Frailty does not worsen postoperative outcomes in sinonasal squamous cell carcinoma.

PURPOSE: Sinonasal squamous cell carcinoma (SCC) is an aggressive malignancy frequently requiring surgical resection and adjuvant treatment. Frailty is a metric that attempts to estimate a patient's ability to tolerate the physiologic stress of treatment. There is limited work describing frailty in patients with sinonasal cancer. We sought to determine the impact of frailty on postoperative outcomes in patients undergoing treatment for sinonasal SCC. MATERIALS AND METHODS: Cases of patients undergoing surgical resection of sinonasal SCC at two tertiary medical centers were queried. Demographic, treatment, and survival data were recorded. Frailty was calculated using validated indexes, including the American Society of Anesthesiologists (ASA) classification, modified 5-item frailty index (mFI-5), and the Charlson Comorbidity Index (CCI). Primary outcomes included medical and surgical complications, readmission, and length of stay (LOS). RESULTS: 38 patients were included. There were 23 (60.5 %) men and 15 (39.5 %) women with an average age of 59.6 ± 12.1 years. MFI-5 was 0.76 ± 0.54 and CCI was 5.71 ± 2.64. No significant association was noted between frailty measures and postoperative outcomes including 30-day medical complications, 30-day surgical complications, any 30-day complication, and readmission. Increased ASA was noted to be predictive of increased length of stay (Incidence Rate Ratio: 1.80, 95 % confidence interval [CI]: 1.16-2.83, p = 0.009). CONCLUSIONS: We found no association between frailty metrics and worsening surgical or medical postoperative outcomes. This suggests that frailty metrics may not be as relevant for sinonasal surgery even for advanced pathologies, given the more limited physiologic impact of minimally invasive surgery.

Primary sinonasal lymphoma: A multi-institutional experience of clinical presentation, treatment, and outcomes.

BACKGROUND: Sinonasal lymphoma (SL) is a heterogeneous, underrecognized neoplastic disorder with limited outcomes data. We sought to better define outcomes by subtype and treatment at 2 referral centers over the past 2 decades. METHODS: Demographics, clinicopathologic data, and treatment outcomes for patients treated for SL were queried from January 1, 2000 to December 31, 2021 at 2 tertiary academic medical centers. RESULTS: Eighty-four patients were included, with an average age at diagnosis of 63.4 ± 15 years. There were 34 females (40.5%). The majority of patients had an Eastern Cooperative Oncology Group (ECOG) score of <2 (76.2%) and the most common presenting symptom was facial swelling/pain (26.2%). The most common primary site was the nasal cavity (36.9%). Diffuse large B-cell lymphoma was the most common subtype (46.4%), followed by extranodal NK/T-cell lymphoma (17.9%). Chemotherapy was the most common treatment strategy (n = 59, 70.2%), followed by radiation therapy (n = 35, 41.7%) and immunotherapy (n = 24, 28.6%). Disease-specific survival rates at 1, 5, and 10 years were 85.7%, 73.6%, and 58.6%, respectively. Eighteen patients (21.4%) developed recurrence. On multivariate analysis, higher ECOG score (p < 0.0001) and history of head and neck radiation (p = 0.048) were associated with worse survival. Younger age was associated with greater risk of recurrence (p = 0.022) and male sex was associated with more treatment side effects (p = 0.012). CONCLUSION: This is the largest multi-institutional analysis of SL characteristics and outcomes. Our work suggests that, although disease control in the first 5 years is reasonable, 10-year outcomes remain challenging. Further studies are needed to investigate new treatment paradigms and risk stratification.

Sinonasal lymphoma: A primer for otolaryngologists.

Objective: Sinonasal lymphomas are a rare entity that commonly present with nonspecific sinonasal symptoms and are often recognized immediately. Through this review, we aim to summarize important principles in diagnosis and treatment of sinonasal lymphomas, with the goal of disseminating the current knowledge of this under-recognized malignancy to otolaryngologists. Methods: Systemic review using PRISMA guidelines of foundational scholarly articles, guidelines, and trials were reviewed focusing on clinical characteristics of key sinonasal lymphoma subtypes, along with available treatments in the otolaryngology, medical oncology, and radiation oncology literature. Results: Sinonasal lymphoma are derived from clonal proliferation of lymphocytes at various stages of differentiation, of which diffuse large B-cell lymphoma (DLBCL) and extranodal natural killer/T-cell lymphoma (ENKTL) are the most common. Diagnosis and staging require biopsy with immunohistochemistry in conjunction with imaging and laboratory studies. Treatment is ever evolving and currently includes multi-agent chemotherapy and/or radiation therapy. Conclusion: Otolaryngologists may be the first to recognize sinonasal lymphoma, which requires a comprehensive workup and a multidisciplinary team for treatment. Symptoms are nonspecific and similar to many sinonasal pathologies, and it is crucial for otolaryngologists to keep a broad differential. Level of Evidence: 5.

Prostate cancer immunotherapy: a review of recent advancements with novel treatment methods and efficacy.

Immunotherapy remains to be an appealing treatment option for prostate cancer with some documented promise. Prostate cancer is traditionally considered as an immunologically "cold" tumor with low tumor mutation burden, low expression of PD-L1, sparse T-cell infiltration, and a immunosuppressive tumor microenvironment (TME). Sipuleucel-T (Provenge) is the first FDA approved immunotherapeutic agent for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC); demonstrating a benefit in overall survival. However various clinical trials by immune checkpoint inhibitors (ICIs) and their combinations with other drugs have shown limited responses in mCRPC. Up to now, only a small subset of patients with mismatch repair deficiency/microsatellite instability high and CDK12 mutations can clinically benefit from ICIs and/or their combinations with other agents, such as DNA damage agents. The existence of a large heterogeneity in genomic alterations and a complex TME in prostate cancer suggests the need for identifying new immunotherapeutic targets. As well as designing personalized immunotherapy strategies based on patient-specific molecular signatures. There is also a need to adjust strategies to overcome histologic barriers such as tissue hypoxia and dense stroma. The racial differences of immunological responses between men of diverse ethnicities also merit further investigation to improve the efficacy of immunotherapy and better patient selection in prostate cancer.

Multi-institutional review of sinonasal and skull base chondrosarcoma: 20-year experience.

BACKGROUND: Chondrosarcomas of the sinonasal cavity and skull base are uncommon malignancies. We sought to provide long-term outcomes at two tertiary care centers. METHODS: Patients with chondrosarcoma treated between 2000 and 2021 were included. The primary outcomes were overall survival (OS) and disease-specific survival (DSS). RESULTS: Thirty-eight patients met inclusion criteria. Fourteen patients had sinonasal (36.8%), 7 petroclival (18.4%), and 17 other primary skull base lesions (44.7%). Twenty-eight patients (73.7%) underwent radiation with an average dose of 67.3 ± 15.1 Gy. Eighteen patients (47.4%) required revision surgery for recurrence. 1, 5, and 10-year OS were 97.3%, 93.1%, and 74.7%. DSS at 5- and 10-year survival was 95.7%. Adjuvant radiation was associated with improved OS (HR: 0.12; 95% CI: 0.02-0.75, p = 0.023). CONCLUSION: We present our experience over the last 20 years treating chondrosarcomas. Favorable survival outcomes can be achieved but recurrence requiring repeat resection is common.

First Reported Case of Extramedullary Plasmacytoma of the Appendix.

An extramedullary plasmacytoma involving the gastrointestinal tract is extremely rare. We report an appendiceal extramedullary plasmacytoma in a 35-year-old man who presented to the emergency department because of upper abdominal pain. Computed tomography (CT) imaging revealed an incidental mass (3.7 × 1.9 × 1.6 cm) at the tip of the appendix. Microscopically, the appendix, periappendiceal soft tissue, and nearby lymph nodes were diffusely infiltrated by plasma cells that were kappa light chain restricted. Subsequent workup included an unremarkable bone marrow biopsy, as well as urine and serum electrophoresis. A diagnosis of kappa-restricted solitary extramedullary plasmacytoma was made. To our knowledge, this is the first case reported of an appendiceal extramedullary plasmacytoma in the medical literature.

Anaplastic Thyroid Carcinoma Histologically Mimicking a Plasmacytoma.

Anaplastic (undifferentiated) thyroid carcinoma (ATC) is a rare malignancy which may arise from transformation of a pre-existing differentiated carcinoma. We report the unique case where a lesion of thyroid origin presented with the histological features of mature plasma cells. Immunohistochemistry confirmed the lesion to be an anaplastic thyroid carcinoma arising from papillary thyroid carcinoma. A tumor mimicking a malignancy of a different cellular origin can lead clinicians to incorrect treatment approaches. Careful correlation with clinical details and knowledge of these unique presentations is important for reaching the correct diagnosis.

Hyams grading as a predictor of metastasis and overall survival in esthesioneuroblastoma: a meta-analysis.

BACKGROUND: Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, represents up to 3% of all sinonasal neoplasms. Hyams histologic grading is a promising tool in predicting metastases and establishing prognoses for this complex tumor. METHODS: A systematic literature search was performed in the PubMed, Ovid MEDLINE, and Cochrane databases. ENB patients with Hyams I-II or III-IV were categorized as low-grade Hyams (LGH) or high-grade Hyams (HGH), respectively. Binary and continuous random-effects models were applied to calculate odds ratios (ORs) for the incidences of neck and distal metastases as well as for 5- and 10-year overall survival rates. RESULTS: Of the 57 screened articles published from 1993 to 2018, 16 (525 patients) and 21 (563 patients) provided data for tumor metastases and overall survival rates, respectively. Neck metastasis was observed in 18.2% of HGH vs 7.9% of LGH patients. Distant metastasis was noted in 20.7% of HGH vs 8.9% of LGH patients. LGH patients had 5- and 10-year overall survival rates of 81.2% and 64.0%, respectively, as compared with 60.9% and 40.6%, respectively, for HGH patients. In comparing HGHs vs LGHs, the collective ORs for neck and distant metastases were 2.08 (95% confidence interval [CI], 1.09-3.99; p = 0.03) and 2.37 (95% CI, 1.07-5.26; p = 0.03), respectively. Moreover, in comparing LGHs vs HGHs, collective ORs for 5- and 10-year overall survival rates were 3.39 (95% CI, 2.09-5.49; p < 0.001) and 3.03 (95% CI, 1.82-5.06; p < 0.001), respectively. CONCLUSION: HGH ENBs, compared with LGH ENBs, are more likely to metastasize to neck or distal targets and to have lower overall survival rates.

The California Telepathology Service: UCLA's Experience in Deploying a Regional Digital Pathology Subspecialty Consultation Network.

BACKGROUND: The need for extending pathology diagnostic expertise to more areas is now being met by the maturation of technology that can effectively deliver this level of care. The experience and lessons learned from our successfully deployed International Telepathology Service (ITS) to a hospital system in China guided us in starting a domestic telepathology network, the California Telepathology Service (CTS). Many of the lessons learned from the ITS project informed our decision-making for the CTS. New challenges were recognized and overcome, such as addressing the complexity and cost-benefit tradeoffs involved in setting up a digital consultation system that competes with an established conventional glass slide delivery system. METHODS: The CTS is based on a hub-and-spoke telepathology network using Leica Biosystems whole-slide image scanners and the eSlide Manager (eSM Version 12.3.3.7055, Leica Biosystems) digital image management software solution. The service currently comprises six spoke sites (UC San Diego [UCSD], UC Irvine [UCI], UC Davis, Northridge Hospital Medical Center [NHMC], Olive View Medical Center [OVMC], and Children's Hospital Los Angeles) and one central hub site (UCLA Medical Center). So far, five sites have been validated for telepathology case consultations following established practice guidelines, and four sites (UCI, UCSD, NHMC, and OVMC) have activated the service. RESULTS: For the active spoke sites, we reviewed the volume, turnaround time (TAT), and case types and evaluated for utility and value. From May 2017 to July 2018, a total of 165 cases were submitted. Of note, digital consultations were particularly advantageous for preliminary kidney biopsy diagnoses (avg TAT 0.7 day). CONCLUSION: For spoke sites, telepathology provided shortened TAT and significant financial savings over hiring faculty with expertise to support a potentially low-volume service. For the hub site, the value includes exposure to educationally valuable cases, additional caseload volume to support specialized services, and improved communication with referring facilities over traditional carrier mail. The creation of a hub-and-spoke telepathology network is an expensive undertaking, and careful consideration needs to be given to support the needs of the clinical services, acquisition and effective deployment of the appropriate equipment, network requirements, and laboratory workflows to ensure a successful and cost-effective system.

Atypical mycobacteriosis of the larynx: an unusual clinical presentation secondary to steroids inhalation.

Vocal cords stiffness can be associated with a variety of etiologic agents, but it is rarely seen with atypical mycobacteria, for example, Mycobacterium avium complex. We report a case of a 35-year-old white woman who is and was maintained on inhaled steroids. She presented with hoarseness and low-grade fever, but her medical history was otherwise unremarkable. Laryngoscopy revealed bilateral scarring of the vocal cords. Vocal cord biopsies were performed. Histologic examination revealed unremarkable laryngeal mucosa, except for abundant subepithelial non-necrotizing granulomata. The differential diagnosis included sarcoid, Klebsiella scleroma, and tuberculosis. Special stains reviewed abundant acid-fast bacilli, later confirmed by a DNA assay on induced deep sputum, consistent with M avium complex. Subsequently, steroids were withdrawn, and the patient was treated with a multiple-drug antituberculous regimen and had a full recovery. This unusual clinical presentation of the atypical mycobacteriosis may be encountered by otolaryngologists and pathologists, and it is critical to recognize it in patients immunocompromised because of steroids.

Selective recurrent laryngeal nerve stimulation using a penetrating electrode array in the feline model.

OBJECTIVES/HYPOTHESIS: Laryngeal muscles (LMs) are controlled by the recurrent laryngeal nerve (RLN), injury of which can result in vocal fold (VF) paralysis (VFP). We aimed to introduce a bioelectric approach to selective stimulation of LMs and graded muscle contraction responses. STUDY DESIGN: Acute experiments in cats. METHODS: The study included six anesthetized cats. In four cats, a multichannel penetrating microelectrode array (MEA) was placed into an uninjured RLN. For RLN injury experiments, one cat received a standardized hemostat-crush injury, and one cat received a transection-reapproximation injury 4 months prior to testing. In each experiment, three LMs (thyroarytenoid, posterior cricoarytenoid, and cricothyroid muscles) were monitored with an electromyographic (EMG) nerve integrity monitoring system. Electrical current pulses were delivered to each stimulating channel individually. Elicited EMG voltage outputs were recorded for each muscle. Direct videolaryngoscopy was performed for visualization of VF movement. RESULTS: Stimulation through individual channels led to selective activation of restricted nerve populations, resulting in selective contraction of individual LMs. Increasing current levels resulted in rising EMG voltage responses. Typically, activation of individual muscles was successfully achieved via single placement of the MEA by selection of appropriate stimulation channels. VF abduction was predominantly observed on videolaryngoscopy. Nerve histology confirmed injury in cases of RLN crush and transection experiments. CONCLUSIONS: We demonstrated the ability of a penetrating MEA to selectively stimulate restricted fiber populations within the feline RLN and selectively elicit contractions of discrete LMs in both acute and injury-model experiments, suggesting a potential role for intraneural MEA implantation in VFP management. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:1606-1614, 2018.

Association of nuclear, cytoplasmic expression of galectin-3 with beta-catenin/Wnt-pathway activation in thyroid carcinoma.

OBJECTIVES: To characterize the localization of galectin-3 in benign and malignant thyroid neoplasms and to correlate this with alterations in beta-catenin and cyclin D1 expression. DESIGN: Immunohistochemical study of 116 paraffin-embedded archival specimens from 113 patients who had undergone thyroidectomy and tissue placed into a commercially available tissue microarray. SETTING: Tertiary care hospital. INTERVENTIONS: Thyroid tissue microarrays were stained by standard immunohistochemical protocols with monoclonal antibodies against galectin-3, beta-catenin, and cyclin D1. MAIN OUTCOME MEASURES: Nuclear and cytoplasmic expression of galectin-3 was correlated with clinical parameters, beta-catenin, and cyclin D1 expression. RESULTS: Both cytoplasmic (56%) and nuclear (42%) galectin-3 expression was observed in most malignant neoplasms but was absent in benign thyroid specimens (P<.001). Among carcinomas, cytoplasmic galectin-3 expression was observed in papillary thyroid carcinomas (82%) and follicular (33%) and medullary (9%) carcinomas but was absent in anaplastic carcinomas (P<.001). Galectin-3 nuclear expression was observed in papillary thyroid carcinomas (62%) and follicular carcinomas (33%) but was undetectable in medullary, anaplastic carcinomas (P<.001). Cytoplasmic but not nuclear galectin-3 was inversely correlated with American Joint Committee on Cancer TNM stage (P = .02). There was a strong correlation between cytoplasmic and nuclear beta-catenin expression and both nuclear (P = .04) and cytoplasmic (P = .003) galectin-3 expression. Similarly, there was a strong association between galectin-3 nuclear (P<.001) and cytoplasmic (P<.001) expression and cyclin D1 expression. CONCLUSION: Cytoplasmic and nuclear galectin-3 expression seem to be associated with activation of the Wnt-signaling pathway in well-differentiated thyroid neoplasms, suggesting that galectin-3 plays a role in thyroid carcinogenesis.

Updates on Immunohistochemical and Molecular Markers in Selected Head and Neck Diagnostic Problems.

CONTEXT: - The head and neck regions have complex anatomic structures. They are not exempted from the rare occurrences of highly unusual, diagnostically challenging malignant neoplasms and mimickers. OBJECTIVE: - To review and update the utility of immunohistochemistry and molecular biomarkers and to pursue diagnostic accuracy on selected rare neoplasms, especially some poorly differentiated malignancies. DATA SOURCES: - Personal experience and information from the literature. CONCLUSIONS: - Head and neck tumors include neoplasms originating from heterogeneous tissue. Using the selected clinical cases, this review illustrates a continuous development of emerging molecular-genetic techniques to assist in the interpretation of uncommon, often poorly differentiated, highly malignant neoplasms. The diagnostic results are appropriately transmitted to the oncologists, radiation oncologists, and surgeons to create a coordinated plan of care for patients with these unusual disorders affecting the head and neck.

Selective Stimulation of Facial Muscles Following Chronic Intraneural Electrode Array Implantation and Facial Nerve Injury in the Feline Model.

BACKGROUND: Our group has previously shown that activation of specific facial nerve (FN) fiber populations and selective activation of facial musculature can be achieved through acute intraneural multichannel microelectrode array (MEA) implantation in the feline model. HYPOTHESIS: Selective stimulation of facial muscles will be maintained in the setting of 1) chronic and 2) acute MEA implantation after FN injury and subsequent recovery. METHODS: This study included seven cats. In three cats with normal facial function, 4-channel penetrating MEAs were implanted chronically in the FN and tested biweekly for 6 months. Electrical current pulses were delivered to each channel individually, and elicited electromyographic (EMG) voltage outputs were recorded for each of several facial muscles. For FN injury experiments, two cats received a standardized hemostat-crush injury, and two cats received a transection-reapproximation injury to the FN main trunk. These four underwent acute implantation of MEA and EMG recording in terminal experiments 4 months postinjury. RESULTS: Stimulation through individual channels selectively activated restricted nerve populations, resulting in activation of individual muscles in cats with chronic MEA implantation and after nerve injury. Increasing stimulation current levels resulted in increasing EMG voltage responses in all patients. Nerve histology showed only minor neural tissue reaction to the implant. CONCLUSION: We have established in the animal model the ability of a chronically implanted MEA to selectively stimulate restricted FN fiber populations and elicit activations in specific facial muscles. Likewise, after FN injury, selective stimulation of restricted FN fiber populations and subsequent activation of discrete facial muscles can be achieved after acute MEA implantation.

Pediatric odontogenic fibromyxoma of the mandible: Case report and review of the literature.

BACKGROUND: Odontogenic fibromyxoma is an uncommon benign tumor arising from the maxillofacial bones. Fibromyxomas are rare in children under 10 years of age. Although this tumor is reported most frequently in the mandible for the general population, it has rarely been reported in the mandible in children <10 years of age. METHODS: We reviewed the 39 reported cases of odontogenic fibromyxoma in children under the age of 10. We add 1 case to the literature. RESULTS: This case represents the seventh case of odontogenic fibromyxoma of the mandible in a child under the age of 10 years reported in the English literature. CONCLUSION: A case of pediatric odontogenic fibromyxoma in the mandible is described. Although rare in the pediatric population, odontogenic fibromyxomas should be included as a differential diagnostic consideration when evaluating tumors of the maxillofacial skeleton. Accurate pathologic diagnosis is critical to ensure proper management.

Unusual polypoid laryngeal myxoma.

Laryngeal polyps, known as vocal cord polyps, are often benign, reactive, polypoid, squamous mucosa with subepithelial hyalinization and edematous stroma. Rarely, a benign mesenchymal myxoma occurring in the vocal cord will present as a polyp. It may have a local recurrence due to inadequate excision and result in airway obstruction. We report a case of a 46-year-old male who had a history of smoking and complained of hoarseness. A polypoid vocal cord mass was removed and the pathologic finding was a benign myxoma. To assure complete excision of the lesion, one should be aware that this rare entity may involve a laryngeal location.

Very delayed cervical lymph node metastases from hyalinizing clear cell carcinoma: report of 2 cases.

BACKGROUND: Hyalinizing clear cell carcinoma (HCCC) is a rare salivary gland neoplasm most often found in the oral cavity. Although it is generally a low-grade malignancy that is treated with wide local excision, there is a growing body of evidence pointing toward the potential for more aggressive behavior. METHODS: We reviewed available records of patients with delayed cervical lymph node metastases from HCCC. RESULTS: Two patients who were treated with wide local resection for HCCC and remained disease-free at the primary site were diagnosed with cervical lymph node metastases 10 and 14 years later. We treated both with neck dissection, and 1 patient received adjuvant radiation therapy. CONCLUSION: These cases illustrate the risk for occult nodal metastases from HCCC with delayed presentation. Clinician awareness of the presence of subclinical metastases in the neck requires thorough long-term surveillance and potential intervention should nodal disease become manifest.

Low-grade salivary duct carcinoma: description of 16 cases.

Low-grade salivary duct carcinoma is a rare neoplasm. We report on 16 patients, with a median age of 64 years. All but one tumor arose from the parotid gland, including one tumor that arose in an intraparotid lymph node; one arose in the submandibular gland. Tumors consist of single to multiple dominant cysts, accompanied by adjacent intraductal proliferation. Cysts are lined by small, multilayered, proliferating, bland ductal cells with finely dispersed chromatin and small nucleoli. Separate, smaller ductal structures are variably filled by proliferating ductal epithelium with cribriform, micropapillary, and solid areas. The overall appearance is very similar to breast atypical ductal hyperplasia and low-grade ductal carcinoma in situ. Foci of definitive stromal invasion were seen in four tumors. Two tumors demonstrated transition from low- to intermediate- or high-grade cytology, with scattered mitotic figures and focal necrosis. S-100 revealed diffuse strong expression in all 9 cases studied. Myoepithelial markers (calponin) highlighted supportive myoepithelial cells rimming the cystic spaces, confirming the intraductal nature of most, or all, of six tumors studied. Nine tumors studied for Her2-neu antigen were uniformly negative. Follow-up was obtained on 13 of our 16 patients. All patients were disease-free after surgery 6 to 132 months (median 30 months). Low-grade salivary duct carcinoma is a low-grade neoplasm with an excellent prognosis; it may be treated by conservative but complete resection. Its resemblance to atypical breast ductal hyperplasia, or micropapillary/cribriform intraductal carcinoma, distinguishes it from high-grade salivary duct carcinoma, papillocystic acinic cell carcinoma, and cystadenocarcinoma.

Immunohistochemical detection of p53 homolog p63 in solid cell nests, papillary thyroid carcinoma, and hashimoto's thyroiditis: A stem cell hypothesis of papillary carcinoma oncogenesis.

Most models suggest that the cell of origin of papillary carcinoma is the mature thyroid follicular epithelial cell. In a recent study, p63 was detected in papillary carcinoma, Hashimoto's thyroiditis, and in squamoid aggregates and solid cell nests (SCNs), embryonic remnants found sporadically in the fully developed thyroid. In the present study, the relationship between solid cell nests and papillary carcinoma was investigated further. Four-micrometer sections from 88 routinely fixed and processed archival thyroidectomy specimens were pretreated with citric acid pH 6.0 for antigen retrieval, then incubated overnight with anti-p63 monoclonal antibody 4A4. Slides were stained with a streptavidin-biotin kit and diaminobenzidine as chromogen and were counterstained with hematoxylin. Squamoid aggregates or SCNs were noted in 21 specimens. Several morphologic variants of SCNs were found, all of which displayed p63 positivity. These included undifferentiated SCNs and those displaying commitment toward squamoid and ciliated glandular differentiation. Small, morphologically inconspicuous aggregates of p63-positive cells were commonly found in Hashimoto's thyroiditis. Commitment of p63-positive undifferentiated cells toward thyroid follicular epithelial differentiation was occasionally noted. One SCN variant, also associated with Hashimoto's thyroiditis, was a floretlike arrangement of p63-positive cells with fusiform nuclei. p63 staining was strong and uniform in some SCNs, but in other SCNs it was compartmentalized and homologous to stem cell-staining patterns in normal squamous or bronchial epithelia. Stem cell-like staining, associated with compartmentalized p63 staining or p63-positive undifferentiated cells, was noted in 7 of 27 papillary carcinomas. p63 immunostaining is a highly sensitive means of detecting SCNs. p63 expression patterns in SCNs and a subset of papillary carcinomas are closely homologous to stem cell-associated p63 staining patterns that have been described elsewhere in squamous and bronchial epithelia. We propose a stem-cell-associated model of papillary carcinoma oncogenesis that suggests that (1) p63-positive embryonal remnants rather than mature follicular cells are the cells of origin of a subset of papillary carcinomas; (2) these p63-positive cells are pluripotent and may stay undifferentiated or undergo benign squamoid or glandular maturation, may undergo thyroid follicular epithelial differentiation, may undergo oncogenic change leading to papillary carcinoma, or may trigger an immune reaction, resulting in lymphoid infiltration and Hashimoto's thyroiditis; and (3) Hashimoto's thyroiditis and papillary carcinoma may therefore be linked etiologically, because both disorders may be initiated by the same population of pluripotent p63-positive embryonal stem cell remnants.

Expression of p63 in papillary thyroid carcinoma and in Hashimoto's thyroiditis: a pathobiologic link?

p63 proteins are p53 homologs that are postulated to regulate squamous stem cell commitment. An immunohistochemical survey of p63 expression in normal thyroid and in reactive, neoplastic, and inflammatory thyroid disorders was performed. Sections from routinely fixed and processed archival thyroidectomy specimens were pretreated with citric acid, pH 6.0, for antigen retrieval, then incubated overnight with anti-p63 monoclonal antibody 4A4. Slides were stained using a streptavidin-biotin kit and diaminobenzidine as a chromagen, and then were counterstained with hematoxylin. The results showed that p63 expression was negative in normal thyroid tissue, nodular goiters, and oncocytic follicular adenomas. Positivity was rare and weak in follicular adenomas. p63-positive foci were commonly found in Hashimoto's thyroiditis (1 or more foci in 78.8% of cases), but rare in Graves' disease. Twenty-seven of 33 papillary thyroid carcinomas (81.8%) displayed p63-positive foci. Staining was uncommon in follicular carcinomas and rare in medullary carcinomas. One case of insular carcinoma was p63-positive. All squamoid structures were p63-positive; p63-positive structures morphologically consistent with solid cell nests were also identified. Based on the results of this study, we conclude that p63 is commonly expressed in papillary thyroid carcinoma and in Hashimoto's thyroiditis. Given the debated association of papillary thyroid carcinoma with Hashimoto's thyroiditis, it is possible that p63 expression may be a potential pathobiologic link between the two disorders. The finding of p63 in benign squamoid nests supports a possible interrelationship between these structures and both Hashimoto's thyroiditis and papillary carcinoma. The high percentage of papillary carcinomas with p63-positive foci appears to distinguish papillary carcinoma from other neoplasms originating in the thyroid.