Colorectal cancer in women: hormone replacement therapy and chemoprevention.

Colorectal cancer (CRC) accounts for 9.4% of new cancer diagnoses among women world-wide. CRC is the third leading cause of incident cancer among women in the United States and has immense impact on morbidity and mortality. We summarize data on CRC pathogenesis and risk in women. We also review the findings from the Women's Health Initiative (WHI) on CRC risk reduction associated with hormone replacement therapy (HRT) use. We then review observational studies since the WHI which evaluated HRT as a chemopreventive agent for CRC among women. The potential mechanisms behind the association between HRT use and CRC are also reviewed. We then discuss the requirements for implementation of chemopreventive agents, and why HRT should not be used for this indication given current knowledge. Further data on the risk-benefit profile of short-term HRT use are needed and will determine whether there is any future role for HRT use in the chemoprevention of CRC.

Mucoepidermoid carcinoma of upper aerodigestive tract: clinicopathologic study of 78 cases with immunohistochemical analysis of Dicer expression.

MicroRNAs (miR) are small noncoding RNAs that are predicted to regulate up to 30% of protein-encoding genes. miR maturation requires functional microRNA machinery, including the Dicer protein. We review our experience with mucoepidermoid carcinoma (MEC) and characterize the prognostic value of Dicer expression. Expression of Dicer was assessed in 78 MEC by immunohistochemistry. Dicer expression was scored semiquantitatively and relative to the internal controls: large excretory/striated ducts or basal/parabasal layers of normal squamous epithelium (mucosa). Dicer scores were then correlated with clinical and pathologic parameters. Dicer over- and/or under-expression were more commonly seen in high-grade MEC (83%) than in low/intermediate grade MEC (35%; p=0.002) and in stage III/IV MEC (80%) than in stage I/II MEC (41%; p=0.04). Abnormal Dicer expression correlates with high-grade and advanced stage, acting as a univariate predictor of poor disease-specific survival (DSS) in MEC. Age and stage were independent predictors of poor DSS on multivariate analysis. Abnormal immunoexpression of Dicer in aggressive MEC suggests a role for miR and miR machinery in tumor progression.

The benefit of combination therapy depends on disease phenotype and duration in Crohn's disease.

BACKGROUND: The impact of combination therapy on disease-related morbidity in patients with established Crohn's disease (CD) or ulcerative colitis (UC) remains to be well-defined. AIM: To examine the effect of combination therapy on disease outcomes in CD and UC. METHODS: Using a multicenter prospective cohort, we classified CD and UC patients as being on monotherapy with anti-TNF or on combination with an immunomodulator. The primary outcome was a composite of new IBD-related surgery, hospitalisations, penetrating complications, need for corticosteroids or new biological at 1 year. Multivariable regression models adjusted for potential confounders. RESULTS: We included 707 patients with CD (45% combination therapy) and 164 with UC (38% combination therapy). Combination therapy was not associated with reduction in the composite outcome in either CD (OR: 0.87, 95% CI: 0.63-1.22) or UC (OR: 1.45, 95% CI: 0.63-3.38). However, while no difference was noted in those with nonstricturing, nonpenetrating CD, a significant reduction in the likelihood of the outcome was seen in those with stricturing or penetrating CD (30% vs 39%, OR: 0.58, 95% CI: 0.37-0.90). A stronger effect was also observed in those with disease duration <5 years (OR: 0.35, 95% CI: 0.14-0.87) compared to those with a longer duration (OR: 0.75, 95% CI: 0.45-1.27). A similar reduction in occurrence of composite outcome was noted with infliximab and with other anti-TNF biologics. CONCLUSION: The benefit of combination immunomodulator-biological therapy is stronger in those with complicated Crohn's disease, particularly early on in their disease course.

Long-term interleukin 2-dependent growth and cytotoxic activity of tumor-infiltrating lymphocytes from human squamous cell carcinomas of the head and neck.

Tumor-infiltrating lymphocytes (TIL) from 16 squamous cell carcinomas of head and neck (SCCH&N) and four nonsquamous cell carcinomas were studied. By immunoperoxidase staining in situ, the tumors studied were found to be infiltrated mainly by CD2+CD3+ cells, and 30-50% of the T-lymphocytes were HLA-DR positive and transferrin-receptor positive. They also contained scarce NKH1+ cells. When TIL as well as autologous peripheral blood lymphocytes (A-PBL) were cultured in 1,000 U/ml of recombinant interleukin 2 (rIL2), TIL proliferated in all but three cases, and A-PBL proliferated in all but two cases. Frequently, but not always, TIL expanded better than A-PBL. The median expansion for TIL was 100-fold and that for A-PBL was 31-fold in long-term cultures maintained for up to 88 days. TIL obtained from untreated primary SCCH&N were initially delayed for up to 20 days in their proliferative response to rIL2, but then grew well. In contrast, TIL and A-PBL from metastatic SCCH&N either did not proliferate or were delayed in their proliferative response for up to 40 or 50 days. A-PBL, when tested early (days 10-20 in culture), showed the highest cytotoxic activity against cultured and fresh tumor-cell targets, whereas TIL were most active later in culture (days 20-30). On a per culture basis, TIL achieved higher antitumor cytotoxicity than A-PBL. By day 80, lytic activities of most TIL cultures declined to undetectable levels. CD3+Leu19- T-lymphocytes were the major expanding cell population in most TIL cultures. However, these cells were poor mediators of antitumor cytotoxicity in TIL or A-PBL cultures as shown in cell sorting experiments. The antitumor effector cells expressed CD3-Leu19+ and/or CD3+Leu19+ phenotypes. On Giemsa-stained smears, these two types of IL2-expanded effector cells had the morphology of large granular lymphocytes. Our results indicate that TIL from human SCCH&N could be expanded and reach high levels of antitumor effector function in long-term cultures with rIL2.

Biology, cytogenetics, and sensitivity to immunological effector cells of new head and neck squamous cell carcinoma lines.

Twenty-one head and neck squamous cell carcinoma (HNSCC) cell lines were established from 89 fresh tumor specimens in order to study the biology of HNSCC lines, establish tumors in nude mice, and evaluate the sensitivity to immunological effector cells of these tumors in vitro and in vivo in nude mice. The lines were established from explants using differential trypsinization and culture for 2 to 20 mo. The explants were derived from 11 different sites. Three pairs of lines were derived from both the primary tumor and metastatic lymph nodes in the same patients. All cultures grew as either compact or diffuse adherent monolayers, and they had a median doubling time of 86 h (range, 33 to 531 h). DNA fingerprinting confirmed that the HNSCC lines were individual isolates. Thirteen of 14 lines tested induced tumors in athymic mice. The histology of each line growing in nude mice was similar to that of the original tumor tissue. Immunocytochemistry showed keratin production in all lines tested. Aneuploidy (36 to 87 chromosomes) was present in all 16 lines studied; the median chromosome number for lines derived from primary tumors was 70, whereas for lines originating from metastatic or recurrent tumors, it was 54. Karyotypic analysis showed deletion of the short arm of chromosome 3 (3p-) in 12 of 16 cell lines and trisomy 6 in 12 of 16 lines. In addition, translocations between chromosomes 9 and 11 or 9 and 12 were each present in five of 16 lines tested. The HNSCC lines were resistant to lysis by natural killer cells, but were efficiently lysed by lymphokine-activated killer cells in 4-h 51Cr release assays. These new lines have allowed us to establish a model of local adoptive immunotherapy of HNSCC in tumor-bearing nude mice, and they provide a resource for future studies of the biology of HNSCC.

Expression of androgen receptor and prostatic specific markers in salivary duct carcinoma: an immunohistochemical analysis of 13 cases and review of the literature.

Salivary duct carcinoma (SDC) is an uncommon, pathologically distinct entity characterized by its morphologic resemblance to ductal carcinoma of the breast and highly aggressive behavior. Approximately two thirds of patients die within 4 years of initial diagnosis despite aggressive, combined surgical resection and radiotherapy. Review of the literature indicates that androgen receptor (AR), a marker frequently detected in prostatic carcinoma, is expressed in over 90% of SDCs, whereas two common breast carcinoma markers, estrogen and progesterone receptors (ER and PR), are expressed in only 1.3% and 6% of the tumors, respectively, by immunohistochemistry. This hormonal profile suggests that SDC, in contrast to its histiologic similarity to ductal carcinoma of the breast, is immunophenotypically more related to prostatic carcinoma. To substantiate this hypothesis, we performed immunohistochemical staining of 13 cases of SDC for the presence of AR and two prostatic markers, prostate specific antigen (PSA) and prostatic acid phosphatase (PAP). Our results showed multifocal, scattered, moderate immunostaining for PAP and diffuse, moderate immunostaining for PSA in seven (58.3%) and two (16.7%) cases, respectively. These results create a potential diagnostic challenge to surgical pathologists who are dealing with a metastatic adenocarcinoma of AR+/PSA+/-/PAP+/- phenotype, particularly in male patients of unknown primary. Metastatic salivary duct carcinoma should be given serious thought if clinical investigation fails to reveal a prostatic primary. The immunophenotypic homology that exists between SDC and prostatic carcinoma also suggests that antiandrogen therapy as used in the treatment of prostatic carcinoma might be beneficial in patients with metastatic SDC when all other conventional modalities fail.

Base of tongue salivary gland tumors.

Salivary tumors of the base of the tongue are encountered infrequently. A retrospective review of medical records from 1955 to 1985 was undertaken to determine the incidence of occurrence and to assess the outcome of the therapy provided. One hundred seventy-eight minor salivary gland tumors of the oral cavity and oropharynx were identified, of which 22 (13%) were located in the tongue base. All were malignant. The most common histologic type was mucoepidermoid carcinoma (10 patients), followed by adenocarcinoma (6 patients), and adenoid cystic carcinoma (6 patients). Thirteen patients were available for a mean follow-up of 5 years. Treatment was most often a combination of wide resection combined with postoperative radiation therapy. Ten patients (77%) are alive, one with persistent disease 8 years after diagnosis. Three patients died within 2 years of diagnosis, one with intercurrent disease. Improved control of disease in this series, when compared to previously reported series, is attributed to adequate surgical therapy and adjuvant radiotherapy. The deaths in our series occurred in patients who were unable to proceed with the recommended therapy. These unusual lesions require aggressive multimodality treatment for improved survival.

Serum gastrin levels in the differential diagnosis of recurrent peptic ulceration due to retained gastric antrum.

If recurrent peptic ulceration follows partial gastrectomy with Billroth II reconstruction, retained antrum on the duodenal stump may be the culprit. Moderate hypergastrinemia and a high basal acid output (BAO) to maximal acid output (MAO) ratio on gastric analysis should alert the clinician. Careful filling of the afferent loop on barium meal or technetium 99m scanning may verify the diagnosis. The secretin provocative test may be helpful in distinguishing retained antrum from the Zollinger-Ellison syndrome by eliciting a decrease in serum gastrin levels in patients with retained antrum and an increase in serum gastrin levels in patients with Zollinger-Ellison syndrome.

Flow cytometric evaluation of adenoid cystic carcinoma: correlation with histologic subtype and survival.

Adenoid cystic carcinoma is an unusual but capricious tumor of salivary gland origin. Characteristically, these tumors follow a relentless clinical course, although some patients experience prolonged disease-free survival. Tumor size, site, and grade have been shown to correlate with tumor behavior. Recent investigation by others has suggested that DNA ploidy as determined by flow cytometry may provide an additional biologic marker of tumor behavior. This study was undertaken to investigate the relationship of DNA ploidy to tumor grade, biologic behavior, and patient outcome. A retrospective comparison of flow cytometric evaluations of paraffin-embedded formalin-fixed tumor specimens with patient outcome and histopathologic grade was undertaken. Follow-up of 4 to 7 years in 26 patients confirmed that the presence of a solid histologic component in the tumor correlated with the presence of recurrent or persistent disease (p = 0.04). Twenty-two of 28 tumors (78%) were found to be aneuploid on at least one section. Comparison of DNA ploidy with either patient outcome or the presence of a solid component did not achieve statistical significance, although a trend was suggested. This study confirms previous studies demonstrating the validity of histopathologic evaluation of tumor grade in the prediction of the biologic behavior of adenoid cystic carcinoma. However, our findings suggest that DNA ploidy has only limited value as an additional marker of tumor behavior in this patient population.

Small cell anaplastic (oat cell) carcinoma of the larynx: report of a case and review of the literature.

The fifth reported patient with primary laryngeal oat cell carcinoma is described. Electron microscopy of tumor cells revealed typical neurosecretory-type granules similar to those described for pulmonary oat cell carcinoma. Analysis of clinical data from all five reported patients revealed that this neoplasm is a virulent one which spreads early and rapidly and kills quickly. Combination chemotherapy and/or radiotherapy, which has significantly prolonged life in patients with oat cell carcinoma of lung, may be indicated as an adjunct to surgery for this rare malignant tumor of the larynx.

Management of inverted papilloma of the nose and paranasal sinuses.

Inverted papilloma of the nose and paranasal sinuses is a neoplastic growth of epithelium which inverts into the underlying stroma rather than proliferating outward from the surface. These neoplasms probably arise from the area of the lateral nasal wall. Inverted papilloma is characterized by its: A. capacity to destroy; B. tendency to recur; and C. association with malignancy. During the past decade, we have come to understand better the histologic, biologic, and anatomic features of this tumor. More studies focusing on inverted papilloma have been published in recent years, and the authors of these reports have advocated more aggressive surgical procedures in the management of this tumor. The application of the technique of lateral rhinotomy and en bloc excision of the lateral nasal wall has dramatically decreased the recurrence rate while providing the patient with quite acceptable cosmetic and functional results. The surgical approach to inverted papilloma associated with squamous cell carcinoma varies with the extent of disease; but a good cure rate, especially with localized tumors, may be achieved with aggressive surgery combined with radiation therapy in these cases. We present a series of 19 patients with inverted papilloma. In 6 of these 19 patients, squamous cell carcinoma was associated with the inverted papilloma; 13 of the patients with inverted papilloma and 3 of the patients with an associated malignancy underwent lateral rhinotomy with en bloc excision of the lateral nasal wall. The tumor did not recur in these patients. The rationale for this surgery, as well as the details of these patient's case histories, form the basis of this report.

Metastasis of malignant melanoma of the nasal mucosa to the small intestine.

Malignant melanoma of the mucous membranes is rare and has a very poor prognosis. When localized in the nose, the tumor becomes apparent late in the course of the disease with nasal obstruction and epistaxis. Distant metastases are uncommon, but any organ of the body can be involved. A case of a malignant melanoma of the nasal mucosa with metastasis to the small intestine is presented, and the natural history of the metastatic disease is discussed.

Management of inverted papilloma.

This paper updates a 1981 report on the management of inverted papilloma. In that report, routine lateral rhinotomy with en bloc resection of the lateral nasal wall, including the entire schneiderian membrane, was recommended. This report emphasizes the use of computed tomography scanning in management planning. Of 33 patients with inverted papilloma treated between 1969 and 1987, 7 had associated squamous cell carcinoma. Twenty-two patients with IP alone were treated with medial maxillectomy; however, 3 patients have been successfully treated with either a Caldwell-Luc/ethmoidectomy or an external ethmoidectomy for localized disease. The use of computed tomography capable of higher resolution allowed preoperative determination of the extent of disease, enabling the surgeon to plan the surgery more precisely. Patients were followed for an average of 9.6 years. Recurrent disease occurred in one patient (4%) following a lateral rhinotomy/medial maxillectomy approach. The principles set forth in this series of patients remain the same as those previously described due to the unique characteristics of this tumor: its ability to destroy bone, its tendency to recur, and its association with malignancy. The technique of lateral rhinotomy and en bloc excision of the lateral nasal wall, followed by meticulous removal of all mucosa in the ipsilateral paranasal sinuses, remains the standard therapy.

Neuromuscular hamartomas of the head and neck.

The neuromuscular hamartoma (also referred to as the neuromuscular choristoma or benign triton tumor) is a rare developmental lesion composed of mature elements of both striated muscle and nerve. To date, less than 20 cases have been reported in the English language literature. The majority of these have involved large nerves, such as the sciatic or brachial plexus, but cutaneous lesions have also been reported. We report 2 cases that involve the head and neck and that are among the few described in this location. The majority of cases have been described in infants and young children. However, 1 of our cases (and at least 1 previously reported case) occurred in an adult. While surgical excision has been the most widely used form of therapy, a few cases have been complicated by and/or associated with a second lesion, such as a fibromatosis or lymphangioma.

Eagle syndrome produced by a granular cell tumor.

Eagle syndrome includes elicitation of pain on swallowing, turning the head, or extending the tongue. The syndrome is thought to be caused by irritation of the glossopharyngeal nerve, most commonly caused by its impingement against an elongated styloid process. We present a rare case of a granular cell tumor presenting as Eagle syndrome. Granular cell tumors orignate from Schwann cells and are most common in the subcutaneous tissue of the head, neck, and oral cavity, especially the tongue. A granular cell tumor is typically benign and solitary, rarely malignant. The differential diagnosis, diagnostic algorithm, and treatment are presented.

Expression of androgen receptor, epidermal growth factor receptor, and transforming growth factor alpha in salivary duct carcinoma.

BACKGROUND: Salivary duct carcinoma (SDC) is a rare, highly aggressive neoplasm that primarily affects the major salivary glands. It is a distinct clinicopathological entity characterized by its morphologic resemblance to ductal carcinoma of the breast, a high incidence of regional lymph node metastasis, and distant dissemination. Frequent expression of androgen receptor (AR) but not estrogen receptor or progesterone receptor in SDCs suggests that SDC bears a close immunophenotypic homology with prostatic carcinoma. An AR-mediated autocrine growth pathway consisting of epidermal growth factor receptor (EGFR) and its ligand, transforming growth factor alpha (TGF-alpha), has been implicated in the carcinogenesis of prostatic carcinoma. Androgens, in the presence of AR, mediate their mitogenic effects on prostatic cancer cells by up-regulating the transcriptional and translational activities of EGFR and TGF-alpha. Through an autocrine mode of action, TGF-alpha produced in the tumor cells binds to its receptor, EGFR, which is also expressed by these cells, resulting in a proliferative response. OBJECTIVE: To investigate whether a TGF-alpha/EGFR autocrine pathway is present in SDCs. DESIGN: Retrospective analysis of the expression of AR, EGFR, and TGF-alpha in 12 SDCs. SETTING: An academic medical center. RESULTS: Salivary duct carcinoma expresses AR, TGF-alpha, and EGFR in 11 (92%), 8 (67%), and 11 (92%) of 12 cases, respectively. CONCLUSION: An AR-mediated TGF-alpha/EGFR autocrine pathway may be implicated in the tumorigenesis of SDC.

Lymphatic mapping with isosulfan blue dye in squamous cell carcinoma of the head and neck.

OBJECTIVE: To determine whether intraoperative lymphatic mapping with isosulfan blue dye and sentinel lymph node biopsy accurately demonstrates the pathway of regional metastases from mucosal sites in squamous cell carcinoma of the head and neck. DESIGN: A prospective clinical study of intraoperative lymphatic mapping. SETTING: An academic tertiary referral center. PATIENTS: Patients with previously untreated squamous cell carcinoma of the head and neck whose surgical treatment included neck dissection. INTERVENTION: Injection of isosulfan blue dye into the mucosa surrounding squamous cell carcinomas of the upper aerodigestive tract during cervical lymphadenectomy. OUTCOME MEASURES: Correlation of the pathologic findings in the blue sentinel lymph node with those in the remaining cervical lymphatics. RESULTS: No blue-stained cervical lymphatics were identified after injection of the mucosa surrounding the primary squamous cell carcinoma with isosulfan dye. CONCLUSION: The technique of intraoperative lymphatic mapping with isosulfan blue dye requires further study before it can be used for the detection of occult cervical metastases in squamous cell carcinoma of the head and neck.

Adult onset laryngeal papillomatosis.

The charts of 22 patients with an onset of laryngeal papillomatosis after age 18 were reviewed retrospectively. The typical patient had hoarseness. Airway obstruction did not occur in this series. One half of the patients had one recurrence or less of their papilloma. The remainder of the patients encountered multiple recurrences. The histologic criteria of mitosis and dysplasia reflected recent past activity and correlated poorly with subsequent clinical behavior. Malignancy did not occur in the larynx of any of these adult onset laryngeal papilloma patients followed from 1 to 20 years.

Extraparotid Warthin's tumor.

Papillary cystadenoma lymphomatosum (Warthin's tumor) is a benign, slowly growing tumor found almost exclusively in the parotid gland or periparotid lymph nodes. Our experience with 14 cases of extraparotid Warthin's tumor (EPWT) over 22 years is presented. All cases occurred in extraparotid lymph nodes and represented 8.0% of 176 Warthin's tumors accessioned during this time. Fourteen cases of EPWT occurred in 13 patients (seven men and six women) between 41 and 77 years old. Three of the 13 patients (23%) had associated Warthin's tumor of the parotid gland. One of these patients also had a metachronous EPWT presented as a contralateral cervical mass. EPWT was discovered incidentally in six patients (46%) undergoing neck dissections for malignancies of the head and neck. Four patients (31%) presented with clinically evident solitary cervical masses. The embryologic basis for such findings is discussed. EPWT is adequately managed by conservative excision.