadjuvant chemotherapy. A mastectomy showed a 12 cm MUMPC with 3 of 6 nodes positive. Histological findings of reduced cellularity and a reduction in the Ki67 index indicated a good response to chemotherapy. Post-operatively, she had further chemotherapy followed by radiotherapy and tamoxifen. Discussion MUMPC is associated with higher rates of lymph node metastasis and lymphovascular invasion than pure mucinous carcinoma and (in some case series) a younger age. The diagnosis is based on a number of features, the most defining being micropapillary formations in the presence of extensive extracellular mucin. In addition, the pathologist should look for: psammomatous calcifications; nuclear pleomorphism; ‘hobnail’ cells; high Ki-67 labelling and p53 expression. High-grade micropapillary DCIS and HER2 positivity are suggestive. MUC1/EMA staining is not reliable in distinguishing MUMPCs from pure mucinous carcinoma. Conclusion MUMPCs behave more aggressively than pure mucinous carcinomas. It is therefore important to distinguish them histologically. Further studies will be important in further delineating their characteristics and behaviour.

The utility of p63, p40, and GATA-binding protein 3 immunohistochemistry in diagnosing micropapillary urothelial carcinoma.

Micropapillary urothelial carcinoma (MPUC) is an uncommon variant of urothelial carcinoma (UC) with an aggressive clinical course. There have been limited studies on the UC markers GATA-binding protein 3 (GATA3), p63, and p40 in MPUC. Our study investigated the immunoreactivity of these 3 markers in MPUC compared with conventional UC of different grades and stages. Immunohistochemistry was performed on 62 cases of high-grade urothelial carcinoma (HGUC), 16 low-grade urothelial carcinoma (LGUC), and 20 MPUC. p63 expression was strong and diffuse in all LGUC, significantly decreased in high stage and HGUC, and virtually absent in MPUC. p40 expression was decreased in HGUC and markedly decreased in MPUC relative to LGUC. These results suggest that loss of p63 expression in a UC appears to be associated with adverse features--including cases with micropapillary differentiation. Decreased GATA3 expression was seen frequently in high-grade and high-pathologic stage (≥pT2) tumors but was retained in MPUC cases. The findings of retained GATA3 expression in MPUC, which often shows a loss of expression of other urothelial markers such as p63, may be helpful for determining the origin of micropapillary carcinoma of unknown primary. Compared with the traditional markers p63 and p40, GATA3 is the most sensitive marker of conventional UC and MPUC.

Histolopathologic approach to direct the management of the axilla in early breast cancer patients

Screening mammography improved early detection of breast cancer and since then, the percentage of patients with node involvement is declining. Sentinel lymph node biopsy (SLNB), although helpful in the diagnostic armamentarium of these patients, has consequential limitations. In these patients, moreover, lymphatic invasion (LI) is of utmost importance to determine the risk of local recurrence. To find an adjuvant histologic approach to assist in pre-operative analysis of the patient's risk for having LI and thus sentinel ± non-sentinel axillary lymph node metastasis, one hundred and twenty patients with early invasive duct carcinoma without axillary lymph node metastasis were evaluated. Logistic regression predictive models were built from 80 patients and validated in the remaining 40 patients. The final stepwise multi-regression analysis identified four sensitive models. In the validation group, model 1 [applicable to tumors grade 3 having micropapillary differentiation (MPD)] correctly identified 92.31% of patients with LI and confirmed LI [positive predictive value (PPV)=83%], but with moderate sensitivity. Model 2 [applicable to tumors without MPD], model 3 [applicable to tumors grade 1/2], and model 4 [applicable to tumors grade 1/2 having no MPD] all had moderate PPV and a high negative predictive value (NPV) rendering these models reliable negative tests. However, as they had high sensitivity, positive results confirm the presence of LI. Patient with tumors grade 3 and MPD might need SLNB and/or axillary lymph node dissection (ALND). Patients having tumors grade 1/2, size <2cm, and no MPD nor extensive retraction artifact, SLNB and/or ALND could be omitted. In tumors grade 1/2 (model 2) and those without MPD (model 3), the proposed models are reliable negative tests rather than a definitive positive one.

Mucinous micropapillary carcinoma of the breast: an aggressive counterpart to conventional pure mucinous tumors

Mucinous micropapillary carcinoma of the breast, also described as "pure mucinous carcinoma with micropapillary pattern," has recently come to attention as an unusual form of invasive breast cancer exhibiting dual mucinous and micropapillary differentiation. Despite increasing awareness of this morphologic variant, its clinical significance has not yet been elucidated. Here, we present 15 additional examples of these rare tumors to highlight some important differences between mucinous micropapillary carcinoma of the breast and ordinary pure mucinous carcinomas. The key features of mucinous micropapillary carcinoma of the breast included (a) largely or entirely mucinous appearance (>90% mucinous morphology), (b) distinctive micropapillary arrangement of the neoplastic cells, (c) intermediate to high nuclear grade, (d) "hobnail" cells, and (e) frequent psammomatous calcifications. In contrast to ordinary pure mucinous carcinomas, 20% of mucinous micropapillary carcinomas of the breast were characterized by human epidermal growth factor receptor 2 positivity, and 23% were p53 positive. More than half of mucinous micropapillary carcinomas of the breast (60%) demonstrated lymphovascular invasion, sometimes extensive. Synchronous axillary lymph node metastases were detected in 33% of patients and, on 2 occasions, involved more than 10 nodes. With a median follow-up of 4.5 years, we identified 1 patient (7%) with chest wall recurrence of mucinous micropapillary carcinoma of the breast after mastectomy. We conclude that mucinous micropapillary carcinomas of the breast constitute a clinically aggressive subset of mucin-producing breast carcinomas characterized by an increased capacity for lymphatic invasion and regional lymph node metastasis, reflective of their dual phenotype. Recognition of the morphologic and biologic heterogeneity within breast cancer subtypes should allow for a more accurate classification of the individual tumors and better patient stratification for treatment.

BK virus–associated urinary bladder carcinoma in transplant recipients: report of 2 cases, review of the literature, and proposed pathogenetic model

Despite strong experimental evidence, BK polyomavirus involvement in human cancers has been controversial. We report 2 cases of kidney ± pancreas transplant recipients with evidence of BK polyomavirus reactivation, who developed aggressive urinary bladder urothelial carcinomas with adenocarcinomatous and/or micropapillary differentiation. Diffuse strong nuclear positivity for viral T antigen, p53, Ki-67, and p16 was observed in both malignancies. The BK polyomavirus role in promoting urothelial neoplasia in transplant recipients may be partly indirect, based on the demonstration by polymerase chain reaction in both tumors of BK polyomavirus with intact open reading frames and close phylogenetic clustering with known replication-competent strains, and viral capsid protein VP1 messenger RNA and intranuclear virions by electron microscopy in 1 tumor. No unique cancer-associated mutations were found, but some viral T antigen mutations were potentially associated with increased rate of viral replication and risk for "rare" carcinogenic events. The BK polyomavirus-induced profound effects on cell activation, cell cycle shift to proliferation, and apoptosis inhibition, in the context of marked immunosuppression, constitute a potentially ideal background for malignant transformation. The long time lapse between transplantation and tumor manifestation, 7 and 11 years, respectively, further supports the concept of multistep carcinogenesis cascade and long-term risk for these patients. We propose a model of changes ranging from viral reactivation to dysplasia to invasive carcinoma. Clinical vigilance is warranted for early diagnosis of BK polyomavirus-related urothelial malignancies in transplant recipients.

Genotypic and phenotypic analysis of familial male breast cancer shows under representation of the HER2 and basal subtypes in BRCA-associated carcinomas

BackgroundMale breast cancer (MBC) is an uncommon and relatively uncharacterised disease accounting for <1% of all breast cancers. A significant proportion occurs in families with a history of breast cancer and in particular those carrying BRCA2 mutations. Here we describe clinicopathological features and genomic BRCA1 and BRCA2 mutation status in a large cohort of familial MBCs.MethodsCases (n=60) included 3 BRCA1 and 25 BRCA2 mutation carries, and 32 non-BRCA1/2 (BRCAX) carriers with strong family histories of breast cancer. The cohort was examined with respect to mutation status, clinicopathological parameters including TNM staging, grade, histological subtype and intrinsic phenotype.ResultsCompared to the general population, MBC incidence was higher in all subgroups. In contrast to female breast cancer (FBC) there was greater representation of BRCA2 tumours (41.7% vs 8.3%, p=0.0008) and underrepresentation of BRCA1 tumours (5.0% vs 14.4%, p=0.0001). There was no correlation between mutation status and age of onset, disease specific survival (DSS) or other clincopathological factors. Comparison with sporadic MBC studies showed similar clinicopathological features. Prognostic variables affecting DSS included primary tumour size (p=0.003, HR:4.26 95%CI 1.63-11.11), age (p=0.002, HR:4.09 95%CI 1.65-10.12), lymphovascular (p=0.019, HR:3.25 95%CI 1.21-8.74) and perineural invasion (p=0.027, HR:2.82 95%CI 1.13-7.06). Unlike familial FBC, the histological subtypes seen in familial MBC were more similar to those seen in sporadic MBC with 46 (76.7%) pure invasive ductal carcinoma of no special type (IDC-NST), 2 (3.3%) invasive lobular carcinomas and 4 (6.7%) invasive papillary carcinoma. A further 8 (13.3%) IDC-NST had foci of micropapillary differentiation, with a strong trend for co-occurrence in BRCA2 carriers (p=0.058). Most tumours were of the luminal phenotype (89.7%), with infrequent HER2 (8.6%) and basal (1.7%) phenotype tumours seen.ConclusionMBC in BRCA1/2 carriers and BRCAX families is different to females. Unlike FBC, a clear BRCA1 phenotype is not seen but a possible BRCA2 phenotype of micropapillary histological subtype is suggested. Comparison with sporadic MBCs shows this to be a high-risk population making further recruitment and investigation of this cohort of value in further understanding these uncommon tumours.

Invasive ductal carcinomas of breast showing partial reversed cell polarity are associated with lymphatic tumor spread

To investigate the relationship between partial reversed cell polarity (PRCP) and lymphatic tumor spread in invasive ductal carcinoma (IDC), not othervise specified (NOS). Immunohistochemistry (EnVision method) was used to examine the expression of epithelial membrane antigen (EMA) and the reversed cell polarity in 199 cases of IDC. Of the 199 cases, including five cases with micropapillary differentiation,30 cases with PRCP and 164 cases of IDC-NOS (without micropapillary differentiation and/or PRCP), lymphovascular invasion was seen in four (4/5), 13(43.3%) and 30 cases (18.3%) respectively; nodal metastasis was seen in four (4/5), 19 (63.3%) and 56 cases (34.1%) respectively. The rates of lymphovascular invasion and nodal metastasis were significantly higher in IDC with PRCP or IMPC than IDC-NOS (P = 0.00); there was however no significant difference between IDC with PRCP and IMPC for lymphovascular invasion and nodal metastasis (P = 0.18, P = 0.64). IDC with PRCP, similar to IMPC, is more likely to show lymphovascular invasion and nodal metastasis. Complete or partial reversal of cell polarity may play a significant role in lymphatic tumor spread.

Invasive Ductal Carcinomas of the Breast Showing Partial Reversed Cell Polarity are Associated With Lymphatic Tumor Spread and may Represent Part of a Spectrum of Invasive Micropapillary Carcinoma

Invasive micropapillary carcinomas (IMPC) of the breast are aggressive tumors frequently associated with lymphatic invasion and nodal metastasis even when micropapillary (MP) differentiation is very focal within the tumors. We have noticed that some breast carcinomas showing lymphatic spread but lacking histologic features of IMPC have occasional tumor cell clusters reminiscent of those of IMPC without the characteristic prominent retraction artifact. To study the clinicopathologic significance of such features, we prospectively selected 1323 invasive ductal carcinomas and determined the presence and extent of MP differentiation and retraction artifact in the tumors. One representative tumor block per case was used for immunostaining for epithelial membrane antigen (EMA). Partial reverse cell polarity (PRCP) was defined as prominent linear EMA reactivity on at least part of the periphery of tumor cell clusters usually associated with decreased cytoplasmic staining. The clinicopathologic features of carcinomas with PRCP were compared with IMPC and invasive ductal (no special type) carcinomas without this feature. Of the 1323 cases, 96 (7.3%) and 92 (7.0%) showed MP features and the presence of PRCP, respectively. We found that the presence of both PRCP and MP features were strongly associated with decreased cytoplasmic EMA immunoreactivity and the presence of lymphatic invasion and nodal metastasis, even if such features were present only very focally. Our results suggest that breast carcinomas with PRCP may have the same implication as MP differentiation and these tumors may represent part of a spectrum of IMPC. Complete or partial reversal of cell polarity may play a significant role in lymphatic tumor spread.

Mixed micropapillary–ductal carcinomas of the breast: a genomic and immunohistochemical analysis of morphologically distinct components

Micropapillary carcinomas (MPCs) can present as a rare histological special type of breast cancer; however, this histological type is more frequently found admixed with invasive ductal carcinomas of no special type (IDC-NSTs). We have previously demonstrated that pure MPCs constitute a distinct entity at the morphological and genetic levels. Here, we sought to determine whether mixed MPCs have genomic aberrations similar to those found in pure MPCs, and to investigate whether the distinct morphological components of MPCs harbour different genetic aberrations. Using high-resolution microarray comparative genomic hybridization (aCGH), we profiled a series of 10 MPCs of mixed histology and 20 IDC-NSTs matched for grade and oestrogen receptor (ER) status. In addition, we generated tissue microarrays containing a series of 24 pure and 40 mixed MPCs and performed immunohistochemical analysis with ER, progesterone receptor (PR), Ki-67, HER2, cytokeratin (CK) 5/6, CK14, CK17, EGFR, topoisomerase-IIalpha, cyclin D1, caveolin-1 and E-cadherin antibodies. In situ hybridization was employed to evaluate the prevalence of HER2, TOP2A, EGFR, CCND1, MYC and FGFR1 gene amplification. Our results demonstrate that mixed MPCs harbour similar patterns of genomic aberrations and phenotype (82.5% luminal and 17.5% HER2) compared to pure MPCs. A comparison between the distinct morphological components of mixed MPCs in a pairwise fashion revealed that both components harbour strikingly similar genomic profiles. When compared to grade- and ER-matched IDC-NSTs, mixed MPCs significantly more frequently harboured amplification of multiple regions on 8q (adjusted Fisher's p value < 0.05). Furthermore, mixed MPCs displayed higher proliferative rates than grade- and ER-matched IDC-NSTs. Our results suggest that micropapillary differentiation in breast cancer may identify a subgroup of more aggressive ER-positive breast carcinomas, even in those featuring a mixed histology, and that mixed MPCs are more closely related to pure MPCs than to IDC-NSTs.

Possible mechanism of metastasis in lung adenocarcinomas with a micropapillary pattern

Micropapillary differentiation in adenocarcinomas has recently been associated with poor prognosis because these tumors are more likely to metastasize. However, no clear explanation exists as to why the presence of a micropapillary pattern is associated with metastasis. A case of primary lung adenocarcinoma with a prominent micropapillary pattern is presented here, with special reference to the immunohistochemical expression of the E-cadherin-mediated system and IQGAP1. Histologically, the tumor was diagnosed as a moderately differentiated papillary adenocarcinoma, showing an extensive micropapillary pattern, with intrapulmonary metastases, pulmonary disseminations, lymphovascular invasions, and lymph node metastases. Immunohistochemically, positive staining for the adhesion molecules E-cadherin, alpha-catenin, and beta-catenin was detected in both the micropapillary and non-micropapillary areas, whereas IQGAP1 was detected in the micropapillary, but not in the non-micropapillary, area. The adhesive function of E-cadherin depends on the integrity of the entire cadherin-catenin-actin network, and thus the expression of IQGAP1 may lead to adherens junction disassembly, and consequently, the release of carcinoma cells organizing in a micropapillary pattern. This is the first report to suggest correlation between adenocarcinoma with a micropapillary pattern and the presence of adhesion molecules, and offers an intriguing first glimpse on the role of the micropapillary pattern in the process of metastasis.