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Background: Tumors lymphocytic infiltration has prognostic and predictive value. However, the mechanisms involved in lymphocyte recruitment remain poorly characterized. High endothelial venules (HEV) are blood vessels specialized in lymphocyte recruitment, recently showing prognostic significance in some types of cancer. Their implications in laryngeal or pharyngeal cancer is largely unknown., Aim of the Study: To investigate the possible presence of HEVs in head and neck cancer., Material and Methods: Oropharyngeal (n = 61), hypopharyngeal (n = 53) and laryngeal (n = 21) squamous cell carcinomas were immunohistochemically studied with the MECA-79 antibody, which specifically recognizes HEVs. Histological and clinical factors were correlated with HEVs' presence., Results: HEVs were present in 34% of tumors, showing significant correlations with oropharyngeal localization, higher lymphocytic response, lower tumor budding, lower T status, absence of distant metastases and better overall and progression-free survival., Conclusion: HEVs represent an important prognostic factor in head and neck cancer., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Objectives: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs) that occur as a consequence of enhanced immune response due to T-cell activation. The objective of this retrospective study was to investigate the association between irAEs and disease outcome in patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC)., Materials and Methods: This study included 89 patients with R/M HNSCC who were treated with nivolumab in our center from October 2015 to January 2020. Overall survival (OS) and post-progression survival (PPS) were calculated from the date of nivolumab initiation or from the date of progression on nivolumab respectively to the date of death or censored at the last date of follow up., Results: Twenty-four patients (27%) developed irAEs, with more common thyroiditis (N = 13, 14.6%). ORR did not differ between patients with irAEs (29.2%) and patients without irAEs (21.9%, p = 0.576). Median PFS was similar between the two groups (3.1 months for patients with irAEs vs. 2.6 months for patients without irAEs, p = 0.412). Median OS was significantly longer in patients with irAEs (17.9 vs. 6.3 months in patients without irAEs, log-rank p = 0.004). Additionally, median PPS was significantly improved in patients who developed irAEs (10.2 months vs. 2.8 months for patients without irAEs, log-rank p = 0.001). In multivariate analysis, the development of irAEs and response to nivolumab were shown to be independent prognostic factors for favorable OS and PPS., Conclusions: The development of irAEs is a strong predictor of improved survival in patients with advanced HNSCC treated with nivolumab., (Copyright © 2020. Published by Elsevier Ltd.)

Radiation therapy (RT) is one of the most effective therapeutic modalities for B‑cell non‑Hodgkin's lymphoma of Waldeyer's ring (WR‑B‑NHL). However, the responsiveness of RT remains controversial and clinical biomarkers are required to predict survival in RT‑treated patients with WR‑B‑NHL. Previous studies have suggested an association between RT and systemic immune responses. In the present retrospective study, the lymphocyte to monocyte ratio (LMR) was identified as a systemic immune indicator in RT‑treated patients with WR‑B‑NHL, and the prognostic value of the LMR with RT and systemic immune responses were evaluated. The optimal cut‑off value of the LMR was selected as 3.14, and a high LMR demonstrated improved prognosis and was considered an independent prognostic indicator in RT‑treated patients, particularly in patients with distant non‑irradiated lesions. Furthermore, reverse transcription‑quantitative polymerase chain reaction and ELISA analysis of irradiated lymphoma cell lines and serum samples from patients with WR‑B‑NHL demonstrated the upregulated expression levels of 4‑1BB ligands, calreticulin and high mobility group box 1 compared with non‑irradiated groups. Additionally, CD8+ T cells and expression levels of interferon‑γ in T cells co‑cultured with irradiated cells were significantly increased compared with non‑irradiated cells. The results indicated that the anti‑programmed cell death protein 1 (PD‑1) antibody may serve a role in lymphoma therapy when combined with RT. The results of the present study demonstrated the prognostic significance of the LMR associated with RT in patients with WR‑B‑NHL and acknowledged the potential use of PD‑1 antibody in RT‑treated lymphomas.

Background: Oral tongue cancer incidence has increased among whites in the United States; however, the cause remains unknown. If an infectious agent is implicated, then elevated risk would be expected among immunosuppressed individuals., Methods: By using population-based registry linkage information from the US Transplant Cancer Match and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) Cancer Match studies, the authors examined the risk of oral tongue squamous cell carcinoma (SCC) among immunocompromised transplantation recipients and HIV-infected individuals. In addition, the risks of oropharyngeal SCC (strongly related to human papillomavirus infection; modestly affected by immunosuppression), other tobacco/alcohol-related oral cavity SCCs (not thought to be infection/immunosuppression-related), and non-Hodgkin lymphoma of oral cavity/pharynx (strongly related to Epstein-Barr virus; profoundly affected by immunosuppression) were evaluated., Results: Compared with the general population, the risk of non-Hodgkin lymphoma was strongly increased (standardized incidence ratio [SIR] > 8.0). The risk of all SCCs was modestly and similarly elevated among transplantation recipients (SIR range, 2.2-2.7; P heterogeneity  = .2); whereas, among HIV-infected individuals, the risk of oral tongue SCC was higher compared with the risk of other SCCs (SIR, 3.0 vs 1.7 [for oropharyngeal SCCs] and 2.3 [for other oral cavity SCCs]; P heterogeneity  < .001). The risk of SCCs was significantly higher among men, older individuals, and whites; and risk increased with the time since transplantation/AIDS onset. The risk of oral tongue SCC was significantly higher among HIV-infected men who have sex with men compared with the average risk in HIV-infected individuals (adjusted incidence rate ratio = 2.0)., Conclusions: Similar modest increases in the risk of oral tongue and other oral cavity SCCs do not suggest that an infectious agent or exposure profoundly affected by immunosuppression underlies the increase in oral tongue cancer. Cancer 2018;124:2515-22. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Pediatric neoplasm with monoclonal proliferation of lymphoplasmacytoid lymphocytes and plasma cells is exceedingly rare and has essentially never been reported in immunocompetent children. Here, we report a previously healthy 13-year-old girl with a pharyngeal mass and enlarged cervical lymph nodes. The pharyngeal mass was composed of CD138, CD79a, MUM-1, IgD, CD20, PAX-5, CD43, λ-restricted monoclonal plasmacytoid, and plasma cells. Scattered CD20, PAX-5 B cells were present in the background. The patient was treated as localized non-Hodgkin lymphoma (stage II) with cyclophosphamide, doxorubicin, vincristine, and prednisone and is in complete remission at 17 months from the last chemotherapy.

Purpose: To investigate, in a large cohort of patients, the immunophenotypic and clinical differences of nasal and extranasal extranodal nasal-type natural killer/T-cell lymphoma of the upper aerodigestive tract (UADT-NKTCL) and examine the relevance of the immunophenotype on the clinical behavior, prognosis, and treatment., Methods and Materials: A total of 231 patients with UADT-NKTCL were recruited. One hundred eighty-one patients had primary location in the nasal cavity (nasal UADT-NKTCL), and 50 patients had primary extranasal UADT-NKTCL., Results: Patients with extranasal UADT-NKTCL had more adverse clinical features, including advanced-stage disease, regional lymph node involvement, B symptoms, and poor performance status, than patients with nasal UADT-NKTCL. In addition, CD56 and granzyme B were less frequently expressed in extranasal UADT-NKTCL. The 5-year overall survival rate was 74.1% for the entire group and 76.0% for early-stage disease. The 5-year overall survival rate for extranasal UADT-NKTCL was similar or superior to that of nasal UADT-NKTCL for all disease stages (76.9% vs 73.4%, P=.465), stage I disease (75.9% vs 79.2%, P=.786), and stage II disease (83.3% vs 50.3%, P=.018). CD56 expression and a Ki-67 proliferation rate ≥ 50% predicted poorer survival for extranasal UADT-NKTCL but not for nasal UADT-NKTCL., Conclusions: Patients with nasal and extranasal UADT-NKTCL have significantly different clinical features, immunophenotypes, and prognosis. Extranasal UADT-NKTCL should be considered as a distinct subgroup apart from the most commonly diagnosed prototype of nasal UADT-NKTCL., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Kaposi's sarcoma (KS) is a human herpes virus-8 (HHV-8)-associated angioproliferative disorder, and its occurrence may be favored by human immunodeficiency virus (HIV) infection and iatrogenic immunosuppression. It has also been postulated that a chronic inflammatory disease of the skin can pave the way to its development. KS generally involves mucosal and cutaneous sites, including the head and neck. An oropharyngeal location is quite common, but laryngeal involvement with possible upper airway obstruction and respiratory distress requiring tracheotomy is rare, and no hypopharyngeal locations have yet been reported. We describe the case of a 68-year-old male patient who developed KS after immunosuppressive treatment for pemphigus vulgaris, an autoimmune bullous disease presenting with blisters and erosions on the skin and the oral mucosa. KS was initially localized to the oral cavity and oropharynx, but subsequent involvement of the laryngeal and hypopharyngeal tract led to acute airway obstruction and the need for tracheotomy. This unique case of pharyngolaryngeal KS suggests that clinicians faced with purple nodular lesions should consider a differential diagnosis of KS in immunocompromised patients, even if they are HIV negative, and should carefully manage the patency of the upper airways.

The aim of this study was to reveal the relationships between the features of the primary tumour, the degree of tumour stage, the presence of human papillomaviruses (HPV) in blood and the severity of Th1/Th2 serum cytokine imbalance in patients with laryngo-pharyngeal cancer. The study was performed on 50 patients (47 men and 3 women), with age ranging from 40 to 83 years (the mean of the patients' ages was 58.4 ± 9.43 years, with a median of 60 years). A control group was represented by age-matched healthy patients (with no clinical diseases). The viral DNA was detected by PCR; the cytokine levels were determined by ELISA. A clear switch from cytokine Th1 to cytokine Th2 in cancer patients, low levels of IL-2 and IFNγ in advanced stages, as well as a positive correlation of increased levels of both IL-2 and IL-12 with the early stages of laryngo-pharyngeal cancer was observed. Loco-regional metastases were correlated with increased levels of IL-8 and IL-10 and drastic decrease of IFNγ. In advanced cancer stages, we found that the most affected were IL-2 and IFNγ correlated with increased levels of Th2 cytokines. Patients with HPV present in both primary tumours and blood showed increased values of IL-4:IL-2 ratio as compared with patients with HPV-positive primary tumours only, demonstrating the aggravation of the immunosuppressive state. The most important finding of our study is that for a correct evaluation of the Th1 to Th2 switch in cancer patients, it is necessary to establish not only the negative/positive correlations between different Th1 and Th2 type cytokines, but also the ratio between them. These parameters allowed us to state that the presence of HPV DNA in blood was associated with the most severe immunological imbalance that could potentially lead to a poor prognosis of these patients. Our findings encourage us to consider that the ratio between different Th1 and Th2 cytokines could represent a useful marker for clinical and pathological evaluation of cancer patients.

Introduction: Tumor microenvironment makes up the stroma of the neoplasm and is the tissue that determines the growth and progression of the tumor and its ability to create metastases. THE AIM OF THE PRESENT STUDY: has been to evaluate the potential role of RCAS1 protein in creating the suppressive tumor microenvironment in pharyngeal squamous cell carcinomas. The immunoreactivity of RCAS1, CD3, CD25, CD68, CD69 and Foxp3 was assessed in the tissue samples of the tumor, in tumor microenvironment and in the reference samples of palatine tonsils in chronic inflammation., Results: A statistically significantly higher RCAS1 antigen immunoreactivity was identified in pharyngeal cancer samples than in the stromal samples, the presence of RCAS1 positive macrophages infiltrating the tumor and its stroma was also noticed. The statistically significantly higher RCAS1 antigen immunoreactivity level was identified in the pharyngeal cancer samples in patients with the presence of lymph node metastases in comparison to patients without metastases. The infiltration of CD68 positive cells (macrophages) was significantly higher in the stromal tissue samples than in cancer samples and it was in both, the tumor and the stroma, significantly higher in patients with the presence of lymph node metastases than in patients without metastases. Additionally the presence of CD3 positive TILs was noticed in the tissue of the tumor and in its stroma, the cells were activated, typified by CD69 immunoreactivity which was higher than in the reference samples, and impaired cytotoxicity with low CD25 antigen immunoreactivity. This observation confirmed the presence of selective immune suppression within the tumor and the stroma., Conclusion: RCAS1, an active factor secreted by the tumor and present in its stroma may play an important role in the phenomenon of tumor escape from host immunological surveillance and in creating the immune tolerance for the tumor cells, as well as in the tumor microenvironment remodeling with creating its suppressive profile enabling the further tumor growth and metastases., (Copyright © 2012 Polish Otolaryngology Society. Published by Elsevier Urban & Partner Sp. z.o.o. All rights reserved.)

Our research thus far has concerned the impact of external electromagnetic fields (50 Hz) and low (0.01-10 mT) induction on adherence capabilities of T lymphocytes obtained from the blood of patients with head and neck tumors. We know that the in vitro adherence capability of T lymphocytes towards surfaces in cancer patients is less than that of control. Previously, we have found that exposure to electromagnetic fields (50 Hz/0.01-10 mT) increases the capability of T lymphocytes, in larynx/pharynx cancer patients, to adhere in vitro to surfaces, achieving almost physiological values, in not only pre-treatment patients but also those receiving treatment in the course of follow-up. The capability of T lymphocytes in controls (voluntary blood donors) to adhere to surfaces was also increased (50 Hz/0.01-0.5 mT). The present study concentrates on the significance of the level of electromagnetic field induction in order to determine whether low induction values can restore T lymphocytes adherence capabilities. Testing a subset of 20 patients showed a statistically significant difference (p<0.05) in the in vitro adherence capacity of T lymphocytes between both 0.01 and 0.05, and 0.1 mT induction levels. In the control group (patients diagnosed with chronic sensorineural hearing loss) there was even a statistically significant difference between induction values of 0.05 and 0.01 mT. A statistically significant difference (p<0.05) was also achieved with induction levels of 1 and 10 mT compared to 0.5, 0.1, and 0.05 mT, respectively. Therefore, we concluded that lower induction values resulted in a more biologically significant response.

Objective: To investigate the alteration of T-lymphocyte subsets and NK activity in patients with squamous cell carcinoma of pharynx and larynx., Method: T-lymphocyte subsets and NK activity were determined by flow cytometry in 123 patients with squamous cell carcinoma of pharynx and larynx. Blood samples of 36 nontumor patients were used as control., Result: The total T lymphocytes were lower in patients with squamous cell carcinoma of pharynx and larynx than control group significantly (P < 0.05). The levels of helper lymphocyte subsets were little lower than those in control group(P > 0.05). On the other hand, the levels of suppressor lymphocytes in patients were higher than those in the control group (P < 0.05). Therefore, the CD4/CD8 ratios in patients were lower than those of the control group statistically (P < 0.05). There was no statistical difference in activated T lymphocytes and total B lymphocytes (P > 0.05), but NK activity in patients were lower than those in control group significantly (P < 0.01). There was no statistical difference in total T lymphocytes between stage I-II and stage III--IV (P > 0.05). The levels of helper lymphocyte subsets in stage I-II patients were little higher than in stage III-IV patients (P > 0.05), but the levels of suppressor lymphocytes in stage I-II patients were lower than in stage III-IV patients (P < 0.01). The CD4/CD8 ratios in stage I-II patients were significantly higher than in stage III-IV patients (P < 0.01). The levels of total B lymphocytes in stage I-II patients were significantly higher than in stage III-IV patients (P < 0.05). The activated T lymphocytes and NK activity did not changed statistically (P > 0.05)., Conclusion: The immune function in patients with squamous cell carcinoma of pharynx and larynx is disordered and lower. With advanced stage disease, not only the cellular immune function in patients decrease gradually, but also the humoral immunity is lower. Analyzing T-lymphocyte subsets and NK activity determined by flow cytometry would be easy and helpful to evaluate the immunologic condition of every patient.

Background: Tumour infiltrating lymphocytes (TIL) are generally considered to represent a host immune response directed against tumour antigens. TIL are also increasingly recognised as possible prognostic parameters. However, the effects observed are variable indicating that results cannot be extrapolated from type of tumour to another. Moreover, it has been suggested that primary solid tumours may be ignored by the immune system and that a meaningful immune response is only mounted in regional lymph nodes., Methods: We have examined the local distribution of immune cells in tumour-related compartments in head and neck squamous cell carcinomas (HNSCC). In a second step, the prognostic impact of these cells on disease-free survival (DFS) was analysed. A total of 198 tissue cores from 33 patients were evaluated using tissue mircroarray technique and immunohistochemistry. Tumour-infiltrating immune cells were identified using antibodies specific for CD3, CD8, GranzymeB, FoxP3, CD20 and CD68 and quantified using an image analysis system., Results: We demonstrate a relative expansion of FoxP3+ regulatory T-cells (Treg) and of cytotoxic T-cells among tumour infiltrating T-cells. We also show that intratumoural CD20+ B-cells are significantly more frequent in metastatic deposits than in primary tumours. Furthermore, we observed a reduced number of peritumoural CD8+ T-cells in metastatic lymph nodes as compared to univolved regional nodes suggesting a local down-modulation of cellular immunity. All other immune cells did not show significant alterations in distribution. We did not observe an association of tumour infiltrating immune cells at the primary site with outcome. However, increased numbers of intraepithelial CD8+ TIL in metastatic tumours as well as large numbers of peritumoural B-cells in lymph node metastases were associated with favourable outcome. Unexpectedly, no effect on patient outcome was observed for Treg in any compartment., Conclusion: Our results suggest that alterations in lymphocyte distribution in regional lymph nodes rather than at the primary tumour site may be relevant for patient prognosis. Moreover, we demonstrate that in addition to cellular immunity humoral immune responses may be clinically relevant in anti-tumour immunity.

Background: The purpose of this study has been to establish the level of RCAS1 - a membrane protein expressed in various cancer cells and able to induce apoptosis of CTLs and NK cells in pharyngeal and laryngeal cancer and its clear surgical margin - with respect to clinicopathological features and to patient's follow up and evaluate its possible role in cancer relapse., Methods: A total of 122 tissue samples were obtained: 51 samples from laryngeal and pharyngeal squamous cell carcinoma, 51 samples from the clear surgical margins of these tumors, and 20 tissue samples derived from the healthy mucous membranes of the upper respiratory tract mucosa of patients without cancerous tumors. Patients were observed for a total of 4 years following surgical treatment. The level of RCAS1 expression was assessed by immunohistochemistry and Western blot., Results: RCAS1 was identified in all laryngeal and pharyngeal carcinomas and in almost all the clear surgical margin samples. The level of RCAS1 expression was significantly higher in the cancerous samples than in the clear surgical margins and was determined to be related to the grade of the cancer and the presence of lymph node metastases. In cases of cancer relapse, significantly higher levels of RCAS1 expression were observed in the clear surgical margins., Conclusion: Selective cytotoxic immune cell suppression concomitant with tumor growth and associated with RCAS1 expression seems to be an important event connected with cancer relapse.

The TAG-1, TAG-2a, TAG-2b, and TAG-2c cancer/testis genes, known to be expressed in an unusually high percentage of melanoma cell lines, are shown here to be expressed in a variety of tumor lines of diverse histologic type, including cancers of the brain, breast, colon, lung, ovary, pharynx, and tongue. The genes are also expressed in fresh, uncultured melanoma, and ovarian cancer cells. Epitope prediction algorithms were used to identify potential HLA-A1, HLA-A2, HLA-A3, HLA-B7, and HLA-B8 epitopes, and these potential epitopes were tested for their ability to stimulate a peptide-specific cytotoxic T lymphocyte response using lymphocytes from healthy donors. Two HLA-A2-restricted epitopes (SLGWLFLLL and LLLRLECNV) were identified using this approach. Cytotoxic T lymphocytes specific for each of these peptides were capable of recognizing tumor cells expressing both the corresponding class I major histocompatibility complex encoded molecule and the TAG genes. These results indicate that TAG-derived peptides may be good components of a therapeutic vaccine designed to target melanoma and a variety of epithelial cell-derived malignancies.

The authors were monitoring adherence ability of T lymphocytes in vitro in patients with laryngeal and pharyngeal carcinoma at the presence of tumor-specific and viral LDH antigen. The results were assessed and expressed in percent of non adherent T lymphocytes (NAL). First, NAL in patients before initiating the treatment was compared with NAL control group (voluntary blood donors). The ability of the adherence in T lymphocytes in the control group is statistically significantly higher. Further on, NAL in the course of a successful oncological treatment was monitored at the interval of 6 months following the treatment, and further on at yearly intervals. NAL level drops statistically significantly within 6 months and then hold on at levels with no statistical difference unlike the control group, however, the ability of T lymphocyte in patients to adhere remains statistically significantly lower. Statistically significantly higher levels of NAL are at the presence of LDH viral antigen. Further on, the authors were following the influence of magnetic sinusoidal field of power frequency (50 Hz) of a low induction (0.5, 0.1, and 0.05 mT) on NAL. NAL values under the influence of an experimental magnetic field before initiating the treatment as well as in the course of a successful oncological treatment are statistically significantly lower. It means that magnetic filed increases the adherence ability of T lymphocytes in patients with laryngeal and pharyngeal cancer in vitro.

Tumor-specific peptide-pulsed dendritic cells (DC) were administered via different routes to a group of patients with head and neck cancers. The migration and homing patterns of such antigen-stimulated cells was carefully studied employing single photon emission computed tomography (SPECT). The DC administered directly into the nasal submucosa quickly migrated very rapidly to the regional neck lymph nodes in the neck. However, after inoculation of the cells into the palatine tonsils, the DCs remained close to the site of administration and did not migrate to the regional lymph nodes or to other mucosal regions. After nasal submucosal administration of the DC, tumor-antigen-specific cytotoxic T cells were detected in the ipsilaterals but not in the contra lateral lymph nodes. These results suggest that after antigen processing, the regional lymph nodes serve as inductive sites for development of mucosal immune responses and for induction of memory cells during the local immunological responses in the nasopharyngeal-associated lymphoid tissue in man.

Solitary fibrous tumors are benign neoplasms of mesenchymal origin. They usually arise from the visceral or parietal pleura and peritoneum, although they have been found in many areas throughout the body. We report a case of solitary fibrous tumor of the parapharyngeal space. Microscopically, the tumor contained spindle cells with areas of marked hypercellularity without a definitepattern. Consistent with a benign lesion, there were few mitoses and no necrosis. The tumor cells stained strongly positive for CD34 and vimentin. At the 2-year follow-up, the patient was well and free of local and/or distant disease.

Conclusion: The possible roles of CD44st, CD44v5 and CD44v6 in the prognosis of head and neck cancer deserve further elucidation and evaluation with long-term patient follow-up., Objective: Standard CD44 (CD44st), CD44 variant 5 (CD44v5) and CD44 variant 6 (CD44v6) are expressed in human malignant cells and tissues. The mechanism of their expression remains unclear, but has been reported to be associated with the progression and metastasis of malignancies. Recently, it has frequently been reported that the prognosis of head and neck cancer is associated with expression of the cell adhesion molecule CD44., Material and Methods: We investigated correlations between the soluble adhesion molecule CD44 and clinicopathologic variables, for example, age, sex, histologic grade, tumor size, lymph node status, distant metastasis and TNM stage. The pre- and post-treatment serum levels of CD44st, CD44v5 and CD44v6 were determined by means of ELISAs in 81 patients with head and neck cancer and 20 healthy volunteers (controls)., Results: In the cancer patients, the pre-treatment median serum levels of CD44st, CD44v5 and CD44v6 were 327 +/- 134, 312 +/- 118 and 211 +/ 110 ng/ml, respectively. The corresponding post-treatment levels were 185 +/- 103, 177 +/- 90 and 110 +/- 65 ng/ml. In the healthy volunteers, the median serum levels of CD44st, CD44v5 and CD44v6 were 133 +/- 40, 142 +/- 39 and 86 +/- 22 ng/ml, respectively. In the cancer patients, there was no significant correlation between the serum levels of CD44st, CD44v5 and CD44v6 and the clinicopathological variables. The pre-treatment serum levels of CD44st, CD44v5 and CD44v6 were closely associated with TNM stage (p = 0.0017, 0.0005 and 0.0046, respectively). The median pre-treatment serum levels of CD44st, CD44v5 and CD44v6 were significantly higher than those in the control group (p = 0.0002, 0.0065 and 0.0038, respectively). The median post- treatment serum levels of CD44st, CD44v5 and CD44v6 were significantly lower than the pre-treatment levels (p = 0.0003, 0.0027 and 0.0034, respectively).

We investigated tumor-free mucosa and squamous cell carcinomas of the oral cavity, the pharynx, and larynx with respect to the presence of stromal CD34+ fibrocytes and alpha-smooth muscle antigen (SMA)-positive myofibroblasts. Additionally, stromal expression of CD117 was analyzed. A total of 39 squamous cell carcinomas were assessed immunohistochemically. In all cases investigated, CD34+ fibrocytes were found in the tumor-free stroma, whereas alpha-SMA-positive myofibroblasts were lacking. Areas of lymphocytic infiltration disclosed a focal reduction of CD34+ fibrocytes. CD117 expression was absent from the tumor-free stroma. Of 39 squamous cell carcinomas, 33 were free of stromal CD34+ fibrocytes, and, in 31 carcinomas, stromal alpha-SMA-positive myofibroblasts occurred at least focally. CD117-positive stromal spindle cells were found in 25 carcinomas. Compared with tumor-free mucosa, the number of tissue mast cells was significantly increased in carcinomas. We conclude that stromal remodeling induced by invasive carcinomas is characterized by a loss of CD34+ fibrocytes and subsequent gain of alpha-SMA-positive myofibroblasts. The diagnostic impact of this finding is, however, limited by the fact that chronic inflammation may also be accompanied by a focal loss of CD34+ fibrocytes.

Objective: Tumors arising from different sites of the head and neck area have very different clinical behavior. Loss or reduction of expression of adhesion molecules has been assumed to play a critical role in the development of head and neck carcinomas. The aim of this study is to determine if there are differences in the expression of adhesion molecules E-cadherin, CD44s, and CD44v6 in pharyngeal and laryngeal squamous-cell carcinomas., Materials and Methods: E-cadherin, CD44s, and CD44v6 expression was determined by immunohistochemistry in paraffin-embedded tissue specimens from 72 patients with squamous-cell carcinoma, 37 of the pharynx and 35 of the larynx., Results: Expression of CD44s was significantly lower in pharyngeal than in laryngeal tumors (P =.01). No differences in the expression of E-cadherin and CD44v6 were observed between these sites., Conclusions: These data suggest that there are some differences at molecular level between the different subsites of head and neck cancer.

Background: Neck metastasis is a major prognostic factor of head and neck carcinoma, but its preoperative detection is currently unreliable. Molecular markers of the metastatic potential of a carcinoma would help to avoid unnecessary neck dissection in patients with nonmetastatic cancer., Methods: The fractions of cancer cells immunostained for proliferating cell nuclear antigen (PCNA) and Ki67 were determined in 80 preoperative biopsy specimens of head and neck carcinomas. The value of both indexes to detect metastasis in the subsequent neck dissection was compared with that of the clinical and radiologic examinations., Results: PCNA and Ki67 indexes correlated with neck metastasis. Cutoff points were determined for both indexes to discriminate metastatic from nonmetastatic carcinomas. By multivariate logistic regression, these indexes were significant predictors of metastases, together with clinical T stage and neck palpation., Conclusion: The fraction of cancer cells immunolabeled for PCNA or Ki67 in preoperative biopsy specimens is helpful to predict neck metastasis., (Copyright 2003 Wiley Periodicals, Inc.)

With the aim of identifying tumor-associated antigens that could be potential markers and/or targets of diagnostic and/or therapeutic approaches, we studied the occurrence of circulating IgG antibodies to human stromelysin-3, collagenase-3, galectin-3 and mesothelin, by Western blot against their purified recombinant forms, in the sera of 50 patients with pharynx/larynx squamous cell carcinoma (PLSCC), as well as in the sera of 50 healthy blood donors. Overall, antibodies to collagenase-3 were detected in 50% of all the cancer patients and 16% of the blood donors examined; this percentage difference was statistically significant (p = 0.00066). With respect to anti-galectin-3 antibodies, the percentages were 32% and 18%, respectively, but they were not statistically different (p = 0.16). Low levels of antibodies to stromelysin-3 and to mesothelin were detected in sera from only two cancer patients. No significant correlations were found in the present study between the presence of antibodies to these proteins and tumor site, clinical and T stages, lymph node involvement, DNA ploidy and histological grade of differentiation of the primary tumors. To our knowledge, this is the first report on the detection of circulating IgG to collagenase-3 in cancer patients. Some of the percentages found here in certain groups of patients are among the highest reported of circulating antibodies to any tumor component studied so far. The monitoring and the use of human antibodies to collagenase-3 could be of diagnostic and therapeutic interest.

In recent studies, we have demonstrated that fibrin is present in association with tumor cells in oral squamous cell carcinoma (OSCC) in vivo. We hypothesized that this fibrin can directly induce the expression of known angiogenic factors from oral tumor cells. Since IL-8 is known to be the major inducer of angiogenesis caused by these cells, we examined the ability of fibrin to stimulate IL-8 expression from OSCC cells in vitro. A physiologically relevant concentration of fibrin was found to cause a dose and time-dependent stimulation of IL-8 expression from oral and pharyngeal tumor cells but not from a non-tumorigenic oral cell line. Fibrinogen, thrombin and collagen were all unable to induce significant IL-8 expression, establishing the specificity of fibrin in causing this response. Gel filtration chromatography confirmed the molecular identity of the IL-8 antigen detected in the ELISA system used. These results suggest that fibrin may promote angiogenesis in oral tumors in vivo by directly upregulating the expression of IL-8 from tumor cells.

Analysis of 1,060 xenotransplants derived from cancer cell lines as wel as spontaneously occurring tumors from the larynx, pharynx, mammary gland, uterine cervix, and vulva revealed that tumor regression induced by treatment with monoclonal antibodies (EMD 55900 and EMD 72000 against the epidermal growth factor receptor (EGFR) could be enhanced by tumor necrosis factor alpha (TNF-alpha) treatment in vivo. Moreover, tumor that primarily do not respond to antibody treatment can be made suscep tible by additional TNF-alpha treatment. To investigate the in vivo effects of monoclonal antibodies, we treated tumors derived from cell lines (A431 and Detroit 562) as well as spontaneously occurring squamous cell carci nomas and adenocarcinomas (transplanted on NMRI-nu/nu mice) gener ally with EMD 55900 (40 microg/g mouse) and its humanized version EMD 72000 (40 microg/g mouse). When treated with EMD 55900 and EMD 72000 carcinomas with an EGFR concentration of > or = 70 fmol/mg protein showed significant reduction in tumor size compared with untreated controls. The degree of tumor regression correlated with the EGFR concentration of the tumor. In mice treated with TNF-alpha (0.5 microg/g mouse) and EMD 55900 72000 simultaneously, we observed enhanced antitumor effects up to complete tumor eradication. Carcinomas with an EGFR concentration <70 fmol/mg protein could be made susceptible to treatment with EMD 55900 and EMD 72000 by simultaneous treatment with TNF-alpha, resulting in a significant reduction in tumor size.

The state of the local immunity system of the oral cavity was studied by the level of saliva immunoglobulins in patients with different processes on their mucous membranes: herpetic infection, respiratory allergosis and malignant tumors of the mouth cavity and the laryngopharynx. The suppression of the production of sIgA, was accompanied by the enhanced production of antibodies to the most widespread herpesviruses (herpes simplex virus, cytomegalovirus and Epstein-Barr virus). The maximum levels of serum IgG to herpesviruses were determined in patients with malignant tumors. The role of herpesviruses in the pathogenesis of immunodeficient states is discussed.

The immunomodulating effect of primary surgical intervention in 33 patients with squamous cell carcinoma of the oral cavity, pharynx, and larynx was analyzed prospectively. An operation time of longer than 7 hours was significantly associated with a decrease of total lymphocyte counts, CD4(+) T lymphocytes, and CD8(+) T lymphocytes. The CD4/CD8 ratio as a marker for the downregulation of the cellular immune response was slightly decreased but still in the normal range. CD4(+) lymphocyte counts increased within 7 days, and CD8(+) lymphocytes increased 4 weeks after the operation. The in vitro stimulation of the lymphocytes was impaired for 1 to 4 weeks. Release of interleukins, interferon-gamma, and tumor necrosis factor-alpha remained low despite the surgical trauma. The decreased lymphocyte counts, especially CD4(+) and CD8(+) lymphocytes, were significantly associated with duration of operation and volume of blood loss. Extension of trauma, age, type of anesthesia, and type of intensive care intervention were not associated with specific immunomodulating effects. However, these factors might be responsible for suppression of the immune system, which is expressed by lymphocyte depletion, lymphocyte dysfunction, and impaired upregulation of cytokine secretion.

Background: Cancer surgery is known to lead to a deterioration in host defence mechanisms and an increase in susceptibility to infection after operation. Filgrastim enhances important antimicrobial functions of neutrophils including chemotaxis, phagocytosis and oxidative killing mechanisms., Methods: The effects of additional (all patients received perioperative 3 ' 25 mg kg-1 cefotiam and 1 ' 20 mg kg-1 metronidazole) preoperative prophylaxis with filgrastim (5 microg kg-1 12 h prior to surgery plus 5 microg kg-1 0 h prior to surgery) on neutrophil phagocytosis and reactive oxygen radical production and postoperative infections in 24 patients undergoing cancer neck dissection were studied. Phagocytic capacity was assessed by measuring the uptake of fluorescein isothiocyanate-labelled Escherichia coli and Staphylococcus aureus by flow cytometry. Reactive oxygen generation after phagocytosis was estimated by determining the amount of dihydrorhodamine 123 converted to rhodamine 123, intracellularly., Results: In the filgrastim-treated patients a higher neutrophil phagocytic capacity was seen intraoperatively, and 1-5 days postoperative, but not prior to surgery. Reactive oxygen radical production was significantly higher in filgrastim-treated patients prior to surgery, intraoperative and postoperative (1-5 days). 2/12 (17%) patients had postoperative infections in the filgrastim group and 9/12 (75%) patients had infections in the placebo group (P < 0.001). In particular, wound infections were recorded more often in the placebo group (1/12 vs. 6/12; P = 0.004)., Conclusion: We conclude that filgrastim enhances perioperative neutrophil function and could be useful in the prophylaxis of postoperative wound infections in patients undergoing cancer neck dissection.

Human leukocyte antigen (HLA) class I molecules on hematopoietic cancers and melanomas inhibit attack by natural killer lymphocytes, but previous studies have not consistently demonstrated that carcinoma cells are protected by HLA class I expression. We investigated whether HLA class I molecules protect oral and pharyngeal squamous cell carcinoma cells from natural killer lymphocyte attack. Squamous cell carcinoma cell lines expressed varying levels of HLA class I, which correlated inversely with cytolysis by natural killer-enriched polyclonal lymphocytes. Cytolysis was increased by the presence of anti-HLA class I blocking monoclonal antibody (mAb). Subclones of the NK-92 human natural killer lymphoma cell line were derived by treatment with 5-aza-2'-deoxycytidine and limiting dilution cloning. NK-92 subclones expressed distinct sets of HLA class I-specific receptors. Some NK-92 subclones differentially lysed hematopoietic cells and squamous cell carcinoma cells, even in the presence of anti-HLA class I blocking mAb. This suggests that natural killer cells recognize different non-HLA ligands on hematopoietic and squamous cell carcinoma cells. In the presence of anti-HLA class I monoclonal antibody, other NK-92 subclones increased cytolysis of squamous cell carcinoma cells with moderate-to-high HLA class I levels. Anti-HLA class I mAb also increased natural killer cell attack of squamous cell carcinoma cells that were adherent to plastic. These data suggest that natural killer cell recognition of squamous cell carcinoma cells depends upon the balance of stimulatory and inhibitory ligands.

The quantitative expression of E-cadherin, thrombomodulin, CD44H and CD44v6 in 32 specimens of primary tumours of pharynx/larynx squamous cell carcinoma and their lymph node metastases was studied by immunohistochemistry. With the aim of obtaining comparative and objective data, image acquisition conditions were kept unaltered for all the measurements and the immunostaining intensity was quantified by applying an image processing system. On the one hand, correlations were only observed between CD44H and CD44v6, both in primary tumours and metastases, and between E-cadherin and TM in metastases. On the other hand, statistical analyses of paired data did not show significant differences in the expression of these markers between the two tumour sites. In agreement with previous reports, E-cadherin expression was rather low or negative in primary tumours and metastases of the three poorly differentiated specimens we studied, as well as that of TM, but otherwise some of these samples showed intermediate immunostaining levels of CD44H/CD44v6. It may be concluded from the present study that the quantitative expression of these adhesion molecules in well established lymph node metastases of pharynx/larynx squamous cell carcinoma is essentially unaltered in relation to their primary sites.

The in vitro responsiveness of peripheral blood mononuclear cells (PBMC) T lymphocytes was studied in 81 patients with limited or extended head and neck squamous cell carcinoma (HNSCC), as judged by T, N and T + N stages. Patients included in the study were males below 80 years of age, without auto-immune disease or cachexia, who were not taking any immuno-active medication at the time of diagnosis. The patients were divided into groups according to TNM stage T0-2 vs T3-4, N0-1 vs N2-3 or T + N0-3 vs T + N4-7. When cells from patients with early and late stage, according to T, N or T + N stage, were compared, we found a decreased level of mitogen stimulated T-cells and decreased spontaneous proliferation with increasing disease stage. The same was true if the in vitro mitogenesis of T-cells was analysed separately, depending on the laryngeal or oral cavity/pharyngeal origin of the patients' tumours. If the patients were divided into two groups based on N stage, decreased gamma-interferon, and to some extent interleukin (IL-2), but not IL-4 levels, were found to be related to the disease stage.

84 patients with cancer of the upper digestive tract and 89 matched controls were examined. Lower than normal albumin concentrations were observed with an odds ratio for disease of 14 (95% confidence interval 4.5-46). Among the patients, low concentrations of serum total protein and albumin were also associated with a higher risk of dying. An essential finding was an electrophoretic serum pattern of "active process" without the production of gammaglobulins occurring in about half of the patients. This observation, when lasting for several months, seems to indicate a possible malignancy. However, one fifth of the patients had normal electrophoresis. On the other hand, 15% of the controls also had an "active process" pattern-with or without the production of immunoglobulins. With regard to the participants' patient-versus-control status, the electrophoretic serum protein pattern was of greater predictive importance than information concerning high or low erythrocyte sedimentation rate.

Recent studies have identified that mucin antigens and Lewis X (Lex)-related antigens behave like oncodevelopmental tumor-associated antigens in several human adenocarcinomas. However, the expression of these antigens in pharyngeal and laryngeal squamous cell carcinomas (SCC) and in the precursor lesion is not fully elucidated yet. In the present study, the expression of mucin core protein antigens associated with the MUC1 gene product (DF3 antigen, mammary-type apomucin) and the MUC2 gene product (intestinal-MRP antigen, intestinal-type apomucin) mucin carbohydrate antigens that are associated with the earliest steps in mucin glycosylation (Tn, sialyl-Tn and T), and Lex-related antigens (Lex, Ley and sialyl Lex-i) in biopsy or resected specimens from 26 normal squamous epithelia (NSE), 49 dysplastic squamous epithelia (DSE) and 51 SCC were examined. The DF3 antigen was not expressed in NSE (0%), whereas it was expressed in 20 DSE (41%) and in 31 SCC (61%). The intestinal-MRP antigen showed no expression in NSE, DSE or SCC. The Tn antigen showed no expression in NSE, but showed low expression rates in DSE (14%) and in SCC (16%). The sialyl-Tn and T antigens were expressed in NSE, as well as in DSE and SCC. The T antigen expression increased with progression from NSE to DSE to SCC, while the sialyl-Tn antigen did not show such a tendency. Any of the three Lex-related antigens showed no characteristic expression in DSE and SCC. In the eight antigens examined, only DF3 antigen was an effective marker for DSE and SCC in the pharyngeal and laryngeal region. Cytoplasmic expression of DF3 and sialyl-Tn antigens were more frequently seen in SCC than in DSE, and might be useful to differentiate SCC from DSE.

We report a 65-year-old Japanese woman with Kaposi's sarcoma (KS). The eruption first occurred on the legs while she was admitted for treatment of poorly differentiated lung cancer. Approximately eight months after the evolution, cutaneous tumors rapidly spread to the forearms, trunk, and pharynx. At that time, the patient had received systemic corticosteroid (10-40 mg/day of prednisolone) for about three months to reduce pulmonary inflammation. The laboratory data showed anemia, lymphopenia, hypogammaglobulinemia, and a decreased T cell count, although the serological test for HIV infection was negative. The patient was treated with radiation (X-ray for KS of pharynx and electron beam for KS of lower legs) and local intralesional injection of vinblastine. Although both therapies were very effective and well tolerated, she died of bacterial pneumonia and sepsis. Autopsy revealed KS tumors, unknown before death, in both lungs, the esophagus, and the stomach. The left lung cancer had disseminated and metastasized to the right lung, pleura, mediastinum, and abdominal cavity. It is suspected that chronic respiratory distress and systemic use of corticosteroids might have induced the rapid extension of KS.

The effect of locoregional postoperative radiation therapy on cellular immunity was investigated in 11 patients with head and neck cancer. During the course of the radiation therapy, total lymphocyte counts, CD8+ lymphocyte counts and especially CD4+ lymphocyte counts decreased significantly. The mean CD4+ lymphocyte counts dropped from 739/microliters to 183/microliters (p < 0.001) and the average CD4+/CD8+ ratio also decreased significantly. In addition all patients showed impaired in vitro lymphocyte stimulation responses to several mitogens, with reductions found to be 10% to 50% of normal responses. Within 3-4 weeks after radiation therapy there was a slight increase of CD4+ lymphocyte counts and the in vitro lymphocyte stimulation responses showed a tendency to normalization. These results indicate that locoregional postoperative radiation therapy in patients with head and neck cancer can induce a severe impairment of cellular immunity.

A xenogeneic human head and neck squamous cell carcinoma (HNSCC) model in immunocompetent mice was evaluated for its requirement of cyclosporine for progressive tumor growth. Tumor growth and T cell functions were assessed in mice receiving cyclosporine treatment for various lengths of time. Tumor cells were injected s.c. on day 1 and cyclosporine was injected i.p. daily on days 1, 1-7, 1-14, 1-21, or for the entire 28 days of tumor growth. All mice developed tumors. These tumors were confirmed to be squamous carcinomas of human origin histologically and by positive staining for human MHC class I antigen expression. Tumors were largest in mice that received cyclosporine for days 1-21 or days 1-28. Increased tumor size was associated with increased serum levels of tumor-reactive antibodies, an increased intratumoral frequency of CD4+ and CD8+ cells, but a diminished production of interleukin-2 (IL-2) by the tumor infiltrate. Also correlating with increasing tumor size was splenomegaly, a decline in the frequency, but not the absolute levels, of splenic CD4+ and CD8+ cells, and a diminished capacity to proliferate in response to concanavalin A and to be stimulated to secrete IL-2. The HNSCC tumors contributed to the immune decline since T cell functions were more depressed in the tumor bearers than in control mice receiving only cyclosporine treatment. These results demonstrate that human HNSCC tumor xenografts can grow in mice even with limited cyclosporine treatment, and that the survival of these xenografts may, in part, be due to a tumor-induced decline in select T cell functions.

The expression of the argyrophilic nucleolar organizer regions (AgNORs) has been analyzed in renal, bladder, and pharyngeal carcinomas, multiple myeloma (MM), and skin melanocytic lesions to clarify their role in tumor detection and prognosis. Sections from formalin-fixed, paraffin-embedded biopsies were stained with the method of Ploton; the mean AgNOR number per nucleus (AgNOR count) and their distribution (configuration) were assessed examining 100 neoplastic cells. AgNOR counts and histologic grade were highly associated in bladder urotheliomas (6.01 for grade 1 [G1], 7.69 for G2, 13.35 for G3; p < 0.00001) and MM (3.18 for G1, 4.36 for G2, 6.13 for G3; p < 0.0001); they were not associated in renal cell carcinomas (5.35 for G1, 5.92 for G2, 7.99 for G3; p = 0.132) and pharyngeal carcinomas (11.1 for G2, 10.27 for G3; p = 0.08). AgNOR number was also related to the degree of malignancy in melanocytic lesions (2.93 for common blue nevus, 2.89 for benign nevus [BN], 3.69 for cellular blue nevus [CBN], 7.71 for malignant melanoma, and 8.33 for malignant cellular blue nevus [MCBN]; p < 0.00001). Association between AgNOR counts and pathologic stage was found in bladder carcinomas (6.43 for pTa, 10.19 for pT1, 12.57 for pT2-4; p < 0.00001) and MM (3.06 for cases with percentage of bone marrow plasma cells [BMPC%] < or = 20, 4.28 for BMPC% 21 to 50, 5.14 for BMPC% > 50; p < 0.0001]; no correlation was found in pharyngeal (11.18 for T1, 10.08 for T2, 10.68 for T3, 11.47 for T4; p = 0.18) or renal cell carcinomas (6.06 for pT2, 6.31 for pT3; p = 0.78). Few, large and grouped AgNORs were found in well-differentiated bladder carcinomas, MM, and benign melanocytic lesions; numerous, small and dispersed AgNORs were seen in poorly differentiated bladder, renal and pharyngeal carcinomas, MM and malignant melanocytic lesions. Significant association with prognosis was found in pharyngeal carcinomas (5-year survival: 68% for cases with < or = 10.31 AgNOR/cell, 20% for cases with > 10.31 AgNORs) and MM (5-year survival: 46% for cases with < or = 4.62 AgNOR/cell, 7% for cases with > 4.62 AgNORs; in MM the configuration too was related to prognosis: median of survival 72 months for tightly grouped, 16 for partially grouped, and 11 for dispersed AgNORs). Our results indicate that AgNOR number and configuration are useful in detection and prognosis of some neoplasias. They permit a rapid evaluation of morphology and tumor cell kinetics even on small biopsies.(ABSTRACT TRUNCATED AT 400 WORDS)

The expressions and cellular distributions of two pairs of adhesion molecules CD2/LFA-3 (leukocyte function-associated antigen-3) and LFA-1/ICAM-1 (intercellular adhesion molecule-1) were examined in inflammatory cellular infiltrates of advanced squamous cell carcinomas of the head and neck by immunohistochemical techniques including double-staining methods. Thirteen patients were investigated using the following monoclonal antibodies (mAbs): CD2, LFA-3 (CD58), ICAM-1 (CD54), LFA-1 (CD11a), the alpha/beta and gamma/delta T-cell receptor, pan T cells and broadly distributed monocyte/macrophage (m/m phi) [Fc gamma RII (CD32), 25F9, RM3/1]. LFA-3 staining was observed on a high number of cells (968 +/- 112 cells/mm2), correlating to the number of Fc gamma RII (CD32; P < 0.01), 25F9 (P < 0.05) and RM3/1 (P < 0.05) positive m/m phi. Its ligand CD2 was found on 365 +/- 126 cells/mm2, representing about 50% of CD3+ cells (730 +/- 286 cells/mm2). CD2 positivity correlated to CD3 and CD8 (P < 0.01) but not to CD4+ T cells. LFA-1 and ICAM-1 were expressed on lymphocytes as well as on m/m phi. ICAM-1+ cells (902 +/- 205 cells/mm2) correlated to CD3+, CD8+ and RM3/1+ cells (P < 0.01). LFA-1 positivity (803 +/- 255 cells/mm2) showed correlations to nearly all investigated antigens, as well as to CD4+ T cells (P < 0.05). These results show that different m/m phi subsets display distinct patterns of adhesion molecule expressions suggesting different pathways of regulation. The CD3+ lymphocyte population revealed a lack of CD2 expression that was more pronounced in the CD4+ subset and indicated impaired lymphocyte function.

Circulating acute-phase proteins may mediate adverse reactions in patients receiving biologic response modifiers, including inhibition of immune responsiveness and clinical toxic effects. Nine patients with unresectable head and neck squamous cell carcinoma were prospectively examined for levels of acute-phase proteins during interleukin 2/interferon alfa immunotherapy and for clinical toxic effects. Simultaneous determination of the in vitro immunomodulatory capacity of autologous serum on the induction of lymphokine-activated killer cells was assessed in 4-hour chromium release assays. Of the seven acute-phase proteins analyzed, haptoglobin and C-reactive protein levels were elevated before therapy was started. Toxic events leading to cessation of interleukin 2/interferon alfa therapy had a high correlation with elevated C-reactive protein and lowered C3 component of complement levels. No relationship was noted between serum levels of acute-phase proteins and induction inhibition of lymphokine-activated killer cell cytotoxicity. The role of C-reactive protein and complement degradation products in mediating interleukin 2/interferon alfa toxicity requires further investigation.

The proliferative activity of pharyngeal carcinoma has been investigated by means of monoclonal antibody PC10 against proliferating cell nuclear antigen (PCNA/cyclin) and argyrophilic nucleolar organizer region (AgNOR) analysis in formalin-fixed, paraffin-embedded biopsies from 45 primary squamous and undifferentiated carcinomas, prior to therapy. The correlation between AgNOR counts and PCNA(PC10) scores was highly significant (r = 0.73; P < 0.0001) as determined by Pearson's correlation coefficient. Moreover, the univariate Kaplan-Meier survival analysis showed a significant correlation between 3- and 5-year survival rates and the mean AgNOR number per tumour cell (P = 0.0003) or the percentage of PCNA(PC10)-positive cells (P = 0.0001). Our results indicate that both AgNOR counts and PCNA(PC10) scores are reliable markers of the proliferative activity of pharyngeal carcinoma in small, routinely processed biopsies, in which they can allow simultaneous evaluation of the histology and tumour cell kinetics.

Fc receptors are important effector molecules of neutrophilic granulocytes (polymorphonuclear neutrophils [PMN]), connecting phagocytic cells and the specific immune response. Neutrophils from healthy donors express the low-affinity receptors for IgG Fc gamma RII (CD32) and Fc gamma RIII (CD16), but not the high-affinity receptor Fc gamma RI (CD64). The latter has been found on neutrophils from patients with certain bacterial infections and can be induced in vitro after incubation with interferon-gamma. We show here that neutrophils strongly express Fc gamma RI after in vivo application of recombinant human granulocyte colony-stimulating factor (rhG-CSF). PMN from patients receiving rhG-CSF displayed higher cytotoxicity against Daudi lymphoma cells in vitro compared with control patients and with healthy donors. Fab fragments against Fc gamma RII (monoclonal antibody [MoAb] IV.3) inhibited neutrophil-mediated cytotoxicity of healthy donors but not of patients during rhG-CSF therapy. Therefore, expression of Fc receptors by PMN was investigated by flow cytometry and the mean fluorescence intensity (MFI) was compared. After staining with MoAb 32.2 against Fc gamma RL, the median MFI of neutrophils from G-CSF patients (median, 4.78; range, 2.40 to 8.50; n = 5) was significantly higher (P = .002 and P = .001, respectively) than the median MFI of patients not receiving G-CSF (median, 1.23; range, 1.01 to 1.58; n = 6) and the median MFI of healthy donors (median, 1.04; range, 0.67 to 1.12; n = 6). Fc gamma RI disappeared after the discontinuing of the G-CSF injections, but was reinduced during the next treatment cycle with rhG-CSF. The high expression of Fc gamma RI during rhG-CSF therapy correlated with enhanced cytotoxicity. In vitro incubation with rhG-CSF also enhances cytotoxicity, but only minor increments in Fc gamma RI expression were observed. Thus, during in vivo application of rhG-CSF neutrophils acquire an additional potent receptor for mediating tumor cell killing in vitro by induction of the high-affinity receptor for IgG (Fc gamma RI, CD64).

Eighteen of 25 patients had squamous cell carcinoma in the supraglottic region. Anergy to skin test antigen (DNCB) and T-cell mitogen (PHA) was observed in 17 patients with laryngeal and laryngopharyngeal malignancies. Chemo-immunotherapy did not improve the skin reactivity to either agents. However, a rise in absolute T-cell counts was observed following combined therapy. Moreover, T-lymphopenia was detected in the patient group prior to therapy as compared to mean T-cell counts in normal control subjects.

Basaloid-squamous carcinoma of the larynx, pharynx and base of tongue and the so-called adenoid cystic carcinoma of the oesophagus are rare but distinctive tumours associated with a grave prognosis. They occur most commonly in elderly males and present at an advanced stage. Our study of four such laryngeal tumours and five such oesophageal tumours shows that they are histologically and immunohistochemically identical, providing support for the idea that they are the same tumour type. They show a biphasic pattern in which basaloid tumour is intimately associated with a neoplastic squamous component which can be invasive or in situ. The basaloid component is in the form of invasive lobules with frequent comedo-necrosis and hyalinization. The constituent cells possess pale pleomorphic nuclei with frequent mitoses. Immunoreactivity for cytokeratin in the basaloid component is remarkable for its absence or weak and focal nature. Review of the literature shows that only a few cases of 'adenoid cystic carcinoma' of the oesophagus are bona fide examples of adenoid cystic carcinoma as it occurs in the salivary glands, while the others are identical to basaloid-squamous carcinoma of the upper aerodigestive tract. Their distinction is important because genuine adenoid cystic carcinoma is much less aggressive than basaloid-squamous carcinoma.

Although the number of carcinomas of the upper aerodigestive tract is increasing, there are not many reports in the literature about familial occurrence. Epidemiological studies have shown that the major causative factors are tobacco and alcohol abuse. But the possibility of an endogenous susceptibility is also discussed. A possible explanation is failure of the immune defense system. The author was able to examine immunologic patterns in three siblings with cancer of the upper aerodigestive tract. The results obtained so far indicate normal numbers of lymphocyte subpopulations in the peripheral blood, but with impaired function.

The NK activity has been examined in a 4-hour 51Cr release assay in 59 untreated patients with laryngeal carcinoma, 46 untreated patients with nasopharyngeal carcinoma and 18 untreated patients with other head and neck carcinomas. The kinetic changes of NK activity in 10 patients with laryngeal carcinoma before and after surgery was also observed. The results showed that the NK activity of patients was significantly lower than that of the normal control and decreased progressively in the advanced cases. A significant decrease in NK activity in laryngeal carcinoma patients was found 3-5 days after surgery, and an increase in activity was seen more than one week later. These results suggest that the test of NK activity in untreated laryngeal carcinoma patients might be a parameter to predict the course and prognosis of the disease.

The percentages of early and late E-RFC were measured in 25 proven cases of squamous cell carcinoma of the larynx and laryngopharynx. Both counts were depressed significantly in the patients compared to the controls (p less than 0.001). There was also a significant correlation of these counts with the severity of the disease, but there was no correlation between the counts and the duration of the disease.

Radiation therapy and/or chemotherapy are the treatment modalities of choice in lymphomas. Except for Burkitt's tumor, surgery is usually indicated only when percutaneous biopsy fails to establish the histologic diagnosis. We have described a patient with glomerulonephritis and anasarca secondary to an IgM-producing parapharyngeal lymphoma. After resection of all palpable tumor by an excisional biopsy, the monoclonal gammopathy and secondary nephrosis promptly cleared. With chemotherapy and mantle irradiation, the patient is in remission at three years. It is not now clear whether surgery will become useful as an adjunctive therapy for localized head and neck lymphomas. This will depend on whether local failure rates can be improved solely by using new combinations of irradiation and/or cytotoxic agents, and whether the morbidity of such therapy will outweigh the therapeutic gain.