Carmen Gomez-Fernandez

Docetaxel, Cisplatin, and Trastuzumab As Primary Systemic Therapy for Human Epidermal Growth Factor Receptor 2–Positive Locally Advanced Breast Cancer

PURPOSE To evaluate the efficacy and safety of docetaxel, cisplatin, and trastuzumab as primary systemic therapy for human epidermal growth factor receptor 2 (HER2) -positive, locally advanced breast cancer (LABC). PATIENTS AND METHODS Forty-eight patients with immunohistochemistry-confirmed HER2-positive LABC or inflammatory breast cancer received 12 weeks of docetaxel, cisplatin, and trastuzumab with filgrastim, followed by surgery, adjuvant doxorubicin and cyclophosphamide, and locoregional radiotherapy with or without tamoxifen. The primary end point was pathologic complete response (pCR) in breast. RESULTS Baseline mean tumor size was 9.2 cm (range, 4 to 32 cm). pCR occurred in breast in 11 patients (23%; 95% CI, 12% to 37%) and breast and axilla in eight patients (17%; 95% CI, 8% to 30%). pCR rates in breast (HER2 positive, seven of 30 patients, 23% v HER2 negative, four of 18 patients, 22%; P > .05) and breast and axilla (four of 30 patients, 13% v four of 18 patients, 22%, respectively; P > .05) were similar regardless of HER2 status by fluorescence in situ hybridization (FISH). At a median follow-up time of 43 months, 4-year progression-free survival (PFS) rate was 81% (95% CI, 64% to 90%); overall survival (OS) rate was 86% (95% CI, 71% to 94%). In patients with pCR in breast and axilla, PFS and OS rates were 100% (95% CI, inestimable). In patients without pCR, PFS rate was 76% (95% CI, 57% to 88%; P = .15, log-rank test), and OS rate was 83% (95% CI, 66% to 92%; P = .21). Survival rates were similar regardless of FISH status. There were only two grade 4 adverse events. CONCLUSION Twelve weeks of docetaxel, cisplatin, and trastuzumab is clinically active and leads to excellent survival in patients with large, HER2-positive tumors.

Searching for mammary analog secretory carcinoma of salivary gland among its mimics

Mammary analog secretory carcinoma of salivary gland is a recently described entity with unique morphologic, clinical, and genetic characteristics, including the characteristic t(12;15)(p13;q25) with ETV6-NTRK3 translocation found in secretory carcinomas of the breast. Before their initial description, these salivary gland tumors were generally diagnosed as acinic cell carcinoma or adenocarcinoma. For the purpose of this study, all cases of salivary gland acinic cell carcinoma, cribriform cystadenocarcinoma, and adenocarcinoma, not otherwise specified (NOS), diagnosed over a 10-year period were retrieved from our surgical pathology files. There were a total of 11 cases diagnosed as acinic cell carcinoma, 10 cases of adenocarcinoma, NOS, and 6 cases of cribriform cystadenocarcinoma. All slides were reviewed by two pathologists (AP, CGF) and tumors that show morphologic features of mammary analog secretory carcinoma according to the recent literature were selected. This process narrowed down the initial number to six cases originally diagnosed as acinic cell carcinoma, three cases originally diagnosed as adenocarcinoma, NOS, and one case originally diagnosed as cribriform cystadenocarcinoma. The 10 cases were subjected to immunohistochemistry for S-100, mammaglobin, and ANO1, as well as fluorescence in situ hybridization analysis for t(12;15)(p13;q25) with ETV6-NTRK3 fusion rearrangement. The ETV6-NTRK3 gene rearrangement was detected in three tumors. These three tumors, initially diagnosed as acinic cell carcinomas, stained positive for S-100 and mammaglobin, and negative for ANO1 by immunohistochemistry. Two of the three patients were male (2/3). In summary, mammary analog secretory carcinoma is a newly described diagnostic entity that should be in the differential diagnosis of salivary gland tumors that morphologically mimic other neoplasms, mainly acinic cell carcinomas. They differ from conventional acinic cell tumors immunohistochemically and molecularly. Positivity for mammaglobin and S-100, and negativity for ANO1 are useful screening tools before confirmatory molecular studies.

MUC4 and ERBB2 expression in major and minor salivary gland mucoepidermoid carcinoma

Peptide sequence homology between the gene product of human MUC4 and rat sialomucin complex (SMC) has recently been reported. Each contains a mucin subunit with antiadhesive activity linked to the plasma membrane by means of a transmembrane subunit with two epidermal growth factor (EGF)–like domains that act as ligand for ErbB2. This study investigates MUC4 and ErbB2 receptor expression in major and minor salivary gland mucoepidermoid carcinoma and correlates patterns of expression with clinical outcomes.

Immunohistochemically Determined Estrogen Receptor Phenotype Remains Stable in Recurrent and Metastatic Breast Cancer

We evaluated the estrogen receptor (ER) phenotype of recurrent and/or metastatic breast cancers and compared it with the ER status of the primary tumor in 278 cases. All patients had undergone surgical excision of the primary tumor, followed by observation only or treatment modalities that included radiation and/or chemotherapy or hormonal therapy. The immunohistochemical expression of ER was evaluated by using monoclonal antibody ER-1D5 and heat-induced antigen retrieval. At diagnosis, 165 patients had locoregional disease and 7 had distant metastases. Local recurrences and/or distant metastases occurred from 2 months to 21 years after the diagnosis of the primary tumor. Overall, 159 primary tumors (57.2%) were positive for ER. In 269 cases (96.8%), the ER status of the primary and metastatic tumors was the same. In 9 patients with ER+ primary tumors, the metastases were ER-. There were no ER- primary tumors with ER+ metastases. The time to distant metastasis was significantly longer for ER+ tumors. The immunohistochemically determined ER phenotype of primary breast cancers remains stable in most recurrent and metastatic disease.

Immunohistochemical expression of estrogen receptor in adenocarcinomas of the lung: the antibody factor.

BackgroundImmunohistochemistry for estrogen receptor may be used to distinguish metastatic breast cancers from adenocarcinomas of other sites, including those of the lung. The estrogen receptor exists as 2 subtypes, α and β. Estrogen receptor α is the predominant subtype expressed by more than two-thirds of human breast cancers. Adenocarcinomas of lung origin may also express estrogen receptor, primarily the β subtype. Human estrogen receptor α is highly homologous to estrogen receptor β and consequently, antibodies used to detect estrogen receptor α in breast carcinomas may detect estrogen receptor β in pulmonary adenocarcinomas. We investigated the immunohistochemical expression of estrogen receptor in proven primary lung adenocarcinomas using 3 anti-estrogen receptor α antibodies: mouse monoclonal 1D5, 6F11, and rabbit monoclonal SP1. DesignNinety-two pulmonary adenocarcinomas (53 women and 39 men) confirmed by clinical presentation and positive immunohistochemistry for thyroid transcription factor-1 (TTF-1) were included in this study. There were 19 incisional biopsies and 73 excisional specimens. Immunohistochemistry for estrogen receptor using antibodies 1D5, 6F11, and SP1 was performed on formalin-fixed, paraffin-embedded tissue following antigen retrieval. Any nuclear reactivity for estrogen receptor was considered a positive result. ResultFocal positive nuclear reaction for estrogen receptor was detected in 7 (7.6%) cases of primary pulmonary adenocarcinoma using antibody 1D5, 13 (14.1%) using 6F11, and 25 (27.2%) using SP1. The differences in reactivity for estrogen receptor in pulmonary adenocarcinomas between SP1 and 1D5, and between SP1 and 6F11 were statistically significant (P<0.001). Positive cases showed only a focal pattern of staining with each of the 3 antibodies. There was no significant difference in reactivity for estrogen receptor in pulmonary adenocarcinomas of men and women. Positive staining was highest in nonmucinous bronchioloalveolar adenocarcinomas for all of the antibodies, and for SP1, variation by histologic subtype was significant (P<0.001). ConclusionsSP1 has a significantly higher detection rate for the expression of estrogen receptor in pulmonary adenocarcinomas when compared with either 1D5 or 6F11. Caution should therefore be exercised in the use of this antibody alone in distinguishing a metastatic breast from a primary pulmonary adenocarcinoma.

MUC4 and ErbB2 expression in squamous cell carcinoma of the upper aerodigestive tract: correlation with clinical outcomes.

Objectives/Hypothesis: Expression of the membrane mucin MUC4 has been associated with a variety of malignancies, including squamous cell carcinoma of the upper aerodigestive tract. MUC4 modulates cell signaling pathways as an intramembrane ligand of ErbB2. The hypotheses of the study were that MUC4 expression would correlate with ErbB2 expression and that MUC4 expression would correlate with clinical outcomes in squamous cell carcinoma of the upper aerodigestive tract.

Adult renal cell carcinoma with rhabdoid morphology represents a neoplastic dedifferentiation analogous to sarcomatoid carcinoma

Renal cell carcinoma (RCC) with rhabdoid morphology (RCC-RM) is a recently described variant of RCC, which has an aggressive biologic behavior and poor prognosis, akin to sarcomatoid RCC. The current World Health Organization classification of RCC does not include the rhabdoid phenotype as a distinct histologic entity. The aim of this study is to investigate whether RCC-RM represents a dedifferentiation of a classifiable-type World Health Organization RCC or a carcinosarcoma with muscle differentiation. We reviewed 168 cases of RCC obtained between 2003 and 2008. From these cases, 10 (6%) were found to have areas of classic rhabdoid morphology. Immunohistochemistry for cytokeratin, epithelial membrane antigen, desmin, CD10, and CD117 was performed in each case using the labeled streptavidin-biotin method. Rhabdoid differentiation was identified in association with conventional-type RCC (9) and with unclassifiable-type RCC with spindle cell morphology (1). In all cases, both the rhabdoid and nonrhabdoid tumoral areas were positive for cytokeratin and epithelial membrane antigen and negative for desmin. Cytokeratin positivity in the rhabdoid areas was focal. In cases associated with conventional-type RCC, CD10 was positive in both the rhabdoid and nonrhabdoid foci. CD117 was negative in these tumors. The unclassifiable-type RCC with spindle cell morphology was negative for both CD10 and CD117. The similar immunophenotype between the rhabdoid and nonrhabdoid tumoral foci supports the origin of the rhabdoid cells from the classifiable-type RCC. Areas of rhabdoid morphology do not represent muscle metaplastic differentiation. Renal cell carcinoma with rhabdoid morphology may represent a dedifferentiation of a classifiable-type RCC, similar to that of sarcomatoid differentiation. The recognition of RCC-RM is important as it allows for the inclusion of these high-grade malignancies into a category associated with poor prognosis despite lacking the spindle cell component classically identified as sarcomatoid change.

Low biopsy volume in ureteroscopy does not affect tumor biopsy grading in upper tract urothelial carcinoma

OBJECTIVES Urothelial carcinomas (UC) from the upper urinary tract represent 7%-10% of all kidney malignancies. With current ureteroscopic (URS) techniques, small tissue samples are usually the only available histopathologic material for evaluation, representing a diagnostic challenge. Precision in diagnosis is essential for treatment decision making. There has been much debate as to whether tumor grade and stage found on biopsy agree with final pathology. The purpose of this study is to evaluate whether URS biopsy volume affects tumor grading and staging agreement between biopsy and nephroureterectomy (NU) specimens. MATERIALS AND METHODS We reviewed 137 URS biopsies in 81 patients with suspected upper urinary tract UC performed from April 2002 to April 2011. Of those, 54 patients had both the URS biopsy and NU performed at our institution and were available for review. Biopsy dimensions were recorded to calculate estimated ellipsoid volume, and 2 urological pathologists independently evaluated histologic grade (ISUP/WHO 2004), (based on pleomorphism and mitosis) and depth of invasion. Statistical analysis was performed to evaluate URS biopsy and NU specimen grade and stage concordance. In addition, univariable and multivariable analyses was performed to assess the effect of biopsy volume on agreement. RESULTS Of the 54 patients studied, low grade and high grade UC biopsy were found in 8 (15%) and 46 (85%), URS biopsies, respectively. Regarding biopsy stage, 51 (94%), 1 (2%), and 2 (4%) were stage Ta, T1, T2, respectively. Grade concordance was 92.6%, (95% CI: 82.4%-98.0%). Stage concordance was 43% (95% CI: 28.7%-55.9%). Multivariable analysis showed biopsy volume did not affect tumor assessment of grade (P = 0.81) or stage (P = 0.44). CONCLUSIONS Histologic grade assigned on the URS biopsy sample accurately predicts histologic grade in the resected specimen (92.6%), even when the biopsy volume is small. Grading in URS biopsies provides sufficient information for clinical decision making that is independent of sample volume.

MANAGEMENT OF THE NECK IN MERKEL CELL CARCINOMA OF THE HEAD AND NECK: UNIVERSITY OF MIAMI EXPERIENCE

We reviewed management of the cervical lymph nodes in patients with Merkel cell carcinoma (MCC) of the head and neck.

MUC4 (Sialomucin Complex) Expression in Salivary Gland Tumors and Squamous Cell Carcinoma of the Upper Aerodigestive Tract

OBJECTIVES: This study investigates MUC4 expression in normal squamous epithelia and squamous cell carcinoma (SCC) of the upper aerodigestive tract (UADT), and in salivary gland neoplasms. STUDY DESIGN: MUC4 antigens in tumor and adjacent normal tissue are localized by immunocytochemical studies. Fresh frozen tissues from surgical resection specimens are further analyzed by Western blot. RESULTS: MUC4 is identified by immunocytochemical staining throughout the normal UADT mucosa, in 34 of 40 primary UADT SCC, and in 11 of 12 metastatic cervical lymph nodes. A trend toward decreased MUC4 staining in moderately and poorly differentiated tumors is noted. Immunoblots show MUC4 in 4 of 5 SCC analyzed. Immunocytochemical staining of MUC4 in 13 major and minor salivary gland neoplasms reveal variable staining of normal and neoplastic tissue. MUC4 is demonstrated in immunoblots of normal parotid tissue and in the single parotid malignancy analyzed, but is not demonstrated in one minor salivary gland malignancy. These findings characterize normal UADT mucosal and salivary MUC4 expression, and MUC4 expression in SCC of the UADT and in salivary gland tumors. SIGNIFICANCE: Correlation of MUC4 expression with clinical outcomes may establish MUC4 as a potential molecular prognostic marker for these tumors.