Metastatic squamous cell carcinoma of an unknown primary localized to the neck. Advantages of an aggressive treatment

Treatment of patients with squamous cell carcinoma (SCC) of an unknown primary localized to the neck is still controversial, particularly regarding advanced disease. We reviewed 41 such patients treated with surgery and/or radiotherapy (RT) (n = 25) or with combined modality treatment including chemotherapy (CH) (n = 16). The male to female ratio was 28 to 13, and the median age was 58 years (range, 32 to 94 years). There were 27 (66%) patients with poorly differentiated SCC and 8 with moderately differentiated or well-differentiated cancer. Twenty-three (56%) patients had N3 disease, 16 (39%) had N2, and 2 had N1. The majority of N3 patients have been treated with CH and RT (n = 12) or with RT alone (n = 9). The combined CH-RT was well tolerated, with no life-threatening toxicity. The complete response (CR) to CH-RT was 81% (11 patients have no evidence of disease [NED] currently). The median survival time of this group was 37+ months. Of the 25 patients who had surgery and/or RT as their first planned treatment, 7 (28%) have NED currently. The median survival time of this group was 24 months. Patients with N3 disease who received CH had a higher CR rate and a longer survival time as compared with those treated with surgery and/or RT, despite a higher (N3) stage of disease. These findings warrant further investigation in randomized cooperative studies.     

Radiotherapy and cisplatin in metastatic squamous cell carcinoma of an unknown primary tumor localized to the neck. A phase II study.

13 male and 8 female patients with metastatic squamous cell carcinoma (SCC) of an unknown primary tumor localized to the neck were treated with radiotherapy (RT) and cisplatin (CDDP). There were 12 (58%) and 9 (42%) patients, while no patient had N1 disease. All patients underwent biopsy. RT was given to all possible sites of the primary tumor (nasopharynx, pyriform sinus, and the base of the tongue). The RT dosage planned for the whole neck or supraclavicular area was 45 Gy, increasing to 60-70 Gy on the metastatic site. CDDP was given at a dose of 30 mg/m2, once weekly during the RT course. We observed 15 (72%) complete responses (CR) and 3 (14%) partial responses, while 3 (14%) patients did not respond to therapy. 12 (58%) patients are with no evidence of disease (NED) currently. The median survival time was 34+ months (range, 18+ to 50+ months). We observed two groups of toxicities: gastrointestinal and kidney toxicity. The majority of patients experienced grade 3 (RTOG) toxicity and no patient experienced grade 4 toxicity. This treatment appears to be effective and suitable for patients with metastatic SCC of an unknown primary tumor localized to the neck.     

Metastatic carcinoma of the neck from an unknown primary

From 1974 to 1984, 31 patients with metastatic carcinoma to the neck from an unknown primary were treated with radiation therapy. On review, three groups were identified based on presentation and treatment. Group I consists of 19 patients treated with curative intent. They all presented with cervical adenopathy, 11 patients with N1 disease, 2 with Stage N2A disease, 1 with Stage N2B disease, 4 with N3A disease, and 1 with unknown stage. The majority of patients were treated with portals encompassing the nasopharynx, oropharynx, hypopharynx, and neck to a dose of 5000 rad followed by boosts of 1000-1500 rad. The overall 2-year NED survival in this group was 63% (12/19). The most significant prognostic factor was the stage of the metastatic nodes. The NED survival rate for the 14 patients with Stage N1 and N2 was 86% (12/14). Histology of the lesions was not an important factor in the outcome. In Group II there are six patients who received palliative treatment because of large, fixed, cervical nodes. Three of these patients (50%) died within 2 months of completion of treatment. Group III consists of six patients who presented with supraclavicular adenopathy. All had persistent or recurrent disease within 19 months. We have concluded that in patients with metastatic carcinoma to the cervical nodes from an unknown primary, radiation therapy to the neck and suspected areas of primary disease may play an important role in cure, particularly in early stage disease.     

Larynx-sparing radiotherapy for squamous cell carcinoma from an unknown head and neck primary site

The objective of this study was to evaluate the efficacy of larynx-sparing radiotherapy (RT) alone or in combination with a neck dissection for patients with squamous cell carcinomas metastatic to cervical lymph nodes from an unknown head and neck primary site. Seventeen patients were treated with curative intent between 1997 and 2002; 16 of 17 patients had follow up for at least 2 years. No patient developed a squamous cell carcinoma in a head and neck mucosal site after treatment. One patient (6%) had persistent nodal disease and 1 patient (6%) had recurrent nodal disease 1 year after completing RT. No patients experienced distant metastases. The 5-year cause-specific and overall survival rates were 88% and 82%, respectively. Based on our limited experience, larynx-sparing RT appears to result in a high likelihood of local-regional control and survival and likely reduces both acute and late toxicity.     

Value of neck dissection in patients with squamous cell carcinoma of unknown primary.

Lymph node metastases of cancer of an unknown primary (CUP syndrome) are responsible for 3-5% of the malignant diseases in the head and neck area. More than 70% of these patients show lymph node metastases of an unknown squamous cell carcinoma. The survival depends immediately on number and location of lymph node metastases. For a curative approach modified radical neck dissection combined with postoperative radiation therapy with or without chemotherapy should be considered in N1-N3 lymph node status. A radical neck dissection with postoperative radiation therapy should only be approved in cases of infiltration of the internal jugular vein, the accessory nerve and/or the sternocleidomastoid muscle. The different prognosis of patients with upper cervical and lower cervical lymph nodes should influence the indication and the extent of a neck dissection in the contralateral N0 neck.     

Cervical lymph node metastases of squamous cell carcinoma from an unknown primary

Cervical lymph node metastases of squamous cell carcinoma from occult primary constitute about 2-5% of all patients with carcinoma of unknown primary site (CUP). Metastases in the upper and middle neck are generally attributed to head and neck cancers, whereas the lower neck (supraclavicular area) involvement is often associated with primary malignancies below the clavicles. The diagnostic procedures include physical examination with thorough evaluation of the head and neck mucosa using fiber-optic endoscopy, biopsies from all suspicious sites or blindly from the sites of possible origin of the primary, computer tomography and/or magnetic resonance. A systematic tonsillectomy in the absence of suspicious lesions is often recommended since up to 25% of primary tumors can be detected in this site. The thoracic primary (tracheal, bronchial, lung, esophagus) has to be excluded, especially in the case of lower neck involvement. Positron emission tomography (PET) with fluoro-2-deoxy-D-glucose allows detection of primary tumor in about 25% of cases, but this procedure is still considered investigational. Therapeutic approaches include surgery (lymph node excision or neck dissection), with or without postoperative radiotherapy, radiotherapy alone and radiotherapy followed by surgery. In early stages (N1), neck dissection and radiotherapy seem to have similar efficacy, whereas more advanced cases (N2, N3) necessitate combined approaches. The extent of radiotherapy (irradiation of bilateral neck and mucosa versus ipsilateral neck radiotherapy) remains debatable. A potential benefit from extensive radiotherapy should be weighted against its acute and late morbidity and difficulties in re-irradiation in the case of subsequent primary emergence. The role of other methods, such as chemotherapy and hyperthermia, remains to be determined.     

原发灶不明颈部转移性鳞癌的诊治

原发灶不明的颈部转移性癌约占头颈部恶性肿瘤的5％,可以分为转移性鳞癌和转移性腺癌,至今仍是临床诊治的一个难题。由于原发灶不明的转移性癌的临床治疗只能以治标为主,治疗效果不佳。所谓原发灶不明,其实是有原发灶,由于病灶较小、部位隐匿或位于黏膜下等原因而不易发现;且肿瘤的生物学行为又较恶劣,较早发生淋巴结转移。临床仔细寻找原发病灶尤为重要,只有找到原发病灶,标本兼治,临床治愈率才能改善。20世纪50年代初,美国纽约纪念医院的Martin教授最早提出：“2周内找不到原发病灶的颈部转移性癌,即诊断为原发灶不明的颈部转移性癌”。随着医学理念的更新,诊疗技术的进步,我们认为用时间概念来作为一个诊断标准不够科学,因此提出：“经临床仔细检查直到治疗开始前仍未发现原发病灶的颈部转移性癌,可以诊断为原发灶不明的转移性癌”。以上概念是否准确大家可以讨论,本文主要讨论原发灶不明的颈部转移性鳞癌。     

Antibodies against human papillomaviruses as diagnostic and prognostic biomarker in patients with neck squamous cell carcinoma from unknown primary tumor

Treatment of patients with neck lymph node metastasis of squamous cell carcinoma (SCC) from unknown primary tumor (NSCCUP) is challenging due to the risk of missing occult tumors or inducing toxicity to unaffected sites. Human papillomavirus (HPV) is a promising biomarker given its causal link to oropharyngeal SCC and superior survival of patients with HPV‐driven oropharyngeal SCC and NSCCUP. Identification of HPV‐driven NSCCUP could focus diagnostic work‐up and treatment on the oropharynx. For the first time, we assessed HPV antibodies and their prognostic value in NSCCUP patients. Antibodies against E6 and E7 (HPV16/18/31/33/35), E1 and E2 (HPV16/18) were assessed in 46 NSCCUP patients in sera collected at diagnosis, and in follow‐up sera from five patients. In 28 patients, HPV tumor status was determined using molecular markers (HPV DNA, mRNA and cellular p16^INK4a). Thirteen (28%) NSCCUP patients were HPV‐seropositive for HPV16, 18, 31, or 33. Of eleven patients with HPV‐driven NSCCUP, ten were HPV‐seropositive, while all 17 patients with non‐HPV‐driven NSCCUP were HPV‐seronegative, resulting in 91% sensitivity (95% CI: 59–100%) and 100% specificity (95% CI: 80–100%). HPV antibody levels decreased after curative treatment. Recurrence was associated with increasing levels in an individual case. HPV‐seropositive patients had a better overall and progression‐free survival with hazard ratios of 0.09 (95% CI: 0.01–0.42) and 0.03 (95% CI: 0.002–0.18), respectively. For the first time, seropositivity to HPV proteins is described in NSCCUP patients, and high sensitivity and specificity for HPV‐driven NSCCUP are demonstrated. HPV seropositivity appears to be a reliable diagnostic and prognostic biomarker for patients with HPV‐driven NSCCUP.     

Follicular dendritic cell tumor as an unknown primary tumor

A 70-year-old Japanese man presented to our hospital with a 1-month history of progressive general fatigue and anorexia. A physical examination revealed severe anemic condition, mild persistent splenomegaly, and no palpable surface lymph nodes. He had pleural effusion and ascites, though no malignant cells were detected in the effusion. He eventually died without any diagnosis of his disease. Immunohistochemical staining of his tumor after autopsy showed atypical cells that were negative for epithelial membrane antigen (EMA), keratin (AE1/3), keratin-20, vimentin, factor VIII, leukocyte common antigen (LCA/T200; CD45), myeloperoxidase (MPO), terminal deoxynucleotidyl tranferase (TdT), lysozyme, CD1a, CD3, CD4, CD10, CD15, CD20 (L26), CD21, CD23, CD34, CD43, CD56, CD68, CD79a, CD138, and EBER-1 in situ. Only a few scattered cells expressed CD30, but they showed no staining for anaplastic large-cell lymphoma kinase (ALK). A few scattered cells expressed S-100 antigen and the majority of cells dominantly expressed dendritic cell-associated antigens (CD35, FDC, Ki-M1p). In conclusion, we found this unknown primary tumor to be consistent with a follicular dendritic cell tumor with anaplastic features.     

颈部囊性转移性鳞癌误诊鳃裂癌四例分析

目的阐明鳃裂癌的诊断需慎重。方法对4例误诊为鳃裂癌的颈部囊性转移性鳞癌进行回顾性分析。结果4例颈部囊性转移性鳞癌患者的原发灶均被发现,2例原发灶在杓会厌皱襞,1例在腭扁桃体,1例在头顶皮肤。原发灶发现的时间为自首次手术时至首次手术后41个月。结论4例中无一例为鳃裂癌,因此鳃裂癌的诊断需有严格的诊断标准。     

Hyperthermia and radiotherapy for inoperable squamous cell carcinoma metastatic to cervical lymph nodes from an unknown primary site.

INTRODUCTION: Neck node metastases from an unknown primary carcinoma represent an infrequent but challenging problem for oncologists. The management of such patients is controversial, but radiotherapy alone or as part of a multimodal approach is often indicated. Patients with inoperable lesions usually receive radiotherapy alone at palliative doses. In an attempt to increase local control in patients with locally advanced neck disease from an unknown primary carcinoma, local hyperthermia was combined with definitive radiotherapy. MATERIAL AND METHODS: Between 1982 and 1993, radiotherapy and local microwave hyperthermia were used to treat 15 patients with metastatic neck nodes from an unknown primary site. The patients had previously undergone only biopsy or fine needle biopsy, and showed no signs of metastases beyond the clavicle. Radiation to the nodes and the potentially primary sites in the head and neck was delivered by a 6 MV linear accelerator or a Cobalt 60 unit, to a total dose of 57.50-74.40 Gy (median 70 Gy). Hyperthermia was added using a BSD 1000 unit at an operating frequency of 280-300 MHz for 2-7 sessions (mean 3.1; median 2) at a desired minimum temperature of 42.5 degrees C. Two patients also received i.v. cisplatin 20 mg/m2/week as a radiosensitizer. RESULTS: Nine patients achieved a complete, and four a partial response for an overall response rate of 86.5%. Acute and late toxicity was mild: four patients experienced pain during hyperthermia, two moist cutaneous desquamation, and one cutaneous necrosis. The actuarial probability of maintaining local control at 5 years is 64.5% and the actuarial overall survival 29%. Five patients developed distant metastases and died of disease, two experienced nodal recurrence and two died of other unrelated causes. CONCLUSION: The addition of local microwave hyperthermia to radiotherapy in the treatment of metastatic squamous cell carcinoma of the neck in patients with an unknown primary site leads to good local control with moderate toxicity. No definite conclusions are possible because of the small number of patients involved in this phase II trial.     

Genomic and neoantigen evolution from primary tumor to first metastases in head and neck squamous cell carcinoma

Head and neck cell squamous-cell carcinomas (HNSCC) are a group of common cancers typically associated with tobacco use and human papilloma virus infection. Up to half of all cases will suffer a recurrence after primary treatment. As such, new therapies are needed, including therapies which promote the anti-tumor immune response. Prior work has characterized changes in the mutation burden between primary and recurrent tumors; however, little work has characterized the changes in neoantigen evolution. We characterized genomic and neoantigen changes between 23 paired primary and recurrent HNSCC tumors. Twenty-three biopsies from patients originally diagnosed with locally advanced disease were identified from the Washington University tumor bank. Whole exosome sequencing, RNA-seq, and immunohistochemistry was performed on the primary and recurrent tumors. Within these tumors, we identified 6 genes which have predicted neoantigens in 4 or more patients. Interestingly, patients with neoantigens in these shared genes had increased CD3+ CD8+ T cell infiltration and duration of survival with disease. Within HNSCC tumors examined here, there are neoantigens in shared genes by a subset of patients. The presence of neoantigens in these shared genes may promote an anti-tumor immune response which controls tumor progression.     

Pulmonary squamous cell carcinoma following head and neck squamous cell carcinoma: metastasis or second primary?

PURPOSE: To distinguish a metastasis from a second primary tumor in patients with a history of head and neck squamous cell carcinoma and subsequent pulmonary squamous cell carcinoma. EXPERIMENTAL DESIGN: For 44 patients with a primary squamous cell carcinoma of the head and neck followed by a squamous cell carcinoma of the lung, clinical data, histology, and analysis of loss of heterozygosity (LOH) were used to differentiate metastases from second primary tumors. RESULTS: Clinical evaluation suggested 38 patients with metastases and 6 with second primaries. We developed a novel interpretation strategy based on biological insight and on our observation that multiple LOH on different chromosome arms are not independent. LOH analysis indicated metastatic disease in 19 cases and second primary squamous cell carcinoma in 24 cases. In one case, LOH analysis was inconclusive. For 25 patients, LOH supported the clinical scoring, and in 18 cases, it did not. These 18 discordant cases were all considered to be second primary tumors by LOH analysis. CONCLUSIONS: A considerable number of squamous cell lung lesions (50% in this study), clinically interpreted as metastases, are suggested to be second primaries by LOH analysis. For these patients, a surgical approach with curative intent may be justified.     

Differential diagnosis between primary lung squamous cell carcinoma and pulmonary metastasis of head and neck squamous cell carcinoma

Differentiation between lung squamous cell carcinoma and pulmonary metastasis of head and neck squamous cell carcinoma is clinically important because the prognoses and therapeutic options are considerably different. However, the clinical, pathological, and immunohistochemical diagnostic methods have not yet been fully established. Although various molecular methods have been developed, they have not yet been practically applied. A combined approach involving molecular and immunohistochemical analysis, such as one that uses antibodies selected on the basis of comprehensive genetic analysis results, may be effective. We suggest a new diagnostic criteria using the clinical characteristics and the result of immunohistochemical analysis. However, there are two underlying problems in the development of new diagnostic methods: tumor heterogeneity and determination of the diagnostic accuracy.     

Hyperthermia and radiotherapy for inoperable squamous cell carcinoma metastatic to cervical lymph nodes from an unknown primary site

Introduction: Neck node metastases from an unknown primary carcinoma represent an infrequent but challenging problem for oncologists. The management of such patients is controversial, but radiotherapy alone or as part of a multimodal approach is often indicated. Patients with inoperable lesions usually receive radiotherapy alone at palliative doses. In an attempt to increase local control in patients with locally advanced neck disease from an unknown primary carcinoma, local hyperthermia was combined with definitive radiotherapy. Material and methods: Between 1982 and 1993, radiotherapy and local microwave hyperthermia were used to treat 15 patients with metastatic neck nodes from an unknown primary site. The patients had previously undergone only biopsy or fine needle biopsy, and showed no signs of metastases beyond the clavicle. Radiation to the nodes and the potentially primary sites in the head and neck was delivered by a 6MV linear accelerator or a Cobalt 60 unit, to a total dose of 57.50-74.40Gy (median 70Gy). Hyperthermia was added using a BSD 1000 unit at an operating frequency of 280-300MHz for 2-7 sessions (mean 3.1; median 2) at a desired minimum temperature of 42.5^oC. Two patients also received i.v. cisplatin 20 mg/ m2/week as a radiosensitizer. Results: Nine patients achieved a complete, and four a partial response for an overall response rate of 86.5%. Acute and late toxicity was mild: four patients experienced pain during hyperthermia, two moist cutaneous desquamation, and one cutaneous necrosis. The actuarial probability of maintaining local control at 5 years is 64.5% and the actuarial overall survival 29%. Five patients developed distant metastases and died of disease, two experienced nodal recurrence and two died of other unrelated causes. Conclusion: The addition of local microwave hyperthermia to radiotherapy in the treatment of metastatic squamous cell carcinoma of the neck in patients with an unknown primary site leads to good local control with moderate toxicity. No definite conclusions are possible because of the small number of patients involved in this phase II trial.     

Metastatic renal cell carcinoma to the head and neck area

AIMS AND BACKGROUND: Metastases of renal cell carcinoma to the head and neck are rare. We report on three cases with tumor spread to this area (nasal cavity, tongue and larynx) and present a review of the literature. PATIENTS: The first patient presented with lung and nasal cavity metastases five years after renal tumor resection. In patient 2 the diagnosis of primary renal carcinoma and lung and tongue metastases was concomitant. In case 3 a primary kidney tumor was not suspected until radical resection of a tongue lesion was performed. RESULTS: The first two patients received radiation therapy. They had been previously treated with interleukin + interferon and vinblastine + interleukin 2 and achieved a survival of 14 and 16 months, respectively. The third patient has not been given any treatment to date (apart from surgery) and remains asymptomatic four years after diagnosis. CONCLUSIONS: In patients with cell carcinoma the occurrence of lesions in the head and neck area may suggest metastases. In some cases they may precede the diagnosis of a renal tumor and mimic a primary head and neck tumor; otolaryngologists should be aware of this possibility. An individualized treatment approach is recommended. In the case of solitary metastases a surgical excision should be performed as palliation, if not cure.     

60例原发灶不明的颈转移性鳞癌的放射治疗

目的：探讨颈淋巴结的临床分期和不同大小的放射治疗野对原发灶不明的颈转移性鳞癌的预后影响。方法：回顾性分析本院1989年1月至1997年12月间收治的60例原发灶不明的预转移性鳞癌（不包括锁骨上区转移者）的临床资料。结果：全组病例5年总的生存率为68．5％,其中N1,N2和N3病例的5年生存率分别为100％,68．0％和40．9％（χ^2=0.729,P=0.026),而单侧颈部,全颈部和扩大野照射者的5年生存率分别为66．5％,74．5％和54．6％（χ^2=1.38,P=0.501),Cox比例风险模型分析发现颈淋巴结分期对生存率的影响有显著性意义（P＝0．032）,5年颈部局部控制率为65．6％,其中N1,N2和N3病例的5年局部控制率分别为100％,63．2％和34．6（χ^2=5.51,P=0.064),而单侧颈部,全颈部和扩大野照射者的5年局部控制率分别为87．6％、51．0％和72．7％（χ^2=2.55,P=0.279）,5年原发病灶的出现率为21．2％,小野（单侧颈部或全颈部照射）和扩大野照射的5年原发灶出现率分别为23．3％和12．5％（χ^2=0.52,P=0.469),结论：颈淋巴结的临床分期是影响生存率的重要预后因素,并且随着期别的升高,颈部局控率有下降的趋势;小野较扩大野照射的原发灶出现率有增加的趋势,但不同大小照射野治疗的颈部局部治疗率和生存率无明显差异。     

Conservative neck surgery in squamous cell carcinoma.

Squamous cell carcinoma of the upper aerodigestive tract metastasises to lymph nodes in the upper-deep cervical group. Control of these metastases is the single most important prognostic factor in the management of this disease. Traditionally, surgical control was achieved by the radical neck dissection, a mutilating procedure with significant morbidity. Contemporary research has led to an improved understanding of the patterns of nodal metastases. This has led to the evolution of more conservative techniques that still produce comparable results of control. This paper describes this evolutionary process, and the current management thinking.