Expression of immune checkpoint molecules TIGIT and TIM-3 by tumor-infiltrating lymphocytes predicts poor outcome in sinonasal mucosal melanoma.

BACKGROUND: Sinonasal mucosal melanoma (SNMM) is a rare but aggressive tumor with a poor prognosis. The co-inhibitory receptors T cell immunoglobulin and mucinodomain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3) and T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) are promising new targets in anti-cancer immunotherapy. The expression profiles of these immune checkpoint molecules (ICMs) and potential prognostic implications have not been characterized in SNMM yet. METHODS: Immunohistochemical staining for TIGIT, LAG-3 and TIM-3 was performed on tumor tissue samples from 27 patients with primary SNMM. Associations between ICM expression and demographic parameters, AJCC tumor stage, overall survival, and recurrence-free survival were retrospectively analyzed. RESULTS: SNMM patients with low numbers of TIGIT+ and TIM-3+ tumor infiltrating lymphocytes (TILs) in the primary tumor survived significantly longer than patients with a high degree of TIGIT+ and TIM-3+ TILs. High infiltration with TIM-3+ or TIGIT+ lymphocytes was associated with the higher T4 stage and decreased 5-year survival. CONCLUSION: We identified high densities of TIM-3+ and TIGIT+ TILs as strong negative prognostic biomarkers in SNMM. This suggests that TIM-3 and TIGIT contribute to immunosuppression in SNMM and provides a rationale for novel treatment strategies based on this next generation of immune checkpoint inhibitors. Prospective studies with larger case numbers are warranted to confirm our findings and their implications for immunotherapy.

Human papillomavirus and infiltration of CD8- and Foxp3-positive immune cells in sinonasal inverted papillomas.

Background: Sinonasal inverted papilloma (IP) is a benign tumor with a high risk of local recurrence and a potential to malignify and Human papillomavirus (HPV) has been suggested an etiological factor. p16INK4a (p16) overexpression is considered a surrogate marker for HPV, but whether p16 and HPV correlate to IP is uncertain. Besides, a prognostic role of tumor infiltrating lymphocytes (TILs) are observed in many tumors, however their role in IP is sparsely studied. Aims/objectives: We hence analyzed IPs for the presence and the prognostic role of HPV and p16 overexpression together with CD8+ and FoxP3+ TILs in a population-based study. Material and methods: 98 IP patients diagnosed 2001-2010 were identified from the Swedish Cancer Registry and analyzed for HPV by PCR and p16, CD8 and FoxP3 was by immunohistochemistry. Results: In total, 12.2% of the IPs were HPV-positive (nine HPV-11, two HPV-6 and one HPV-45). Patients with HPV-positive lesions were younger (p = .003) and tended to present with more dysplasia. No correlation was observed between TILs and prognosis. Conclusions and significance: Our data suggests that patients with HPV-positive IPs present with different clinical characteristics, suggesting possibly different disease entities. Moreover, recurrences may occur >5 years, which should be considered in the follow-up.

Pseudoprogression with subsequent complete response and severe thrombocytopenia to checkpoint inhibitor immunotherapy in a patient with advanced mucosal melanoma of the sinonasal cavity.

In this case report, we describe a patient with an inoperable mucosal melanoma of the sinonasal cavity who achieved an ongoing complete response to combined immunotherapy with ipilimumab and nivolumab after initial pseudoprogression. Despite massive enlargement of the tumor 9 weeks after treatment initiation, we decided to continue with checkpoint inhibitor immunotherapy because of lacking potent therapeutic alternatives and the possibility of pseudoprogression. In the computed tomography scan 3 months later, the tumor was no longer detectable. To date, the patient is still in remission. However, she developed severe immune-related thrombocytopenia and neutropenia that are rarely encountered with checkpoint inhibitor immunotherapy. Thrombocytopenia did not respond to corticosteroids, but rapidly improved after the administration of single-dose intravenous immunoglobulin. This exceptional case highlights the effectiveness of combined immunotherapy with ipilimumab and nivolumab in mucosal melanoma, the phenomenon of pseudoprogression, as well as the rare event of immune-related hematological side effects.

Expression of PAX3 Distinguishes Biphenotypic Sinonasal Sarcoma From Histologic Mimics.

Biphenotypic sinonasal sarcoma (BSNS) is a distinctive, anatomically restricted, low-grade spindle cell sarcoma that shows considerable histologic overlap with other cellular spindle cell neoplasms. This tumor type shows both myogenic and neural differentiation, which can be demonstrated by immunohistochemistry; however, the available diagnostic markers are relatively nonspecific. BSNS is characterized by PAX3 rearrangements, with MAML3 as the most common fusion partner. Our aim was to determine whether immunohistochemistry using a monoclonal PAX3 antibody could distinguish BSNS from potential histologic mimics, as well as to evaluate a widely available polyclonal PAX8 antibody, which is known to cross-react with other paired box transcription factor family members. Immunohistochemistry for PAX3 and PAX8 was performed on whole sections of 15 BSNS (10 with confirmed PAX3 rearrangement) and 10 cases each of the following histologic mimics: malignant peripheral nerve sheath tumor, monophasic synovial sarcoma, spindle cell rhabdomyosarcoma (RMS), solitary fibrous tumor, sinonasal hemangiopericytoma, and cellular schwannoma, as well as alveolar RMS (which harbors PAX3 or PAX7 gene rearrangements). BSNS showed consistent expression of PAX3 (15/15), all multifocal-to-diffuse and most with moderate-to-strong intensity of staining. One single case of spindle cell RMS showed PAX3 expression (1/10), and all other histologic mimics were completely PAX3-negative. In contrast, nuclear staining for PAX8 was present in all 15 BSNS, 7/10 malignant peripheral nerve sheath tumor, 3/10 cellular schwannomas, 2/10 sinonasal hemangiopericytomas, 1/10 synovial sarcoma, 1 spindle cell RMS, and 1 solitary fibrous tumor. All cases of alveolar RMS were positive for PAX8, and most were also positive for PAX3 (8/10). Immunohistochemical expression of PAX3 is highly sensitive (100%) and specific (98%) for BSNS. A polyclonal PAX8 antibody also stains BSNS (likely due to cross-reactivity with PAX3) but has much lower specificity (75%), with frequent expression in numerous mimics.

[Clinicopathologic and molecular genetic characterizations of biphenotypic sinonasal sarcoma].

Objective: To investigate the clinicopathologic characteristics, immunophenotypes, molecular genetics, and diagnostic and differential diagnostic features of biphenotypic sinonasal sarcoma (BSNS). Methods: Three cases of BSNS were retrieved, the histomorphology, immunophenotype and molecular genetics were analyzed with review of literature. Results: There were 2 male and 1 female patient aged 45, 29 and 40 years, respectively.Computed tomography and magnetic resonance imaging examinations showed a large polypoid mass occupying the sinonasal cavity in all 3 patients. Microscopically, these tumors were un-circumscribed and composed of cellular spindle-shaped cells arranged in long and interlaced fascicles. A hemangiopericytoma-like growth pattern was frequently identified. The overlying hyperplastic respiratory epithelium invaginated down into the tumor forming a cystic (2 cases), glandular (1 case) structures and inverted in a papilloma-like (1 case)pattern, and foci of eosinophilic metaplasia were also noted in 2 of the three cases. The tumor nuclei were bland-appearing, mitoses were scarce and necrosis was absent. Immunohistochemically, the tumor cells showed co-expression of neural and myogenic markers in all the 3 cases, including that 3/3 showed diffuse and strong positivity of S-100 protein, 3/3 positivity of smooth muscle actin (1 diffuse and 2 focal), 1/2 diffuse positivity of calponin, 1/3 focal positivity of desmin, and 1/1 focal positivity of MyoD1.In addition, 1 detected for ß-catenin showed focal nuclear positivity. None of the 3 showed positivity to cytokeratin, CD34 or SOX10 in the tumor cells.Ki-67 showed an index <5%, 10% and <2%, respectively. Fluorescence in situ hybridization analysis showed rearrangements of PAX3 gene in all 3 cases. In case 3, reverse transcription polymerase chain reaction, followed by Sanger sequencing, demonstrated an in-frame fusion between PAX3 and FOXO1.Follow-up information (range 3-15 months)showed no evidence of local recurrence or distant metastasis in three cases. Conclusions: BSNS is a newly described entity which can be readily confused with a variety of benign and malignant spindle cell tumors encountered in the sinonasal cavity; immunohistochemistry co-expression of neural and myogenic markers and PAX3 gene rearrangement can help distinguish this tumor from its many mimickers.

[Clinicopathologic analysis of extranodal non-hodgkin lymphoma of the sinonasal cavities: a 15-case report].

Objective:To investigate the clinical manifestation, imaging and histological features of different histological subtypes of non-Hodgkin's lymphoma of nasal cavity and paranasal sinuses.Method:Fifteen NHL patients of the sinonasal region were collected from the Department of Otolaryngology of Peking University Third Hospital from 2010 to 2016. HE staining and immunohistochemical staining were performed. The clinical characteristics and imaging features of different subtypes were described and analyzed.Result::We analyzed a total of 6 patients with localized sinonasal diffuse large B cell lymphoma and 9 patients with localized sinonasal extranodal NK/T cell lymphoma. The age distribution for these two subtypes is very distinct. The median age of the patients with localized sinonasal extranodal NK/T cell lymphoma was 39 years. There were 5 males and 4 females. Nine sinonasal NHLs were NK/T-cell lymphoma, nasal type, all of which were infected with EBV. The median age of the patients with localized sinonasal diffuse large B cell lymphoma was 64 years. There were 3males and 3 females. Symptoms for patients with SN-DLBCL and SN-ENKTL were significantly different in epiphora, proptosis, diplopia and nasal congestion (P=0.18, 0.004, 0.18, 0.18). Imaging features for patients with SN-DLBCL and SN-ENKTL were significantly different in tumor extended to orbit and inferior turbinate (P>0.05). Positive staining for CD 56 was detected in 9 patients, for CD 3 in 9 patients, for EBER in 9 patients. The Hans algorithm identified 1 patient with the germinal center B-cell (GCB) subtype and 5 with the non-GCB subtype.Compared with the control group, the observation group was significantly better than the control group (P < 0.01).Conclusion:Early symptoms of epiphora, proptosis, diplopia, and images finding with orbital invasion should be highly suspected of diffuse large B cell lymphoma. Positive staining for CD 56 and EBER were detected in all patients with extranodal NK/T cell lymphoma, and positive staining for CD20 was detected in all patients with SN-DLBCL.

Biphenotypic sinonasal sarcoma: an expanded immunoprofile including consistent nuclear ß-catenin positivity and absence of SOX10 expression.

Biphenotypic sinonasal sarcoma (BSNS) is a recently recognized low-grade sarcoma that exhibits both neural and myogenic differentiation. This unique dual phenotype stems from recurrent rearrangements in PAX3, a transcription factor that promotes commitment along both lineages. While identification of PAX3 rearrangements by fluorescence in situ hybridization (FISH) can confirm a BSNS diagnosis, this assay is not widely available. This study evaluates whether an expanded immunohistochemical panel can facilitate recognition of BSNS without molecular analysis. Eleven cases of BSNS were identified from the surgical pathology archives of two academic medical centers. In 8 cases, the diagnosis was confirmed by FISH using custom probes for PAX3. In 3 cases, FISH failed but histologic and immunophenotypic findings were diagnostic for BSNS. All 11 BSNS (100%) were at least focally positive for S100 as well as calponin and/or smooth muscle actin. In addition, 10 (91%) of 11 expressed nuclear ß-catenin, 8 (80%) of 10 expressed factor XIIIa, 4 (36%) of 11 expressed desmin, and 3 (30%) of 10 expressed myogenin. All 11 tumors were negative for SOX10. While no single marker resolves immunohistochemical overlap between BSNS and its histologic mimickers such as nerve sheath tumors, an extended immunohistochemical panel that includes ß-catenin and SOX10 helps to support the diagnosis of BSNS without the need for gene rearrangement studies.

Anti-Hu Antibody Associated Paraneoplastic Cerebellar Degeneration in Head and Neck Cancer.

BACKGROUND: Paraneoplastic syndromes are most frequently associated with small cell lung carcinoma, hematologic and gynecologic malignancies while reports in head and neck cancer are rare. CASE PRESENTATION: We present the case of a 60-year old female patient who developed paraneoplastic cerebellar degeneration upon locoregional recurrence of a poorly differentiated spindle cell carcinoma of the nasal cavity and paranasal sinus. The neurological symptoms, especially ataxia, stabilized after resection of tumor recurrence and concomitant chemoradiotherapy whereas anti-Hu-antibodies remained positive. Despite the unfavorable prognosis of paraneoplastic neurological disorders associated with onconeural antibodies, the patient achieved long-standing stabilization of neurological symptoms. CONCLUSION: We report the first patient with anti-Hu antibodies and paraneoplastic cerebellar degeneration associated with a spindle cell carcinoma of the head and neck. We recommend that evaluation of neurological symptoms in patients with this tumor entity should also include paraneoplastic syndromes as differential diagnoses and suggest early extensive screening for onconeural antibodies.

[Different methods of antigen retrieval impact on Pan of sinonasal inverted papilloma].

OBJECTIVE: To explore different conditions and buffers of antigen retrieval which affect the CK of SNIP on immunohistochemical staining results. METHOD: Dividing paraffin tissue sections of 11 patients into four groups. Using the Image-Pro Plus Image analyzer and taking five horizons for each section to calculate an average of 200 areas, measured standard optical density of the positive reaction areas. RESULT: It is divided into four groups: high temperature and high pressure citrate buffer retrieval, microwave EDTA buffer retrieval, microwave citrate retrieval, high temperature and high pressure EDTA buffer retrieval. The standard optical density of positive reaction areas respectively express: 0.324 ± 0.051, 0.325 ± 0.056, 0.303 ± 0.061, 0.365 ± 0.023. The rates of CK positive expression with high temperature and high pressure EDTA buffer retrieval is batter than other repairing groups in the same paraffin tissue sections (P < 0.05). CONCLUSION: For the Pan of Sinonasal inverted papilloma, the method of high temperature and high pressure EDTA buffer antigen retrieval can achieve the ideal staining results? which is worth while to promote and maybe as a bet? ter guide of clinic work.

Non-Hodgkin's lymphoma of nasal cavity and paranasal sinuses. A clinicopathological and immunohistochemical study.

Aim of this study was to investigate the clinical characteristics, management and prognosis of non-Hodgkin lymphomas of the nasal cavity and paranasal sinuses. Overall 12 patients with non-Hodgkin malignant lymphoma, at our Institute, were studied over an eight-year period from 1997 to 2005. Patients' data collected were age, sex, presenting signs and symptoms, histology, treatment, complications, and outcome. Also available were computerised tomography findings, and paraffin-embedded tissue bocks. Mean age was 62 years (range: 42-81), with a male dominance (male to female ratio: 7:5). Most patients had not presented any specific symptoms, such as nasal obstruction, headaches, epistaxis and facial swelling. Using immunocytochemistry on paraffin-embedded tissue sections, the predominance of large B-cell subtype was detected. Treatment administered: only radiotherapy (stage IEA) or in combination with chemotherapy (IIE-IVE). Of these patients, 5 died from the disease, 4 survived without disease, 2 survived with the disease, and one died of non-related causes. Non-Hodgkin's lymphomas are relatively rare. Early diagnosis, based mainly on tissue biopsy and computerised tomography, is essential in the management of non-Hodgkin lymphoma.

Salivary duct carcinoma in the sinonasal tract.

Salivary duct carcinoma (SDC) is an uncommon malignant tumor, characterized by aggressive behavior and poor prognosis. SDC usually arises from ductal epithelium of the major salivary glands, and it is quite infrequent elsewhere. We present a rare case of a 73-year-old man with SDC, which is possibly originated from the paranasal sinuses or the lacrimal system. Microscopic evaluation revealed that the tumor cells, with pleomorphic nuclei and abundant eosinophilic cytoplasm, formed cell nests and duct-like structure. A cribriform growth pattern was also seen. Immunohistochemical staining was positive for cytokeratins (CAM 5.2 and 34betaE12), gross cystic disease fluid protein 15 (GCDFP-15), and androgen receptor protein, while p63 and involucrin were negative. The patient already had multiple metastasis of the tumor in the lung at diagnosis, and he could not undergo definitive surgical procedures, because of severe restrictive lung disease. Although SDC in the sinonasal tract is quite rare, SDC should be in the differential diagnosis in these regions, due to its aggressive behavior and poor prognosis.

Sino-orbital chloroma presenting as unilateral proptosis in a boy.

Granulocytic sarcoma or chloroma is an unusual localized tumor composed of cells of myeloid origin. Involvement of the orbit and the ethmoid sinuses and presenting as proptosis is rare. Diagnosis could be difficult and delayed when there are no other systemic manifestations, especially with normal peripheral blood and bone marrow picture. We present one such case with unilateral proptosis as the sole presenting sign that posed a diagnostic challenge to us. Orbital decompression by an otolaryngologist may have a role in managing such a case.

Clinicopathologic study of non-Hodgkin lymphoma in sinonasal and hard palate regions in 15 Japanese cases.

Non-Hodgkin lymphomas of the sinonasal region have been the subject of numerous studies. Previous reports have suggested that nasal lymphomas occurring in Orientals are mostly of the natural killer cell (NK)/T-cell phenotype which contrasts with the preponderance of the B-cell type in western populations. Recent studies indicated that NK/T-cell lymphoma constitutes the clinical condition of lethal midline granuloma. These reports led us to question whether all NK/T lymphomas are always lethal midline granuloma. We have investigated a series of 15 cases of non-Hodgkin lymphomas in the nasal and/or paranasal sinuses clinically, immunohistochemically and for the presence of Epstein-Barr virus (EBV). This study showed that the presence of EBV was common in nasal NK/T lymphoma, and this type of lymphoma was clearly highly frequent in other types of nasal lymphoma in our department. Moreover, in 4 cases of NK/T-cell lymphomas, the clinical features of lethal midline granuloma did not appear, indicating that NK/T lymphomas are not always lethal midline granuloma.

HIV and plasmablastic lymphoma manifesting in sinus, testicles, and bones: a further expansion of the disease spectrum.

Patients with HIV infection are at increased risk for B-cell neoplasms and plasma cell dyscrasias. Both B cell and plasma cell tumors tend to be intermediate or high grade and are frequently associated with Epstein-Barr virus. Patients with HIV infection are also at higher risk of acquiring plasmablastic lymphoma. Until this time, only sinus, oral gastrointestinal, and lung manifestation have been noted. In this report we describe a 41-year-old male with HIV infection who developed multiple pleomorphic, extramedullary plasmablastic lymphomas associated with Epstein-Barr virus. We review the clinical and immunological features of his malignancy and thereby expand the spectrum of disease to include additional sites (bones, testicles) not previously reported.

Simultaneous nonparotid cranial mucosa-associated lymphoid tissue lymphoma and common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a condition characterized by low levels of immunoglobulin (Ig) G and either IgA or IgM in the presence of recurrent infections. This disorder is associated with an increased risk of malignancy. Mucosa-associated lymphoid tissue (MALT) lymphoma is a recently recognized form of non-Hodgkin's lymphoma that is not often present in the head. MALT lymphoma in patients with CVID is rare, and until now, it has not been reported in a cranial location outside of the parotid gland. We report the cases of 2 patients who had CVID and cranial MALT lymphoma outside of the parotid gland, and we describe their successful treatment with chemotherapy.

Sinonasal haemangiopericytoma: a case report.

Haemangiopericytoma (HPC) is a rare vascular tumour that is thought to originate from the vascular pericytes of Zimmerman. HPC may arise in any part of the body, and from 15 to 30% of these tumours are found in the head and neck, with a rare involvement of the sinonasal region The main symptoms of nasal HPC, epistaxis and nasal obstruction, are not typical. The final diagnosis is based on the histopathology and immunochemistry, and whether the tumour is benign or malignant is defined on the basis of the clinical history. HPC located in the sinonasal area is generally benign. We report the case of a young woman with a sinonasal mass histologically proven to be haemangiopericytoma. The patient underwent surgical treatment by means of mid-facial degloving after embolisation of the maxillary artery. After a careful 3-year follow-up, the patient is disease free and healthy.

Vision-threatening complications of nasal T/NK lymphoma.

PURPOSE: Nasal T/NK lineage lymphoma, previously known as lethal midline granuloma, is common among Oriental, Native-American, and Hispanic patients and is invariably associated with Epstein-Barr virus. Nasal localization, local necrosis, angioinvasion, and aggressive behavior are hallmarks of the disease. Ophthalmologic symptoms and signs may precede lymphoma diagnosis or complicate its disease course. We aim to define the incidence and disease pattern of ophthalmic involvement. DESIGN: Retrospective single-institution consecutive interventional case series. METHODS: Records of all lymphoma patients from 1996 to 2000 were retrieved from a computer database, and the primary sites and lineage were reviewed. Nasal T/NK lymphoma was defined by a combination of morphology, positive CD3 epsilon and CD56 expression, in situ hybridization staining for Epstein-Barr virus expressed RNA (EBER), and negative staining for B cell markers (CD20 and CD79a). RESULTS: Thirty-five consecutive patients with T/NK lymphoma were identified. Primary nasal or nasopharyngeal disease was found in 24 patients. Six (25%) of the 24 patients suffered from vision-threatening complications of two distinct categories, namely uveitis/vitritis and orbital infiltration. The former preceded the diagnosis of lymphoma in two patients and also led to novel ocular complications like rhegmatogenous retinal detachment and macular hole that were successfully managed by ocular surgery. In four patients, orbital extension of lymphomatous disease accompanied biopsy-proven in-field disease relapse. Generally, the prognosis is grave, but remission can still be achieved with aggressive combined chemotherapy and radiotherapy. CONCLUSION: Both oncologists and ophthalmologists should be aware of ocular complications when dealing with known or suspected cases of T/NK lymphoma at diagnosis and relapse. Regular ophthalmic assessment of these patients is warranted.