Kenneth D. McClatchey

Chondrosarcoma of the head and neck

Chondrosarcoma is a malignancy rarely encountered in the head and neck. In an attempt to define this tumors characteristics and response to therapy, all cases of chondrosarcoma treated at the University of Michigan over the past 25 years were retrospectively studied. Fourteen cases originating in the nose and paranasal sinuses, mandible, temporal bone, and larynx were reviewed. Aggressive surgical resection was the mainstay of treatment, and resulted in an overall survival of 70%, with an average follow‐up of 3.5 years. Survival was highest in primary temporal bone lesions, and lowest in paranasal sinus lesions. Unre‐sectable lesions were not cured by other modalities. This study, therefore, continued to support the crucial role of wide surgical resection in the treatment of head and neck chondrosarcoma, but conservative resection, when needed to preserve important structures, has resulted in long‐term survival.

Radiation-associated sarcoma: A review of 23 patients with postradiation sarcoma over a 50-year period

Between 1934 and 1983, 23 patients with well-documented diagnosis of radiation-associated sarcoma (RAS) were seen at the University of Michigan Medical Center. The median latent period from irradiation to diagnosis of RAS was 13 years with a minimum latent period of 3 and a maximum of 34 years. All sarcomas originated in previously normal tissues within the irradiated field. Pathology slides available in all patients were reviewed by the same pathologist for the purpose of the study, and the diagnosis of sarcoma was confirmed histologically. There were five bone sarcomas and 18 soft tissue sarcomas. Thirteen patients developed radiation- associated sarcoma following megavoltage treatment with a minimum total radiation dose of 25 Gy in 2½ weeks. The other 10 patients received orthovoltage and/or brachytherapy irradiation alone or combined with external beam radiation. In this group, the radiation doses ranged from 25 Gy to 72 Gy except for one patient who received 8 Gy delivered by orthovoltage irradiation as treatment of knee arthritis. Four patients were originally treated for benign conditions. All the other patients (n = 19) received radiation therapy for a variety of primary malignancies including carcinoma of the cervix (n = 4), brain gliomas (n = 13), Wilms tumors (n = 2) and retinoblastomas (n = 2), among others.

Minor salivary gland tumors. A histologic and immunohistochemical study

Clinical, histologic, and immunohistochemical data were reviewed and evaluated on 238 oral minor salivary gland tumors. Benign neoplasms accounted for 65% of the total. Pleomorphic adenomas were the most common of all neoplasms, and mucoepidermoid carcinomas were the most frequently encountered malignancies. Pleomorphic adenomas and adenoid cystic carcinomas stained positive for S‐100 protein. Immunohistochemistry was believed to be of potential assistance in diagnosis of salivary gland tumors and in prediction of histogenesis.

Lymphocyte subpopulations infiltrating squamous carcinomas of the head and neck: Correlations with extent of tumor and prognosis

Because little is known about the mechanisms involved in local tumor-host immune reactions in squamous carcinoma of the head and neck, a study was undertaken to better characterize the types of immune cells present at the local tumor site and determine their relationship to tumor extent, systemic cellular immune parameters, and clinical outcome. In 40 untreated patients, lymphocyte subsets (LS) at the tumor-host interface were quantitated immunohistologically from serial sections of frozen tumor specimens and correlated with concurrently measured peripheral LS levels and in vitro lymphocyte reactivity to phytohemagglutinin (PHA). The majority of infiltrating lymphocytes were T cells with rare B or Leu 7 cells. Proportions of T4 and T8 were similar in peritumor stroma; however, T8 cells predominated tumor parenchyma. Stromal and parenchymal infiltration by LS were not related to peripheral blood LS levels, lymphocyte reactivity, or tumor site. However, parenchymal T11 and T4 cell infiltration was less in advanced primary tumors (T3, T4) than in early tumors (T1, T2) (P = 0.01, P = 0.067, respectively), as was peripheral lymphocyte reactivity to PHA (P = 0.013). Short-term disease-free interval and actuarial survival differed significantly—according to parenchymal T11 and T4 cell infiltration—and were not related to T8, leu 7, and B-cell infiltration. The findings extend prior studies of lymphocytic infiltration in head and neck cancer and demonstrate the potential importance of differences in tumor stromal and parenchymal infiltration. Together with recent evidence that T4 cells are critical for lymphokine production and for the proliferation of cytotoxic effector cells, the current results suggest that T4 cells play a critical role in the local immune response in squamous carcinoma of the head and neck.

Overexpression of p53 Predicts Organ Preservation Using Induction Chemotherapy and Radiation in Patients with Advanced Laryngeal Cancer

A critical research frontier in head and neck oncology involves defining the use of induction chemotherapy regimens to allow organ preservation and to avoid functionally debilitating surgical resections. Completed clinical trials in laryngeal cancer indicate that such an approach is feasible, but progress thus far has been limited by our inability to predict which patients are likely to respond to chemotherapy and preserve their larynx. Mutation of the p53 tumor-suppressor gene is the most common genetic alteration identified thus far in human cancers, and it may be important in regulation of cell proliferation and chemosensitivity. To determine whether p53 overexpression predicts chemotherapy response, organ preservation, and survival in patients with advanced laryngeal cancer, we analyzed immunohistologic expression of p53 in tissue sections from 178 patients with advanced laryngeal cancer who were entered in the Department of Veterans Affairs Laryngeal Cancer Cooperative Study, a multiinstitutional clinical trial comparing induction chemotherapy (cis-platinum and 5-fluorouracil) plus radiation therapy (94 patients) to surgery plus postoperative radiation therapy (84 patients). Larynx preservation was significantly higher in the group of patients whose tumors overexpressed p53 (74% vs. 52.5%; p = 0.03). The presence of p53 overexpression did not predict survival in either the surgery or the chemotherapy groups (p = 0.82 and p = 0.53).

In Vitro Radiation Resistance Among Cell Lines Established From Patients With Squamous Cell Carcinoma of the Head and Neck

Twenty‐five squamous cell carcinoma (SCC) cell lines from 20 patients with head and neck cancer were assessed for radiosensitivity in vitro using a 96‐well plate assay. Four non‐SCC lines were also tested. Radiation sensitivity of individual cell lines was compared using the area under the survival curve (AUC) as a measure of the mean inactivation dose. Tumor lines were tested with either a cobalt‐60 (60Co) γ‐irradiator having a dose rate of 100 cGy/minute or with a 4‐meV photon beam having a dose rate of 200 cGy/minute. The mean AUC of the 25 SCC cell lines was 188 ± 7 (SEM) cGy (range, 100 to 250 cGy) whereas the four non‐SCC lines had a mean AUC of 225 ± 9 cGy. The SCC cell lines with mean inactivation dose values greater than 188 cGy were classified as relatively radioresistant whereas those with values less than 188 cGy were considered relatively radiosensitive. In seven cases SCC cell lines were derived from patients who had already received radiation therapy. In four of these cases the tumor cell lines were radioresistant (AUC, 210 to 250) but in the other three cases the tumor lines were radiosensitive (AUC, 160 to 180). Thus, failure of a tumor to respond to radiation did not always select for radioresistant cells. The mean of the AUC for cell lines from previously irradiated patients (197 ± 11 cGy) did not differ significantly from that of the cell lines from patients who received no prior radiation therapy (182 ± 9 cGy). However, among radiation‐resistant lines those from the four previously irradiated patients were significantly more resistant (mean AUC = 235 ± 9) than seven other radioresistant lines from nonirradiated patients (mean AUC, 208 ± 4) (P = 0.0194). In four cases more than one cell line was derived from different tumor specimens in the same patient. In each of these cases the lines from the same patients were similar to one another in their degree of radioresistance. Based on these observations the authors conclude that the degree of in vitro radiation resistance is an inherent property of some squamous cell tumors.

Studies on the endogenous flora of the human breast

Identification of the endogenous microbiological flora of the human breast and its role in breast infections following subglandular augmentation or reduction mammaplasty was undertaken. A total of 231 cultures were performed on 59 breasts in 30 patients. Patients were followed for 12 months.No fungus was cultured from any specimen. Of the breasts cultured 53% were positive for coagulase-negative staphylococcus. Other aerobes found included diphtheroids, lactobacillus, D-enterococcus, micrococcus, and α-hemolytic streptococcus. Propionibacterium acne was the most frequent anaerobic bacteria cultured. Other anaerobes included peptococcus and clostridium sporogenes. There was no correlation with respect to the type of bacterium and the depth within the breast where the culture specimens were taken. Postoperative wound infections developed in 2 of 19 patients undergoing reduction mammaplasty. Bacteria identical to those cultured at the time of surgery were again cultured from the wound. Twenty subglandular augmentation mammaplasties were performed with a 25% capsular rate at one year. Two capsules were associated with no bacterial growth at the time of mammaplasty surgery, whereas three were associated with coagulase-negative staphylococcus, Propionibacterium acne, and diphtheroids, respectively. Of the 15 breasts with no capsular contracture after one year, operative culture revealed coagulase-negative staphylococcus in 8 and no bacterial growth in 7.Even breast tissue located deep within the gland away from the nipple contains a flora that is similar to that of normal skin. Cases of infection in which the endogenous bacteria were correlated with later infection was documented.

Squamous carcinoma of the head and neck in organ transplant recipients: possible role of oncogenic viruses.

A consistently increased incidence of malignancies in renal transplant recipients has been attributed to the effect of chronic immunosuppression required to prevent transplant rejection. Tumors arising in such patients offer a unique opportunity to study the interactions of the immune system and tumor development. A series of three cases of head and neck squamous cell carcinoma arising in patients after renal, cardiac, or bone marrow transplantation are reported. Patient ages at tumor diagnosis were 18, 29, and 53 years, respectively. Time from transplant to diagnosis of tumor ranged from 7 months to 12 years. Only the youngest patient lacked a history of exposure to the traditional predisposing factors of tobacco and alcohol use. Histo‐pathologic examination in all three tumors showed features of koilocytosis with hyperkeratosis and parakeratosis suggestive of papillomavirus infection. Squamous carcinoma cells from one of these patients have been successfully established in cell culture. Immune system impairments secondary to the use of antirejection drugs could allow the expression of oncogenic viruses. A recent report of human papillomavirus (HPV) DNA in a primary and metastatic perianal squamous cell carcinoma from a renal transplant recipient, as well as the reported presence of HPV in benign and malignant neoplasms of the upper aerodigestive tract suggests that HPV infection could play a role in the development of squamous carcinomas in transplant recipients. Further studies of HPV invection in cultured cell lines derived from head and neck tumors occurring in immunosup‐pressed patients are needed to define this relationship.

Evaluation of Axillary Sentinel Lymph Node Biopsy by Immunohistochemistry and Multilevel Sectioning in Patients With Breast Carcinoma

BACKGROUND Axillary lymph node dissection for evaluation of the presence or absence of metastatic disease is the single most important prognostic factor for patients with newly diagnosed primary breast cancer. Recently, sentinel lymph node (SLN) biopsy is being investigated as an alternative to the evaluation of the entire axilla. We evaluated whether the application of multilevel sectioning and immunohistochemistry in SLNs will increase the accuracy of detection of metastatic deposits. METHODS Between October 1998 and July 1999, 38 patients with breast carcinoma (25 ductal, 5 lobular, 4 tubular, and 4 mixed ductal and lobular) underwent successful SLN biopsy followed by complete axillary node dissection. Sentinel lymph nodes were localized with a combination of isosulfan blue dye and radionuclide colloid injection. Frozen sections and permanent sections of SLNs were examined. All negative SLNs were examined for micrometastases by 3 additional hematoxylin-eosin (H&E)-stained sections and immunohistochemistry with the cytokeratins AE1/AE3. RESULTS Sentinel lymph nodes were successfully identified surgically in 38 (93%) of 41 patients. There was a 97% correlation between the results of the frozen sections and the permanent H&E-stained sections. Twelve (32%) of 38 patients showed evidence of metastatic disease in their SLN by routine H&E staining. In 7 (58%) of 12 patients with positive nodes, the sentinel node was the only positive node. The 26 patients with negative SLN examination by H&E were further analyzed for micrometastases; 5 (19%) were found to have metastatic deposits by immunohistochemistry. Of these patients, 2 were also converted to node positive by detection of micrometastatic disease by examination of the additional H&E levels. CONCLUSIONS Sentinel lymph nodes can be accurately identified in the axilla of breast cancer patients. Evaluation of SLNs provides reliable information representative of the status of the axilla in these patients. Immunohistochemistry and, to a lesser degree, detailed multilevel sectioning are able to further improve our ability to detect micrometastatic disease in SLNs of breast cancer patients.

Predictive markers for response to chemotherapy, organ preservation, and survival in patients with advanced laryngeal carcinoma.

OBJECTIVE: A systematic retrospective study of the largest randomized trial of induction chemotherapy and radiation for advanced laryngeal cancer was undertaken to determine whether specific tumor or biologic factors were predictive of chemotherapy response, organ preservation, or survival. METHODS: The variables analyzed included clinical and histologic factors, immunohistochemical expression of proliferating cell nuclear antigen and p53, and adjusted DNA index measurements. Variables were evaluated for correlation with outcomes of tumor response, organ preservation, and survival. RESULTS: Multivariate analysis revealed that the best predictor of complete response to induction chemotherapy was low T class. The full multivariate model for predicting larynx preservation in patients treated with induction chemotherapy plus radiation shows that T class, p53 overexpression, and elevated proliferating cell nuclear antigen index were independent predictors of successful organ preservation. CONCLUSIONS: These predictive markers should be included in future clinical trials of advanced laryngeal cancer to determine their usefulness prospectively.