Robert A. Mickel

Major complications following tracheoesophageal puncture for voice rehabilitation

The successful use of the tracheoesophageal voice prosthesis for speech rehabilitation of the total laryngectomy patient has lead to common application of this device. Although the creation of a tracheoesophageal fistula is a simple procedure, it is not without complications. A review of 104 patients who underwent this procedure indicated a complication rate of 25%. Complications were related primarily to the fistula and included migration and progressive enlargement of the puncture, persistent or recurring infection of the fistula site, aspiration pneumonia, and death. Other problems included aspiration of the prosthesis, vertebral osteomyelitis, and tracheal stomal and esophageal stenosis. Many of these patients required hospitalization, intravenous antibiotics, and major surgical procedures to treat these complications. Guidelines for early identification and management of these problems as well as methods to prevent complications are discussed.

The sphenoid sinus--a site for metastasis.

While metastatic tumors to the nose and the paranasal sinuses overall are unusual, metastasis to the sphenoid sinus is exceedingly rare. Presented are 26 cases of metastasis to the sphenoid sinus. Seven were treated at UCLA between 1955 and 1988, and 19 additional cases were discovered from a search of the medical literature. The patients ranged from 14 months to 79 years of age. The most common tumor sites from which sphenoid metastases arose were the prostate and the lung. In 11 of the 26 cases, the sphenoid sinus metastasis was the first presentation of malignancy. Patients manifested signs and symptoms that were indistinguishable from those from primary tumors of the sinus. They included headache, facial pain, visual changes, and single or multiple cranial neuropathies. While cure of patients with sphenoid metastasis has not been reported, significant palliation with resolution of morbidity is possible in many patients with radiation therapy. Although metastasis to the sphenoid sinus is an uncommon entity, when present, signs and symptoms relating to this metastasis are frequently the first presentation of disease. As such, patients with sphenoid sinus symptoms suggestive of sphenoid sinus malignancy should be vigorously evaluated for the possibility of primary as well as metastatic tumor of the sinus.

Hierarchical immunosuppression of regional lymph nodes in patients with head and neck squamous cell carcinoma.

Patients with head and neck squamous cell carcinomas (HNSCCs) manifest defects in cell-mediated immune function. Previous studies in this laboratory have demonstrated regional alterations in the immunocompetence of draining lymph nodes (LNs) in HNSCC patients. In this investigation, we studied functional activity of lymphocytes from lymph nodes in different locations in the radical neck dissections (RNDs) from patients undergoing operations for HNSCC. Lymphocytes from nodes close to the primary tumor (“near” lymph nodes or NLN) exhibited a significant decrease in interleukin-2 (IL-2)-activated cytotoxicity when compared to lymphocyes from distant nodes (“far” lymph nodes or FLN). In addition, co-culture experiments suggested the existence of a soluble regulatory factor, produced by lymph nodes, that inhibited the development of lymphokine-activated killer (LAK) cells in vitro. Further experiments with conditioned supernatants from the lymph node cells confirmed the presence of this soluble inhibitory factor. The inhibitory effect is significantly greater in NLNs than in FLNS. This hierarchical phenomenon suggests a regional network of immunosuppression in HNSCC patients. It is likely that tumor- and lymph node-induced suppression plays a role in limiting the efficacy of current immunotherapy protocols in human beings. A greater understanding of mechanisms of local inhibition of immune function will aid in improving adoptive immunotherapy for treatment of cancers in human beings.

Importance of iron repletion in the management of Plummer-Vinson syndrome.

Plummer-Vinson syndrome (PVS) is characterized by iron deficiency anemia, upper esophageal stricture, cervical dysphagia, and glossitis. The precise role of iron deficiency in PVS has yet to be defined and remains a subject of much debate. A 29-year-old woman with PVS is presented. The patient had a 4-year history of severe iron deficiency anemia, a 2-year history of progressive dysphagia and weight loss, and a greater than 90% benign upper esophageal stricture. Iron therapy alone resolved her dysphagia and anemia, and a follow-up esophagram 1 year later showed a residual stenosis of less than 30%. The development of severe iron deficiency anemia in this patient 2 years before the onset of dysphagia, as well as the response of the stricture to iron repletion, supports the theory that iron deficiency can cause dysphagia and upper esophageal strictures. The occurrence of glossitis, gastritis, and esophagitis in iron deficiency demonstrates the adverse effects of iron depletion on the rapidly proliferating cells of the upper alimentary tract.

Horner's Syndrome and Thyroid Neoplasms

Although thyroid goiter is a common condition, it rarely results in Horner’s syndrome. We report a case of a patient with an intrathoracic multinodular goiter complicated by Horner’s syndrome. Benign thyroid disease was confirmed pathologically, and the patient’s symptoms improved after surgery. In the literature, the major cause of Horner’s syndrome is neoplasia, with malignant lesions being twice as frequent as benign tumors. An extensive review of the literature demonstrates a different repartition for thyroid neoplasia: including our case, 38 cases of Horner’s syndrome secondary to a benign thyroid tumor are described, against only 8 cases caused by a thyroid carcinoma. We conclude that contrary to the commonly held opinion, Horner’s syndrome is more often due to benign thyroid diseases than to thyroid malignancies.

Malignant melanoma of cervical and parotid lymph nodes with an unknown primary site

Forty‐six patients with malignant melanoma metastatic to cervical or parotid lymph nodes with an unknown primary site were treated at UCLA Medical Center from 1964 through 1991. Treatment consisted of parotidectomy and/or neck dissection with or without adjuvant therapy. The initial presentation was a cervical mass in 74% and a parotid mass in 26% of patients. Metastasis distal to the head and neck nodal basins developed in 22% of patients.

Suppression of Lymphokine-Activated Killer Cell Cytotoxicity by a Soluble Factor Produced by Squamous Tumors of the Head and Neck

Incubation of human peripheral blood lymphocytes (PBL) in the presence of interleukin-2 results in the generation of lymphokine-activated killer (LAK) cells that are highly cytotoxic to a variety of autologous and allogenic tumor targets. We have identified a noncytotoxic, soluble factor, produced by human squamous cell cancers of the head and neck, that profoundly inhibits the generation of LAK cytotoxicity. Inhibition of the generation of cytotoxicity was demonstrated with coculture of PBL and freshly disaggregated tumor cells in a Transwell two-chamber system. Alternatively, Inhibition occurred when LAK cells were generated in the presence of tumor-conditioned supernatants alone. These effects were not observed with conditioned supernatants from autologous or allogenic lymphocytes, human fibroblasts, or the erythroleukemia cell line K562. The presence of this inhibitory factor(s) was not required during the entire period of LAK generation. Suppression of cytotoxicity, measured after 4 days of LAK generation, could also be demonstrated when the conditioned tumor supernatant was present in only the last 24 hours of incubation. Suppression is mediated by a heat-labile factor with a molecular weight of >75 kd. These results suggest that LAK cytotoxicity may be significantly impaired by soluble immunoregulatory factors present within the tumor milieu of squamous cell carcinomas of the head and neck. Further characterization of these factors may lead to the development of more rational and effective forms of immunotherapy.

Carcinoma-in-situ occurring in a Zenker's diverticulum

(Editorial Comment: The authors call attention to the potential for carcinoma arising from the mucosa lining a Zenker’s diverticulum. Invasive carcinoma may be suspected based on radiographic findings of barium esophagram.) The pathophysiology of a pharyngoesophageal diverticulum was first discussed by Zenker and von Zeimssen in 1874.’ The pharyngeal outpouching occurs in a weakened area between the cricopharyngeal and thyropharyngeal portions of the inferior constrictor muscle known as “Killian’s dehiscence.” Lack of a coordinated relaxation of the cricopharyngeus muscle during swallowing results in a high-pressure zone opposite this area of weakness.* Negus suggested that with repeated incoordinate swallowing this muscular dehiscence widens, allowing mucosal protrusion through the defect3 Over time, the diverticulum enlarges, and then descends into the neck. Patients become symptomatic as the diverticulum fills with food causing esophageal compression and dysphagia. Squamous cell carcinoma occurring in a pharyngoesophageal diverticulum was first described in 1933.* Since that time, approximately 30 cases of invasive carcinoma in a diverticulum have been reported. Carcinomain-situ occurring in a pharyngoesophageal diverticulum is much rarer. Bullock and Snyder reported identifying the first such case in 19525; however two earlier articles described patients with invasive carcinomas in a Zenk

Inhibition of Head and Neck Squamous Cell Carcinoma Cell Lines by Transforming Growth Factor-β

Transforming growth factor-beta is known to be a potent autocrine growth inhibitor produced by a wide variety of cells, including cells of the immune system. Other investigators have noted that the growth of nontransformed keratinocytes is inhibited by transforming growth factor-beta, whereas various carcinoma cell lines are resistant to these effects. Head and neck squamous cell carcinoma cells are known to have surface receptors for this cytokine. We thus assessed the effect of transforming growth factor-beta on the growth of head and neck squamous cell carcinoma cell lines. Four head and neck squamous cell carcinoma cell lines were incubated with varying concentrations of transforming growth factor-beta, and cytotoxicity was evaluated with a methylene blue colorimetric assay. After culturing in transforming growth factor-beta for 4 days, inhibition of growth was detected in CAL-27 (maximal inhibition at 5.0 ng/ml), UMSCC-1, and UMSCC-19 (maximal inhibition at 50 ng/ml) cell lines. One other cell line, UMSCC-8 was found resistant to the inhibitory effects of transforming growth factor-beta. Kinetics analysis experiments revealed minimal inhibition before day 2 of incubation, at which time inhibition increased linearly to day 4. Assessment of double-stranded DNA fragmentation suggested that DNA fragmentation occurs before significant cytotoxicity. Electron microscopic analysis and gel electrophoresis of extracted DNA revealed morphologic features consistent with apoptotic cell death. Our findings indicate that transforming growth factor-beta significantly inhibits the growth of head and neck squamous cell carcinoma cell lines by inducing apoptotic cell death.

Lymphokine-activated killing of autologous and allogeneic short-term cultured head and neck squamous carcinomas

Interleukin‐2‐(IL‐2)‐activated lymphocytes have been shown to kill a variety of continuously cultured allogeneic (nonself), natural killer cell‐sensitive and resistant cell lines, and some autologous (Belt) tumor cells. Lymphokine‐activated killer (LAK) cytotoxicity of autologous head and neck squamous cell carcinoma (HNSCC) cells has not been previously demonstrated, and efforts to demonstrate this have been hampered by the lack of a reliable and reproducible method of obtaining satisfactory tumor targets. In this study, fresh tumor cells were enzymatical‐ly dissociated, enriched by adherence to plastic, and used in a 3‐hour chromium‐51 cytotoxicity assay. Peripheral blood lymphocytes (PBLs) were incubated for 3 days with or without added IL‐2. IL‐2‐activated PBLs showed significant cytotoxicity against autologous and allogeneic targets, while only low levels of tumor lysis occurred with unstimulated PBLs. These findings suggest the possible use of IL‐2‐activated lymphocytes in the adoptive immunotherapy of HNSCC patients.