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Year : 2016  |  Volume : 12  |  Issue : 1  |  Page : 209-214

Nasopharyngeal carcinoma with headaches as the main symptom: A potential diagnostic pitfall

1 Department of Clinical Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
2 Department of Oncology, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan, China

Date of Web Publication13-Apr-2016

Correspondence Address:
Li Xiang
Department of Oncology, Affiliated Hospital of Luzhou Medical College, 25 Taiping Road, Luzhou-646 000, Sichuan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.157334

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 > Abstract 

Background: The aim of this study was to investigate medical-related reasons for misdiagnosis of nasopharyngeal carcinoma. (NPC) patients presenting with headaches alone or accompanied by other symptoms.
Patients and Methods: Two-hundred and nineteen NPC cases describing headaches as one of the initial symptoms during primary treatment were selected for this prospective study. Medical records were carefully collected and all data were summarized for final analyses.
Result: Distributions of NPC stage in the patients were: Stage II, 1.4%; stage III, 46.6%; stage IVA, 36.1%; stage IVB, 7.7%; and stage IVC, 8.2%. The ratio of men to women was 2.42:1 (155/64 cases). The total misdiagnosis rate was 43.4%. Patients that only complained of headaches had the highest misdiagnosis rate of 86.4% (19/22 cases). The lowest misdiagnosis rate of 10.9% (5/46 cases) was observed in patients with both headaches and epistaxis. The misdiagnosis rate in rural hospitals was more than two times that in provincial hospitals. Neurosurgery departments had a 100% misdiagnosis rate.
Conclusion: Frequently, headaches are the only prominent symptom of NPC. Due to the various clinical manifestations, NPC patients encounter a high misdiagnosis rate, which leads to unsatisfactory treatment outcomes. Improved awareness of the various nonspecific symptoms of NPC by nonspecialist physicians will be a pivotal step in decreasing the misdiagnosis rate.
Mini Abstract: The misdiagnosis rate of nasopharyngeal carcinoma (NPC) patients with headaches was 43.4%. Improved awareness of the various nonspecific symptoms of NPC is a pivotal step in decreasing the misdiagnosis rate.

Keywords: Headaches, misdiagnose, nasopharyngeal carcinoma

How to cite this article:
Wu ZX, Xiang L, Rong JF, He HL, Li D. Nasopharyngeal carcinoma with headaches as the main symptom: A potential diagnostic pitfall. J Can Res Ther 2016;12:209-14

How to cite this URL:
Wu ZX, Xiang L, Rong JF, He HL, Li D. Nasopharyngeal carcinoma with headaches as the main symptom: A potential diagnostic pitfall. J Can Res Ther [serial online] 2016 [cited 2022 Nov 26];12:209-14. Available from: https://www.cancerjournal.net/text.asp?2016/12/1/209/157334

 > Introduction Top

Nasopharyngeal carcinoma (NPC) is particularly common in southern China.[1] Due to the internal location of NPC and varied clinical symptoms, most patients are in a locally advanced stage before diagnosis.[2] Headaches are the main symptom because of the skull-base invasion, intracranial metastases, or skull-base osteoradionecrosis. Lack of knowledge about NPC and the nonspecific symptoms makes initial and accurate diagnosis difficult in cases with intracranial or skull lesions. We present a series of patients with NPC complaining of headaches and in which a nonspecialist played a critical role in the diagnosis and management.

 > Patients and Methods Top

Untreated NPC patients were confirmed by pathological diagnosis and recruited during May 2009–June 2014 in our cancer center. All patients claimed to have a headache alone or a headache accompanied by other symptoms like neck mass, nasal congestion, blood secretion, diplopia, tinnitus, ear problems, etc. The following medical examinations were performed to determine the precise pretreatment stage: General physical examination, hematological indices, nasopharyngeal fiberscope, chest X-ray or computed tomography (CT), ultrasound of abdomen, magnetic resonance imaging (MRI) nasopharynx and cervical part, whole-body bone scan or position emission tomography (PET). Staging was conducted according to the seventh edition of the American Joint Committee on Cancer (AJCC).[3]

Exclusion criteria were as follows: Lack of pathological diagnosis, unclear medical history, previous confirmed malignant tumors, and/or previous radiotherapy or chemotherapy.

Attending doctors carefully collected medical records when patients were hospitalized. Medical records included general patient information, initial symptoms and the time of appearance, initial diagnosis time and result, diagnosing hospital type, diagnosis department, and accuracy and time of diagnosis. All data were summarized for final analysis.

 > Results Top

Patient characteristics

Two-hundred and nineteen participants (155 males and 64 females) entered our prospective trial. The median age was 46 years (range: 23–71 years). The incidence in patients less than 30 years old was only 6.8% (15/219). The 30–59-year-old patients accounted for 59.4% (130/219). We observed a significant number (33.8%, 74/219) of NPC cases in patients of 60 years and older. The majority of patients were in locally advanced stages. According to the 7th AJCC staging guidelines, individuals were classified as follows: 1.4% stage II (three cases), 46.6% stage III (102 cases), 36.1% stage IVA (79 cases), 7.7% stage IVB (17 cases), and 8.2% stage IVC (18 cases). Education levels in patients were as follows: 31.1% had a primary school degree (68 subjects), 57.5% had a middle school degree (126 patients), and 11.4% had a college degree (25 patients).

Misdiagnosis rate

One-hundred and twenty-four patients were confirmed or suspected of having NPC during the initial visit. The definitive diagnosis rate was 56.6% (124/219), making the misdiagnosis rate 43.4% (95/219). These cases were misdiagnosed as sinusitis, nervous headache, intracranial tumors, otitis media, or tuberculosis. The diverse and nonspecific symptoms resulted in late diagnosis of NPC.

The influence of symptoms on misdiagnosis

Headaches alone

There were 22 patients who only suffered from a headache. Twenty-one patients were assigned to Departments of Neurology, and only one patient was assigned to a neurosurgery department. In the neurology departments, 12 of the 21 patients had a brain CT that failed to detect nasopharyngeal lesions due to insufficient lower edge settings, or indistinct delineation of the skull base. Those 12 patients were treated for a nervous or vascular headache. All of these patients were given over-the-counter medication for pain relief. However, because the pain did not respond well to the prescribed medication, brain MRI was arranged, and following this a diagnosis of NPC was given. The remaining six patients with hypertension who did not receive a brain CT were diagnosed with unstable blood pressure and subjected to antihypertensive therapy. Fortunately, three of the patients did receive an initial brain CT that included parts of the nasopharynx, and therefore did reveal nasopharyngeal tumors with upward invasion into the skull base. Consequently, those three cases received an initial diagnosis of NPC.

The remaining 60-year-old male patient had daily headaches involving the left temporal and parietal lobe areas for 6 months. A cranial CT was done in our outpatient facilities. He was diagnosed with hematencephalon and hospitalized by the neurosurgery department. The cranial computed tomography angiography (CTA) revealed a left temporal lobe brain hemorrhage. Subsequent brain enhanced MRI analysis revealed a regular margin ovoid mass in the left temporal lobe with several hemorrhages [Figure 1]. The neurosurgeons made a preliminary diagnosis of glioma or tumor apoplexy.
Figure 1: A 60-year-old man suffered from headaches for 6 months. Cranial computed tomography (CT) demonstrated hematencephalon (a and b). Brain magnetic resonance imaging (MRI) revealed a homogeneously enhanced mass in the left temporal lobe accompanied with a few hemorrhages (c and d). The second MRI demonstrated a homogeneously enhanced mass in the nasopharyngeal hanging wall and bilateral wall, with disappearing infundibuliform recesses. The mass had also invaded the parapharyngeal spaces. The lymph nodes surrounded bilateral carotid sheath (e and f)

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Under general anesthesia, craniotomy surgery and resectioning of the mass in the left temporal lobe were performed on the patient. The postoperative pathology (pathological number: 2014-00140) revealed a left temporal lobe malignant tumor and a metastatic squamous cell carcinoma. These findings were corroborated by strong positive immunohistochemisty staining for P63 and pancytokeratin (PCK), and negative staining for vimentin and S-100 proteins [Figure 2].
Figure 2: Postoperative histology revealed a metastatic squamous cell carcinoma, consistent with nasopharyngeal carcinoma (NPC) due to confirmation by immunohistochemistry (a) hematoxylin and eosin staining, ×200; (b) strong immunohistochemistry staining of P63 in tumor cell cytoplasm, ×400; and (c) positive pancytokeratin (PCK) in tumor cell nuclei, ×400)

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The second MRI of the nasopharynx showed thickening of the soft tissue in the nasopharyngeal hanging wall and bilateral wall with disappearing infundibuliform recesses. The mass had also invaded the parapharyngeal spaces, skull base, and left cavernous sinus. Soft tissue nodules surrounded the bilateral carotid sheath, which were likely to be metastatic lymph nodes caused by NPC [Figure 1]. Endoscopy revealed a rough mass with clear boundaries in the left pharyngeal recess. The histological findings and radiological examination resulted in NPC diagnosis, and radiochemotherapy was initiated. The patient received one cycle of cisplatin and taxotere chemotherapy as a preradiotherapy treatment to reduce the primary disease.

Based on the data we gathered, the misdiagnosis rate was 86.4% (19/22) in the patients that initially presented only with headaches. The neurologists were misled by the nonspecific symptoms of nasopharyngeal cancer.

Headaches accompanied by palpable lymph nodes in neck

Fifty-six patients complained of headache and neck mass. Among them, 30 patients first visited general surgeon and five of those patients were directly referred to the oncology department as they were suspected to have NPC. The remaining 25 patients received a cytological examination of the cervical lymph nodes. The results demonstrated metastatic squamous cell carcinoma in 22 patients, whereas three patients were initially diagnosed with lymphadenitis and were prescribed anti-inflammatory therapy. This treatment failed, further aggravating the headaches and stability of the lymph nodes. The patients returned to the oncology department 2 weeks later, where a definitive diagnosis of NPC was confirmed by endoscopic biopsy of the primary tumor. The remaining 26 patients went directly to oncology and were diagnosed with NPC. Therefore, 31 patients received a primary diagnosis of nasopharyngeal cancer.

The misdiagnosis rate of patients presenting with a headache and a cervical lymph node mass was 44.6% (25/56). It is likely that these patients knew that enlarged lymph nodes are a warning sign of cancer. Consequently, the misdiagnosis rate was lower than the group only suffering from headaches. However, some patients underwent unnecessary lymph node biopsies that could have increased the risk of distant metastasis.

Headaches accompanied by ear symptoms (including tinnitus and diminished hearing).

 Eustachian tube More Details occlusion can occur secondary to a tumor in the ostium pharyngeum tubae auditivae region, causing a circulation disorder of inner ear lymph as well as tympanic negative pressure. Because of the anatomical changes, the patients were plagued by ear problems like tinnitus, aural fullness, and hearing loss. A total of 17 patients were primitively diagnosed with otitis media. Six patients received the misdiagnosis in the otolaryngological department and three patients were misdiagnosed due to the negative findings by nasopharyngeal endoscopy. The remaining 27 patients received a diagnosis of NPC in otolaryngology or neurology departments. Accordingly, the misdiagnosis rate was 38.6% (17/44) in this subpopulation of patients.

Headaches and nasal problems (including nasal congestion and blood secretion)

Contact bleeding is one of the only prevalent symptoms of nasopharyngeal cancer patients. Bleeding can provide a direct reference for doctors to make an accurate diagnosis. Hence, the rate of correct diagnosis is almost 90% in patients with headaches and epistaxis. In all 46 patients, the symptoms of only five patients were mistaken for sinusitis by a neurology department.

In patients with a rhinobyon, however, the accurate diagnosis rate is only 48.7% (19/39 patients). Twenty patients were misdiagnosed with chronic sinusitis or an upper respiratory tract infection, because the clinical manifestations did not help the doctors distinguish NPC from other common diseases. Unfortunately, neither patients nor doctors considered an NPC diagnosis until the cervical lymph nodes were enlarged, or until other new symptoms appeared, which were a sign of advanced stage NPC.

Headaches accompanied by neurological or ocular symptoms

In this subpopulation of patients suffering from neurological symptoms of diplopia, facial numbness, proptosis, and impaired vision; the misdiagnosis rate of 75% (9/12 patients) ranked second among all groups. Nine patients were first diagnosed with glaucoma, peripheral neuropathy, facial neuritis, and intracranial tumors by oculists and neurologists [Table 1].
Table 1: Influence of initial concomitant symptoms on misdiagnosis of NPC patients with headaches at the first visit

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Effect of hospital type and department on misdiagnosis

Eighty-eight patients (41.2%) first chose a provincial hospital, while 111 cases (50.7%) chose a municipal hospital. Only 20 cases (9.1%) initially selected the country hospital. The misdiagnosis rates of the three different hospitals were as follows: 29.5% (26/88) for the provincial, 48.6% (54/111) for the municipal, and 75% (15/20) for the country.

As a result of significant professional advantages in the oncology and otorhinolaryngology departments, misdiagnosis rates were lower. Neurologists and neurosurgeons managed all patients with headaches alone. Nonspecific symptoms caused the doctors to be misguided by the headaches. Unfortunately, misdiagnosis was 100% in neurosurgery departments. Because impaired vision or diplopia is an uncommon symptom of NPC, five patients went to an ophthalmology department without receiving the correct diagnosis. In these cases, the oculist diagnosed glaucoma or retrobulbar neuritis. Nasopharyngeal cancer is very easily confused with other common ailments like nervous headache, sinusitis, otitis media, etc., This confusion is related to the complexity and diversity of symptoms [Table 2].
Table 2: Effect of different hospital grade and departments on misdiagnosis

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 > Discussion Top

The highest incidence rates of NPC are in southern China. Within endemic areas of China, NPC remains a common and fatal disease. The prevention strategy in China relies mainly on secondary prevention, with a goal of achieving earlier detection rates and diagnosis, which would give high-risk populations a clinically valuable survival advantage.[4] Achievements in these areas would provide hope of encouraging results from nasopharyngeal cancer treatment. Patients with early stage (stages I and II) NPC have satisfactory treatment results and a 5-year survival rate of up to 94%. This is significantly different from patients diagnosed with late stage NPC (stages III and IV), who have a 5-year survival rate lower than 80%.[5] Large-scale population screenings for NPC in China have been concentrated in epidemic areas and have increased early diagnosis rates. In the low-incidence provinces, however, it still is difficult to assess the early lesions. In our study, the data indicate that even stage IV NPC accounted for 52% of patients whose initial symptoms include headaches.

There are several major problems causing misdiagnosis of NPC. Firstly, a lack of medical knowledge and poor economic conditions amongst patients contribute to inadequate attention to the clinical symptoms. This is particularly the case during the early onset, as symptomatic treatments would have increased the likelihood of cancer remission. When patients finally go to hospital, they may visit the wrong department based on the symptoms that greatly affect their quality of life. For example, they may see a neurologist for cephalea, an ophthalmologist for visual impairment, or a pulmonologist for hemoptysis. Jiang et al., demonstrated that patient-related factors equally contributed to the iatrogenic factors leading to delays in diagnosis.[6] Physicians who treat headaches must be aware that recurrent or persistent headaches could be the initial or sole manifestation of NPC, and that subtle intracranial lesions at the skull base can be missed by routine brain CT. In our study, majority of patients were diagnosed with NPC after brain or nasopharyx MRI, including the 12 patients who were excluded from a NPC diagnosis due to negative findings on their previous brain CT. Thus, clinicians must understand that the routine setting of a noncontrast brain CT, which is frequently used as a screening tool for headache patients, is limited in detecting possible skull base or nasopharyngeal lesions. For cases suspected to be NPC, brain MRI is essential, even when brain CT has negative findings. Headaches are often the first and most prominent symptom in ascending-type NPC. To facilitate early diagnosis, it is important to recognize headache patterns of ascending-type NPC.[7]

Secondly, if the first doctor is inexperienced with NPC, it is more likely that a wrong diagnosis will be made based on these atypical symptoms. The structures near nasopharynx are complex and can have a lot of lymphatic drainage as well. Nasopharyngeal cancer can encroach upwards towards the skull base and intracranial tissue and extend down to the oral cavity. It has a tendency to infiltrate peripheral organs, such as the middle ear, parapharyngeal space, and infratemporal fossa. Consequently, patients may suffer from symptoms that are not exclusive to NPC. Sometimes, neck mass may be the first clinical manifestation of NPC. Occasionally, blockage of the Eustachian tube can produce a middle ear transudate. Proptosis is a result of the tumor's direct extension into the orbit from the posterior nasal fossa via ethmoid air cells or from the cavernous sinus through to the superior orbital fissure. In addition, headaches or pain in the temporal or occipital regions occur when the tumor extends to the base of the skull.

Doctors can contribute to a delayed NPC diagnosis when they ignore and misjudge the nonspecific early stage symptoms that mimic other diseases. Patients with headaches alone were misdiagnosed with nervous or vascular headaches and only a minority of doctors considered intracranial tumors because of the incomplete image. The misdiagnosis rate of these patients was 86.4%. One patient even had an unnecessary craniotomy. The misdiagnosis rates of neurosurgery departments were highest at 100% (1/1). This phenomenon indicates that nonspecialists do not have a complete understanding of NPC, which is especially obvious during clinical work.

Nasopharyngeal endoscopy is the initial procedure of choice for the detection of NPC, with a definitive diagnosis of NPC confirmed by endoscopic biopsy of the primary tumor.[8] The majority of misdiagnosed patients did not undergo nasopharyngeal endoscopy, which led to adverse outcomes. However, submucosal nasopharyngeal cancer may not be discovered by endoscopy. Three patients had nasopharyngeal endoscopy, but were still misdiagnosed because they had the submucosal type.

Thirdly, the level of a hospital is an important factor in misdiagnosis. The initial diagnosis rate of NPC in provincial hospitals is 70.5%, but dropped to 51.4% in municipal hospitals. The rural hospitals had the lowest diagnosis rates of only 25%. This data indicates that the current distribution of medical resources is extremely unbalanced and that there is a wide gap between the provincial and basic hospitals.

Therefore, we propose that the following measures should be taken to avoid misdiagnosis. Principally, continuing medical education for nonspecialists should be strengthened. This would help ensure that nonspecialists conduct a comprehensive differential diagnosis for patients with headaches, nasal obstruction, and hearing loss. It is important to teach clinical doctors not to simply think of headaches as a sign of intracranial tumors, and that imaging scans should include sufficient ranges to exclude NPC.

Submucosal carcinoma cannot be confirmed by a conventional multiple biopsy. To improve the positive diagnosis rate, physicians should punch the surface tissue and make a deep biopsy through the wound. One patient was definitively diagnosed on the seventh biopsy by our center, providing an example that the clinically suspect cases cannot easily be eliminated.

NPC incidence rises steadily with age, peaking at 40–59 years and then significantly declining. Headaches are the initial symptom that elicits medical attention in almost 20% of cases. Approximately 60–70% of patients suffer from such painful symptoms in the definitive diagnosis.[9] The age distribution of these subgroups from our hospital, however, had a small peak beyond 60 years, which possibly contributed to the difficulty in discriminating NPC from other senile diseases. In our study, we found a similar sex-specific incidence of NPC, with 70.8% male and 29.2% female cases yielding a 2.42:1 ratio. The cancer registry provides timely and dynamic information for making national, regional, and local cancer control policies. As the National Central Cancer Registry (NCCR) continues to expand, primary and secondary prevention of NPC is expected to improve.[10] Nonetheless, a general principle must stand out: If a headache patient cannot be diagnosed with simply a primary headache, particularly without other typical NPC features, further examination to exclude NPC is requisite. Also, fiberoptic nasopharyngoscopy and image scanning of the nasopharynx are equally important. In addition, brain MRI would be more beneficial for this purpose than CT. As far as we know, there have not been pertinent studies of this topic. Our article is the first to analyze the characteristics of these unique patients who presented with headaches as their primary, or only, symptom.

To summarize, this subgroup of NPC patients who presented with only headaches, or headaches accompanied by other atypical presentations, suffered from a high misdiagnosis rate. This was related to the nonspecific symptoms of NPC, low capabilities of the basic hospitals, and patients visiting inappropriate departments that could not provide targeted examination and treatment. Educating hospital staff, a decisive first step for diagnosing early stage NPC, can improve awareness of various nonspecific symptoms and signs of NPC, especially among high-risk populations.

 > References Top

Huang TR, Zhang SW, Chen WQ, Deng W, Zhang CY, Zhou XJ, et al. Trends in nasopharyngeal carcinoma mortality in China, 1973-2005. Asian Pac J Cancer Prev 2012;13:2495-502.  Back to cited text no. 1
Lu H, Peng L, Yuan X, Hao Y, Lu Z, Chen J, et al. Concurrent chemoradiotherapy in locally advanced nasopharyngeal carcinoma: A treatment paradigm also applicable to patients in Southeast Asia. Cancer Treat Rev 2009;35:345-53.  Back to cited text no. 2
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. Nasal Cavity and Paranasal Sinuses. In: Edge SB editor. AJCC Cancer Staging Manual, 7th ed. Philadephia: Lippincott-Raven; 2009. p. 93-102.  Back to cited text no. 3
Ng WT, Choi CW, Lee MC, Law LY, Yau TK, Lee AW. Outcomes of nasopharyngeal carcinoma screening for high risk family members in Hong Kong. Fam Cancer 2010;9:221-8.  Back to cited text no. 4
Mao YP, Li WF, Chen L, Sun Y, Liu LZ, Tang LL, et al. A clinical verification of the Chinese 2008 staging system for nasopharyngeal carcinoma. Ai Zheng 2009;28:1022-8.  Back to cited text no. 5
Jiang F, Hu FJ, Li B, Qin WF, Feng XL, Bao WA, et al. Factors for misdiagnosis of nasopharyngeal carcinoma and relevant countermeasures. Chin J Clin Oncol 2012;39:2026-35.  Back to cited text no. 6
Lee YL, Ho CY. Headache as the sole symptom of nasopharyngeal carcinoma and its clinical implications. ScientificWorldJournal 2012;2012:143829.  Back to cited text no. 7
Chan AT, Felip E, ESMO Guidelines Working Group. Nasopharyngeal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009;20:123-5.  Back to cited text no. 8
Yin WB, Yu ZH, Xu GZ, Hu YM, Wang LH, Wang LH, et al. Nasopharyngeal cancer. In: Yin WB, editor. Radiation Oncology, 4th ed. Bei Jing: Peking Union Medical College Press; 2008. p. 443-4.  Back to cited text no. 9
Xu ZJ, Zheng RS, Zhang SW, Zou XN, Chen WQ. Nasopharyngeal carcinoma incidence and mortality in China in 2009. Chin J Cancer 2013;32:453-60.  Back to cited text no. 10


  [Figure 1], [Figure 2]

  [Table 1], [Table 2]

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