PD-L1 expression associates with favorable survival of patients with cancer of unknown primary (CUP) not treated with checkpoint inhibitors.

PURPOSE: Cancer of unknown primary (CUP) is a heterogeneous entity with limited overall survival (OS) in most patients. Prognostic biomarkers are needed, particularly for treatment stratification. We investigated the impact of programmed death-ligand 1 (PD-L1) expression as prognostic marker in immunotherapy-naïve CUP patients. METHODS: Clinical data from patients with confirmed CUP diagnosis according to ESMO guidelines, treated at the West German Cancer Center, Essen from 2015 to 2021, were analyzed. Patients treated with checkpoint inhibitors were excluded. PD-L1 expression was assessed in tumor tissues following established guidelines. RESULTS: Of a cohort of 132 patients, 62 patients, including 30 patients with prognostically unfavorable CUP, met inclusion criteria and were evaluable for PD-L1 expression. Comparing PD-L1 Tumor Proportional Score (TPS) and Combined Positive Score (CPS) revealed almost complete concordance (96.2 %). Patients with PD-L1-positive CUP (TPS ≥1 %; n = 36; 58 %) had superior overall survival (median not reached) as compared to patients with PD-L1-negative CUP (median 14 months, 95 %CI 10.0-18.0; HR 0.3, p < 0.001). The benefit of PD-L1 positivity (n = 12; 40 %) was maintained in the unfavorable CUP subgroup (median 20 months, 95 %CI 3.0-37.0 versus 10 months, 95 %CI 3.1-16.9; HR 0.4, p = 0.032). In PD-L1-positive CUP there was a positive correlation between the level of PD-L1 expression and survival (TPS ≥50 %: median survival not reached, HR 0.1; TPS 1 to 49 %: OS: 77 months, HR 0.4). CONCLUSION: PD-L1 expression associates with favorable survival in checkpoint inhibitor-naïve CUP patients. This implies a role of cancer immunity in CUP biology and may nominate PD-L1 for patient stratification in further studies and clinical care.

Tracing unknown tumor origins with a biological-pathway-based transformer model.

Cancer of unknown primary (CUP) represents metastatic cancer where the primary site remains unidentified despite standard diagnostic procedures. To determine the tumor origin in such cases, we developed BPformer, a deep learning method integrating the transformer model with prior knowledge of biological pathways. Trained on transcriptomes from 10,410 primary tumors across 32 cancer types, BPformer achieved remarkable accuracy rates of 94%, 92%, and 89% in primary tumors and primary and metastatic sites of metastatic tumors, respectively, surpassing existing methods. Additionally, BPformer was validated in a retrospective study, demonstrating consistency with tumor sites diagnosed through immunohistochemistry and histopathology. Furthermore, BPformer was able to rank pathways based on their contribution to tumor origin identification, which helped to classify oncogenic signaling pathways into those that are highly conservative among different cancers versus those that are highly variable depending on their origins.

Programmed death-ligand 1 expression in carcinoma of unknown primary.

We examined the expression of programmed death-ligand 1 (PD-L1) in carcinoma of unknown primary (CUP) and its potential implications. Tissue microarrays were constructed for 72 CUP cases (histologic subtypes: 22 adenocarcinoma, 15 poorly differentiated carcinoma, 19 squamous cell carcinoma, and 14 undifferentiated carcinoma; clinical subtype: favorable type 17 [23.6%], unfavorable type 55 [76.4%]), with immunohistochemical staining performed for PD-L1 (22C3, SP142, SP263, and 28 - 8), CK7, and CK20 to determine the association between staining results and clinicopathological parameters. In CUP, the PD-L1 positivity rate was 5.6-48.6% (tumor cells [TC] or tumor proportion score [TPS]: 5.6-36.1%, immune cell score [IC]: 8.3-48.6%, combined positive score [CPS]: 16.7%) using different cutoff values for 22C3 (TPS ≥ 1%, CPS ≥ 10), SP142 (TC ≥ 50%, IC ≥ 10%), SP263, and 28 - 8 (TC and IC ≥ 1%). PD-L1 SP142 TC and PD-L1 SP263 IC showed the lowest (5.6%) and highest (48.6%) positivity rates, respectively. The PD-L1 positivity rate did not significantly differ based on the histologic subtype, clinical subtype, or CK7/CK20 across clones. Considering TC κ ≥ 1%, TC κ ≥ 50%, IC κ ≥ 1%, and IC κ ≥ 10%, the PD-L1 positivity rate was TC = 4.2-36.1% and IC = 9.7-48.6%; the overall agreement between antibodies ranged from 69.4 to 93.1%, showing fair or better agreement (κ ≥ 0.21). In CUP, PD-L1 positivity varied depending on antibodies and scoring systems, with no difference observed according to histologic or clinical subtypes.

Carcinoma of Unknown Primary Origin: Application of Immunohistochemistry With Emphasis to Different Cytokeratin 7 and 20 Staining Patterns.

BACKGROUND: Although the primary origin of some carcinomas may be obscure to clinicians, its identification is crucial as it affects prognosis and treatment (especially novel targeted therapies). Immunohistochemistry (IHC) may be helpful in identifying the primary origin of carcinomas. This retrospective survey aimed to evaluate the frequency and accuracy of each IHC marker used to determine the origin of carcinomas. METHODS: The review of pathology department archives revealed 307 cases of cancer of unknown primary origin (CUP) between 2015 and 2020, which were accessible in the department archives. Demographic information, site of biopsy, clinical and pathologic diagnoses, and IHC results of the patients were collected. RESULTS: The patients included 157 (51.15%) men and 150 (48.85%) women. The age of the patients ranged from 14 to 92 years, including 106 (34.5%) expired cases. In 27% of cases, the primary origin of carcinoma remained unknown. The agreement between pathologic and clinical diagnoses was 59%. The most common pattern of cytokeratin (CK) expression in CUP was CK7+/CK20- (55.3%), followed by CK7-/CK20- (19%), CK7+/CK20+ (15%), and CK7-/CK20+ (10.7%), respectively. CONCLUSION: The IHC analysis may improve the diagnosis of CUPs. However, the origin of some cases remains unknown despite an IHC analysis, thereby necessitating the use of more diagnostic procedures or gene expression studies for reaching a definitive diagnosis.

Exploring the biological hallmarks of cancer of unknown primary: where do we stand today?

Cancer of unknown primary (CUP) affects a small percentage of the general population. Nonetheless, a substantial number of these patients have a poor prognosis and consequently succumb to their illness within a year of diagnosis. The natural history of CUP is characterised by early metastasis from the unknown primary site, aggressive course and resistance to conventional chemotherapy. Unfortunately, the processes by which this orphan disease originates and progresses have not been fully elucidated and its biology remain unclear. Despite the conceptual progress in genetic and molecular profiling made over the past decade, recognition of the genetic and molecular abnormalities involved in CUP, as well as the identification of the tissue of origin remain unresolved issues. This review will outline the biology of CUP by exploring the hallmarks of cancer in order to rationalise the complexities of this enigmatic syndrome. This approach will help the reader to understand where research efforts currently stand and the pitfalls of this quest.

Predictors of survival and recurrence after primary surgery for cervical metastasis of unknown primary.

PURPOSE: Cervical metastasis from unknown primary (CUP) is commonly classified as an advanced overall stage. P16 or human papillomavirus (HPV) positivity in metastatic lymph nodes (LN) might be associated with a favorable survival outcome of CUP. Therefore, we evaluated the prognostic values of p16 immuno-positivity in LN and other clinicopathological factors in patients with squamous cell carcinoma CUP (SCCUP). METHODS: This study involved 83 patients who underwent therapeutic neck dissection and panendoscopic examination and biopsy for suspected CUP. P16 immunostaining and HPV typing in LN were performed in 56 patients. Cox proportional hazard regression analyses were used to identify factors associated with overall survival (OS) and disease-free survival (DFS). RESULTS: Postoperatively, primary tumors (PT) were found in 32 (38.6%) patients, mainly (90.6%) in the oropharynx, and not found in 51 (61.4%) patients. The clinicopathological data (except for histological grade) and 5-year OS and DFS rates did not significantly differ between patients with and without PT identification (all P > 0.05). P16 positivity was associated with favorable OS and DFS outcomes in the patients with PT (P < 0.05) but not in those without PT (P > 0.1). Multivariate analyses showed that age (> 60 years) and LN ratio (≥ 0.1) were the independent predictors of OS and DFS outcomes (all P < 0.05). P16 positivity or other factors were not independent factors. CONCLUSION: Age and LN ratio are significant risk factors of survival and recurrence after primary surgery for SCCUP. Prognostic significance of LN p16 positivity should be further studied.

A pitfall of bilateral inferior petrosal sinus sampling in cyclic Cushing's syndrome.

BACKGROUND: Clinical care of patients with cyclic Cushing's syndrome (CS) is challenging. Classical pitfalls include incorrect subtyping, unnecessary surgical procedures and delayed definite treatment. CASE PRESENTATION: A 43-year-old female suffered from a rapidly cycling ectopic CS. She experienced six cycles of severe hypercortisolism within a 2 year period (maximum plasma cortisol 5316 nmol/L, normal range 124.2-662.4 nmol/L; maximum urinary free cortisol 79,469 nmol/24 h, normal range < 414 nmol/24 h) lasting 2-9 weeks. The episodes were associated with pronounced hypokalemia (lowest K+ value recorded 2.4 mmol/l) and progressive signs and symptoms of CS. A bilateral inferior petrosal sinus sampling (BIPSS) performed during a trough phase was false positive for pituitary ACTH overproduction resulting in unnecessary transsphenoidal surgery while a second BIPSS performed during an active phase was indicative for ectopic CS. The 18F-DOPA PET/CT showed a pancreatic lesion, which was subsequently partially removed. Surprisingly, the histopathology was conclusive for ACTH-positive lymph node metastasis located in the retro-duodenal tissue of an occult neuroendocrine tumor WHO grade II. The primary tumor has not been identified so far and, because of the persistent hypercortisolism, the patient underwent bilateral adrenalectomy. Two years later, ACTH levels started to increase progressively. Percutaneous biopsy of a newly identified suspected lesion in the fifth thoracic vertebra revealed a metastasis with positive staining for ACTH, synaptophysin and chromogranin A. Therapy with carboplatin and etoposide was started and, since then, the patient underwent 12 cycles of chemotherapy. CONCLUSIONS: We report the challenging case of a rapidly cycling CS secondary to ACTH-secreting neuroendocrine intestinal tumor of unknown primary. We highlight the importance of performing diagnostic tests only during the phases of active cortisol secretion and as soon as first symptoms appear to avoid pitfalls.

Diagnostic and prognostic value of ARID1A in endometrial hyperplasia: a novel marker of occult cancer.

AT-rich interaction domain 1A (ARID1A) is a tumor suppressor protein involved in endometrioid carcinogenesis. The expression of ARID1A may be lost in the premalignant phase. Our aim was to assess ARID1A as: (i) diagnostic marker to differentiate premalignant endometrial hyperplasia (EH) form benign EH; (ii) prognostic marker for the risk of occult cancer in premalignant EH. A systematic review and meta-analysis were performed by searching electronic databases from their inception to October 2018 for all studies assessing ARID1A in EH by immunohistochemistry. Sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-), and diagnostic odds ratio (DOR) were calculated for both diagnostic and prognostic accuracy. LR+ > 5, LR- < 0.2, DOR > 25 defined good accuracy; LR+ > 10, LR- < 0.1, DOR > 100 defined excellent accuracy. Seven studies with 467 EH were included. As diagnostic marker, ARID1A showed sensitivity = 0.12, specificity = 0.99, LR+ = 4.34, LR- = 0.85, DOR = 5.12. As prognostic marker for occult cancer, ARID1A showed sensitivity = 0.33, specificity = 0.99, LR+ = 20.70, LR- = 0.49, DOR = 49.59. In conclusion, ARID1A loss is highly specific, but little accurate as diagnostic marker of premalignant EH. Instead, ARID1A loss in premalignant EH is an accurate and almost perfectly specific prognostic marker for coexistent cancer.

Detection rate of unknown primary tumour by using somatostatin receptor PET/CT in patients with metastatic neuroendocrine tumours: a meta-analysis.

PURPOSE: The high diagnostic performance of somatostatin receptor positron emission tomography with computed tomography (PET/CT) in neuroendocrine tumours (NETs) was demonstrated by several articles. However, only some studies evaluated the detection rate (DR) of this imaging method in patients with metastatic NETs and unknown primary tumours (CUP-NETs). Therefore, we aimed to perform a meta-analysis to add evidence-based data in this setting. METHODS: A comprehensive computer literature search of studies listed in PubMed/MEDLINE, EMBASE, and Cochrane library databases through December 2018 and regarding the use of somatostatin receptor PET/CT in patients with CUP-NETs was carried out. Pooled DR of CUP-NETs by using somatostatin receptor PET/CT was calculated. A pooled analysis evaluating the percentage of change of management by using somatostatin receptor PET/CT in these patients was also performed. RESULTS: Twelve studies on the use of somatostatin receptor PET/CT in detecting CUP-NETs in 383 metastatic patients were included. The meta-analysis of all these studies provided the following DR on a per patient-based analysis: 56% (95% confidence interval (95% CI): 48-63%). Moderate heterogeneity among the selected studies was found (I2 = 50%), whereas a significant publication bias was excluded by Egger's test (p = 0.45). The most common primary tumour sites were the bowel and the pancreas. A change of management by using somatostatin receptor PET/CT was demonstrated in 20% (95% CI: 10-33%) of patients with CUP-NET. CONCLUSIONS: Somatostatin receptor PET/CT is very useful in detecting CUP-NETs in patients with metastatic disease. More studies on the change of management by using this imaging method in this setting are needed.

Identifying primary site of lung-limited Cancer of unknown primary based on relative gene expression orderings.

BACKGROUND: Precise diagnosis of the tissue origin for metastatic cancer of unknown primary (CUP) is essential for deciding the treatment scheme to improve patients' prognoses, since the treatment for the metastases is the same as their primary counterparts. The purpose of this study is to identify a robust gene signature that can predict the origin for CUPs. METHODS: The within-sample relative gene expression orderings (REOs) of gene pairs within individual samples, which are insensitive to experimental batch effects and data normalizations, were exploited for identifying the prediction signature. RESULTS: Using gene expression profiles of the lung-limited metastatic colorectal cancer (LmCRC), we firstly showed that the within-sample REOs in lung metastases of colorectal cancer (CRC) samples were concordant with the REOs in primary CRC samples rather than with the REOs in primary lung cancer. Based on this phenomenon, we selected five gene pairs with consistent REOs in 498 primary CRC and reversely consistent REOs in 509 lung cancer samples, which were used as a signature for predicting primary sites of metastatic CRC based on the majority voting rule. Applying the signature to 654 primary CRC and 204 primary lung cancer samples collected from multiple datasets, the prediction accuracy reached 99.36%. This signature was also applied to 24 LmCRC samples collected from three datasets produced by different laboratories and the accuracy reached 100%, suggesting that the within-sample REOs in the primary site could reveal the original tissue of metastatic cancers. CONCLUSIONS: The result demonstrated that the signature based on within-sample REOs of five gene pairs could exactly and robustly identify the primary sites of CUPs.

Cutaneous Metastases: A Review and Diagnostic Approach to Tumors of Unknown Origin.

CONTEXT.­: Cutaneous metastases from a distant malignancy are a diagnostic challenge for pathologists. Secondary involvement of the skin by a metastatic process portends a much worse clinical prognosis than any primary cutaneous malignant mimickers. Immunohistochemical staining methods continue to evolve and are of paramount importance in diagnosis. OBJECTIVE.­: To review the clinical, histopathologic, and immunohistochemical staining patterns for commonly encountered entities and discuss potential pitfalls in diagnosis. A practical guide useful in approaching cutaneous metastases of unknown primary is outlined. DATA SOURCES.­: An extensive search and review of literature in PubMed was performed, processed, and condensed. CONCLUSIONS.­: Cutaneous metastases have broad histopathologic patterns. They are nearly always dermal based, with an overall foreign appearance. They can be single papules/nodules or multiple in number, mimicking an inflammatory or infectious process. Ultimately, immunohistochemistry remains an essential diagnostic tool, and clinical correlation is paramount in the workup of these entities.

Carcinoma of Unknown Primary Site (CUP) With Metastatic Renal-Cell Carcinoma (mRCC) Histologic and Immunohistochemical Characteristics (CUP-mRCC): Results From Consecutive Patients Treated With Targeted Therapy and Review of Literature.

BACKGROUND: Carcinoma of unknown primary site (CUP) is a heterogenous group of metastatic cancer with no detectable primary tumor site. Diagnostic assessment occasionally presents CUP with metastatic renal-cell carcinoma (mRCC) histologic and immunohistochemical characteristics (CUP-mRCC). Efficacy and toxicity data for vascular endothelial growth factor inhibitor therapies in CUP-mRCC patients are few. PATIENTS AND METHODS: We retrospectively reviewed consecutive patients with CUP-mRCC at a single institution between 2007 and 2018. Treatment outcomes were assessed from initiation of renal-cell carcinoma-specific therapy, including response rate, progression-free survival, and overall survival. RESULTS: Ten patients with CUP-mRCC were identified. Median age was 64 years. Histologies were clear-cell (30%), papillary type II (20%), and unclassified renal-cell (50%) carcinoma. International Metastatic Renal Cell Carcinoma Database Consortium risk group were favorable, intermediate, and poor in 0, 40%, and 60%, respectively. One patient received empiric first-line chemotherapy. Targeted treatments were pazopanib (n = 7), sunitinib (n = 2), and sorafenib (n = 1). Objective response rate was 40%, progression-free survival was 2.5 months (95% confidence interval, 1.2-3.8), and overall survival was 5.7 months (95% confidence interval, 0-24.0). Stratified for International Metastatic Renal Cell Carcinoma Database Consortium risk, overall survival in intermediate versus poor risk group were 18.6 months and 2.3 months, respectively. Second-line therapy did not result in disease control. No new or unexpected toxicities were observed. CONCLUSION: CUP-mRCC treated with vascular endothelial growth factor-targeted therapy is valid, feasible, and safe even though these patients had several negative prognostic factors. CUP-mRCC patients should be identified among CUP patients for specific renal-cell carcinoma therapy.

Signet-ring cell adenocarcinoma of unknown primary presenting with superior vena cava (SVC) syndrome: rare type of cancer.

A 53-year-old man presented with a 3-month history of progressive, non-productive cough followed by occasional swelling of the face and upper extremities. Physical examination on admission revealed prominent superficial vessels at the neck and upper extremity swelling. Bronchoscopy revealed the superior segment of the right lower lobe was narrow but without visible mass; cell block and biopsy done revealed signet-ring cell carcinoma with an immunohistochemistry pattern favouring the primary site of malignancy as either gastric or of the pancreaticobiliary tree. However, CT scan of the abdomen and pelvis with triple contrast revealed only slight gastric wall thickening; the pancreas was unremarkable. The patient underwent radiotherapy with noted improvement of symptoms. He was then discharged with plans for further work-up on an outpatient basis. This work highlights the importance of a comprehensive histopathological and immunohistochemical work-up which can help predict a site of origin to be able to provide the appropriate management.

cancer of unknown primary: Ancillary testing of cytologic and small biopsy specimens in the era of targeted therapy.

Initial evaluation of patients presenting with a suspected malignancy without a clear clinical or radiologic impression of a primary site (so-called cancer of unknown primary, or CUP) frequently includes fine needle aspiration (FNA) to both establish a diagnosis and procure tissue for additional studies. Careful management of limited specimen material is especially important in the modern era, when molecular studies may take precedence over a more definitive tissue diagnosis. This review summarizes our practice habits when encountering a CUP. Broadly, key morphologic patterns in context of patient history and clinical-radiologic impression should guide the selection of a limited panel of IPOX stains to establish first a broad lineage. Subsequently 1-2 site-specific markers may be used to confirm the diagnosis. In difficult cases, it is helpful to convey the situation to the treating physicians, who may prefer to prioritize molecular testing over pursuit of a more definitive diagnosis. Prudent choice of immunoperoxidase (IPOX) studies, based on both key cytomorphologic criteria and continued communications with the clinical team regarding their needs for treatment planning, is critical in CUP cases.

Renal Cell Carcinoma Presenting as Carcinoma of Unknown Primary Site: Recognition of a Treatable Patient Subset.

BACKGROUND: Improved diagnostic methods, including gene expression profiling, allow identification of the tissue of origin in most patients with carcinoma of unknown primary site (CUP). Patients with an occult renal cell carcinoma (RCC) are of particular interest, because effective treatment for advanced RCC has no overlap with the empiric chemotherapy used traditionally for CUP. We report the clinical characteristics, pathologic features, and response to RCC-specific treatment in CUP patients identified as RCC using a molecular cancer classifier assay (MCCA). PATIENTS AND METHODS: All CUP patients who had an MCCA performed between 2008 and 2013 at a single institution were reviewed. Patients with an RCC diagnosis using MCCA are reported in this article. RESULTS: Twenty-four of 539 CUP patients (4.4%) were diagnosed with RCC using MCCA. None had suspected renal lesions on computed tomography scan; otherwise, clinical characteristics were typical of advanced RCC. Histology was adenocarcinoma or poorly differentiated carcinoma; only 5 of 24 patients had focal features suggestive of RCC (clear-cell 1, papillary 4). Specific MCCA diagnoses included papillary (11) and clear cell (6). Relatively specific renal immunohistochemistry (IHC) stains, when performed, were compatible with RCC in 9 of 11 tumors. Twenty of 24 patients received RCC-specific treatment, and had a median survival of 16 months. CONCLUSIONS: Patients with occult RCC can be identified in the CUP population using MCCA and/or IHC. Papillary carcinoma is more common in this group than in the larger RCC population. Although confirmation from prospective studies is needed, RCC-specific treatment should be considered for this group of patients.

Immunohistochemical Characterization of the Origins of Metastatic Well-differentiated Neuroendocrine Tumors to the Liver.

Metastatic neoplasms of unknown primary site pose a major challenge to patient management. As targeted therapies are now being tailored to neuroendocrine tumors (NETs) of different primary sites, identifying the origin of metastatic NETs has become increasingly important. Compared with more extensive efforts on metastatic adenocarcinomas of unknown primary, the literature on metastatic NETs (often to the liver) is relatively sparse and most studies are based on primary tumors. We sought to study metastatic well-differentiated NETs to the liver to identify markers that predict the site of origin. Eighty-five metastatic NETs to the liver were retrieved from the pathology archive. The primary sites were determined based on either pathologic review of the primary tumors (in most cases) or radiologic/clinical findings. Immunohistochemical labeling for TTF1, CDX2, ISL1, NKX2.2, and PDX1 was performed on either tissue microarrays or whole sections. The primary sites of the NETs in the study cohort included: pancreas (35%), small intestine (32%), rectum (8%), stomach (2%), bile duct (1%), lung (9%), and unknown primary (12%). We found predominant expression of TTF1 in lung carcinoid (63%), CDX2 in small intestinal (89%) and ISL1 in pancreatic NETs (77%), respectively. NKX2.2 was mainly expressed in NETs of the digestive organs. PDX1 was detected in a small percentage of pancreatic, small intestinal and the single bile duct NET. There was no statistically significant association between tumor grade (World Health Organization G1 vs. G2) and the expression of any of the above markers. The 3-marker panel (TTF1, CDX2, and ISL1) had sensitivities of 81%, 89%, and 63%, specificities of 100%, 94%, and 100%, positive predictive values of 100%, 89%, and 100%, and negative predictive values of 84%, 94%, and 96% in separating metastatic NETs into 3 major primary sites: pancreas/rectum, small intestine, and lung, respectively, with an overall accuracy of 82%. Furthermore, this panel predicted a primary site for 6 of the 10 NETs of unknown primary, which reduced the NETs of unknown primary from 12% to 5%. Thus, through immunohistochemical study of a large series of metastatic NETs to the liver, we have demonstrated the utility of a 3-marker panel for the identification of one or more potential primary sites of most metastatic NETs, which could provide practical guidance in patient management.

Metastatic neuroendocrine carcinoma in the skin.

Cutaneous metastases secondary to neuroendocrinetumors are rare. Herein we report a case of a 75-yearoldwoman who presented with a rare cutaneousmetastatic disease. She was previously diagnosed withmetastatic neuroendocrine carcinoma of unknownprimary, with metastases to liver, lung, and bone.Biopsy of the skin lesion demonstrated archetypicalpathology and positive immunohistochemicalstaining for chromogranin A and synaptophysin. Thepatient started palliative chemo-radiation therapyand passed away soon after.

Combined p16 and p53 expression in cervical cancer of unknown primary and other prognostic parameters : A single-center analysis.

BACKGROUND AND PURPOSE: Cervical cancer of unknown primary (CUP) represents an uncommon and heterogeneous subentity of head and neck cancer. However, both optimal diagnostics and therapy remain unclear. An improved understanding of the underlying pathology is essential to enable future tailored therapies and optimized outcomes. MATERIALS AND METHODS: We retrospectively analyzed 53 patients with head and neck CUP and 48 available cervical lymph node specimens. All patients have received radiotherapy between 2007 and 2015. Preradiotherapy involved lymph node specimens were analyzed for p16 and p53 immunoreactivity. The prognostic relevance of the combined p16 and p53 status and other clinical parameters were examined by univariate and multivariate analyses. RESULTS: Median patient age was 61.5 years and median irradiation dose to the involved nodal levels was 66 Gy. Of the 48 evaluated specimens, 13 (27%) were p16-positive and 31 (64.6%) p53-positive. After a median follow up of 32.9 months, patients with p16-negative and simultaneously p53-positive tumors showed a significantly inferior tumor-specific survival (TSS) compared to those with either p16+/p53-, p16+/p53+, or p16-/p53- (univariate: p = 0.055, multivariate: p = 0.038). Other factors with an adverse impact on TSS in the univariate analysis were smoking history (p = 0.032) and nodal stage (p = 0.038). CONCLUSIONS: The combined p16- and p53-expression status in cervical metastases of CUP may represent a simple method for risk stratification. Further validation of these biomarkers in large prospective trials is essential to design rational trials for CUP treatment optimization.

Transoral robotic surgery base of tongue mucosectomy for head and neck cancer of unknown primary.

BACKGROUND: Head and neck cancer of unknown primary (HNCUP) is a source of diagnostic uncertainty. Patients presenting with cytologically positive neck lumps without a clinically identifiable primary, require extensive investigation including imaging, tonsillectomy, panendoscopy and tissue biopsy. Treatment typically involves neck dissection, wide field radiotherapy and chemotherapy. Transoral robotic surgery (TORS) has emerged as an expanding surgical technique for resecting tumours of the oropharynx. Its role in base of tongue (BOT) mucosectomy for HNCUP can alleviate diagnostic uncertainty and provide an adjunct treatment modality with few complications. METHODS: We conducted a 7-year chart review of consecutive patients presenting with HNCUP that were treated with TORS BOT mucosectomy. We examined the efficacy, diagnostic rates and complications associated with TORS BOT mucosectomy when used for treating HNCUP. RESULTS: TORS BOT mucosectomy was performed in seven cases of squamous cell carcinoma of unknown primary. Robotic mucosectomy diagnosed BOT as the primary tumour site in five cases (71.4%). All five cases were p16 positive. Average time before return to normal swallowing function was 2.7 days. There were no major surgical complications. CONCLUSION: TORS BOT mucosectomy is an expanding surgical technique with a key role in head and neck surgery. It can be utilized to good effect where head and neck cancer is diagnosed without an identifiable primary. Incorporating robotic surgery in the diagnostic and treatment pathway offers low complication rates, reduced morbidity and improved tumour identification.

Radiotherapy Characteristics and Outcomes for Head and Neck Carcinoma of Unknown Primary vs T1 Base-of-Tongue Carcinoma.

Importance: Transoral robotic surgery- or transoral laser microsurgery-assisted lingual tonsillectomy may improve the identification rate of hidden base-of-tongue (BOT) carcinoma presenting as head or neck carcinoma of unknown primary (CUP) site. Objective: To evaluate the potential impact of lingual tonsillectomy in CUP site by comparing differences in radiotherapy volumes, dosimetry, and clinical outcomes for CUP site and T1-category BOT carcinoma. Design, Setting, and Participants: Retrospective study of 115 patients treated at a tertiary cancer center between January 1, 2005, and December 31, 2013, that included patients with BOT carcinoma (category T1N1-3M0) and CUP site (category T0N1-3M0) with known p16 status. Fifty-four patients with T1-category BOT carcinoma (50 [92.6%] p16-positive) were treated with definitive intensity-modulated radiotherapy (IMRT), including 34 (63%) who received concurrent chemotherapy. Sixty-one patients with CUP site (38 [62.3%] p16-positive) received definitive (42 [68.9%]) or postoperative (19 [31.1%]) IMRT, including 22 (36%) who received concurrent chemotherapy. Interventions: Definitive or postoperative IMRT, with or without concurrent chemotherapy. Main Outcomes and Measures: Characteristics of mucosal clinical target volume (CTV-T), nodal CTV, and organ-at-risk dosimetry; local, regional, and distant control; cause-specific and overall survival; and Radiation Therapy Oncology Group grade 3 or higher late toxic effects. Results: Of 115 participants, 104 (90.4%) were male; mean (SD) age was 59 (10) years. High-dose CTV-T was prescribed in all 54 patients with BOT carcinoma and 23 (37.7%) with CUP site (effect size [Δ], 62%; 95% CI, 50%-74%). Low-dose CTV-T included mucosal pharyngeal sites outside the oropharynx in no patients with BOT carcinoma and 26 (42.6%) (95% CI, 30%-54%) with CUP site, with greater low-dose CTV-T volume in CUP site than BOT carcinoma (113 vs 84 cm3; Δ, 30 cm3; 95% CI, 10-49 cm3). Bilateral neck irradiation was used in 53 of 54 patients (98.1%) with BOT carcinoma and 46 of 61 (75.4%) with CUP site (Δ, 23%; 95% CI, 12% to 34%). Patients with BOT carcinoma received a higher maximum dose to the mandible (71 vs 67.2 Gy; Δ, 3.8 Gy; 95% CI, 1.6 to 6 Gy), with a nonsignificantly higher maximum dose (66.1 vs 62.8 Gy; 3.2 Gy; 95% CI, -0.1 to 6.5 Gy) and lower mean dose to the larynx (43.8 vs 47.1 Gy; 3.3 Gy; 95% CI, -0.3 to 6.9 Gy). There were no significant differences in local control, regional control, distant control, cause-specific survival, and overall survival between the BOT carcinoma and CUP site groups stratified by p16 status. Grade 3 Radiation Therapy Oncology Group late toxic effects occurred in 2 patients (3.3%) with CUP site (both neck fibrosis) and 5 (9.3%) with BOT carcinoma (2 neck fibrosis, 2 osteoradionecrosis, and 1 dysphagia). Conclusions and Relevance: Intensity-modulated radiotherapy for CUP site or T1-category BOT carcinoma had similar clinical outcomes. Identifying hidden BOT primary carcinoma with novel approaches (eg, transoral robotic surgery and transoral laser microsurgery) may lead to changes in the radiotherapy target volume and dose prescription. Studies are needed to investigate the effect of these differences on quality of life and functional outcomes.