A 52-year-old woman is referred to our dermatology clinic by her primary care physician for swelling and redness of seven old scars. The swelling began 3 months ago.

She is on no regular medications. She has never smoked. She underwent liposuction 7 years ago and appendectomy at age 15.

Laboratory testing shows mild leukopenia, with a white blood cell count of 3.0 × 10⁹/L (reference range 4.2–9.0). Other routine laboratory values are normal, including antinuclear antibody, extractable nuclear antibody, anti-double-stranded DNA, rheumatoid factor, urinalysis, erythrocyte sedimentation rate, C-reactive protein, serum calcium concentration, and liver and renal function tests.

Chest radiography reveals bilateral hilar lymphadenopathy.

Q: What is the next most appropriate diagnostic procedure?

• Skin biopsy
• High-resolution computed tomography (CT) of the chest
• QuantiFERON-TB Gold test
• Ventilatory function tests
• Serum angiotensin-converting enzyme (ACE) level

A: All are appropriate at this point. In this case, skin biopsy and high-resolution CT were performed. Histopathologic examination of one of the scars showed multiple well-demarcated, large, noncaseating epitheloid granulomas with histiocytes and multinucleated giant cells. High-resolution CT confirmed bilateral hilar and mediastinal lymphadenopathy and revealed micronodular densities with a bronchovascular and subpleural distribution.

An interferon-gamma-release assay for tuberculosis—QuantiFERON-TB Gold (Cellestis, Carnegie, Australia)—was negative. Ventilatory function tests showed a normal pattern, while the serum ACE level, electrocardiography, and an eye examination revealed no pathologic findings.

Q: What is the diagnosis?

• Keloids
• Scar sarcoidosis
• Paraneoplastic sign
• Dermatofibrosarcoma protuberans
• Tubercolosis

A: Based on the data outlined above, we made the diagnosis of scar sarcoidosis with involvement of hilar and mediastinal lymph nodes. The patient began systemic treatment with oral prednisone 1 mg/kg/day for 6 weeks, which was then gradually withdrawn, until the skin and hilar lesions resolved completely.

SCAR SARCOIDOSIS

Sarcoidosis is a multisystem disorder of unknown cause characterized by the formation of noncaseating granulomas in the affected organs. Patients may present with symptoms related to the specific organ affected, but they may have no symptoms or only general symptoms such as fever or general malaise.

The skin is involved in 25% of cases and presents so many polymorphous manifestations that sarcoidosis has become known as one of the “great imitators” in dermatology.^1,2

Although sarcoidosis on liposuction scars has not been reported previously, the reactivation of old scars is well known on sites of previous injections, tattoos, herpes zoster, and burns.^2,3

The finding of granuloma is not specific for sarcoidosis (Figure 2). The histologic differential diagnosis of sarcoidosis includes tuberculosis, atypical mycobacteriosis, fungal infection, reaction to a foreign body, rheumatoid nodules, leishmaniasis, Crohn disease, and necrobiosis lipoidica diabeticorum.

The diagnosis of scar sarcoidosis is confirmed only by excluding other conditions via a comprehensive evaluation of clinical manifestations, histology, history, and radiologic and laboratory findings.

It has been suggested that the most satisfying therapy for the patient and physician in sarcoidosis is no treatment at all,⁴ and in fact sarcoidosis often remits spontaneously. Currently, the choice of treatment depends on the degree of systemic involvement, and the oral corticosteroid prednisone remains the first-line treatment. If the condition does not respond, the use of other systemic agents has been reported, but their effectiveness has not been evaluated in controlled clinical trials.

Recurrence is common after the suspension of treatment; therefore, treatment may need to be continued for several years, with frequent checkups.

Skin lesions are a visible clue to the diagnosis. Reactivation of old scars may be the single manifestation of cutaneous sarcoidosis, but it may also precede or accompany systemic involvement, often representing the main sign of an exacerbation or a relapse of systemic sarcoidosis, as in our patient.⁵

A 52-year-old woman is referred to our dermatology clinic by her primary care physician for swelling and redness of seven old scars. The swelling began 3 months ago.

She is on no regular medications. She has never smoked. She underwent liposuction 7 years ago and appendectomy at age 15.

Laboratory testing shows mild leukopenia, with a white blood cell count of 3.0 × 10⁹/L (reference range 4.2–9.0). Other routine laboratory values are normal, including antinuclear antibody, extractable nuclear antibody, anti-double-stranded DNA, rheumatoid factor, urinalysis, erythrocyte sedimentation rate, C-reactive protein, serum calcium concentration, and liver and renal function tests.

Chest radiography reveals bilateral hilar lymphadenopathy.

Q: What is the next most appropriate diagnostic procedure?

• Skin biopsy
• High-resolution computed tomography (CT) of the chest
• QuantiFERON-TB Gold test
• Ventilatory function tests
• Serum angiotensin-converting enzyme (ACE) level

A: All are appropriate at this point. In this case, skin biopsy and high-resolution CT were performed. Histopathologic examination of one of the scars showed multiple well-demarcated, large, noncaseating epitheloid granulomas with histiocytes and multinucleated giant cells. High-resolution CT confirmed bilateral hilar and mediastinal lymphadenopathy and revealed micronodular densities with a bronchovascular and subpleural distribution.

An interferon-gamma-release assay for tuberculosis—QuantiFERON-TB Gold (Cellestis, Carnegie, Australia)—was negative. Ventilatory function tests showed a normal pattern, while the serum ACE level, electrocardiography, and an eye examination revealed no pathologic findings.

Q: What is the diagnosis?

• Keloids
• Scar sarcoidosis
• Paraneoplastic sign
• Dermatofibrosarcoma protuberans
• Tubercolosis

A: Based on the data outlined above, we made the diagnosis of scar sarcoidosis with involvement of hilar and mediastinal lymph nodes. The patient began systemic treatment with oral prednisone 1 mg/kg/day for 6 weeks, which was then gradually withdrawn, until the skin and hilar lesions resolved completely.

SCAR SARCOIDOSIS

Sarcoidosis is a multisystem disorder of unknown cause characterized by the formation of noncaseating granulomas in the affected organs. Patients may present with symptoms related to the specific organ affected, but they may have no symptoms or only general symptoms such as fever or general malaise.

The skin is involved in 25% of cases and presents so many polymorphous manifestations that sarcoidosis has become known as one of the “great imitators” in dermatology.^1,2

Although sarcoidosis on liposuction scars has not been reported previously, the reactivation of old scars is well known on sites of previous injections, tattoos, herpes zoster, and burns.^2,3

The finding of granuloma is not specific for sarcoidosis (Figure 2). The histologic differential diagnosis of sarcoidosis includes tuberculosis, atypical mycobacteriosis, fungal infection, reaction to a foreign body, rheumatoid nodules, leishmaniasis, Crohn disease, and necrobiosis lipoidica diabeticorum.

The diagnosis of scar sarcoidosis is confirmed only by excluding other conditions via a comprehensive evaluation of clinical manifestations, histology, history, and radiologic and laboratory findings.

It has been suggested that the most satisfying therapy for the patient and physician in sarcoidosis is no treatment at all,⁴ and in fact sarcoidosis often remits spontaneously. Currently, the choice of treatment depends on the degree of systemic involvement, and the oral corticosteroid prednisone remains the first-line treatment. If the condition does not respond, the use of other systemic agents has been reported, but their effectiveness has not been evaluated in controlled clinical trials.

Recurrence is common after the suspension of treatment; therefore, treatment may need to be continued for several years, with frequent checkups.

Skin lesions are a visible clue to the diagnosis. Reactivation of old scars may be the single manifestation of cutaneous sarcoidosis, but it may also precede or accompany systemic involvement, often representing the main sign of an exacerbation or a relapse of systemic sarcoidosis, as in our patient.⁵

A 52-year-old woman is referred to our dermatology clinic by her primary care physician for swelling and redness of seven old scars. The swelling began 3 months ago.

She is on no regular medications. She has never smoked. She underwent liposuction 7 years ago and appendectomy at age 15.

Laboratory testing shows mild leukopenia, with a white blood cell count of 3.0 × 10⁹/L (reference range 4.2–9.0). Other routine laboratory values are normal, including antinuclear antibody, extractable nuclear antibody, anti-double-stranded DNA, rheumatoid factor, urinalysis, erythrocyte sedimentation rate, C-reactive protein, serum calcium concentration, and liver and renal function tests.

Chest radiography reveals bilateral hilar lymphadenopathy.

Q: What is the next most appropriate diagnostic procedure?

• Skin biopsy
• High-resolution computed tomography (CT) of the chest
• QuantiFERON-TB Gold test
• Ventilatory function tests
• Serum angiotensin-converting enzyme (ACE) level

A: All are appropriate at this point. In this case, skin biopsy and high-resolution CT were performed. Histopathologic examination of one of the scars showed multiple well-demarcated, large, noncaseating epitheloid granulomas with histiocytes and multinucleated giant cells. High-resolution CT confirmed bilateral hilar and mediastinal lymphadenopathy and revealed micronodular densities with a bronchovascular and subpleural distribution.

An interferon-gamma-release assay for tuberculosis—QuantiFERON-TB Gold (Cellestis, Carnegie, Australia)—was negative. Ventilatory function tests showed a normal pattern, while the serum ACE level, electrocardiography, and an eye examination revealed no pathologic findings.

Q: What is the diagnosis?

• Keloids
• Scar sarcoidosis
• Paraneoplastic sign
• Dermatofibrosarcoma protuberans
• Tubercolosis

A: Based on the data outlined above, we made the diagnosis of scar sarcoidosis with involvement of hilar and mediastinal lymph nodes. The patient began systemic treatment with oral prednisone 1 mg/kg/day for 6 weeks, which was then gradually withdrawn, until the skin and hilar lesions resolved completely.

SCAR SARCOIDOSIS

Sarcoidosis is a multisystem disorder of unknown cause characterized by the formation of noncaseating granulomas in the affected organs. Patients may present with symptoms related to the specific organ affected, but they may have no symptoms or only general symptoms such as fever or general malaise.

The skin is involved in 25% of cases and presents so many polymorphous manifestations that sarcoidosis has become known as one of the “great imitators” in dermatology.^1,2

Although sarcoidosis on liposuction scars has not been reported previously, the reactivation of old scars is well known on sites of previous injections, tattoos, herpes zoster, and burns.^2,3

The finding of granuloma is not specific for sarcoidosis (Figure 2). The histologic differential diagnosis of sarcoidosis includes tuberculosis, atypical mycobacteriosis, fungal infection, reaction to a foreign body, rheumatoid nodules, leishmaniasis, Crohn disease, and necrobiosis lipoidica diabeticorum.

The diagnosis of scar sarcoidosis is confirmed only by excluding other conditions via a comprehensive evaluation of clinical manifestations, histology, history, and radiologic and laboratory findings.

It has been suggested that the most satisfying therapy for the patient and physician in sarcoidosis is no treatment at all,⁴ and in fact sarcoidosis often remits spontaneously. Currently, the choice of treatment depends on the degree of systemic involvement, and the oral corticosteroid prednisone remains the first-line treatment. If the condition does not respond, the use of other systemic agents has been reported, but their effectiveness has not been evaluated in controlled clinical trials.

Recurrence is common after the suspension of treatment; therefore, treatment may need to be continued for several years, with frequent checkups.

Skin lesions are a visible clue to the diagnosis. Reactivation of old scars may be the single manifestation of cutaneous sarcoidosis, but it may also precede or accompany systemic involvement, often representing the main sign of an exacerbation or a relapse of systemic sarcoidosis, as in our patient.⁵

A 22-year-old student was brought in to a college student health center in a wheelchair by campus safety personnel. She appeared drowsy and was crying softly. She complained of a severe headache and said she was “tired of going through this all the time.” The woman said she had seen spots and become dizzy, then had gotten “the worst headache of my life” while sitting in class. She rated the headache pain at 8 on a 10-point scale and also complained of nausea and photophobia.

The history revealed dizziness that made her “feel as if I’m tipping over” and similar headaches during the previous year. The patient said she had seen “a few doctors” for her symptoms, but that they “could never find anything.” The headaches usually occurred on the left side of her head, lasted hours to days, and were only partially relieved with acetaminophen. The patient could not remember whether she had eaten breakfast and was unsure of what day it was. She described herself as frustrated and began to weep again.

She was currently under the care of a psychologist but seemed uncertain why; she said that she was sexually active and used condoms. She had undergone an appendectomy at age 12. She denied taking any medications besides acetaminophen. She denied smoking or drug use, history of migraine headaches, vision or hearing changes, facial weakness, depression, or anxiety. Her family history included a grandfather with diabetes and hypertension and an uncle with heart disease. The family history was negative for migraine or psychiatric illness.

Because of the patient’s weakness, she was assisted onto the examination table by a nurse. Physical exam revealed a pale, slightly sweaty, overweight, tearful young woman who was slow to respond. Her blood pressure was measured at 134/104 mm Hg; pulse, 100 beats/min; respirations, 14 breaths/min; and temperature, 97.0ºF. Point-of-care testing of blood glucose was 91 mg/dL, and hemoglobin was measured at 12.3 g/dL. The ophthalmologic exam was positive for photophobia and revealed slightly disconjugate gaze with horizontal nystagmus during testing of cranial nerves (CN) III, IV, and VI. The otoscopic exam revealed a slightly injected right tympanic membrane, and there were no apparent hearing deficits.

The neurologic exam showed patellar and brachial deep tendon reflexes equal, grips weak and equal, and the pupillary response intact. The patient was able to stand without assistance, although her gait was slightly unsteady. Because the patient was of college age, the clinician ruled out meningitis by negative Kernig’s and Brudzinski’s signs and absence of fever. Subarachnoid hemorrhage was also a concern when the patient mentioned the “worst headache of my life,” indicating the need for emergent imaging.

The patient’s presentation, it was felt, warranted a 911 call. The emergency medical team arrived, and its members began to question the patient. Discrepancies in the patient’s history during the paramedics’ reexamination led them to question whether an emergency department (ED) visit was necessary, but at the clinician’s insistence, they agreed to transport the student to the ED.

The following day, the student health center clinician was contacted by a member of the hospital ED staff with an update on the patient’s status. Shortly after her arrival at the hospital, she underwent MRI and was diagnosed with a vestibular schwannoma. She had surgery that same evening, during which the surgeon removed most of the tumor. Although the ED staff was not at liberty to provide more complete information, they did inform the clinician that the patient would require radiation for the remainder of the tumor.

DISCUSSION
Vestibular schwannoma is also known as acoustic schwannoma, acoustic neuroma, acoustic neurinoma, or vestibular neurilemmoma. These tumors arise from perineural elements of Schwann cells, which commonly form and lead to myelination in the vestibular area of CN VIII¹ (see figure). They occur with equal frequency on the superior and inferior branches of the vestibular nerve and originate only rarely at the cochlear portion of the eighth cranial nerve. Vestibular schwannomas represent approximately 8% to 10% of brain tumors and 80% to 90% of tumors in the cere­bellopontine angle in adults.² Tumors are distributed evenly across genders, but the majority of diagnosed patients are white.³

Most likely because of improvements in diagnostic technology, the incidence of vestibular schwannoma has increased over the past 30 years. One British research team predicts that one in 1,000 persons will receive a diagnosis of vestibular schwannoma in their lifetime.⁴ These tumors are most commonly diagnosed in people ages 30 to 60, with a median age of 55.⁵

A relationship has been demonstrated between neurofibromatosis type 2 (NF2), an autosomal-dominant disease, and the development of vestibular schwannomas.^6,7 NF2 has a birth prevalence of one in about 25,000 persons,^4,8 and those who inherit the responsible gene inevitably develop vestibular schwannomas.⁹ Patients with a confirmed diagnosis of vestibular schwannoma should be screened by a geneticist for the NF2 gene; although the tumors are benign, they can cause compression of the vestibular nerve, leading to deafness and balance disorders.¹⁰ Schwannomas of the spinal nerves can also occur in persons with NF2.¹¹ Compression of the spinal nerves in these patients can lead to significant morbidity and a shortened average life span.¹⁰

NF2 is diagnosed using the following criteria:

1) Bilateral vestibular schwan­nomas

2) Diagnosis of a family member with either NF2 or unilateral vestibular schwannoma, and

3) Juvenile posterior subscapular lens opacities.^9,12,13

Because schwannomas grow slowly, the vestibular system can adapt to the slow destruction of CN VIII. For this reason, patients typically present with unilateral deafness or hearing impairment rather than dizziness.¹¹ Many patients also present with tinnitus and/or vertigo.^14,15

Some vestibular tumors remain stable or even regress; others progress, in some cases causing life-threatening complications.¹⁶ An extremely rare complication of a vestibular schwannoma was reported in one patient: an intratumoral hemorrhage that led to acute neurologic deterioration and death.¹⁷

Since the case patient underwent immediate surgical intervention, it appears she was experiencing significant involvement and it was likely anticipated that without surgical intervention, clinical progression would occur. Her young age could be considered a risk factor for a faster-growing neuroma.¹⁸

Clinical Presentation and Diagnosis
Primary care clinicians commonly see patients with complaints of dizziness, lightheadedness, faintness, or a sensation of spinning or tilting. Vestibular schwannoma should be considered in the differential diagnosis of the patient who presents with these complaints, as well as tinnitus or hearing loss.⁹ The patient with vestibular schwannoma may also have a history of headache, unsteady gait, facial pain, and numbness.¹⁹ A partial differential diagnosis is listed in the table^20,21). The astute clinician will systematically rule out many of these conditions, since certain other features that may be present (eg, rapid onset, vomiting, fever) do not typically occur in the patient with vestibular schwannoma.

Because the symptoms typically associated with vestibular schwannoma are likely to occur bilaterally in patients with other conditions, unilateral symptoms should alert the clinician to investigate further. The patterns and growth rates of vestibular schwannomas are highly variable and currently unpredictable¹⁸ (according to Fortnum et al,¹⁴ at least 50% of tumors do not grow within several years after diagnosis); thus, no clear predictors of tumor growth have been identified to assist in the evaluation of an affected patient,¹⁶ although faster tumor growth rates have been reported in young patients, and Baser et al¹⁸ have called for additional research involving younger persons with vestibular schwannomas.

Standard testing is audiometry followed by MRI, which is considered the most effective means to confirm a diagnosis of vestibular schwannoma.^5,14,22

Treatment for Vestibular Schwannoma
Treatment, whether with surgery or radiation, is associated with significant morbidity and possibly decreased quality of life.¹⁶ Therefore, distinguishing patients whose tumors will grow and pose a threat to them from those whose tumors are likely to remain stable is central to appropriate management.²³

Treatment modalities are considered based on tumor size, growth, presence or absence of tinnitus, and the patient’s preferences and life expectancy.²³ In most cases, decision making is complex and should be customized to meet the patient’s individual circumstances. Patients with similar clinical scenarios have been reported to opt for different treatment choices.²⁴

Four treatment options are currently available for patients with vestibular schwannoma:

Serial observation with periodic MRI studies. Since vestibular schwannomas are benign and slow-growing, conservative manage­ment can be a reasonable option, particularly if the patient is elderly, the tumor is small, and/or little hearing loss has taken place. However, use of observation is associated with a risk for progressive and permanent hearing loss.² Between 15% and 50% of patients who opt for serial observation will undergo subsequent surgical intervention, particularly in cases involving worsening tinnitus, balance problems, or hearing loss.^23-25

Chemotherapy. Agents including bevacizumab (a humanized monoclonal antibody against vascular endothelial growth factor)^8,26,27 and erlotinib (an epidermal growth factor receptor inhibitor) may delay progression or even facilitate regression of vestibular schwannomas.²⁸ Hearing improvement has also been reported in patients with NF2 who were treated with bevacizumab⁸; research is ongoing.²⁶

Fractionated radiotherapy. Hearing may be preserved in 60% to 95% of patients, depending on levels of dosing to the cochlea, but 3% to 7% of patients will need further treatment.^29-31 Radiation treatment is a likely choice in patients with tumors measuring 2.0 cm or less. Larger tumors are considered a surgical disease, and directed radiotherapy may be administered postoperatively (as in the case patient) for residual portions of the tumor.¹⁶

Microsurgery. Compared with other treatment modalities, the emphasis of microsurgery is on removing tumors (particularly larger tumors) rather than controlling their growth.²⁹ The three common approaches are retrosigmoid, middle fossa, or translabyrinthine.^32-34 Preservation of hearing is reportedly better following retrosigmoid or middle fossa microsurgery, compared with a translabyrinthine procedure (because in the latter, the tumor cannot be exposed without damage to the inner ear).^32,35

With any such surgery, risks include cranial nerve damage, leakage of cerebrospinal fluid, and infection.^29,32 Postsurgically, about half of patients report frequent headaches, which are persistent in about half of these cases.^36-38 Another concern is preservation of the facial nerves, with a risk for temporary facial weakness or dysfunction.^3,24,39 Less than 2% of patients who undergo microsurgery require additional treatment.²⁹

Stereotactic radiosurgery. These procedures, which are performed using the Gamma Knife,^® the CyberKnife, or the linear accelerator,^29,40,41 are considered appropriate for patients with smaller tumors and those who are not candidates for conventional surgery.¹ Trigeminal neuropathy, injury to the facial nerves, and hydrocephaly are reported complications of Gamma Knife radiosurgery, but improvements in these technologies are ongoing.^1,2,40

Patient Outcomes
The outcome in a patient with vestibular schwannoma depends on the treatment administered, but prolonged follow-up is typically necessary. For patients being managed through observation, annual brain scans are recommended for 10 years, with subsequent scans every three to five years if no tumor growth is seen. For patients who have had surgery, annual brain scans are advised for the successive eight to 10 years, with decreasing frequency if no tumor remains. In patients who undergo radiation, annual scans are recommended for 10 years, then every two years if no tumor growth is detected.³⁶

Psychosocial experiences vary widely among patients who have undergone treatment for vestibular schwannomas. Some are unable to perform necessary or recreational activities, and others must retire early from work.⁴² Others, however, have minimal disruption in their lives and enjoy a good quality of life. The most difficult consequence of vestibular schwannoma and its treatment, according to patients, is the associated hearing loss.^8,19

THE CASE PATIENT
The 22-year-old patient in this case had an atypical presentation of vestibular schwannoma. Although she did present with vertigo, she also complained of headache, nausea, and photophobia—which are rarely reported in investigations of these tumors. She was also younger than the typical patient and did not report tinnitus.

The case patient reportedly underwent surgery and subsequent radiation to treat the remaining portion of her tumor. She suspended her attendance at the college and, as of this writing, has not re-enrolled. She was lost to follow-up.

CONCLUSION
For the primary care provider, diagnostic challenges require great clinical acumen. Vertigo, headache, hearing loss, and tinnitus are all symptoms seen in the primary care setting; when they occur together, the clinician should be alerted to investigate further. A high level of suspicion is appropriate when a patient complains of longstanding auditory symptoms, with or without headache. Unilateral hearing loss is a common symptom in patients with vestibular schwannomas, although some may present with facial weakness or pain, imbalance, and/or vertigo.

In addition to the history and physical exam, experts recommend that audiometry and MRI be considered, particularly if hearing loss is unilateral. Genetic screening for NF2 should be performed if vestibular schwannoma is found on MRI. Referral to a neurologist, a neurosurgeon, or an otolaryngologist is appropriate.

REFERENCES
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2. Mohammed TA, Ahuja MS, Ju SS, Thomas J. Normal pressure hydrocephalus after Gamma Knife radiosurgery for vestibular schwannoma. J Postgrad Med. 2010;56(3):213-215.

3. Gal TJ, Shinn J, Huang B. Current epidemiology and management trends in acoustic neuroma. Otolaryngol Head Neck Surg. 2010;142(5):677-681.

4. Evans DG, Moran A, King A, et al. Incidence of vestibular schwannoma and neurofibromatosis 2 in the North West of England over a 10-year period: higher incidence than previously thought. Otol Neurotol. 2005;26(1):93-97.

5. Haynes D. Acoustic neuroma diagnosis and treatment options. Hearing Health. 2009;25(3):32. www.drf.org/magazine/36/Summer+2009+Issue/article/272. Accessed May 16, 2011.

6. Sobel RA. Vestibular (acoustic) schwannomas: histologic features in neurofibromatosis 2 and in unilateral cases. J Neuropathol Exp Neurol. 1993;52(2):106-113.

7. Evans DG, Huson SM, Donnai D, et al. A clinical study of type 2 neurofibromatosis. Q J Med. 1992;84(304):603-618.

8. Plotkin SR, Stemmer-Rachamimov AO, Barker FG 2nd, et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med. 2009;361(4):358-367.

9. Evans DGR, Sainio M, Baser E. Neurofibromatosis type 2. J Med Genet. 2000:37(11):897-904.

10. Gusella JF, Ramesh V, MacCollin M, Jacoby LB. Neurofibromatosis 2: loss of Merlin’s protective spell. Curr Opin Genet Dev. 1996;6(1):87-92.

11. Sagar SM, Israel MA. Ch 374. Primary and metastatic tumors of the nervous system. In: Kasper DL, Braunwald E, Fauci AS, et al. Harrison’s Principles of Internal Medicine. 17th ed. New York, NY: McGraw-Hill Companies, Inc; 2008:2601-2610.

12. Evans DGR. Neurofibromatosis 2 [bilateral acoustic neurofibromatosis, central neurofibromatosis, NF2, neurofibromatosis type II]. Genet Med. 2009;11(9):599-610.

13. Arya R, Sahu JK, Kabra M. Neurofibromatosis type II (Wishart type). J Pediatr Neurol. 2009;7(3): 333-335.

14. Fortnum H, O’Neill C, Taylor R, et al. The role of magnetic resonance imaging in the identification of suspected acoustic neuroma: a systematic review of clinical and cost effectiveness and natural history. Health Technol Assess. 2009;13(18):iii-iv, ix-xi, 1-154.

15. Forton GE, Cremers CW, Offeciers EE. Acoustic neuroma ingrowth in the cochlear nerve: does it influence the clinical presentation? Ann Otol Rhinol Laryngol. 2004;113(7):582-586.

16. Nikolopoulos TP, Fortnum H, O’Donoghue G, Baguley D. Acoustic neuroma growth: a systematic review of the evidence. Otol Neurotol. 2010;31(3):478-485.

17. Yates CW, Weinberg M, Packer MJ, Jacob A. Fatal case of tumor-associated hemorrhage in a large vestibular schwannoma. Ann Otol Rhinol Laryngol. 2010;119(6):402-405.

18. Baser ME, Mautner VF, Parry DM, Evans DGR. Methodological issues in longitudinal studies; vestibular schwannoma growth rates in neurofibromatosis 2. J Med Genet. 2005;42(12):903-906.

19. Brooker J, Burney S, Fletcher J, Dally M. A qualitative exploration of quality of life among individuals diagnosed with an acoustic neuroma. Br J Health Psychol. 2009;14(pt 3):563-578.

20. Strupp M, Brandt T. Diagnosis and treatment of vertigo and dizziness. Dtsch Arzetbl Int. 2008;105(10):173-180.

21. Kerber KA. Dizziness and vertigo. In: Andreoli TE, Griggs RC, Benjamin I , Wing EJ, eds. Andreoli and Carpenter’s Cecil Essentials of Medicine. 8th ed. Philadelphia, PA: Elsevier Inc; 2010:1104-1105.

22. Gimsing S. Vestibular schwannoma: when to look for it? J Laryngol Otol. 2010;124(3):258-264.

23. Agrawal Y, Clark JH, Limb CJ, et al. Predictors of vestibular schwannoma growth and clinical implications. Otol Neurotol. 2010;31(5):807-812.

24. Cheung SW, Aranda D, Driscoll CLW, Parsa AT. Mapping clinical outcomes expectations to treatment decisions: an application to vestibular schwannoma management. Otol Neurotol. 2010;31(2):284-293.

25. Myrseth E, Pedersen PH, Møller P, Lund-Johansen M. Treatment of vestibular schwannomas: why, when and how? Acta Neurochir (Wien). 2007;149(7):647-660.

26. Sidney Kimmel Comprehensive Cancer Center, Massachusetts General Hospital, National Cancer Institute. Bevacizumab for symptomatic vestibular schwannoma in neurofibromatosis type 2 (NF2). http://clinicaltrials.gov/ct2/show/NCT01207687. Accessed May 16, 2011.

27. Mautner VF, Nguyen R, Kutta H, et al. Bevacizumab induces regression of vestibular schwannomas in patients with neurofibromatosis type 2. Neuro Oncol. 2010;12(1):14-18.

28. Plotkin SR, Halpin C, McKenna MJ, et al. Erlotinib for progressive vestibular schwannoma in neurofibromatosis 2 patients. Otol Neurotol. 2010;31(7):1135-1143.

29. Arthurs BJ, Fairbanks RK, Demakas JJ, et al. A review of treatment modalities for vestibular schwannoma. Neurosurg Rev. 2011 Feb 9; [Epub ahead of print].

30. Andrews DW, Werner-Wasik M, Den RB, et al. Toward dose optimization for fractionated stereotactic radiotherapy for acoustic neuromas: comparison of two dose cohorts. Int J Radiat Oncol Biol Phys. 2009;74(2):419-426.

31. Thomas C, Di Maio S, Ma R, et al. Hearing preservation following fractionated stereotactic radiotherapy for vestibular schwannomas: prognostic implications of cochlear dose. J Neurosurg. 2007;107(5):917-926.

32. Samii M, Gerganov V, Samii A. Improved preservation of hearing and facial nerve function in vestibular schwannoma surgery via the retrosigmoid approach in a series of 200 patients. J Neuro­surg. 2006;105(4):527-535.

33. Shiobara R, Ohira T, Inoue Y, et al. Extended middle cranial fossa approach for vestibular schwannoma: technical note and surgical results of 896 operations. Prog Neurol Surg. 2008;21:65-72.

34. Schmerber S, Palombi O, Boubagra K, et al. Long-term control of vestibular schwannoma after a translabyrinthine complete removal. Neurosurgery. 2005;57(4):693-698.

35. Phillips DJ, Kobylarz EJ, De Peralta ET, et al. Predictive factors of hearing preservation after surgical resection of small vestibular schwannomas. Otol Neurotol. 2010;31(9):1463-1468.

36. Park JK, Black MP, Vernick DM, Ramakrishna N. Vestibular schwannoma (acoustic neuroma) (2010). www.uptodate.com/contents/vestibular-schwannoma-acoustic-neuroma. Accessed May 16, 2011.

37. Schankin CJ, Gall C, Straube A. Headache syndromes after acoustic neuroma surgery and their implications for quality of life. Cephalalgia. 2009;29(7):760-761.

38. Ryzenman JM, Pensak ML, Tew JM Jr. Headache: a quality of life analysis in a cohort of 1,657 patients undergoing acoustic neuroma surgery: results from the Acoustic Neuroma Association. Laryngoscope. 2005;115(4):703-711.

39. Sriskandan N, Connor SE. The role of radiology in the diagnosis and management of vestibular schwannoma. Clin Radiol. 2010;66(4):357-365.

40. Yang I, Sughrue ME, Han SJ, et al. Facial nerve preservation after vestibular schwannoma Gamma Knife surgery. J Neurooncol. 2009;93(1): 41-48.

41. Unger F, Dominikus K, Haselsberger K. Stereotactic radiosurgery and fractionated stereotactic radiotherapy of acoustic neuromas [in German]. HNO. 2011;59(1):31-37.

42. Tos T, Caye-Thomasen P, Stangerup SE, et al. Long-term socio-economic impact of vestibular schwannoma for patients under observation and after surgery. J Laryngol Otol. 2003;117(12):955-964.

A 22-year-old student was brought in to a college student health center in a wheelchair by campus safety personnel. She appeared drowsy and was crying softly. She complained of a severe headache and said she was “tired of going through this all the time.” The woman said she had seen spots and become dizzy, then had gotten “the worst headache of my life” while sitting in class. She rated the headache pain at 8 on a 10-point scale and also complained of nausea and photophobia.

The history revealed dizziness that made her “feel as if I’m tipping over” and similar headaches during the previous year. The patient said she had seen “a few doctors” for her symptoms, but that they “could never find anything.” The headaches usually occurred on the left side of her head, lasted hours to days, and were only partially relieved with acetaminophen. The patient could not remember whether she had eaten breakfast and was unsure of what day it was. She described herself as frustrated and began to weep again.

She was currently under the care of a psychologist but seemed uncertain why; she said that she was sexually active and used condoms. She had undergone an appendectomy at age 12. She denied taking any medications besides acetaminophen. She denied smoking or drug use, history of migraine headaches, vision or hearing changes, facial weakness, depression, or anxiety. Her family history included a grandfather with diabetes and hypertension and an uncle with heart disease. The family history was negative for migraine or psychiatric illness.

Because of the patient’s weakness, she was assisted onto the examination table by a nurse. Physical exam revealed a pale, slightly sweaty, overweight, tearful young woman who was slow to respond. Her blood pressure was measured at 134/104 mm Hg; pulse, 100 beats/min; respirations, 14 breaths/min; and temperature, 97.0ºF. Point-of-care testing of blood glucose was 91 mg/dL, and hemoglobin was measured at 12.3 g/dL. The ophthalmologic exam was positive for photophobia and revealed slightly disconjugate gaze with horizontal nystagmus during testing of cranial nerves (CN) III, IV, and VI. The otoscopic exam revealed a slightly injected right tympanic membrane, and there were no apparent hearing deficits.

The neurologic exam showed patellar and brachial deep tendon reflexes equal, grips weak and equal, and the pupillary response intact. The patient was able to stand without assistance, although her gait was slightly unsteady. Because the patient was of college age, the clinician ruled out meningitis by negative Kernig’s and Brudzinski’s signs and absence of fever. Subarachnoid hemorrhage was also a concern when the patient mentioned the “worst headache of my life,” indicating the need for emergent imaging.

The patient’s presentation, it was felt, warranted a 911 call. The emergency medical team arrived, and its members began to question the patient. Discrepancies in the patient’s history during the paramedics’ reexamination led them to question whether an emergency department (ED) visit was necessary, but at the clinician’s insistence, they agreed to transport the student to the ED.

The following day, the student health center clinician was contacted by a member of the hospital ED staff with an update on the patient’s status. Shortly after her arrival at the hospital, she underwent MRI and was diagnosed with a vestibular schwannoma. She had surgery that same evening, during which the surgeon removed most of the tumor. Although the ED staff was not at liberty to provide more complete information, they did inform the clinician that the patient would require radiation for the remainder of the tumor.

DISCUSSION
Vestibular schwannoma is also known as acoustic schwannoma, acoustic neuroma, acoustic neurinoma, or vestibular neurilemmoma. These tumors arise from perineural elements of Schwann cells, which commonly form and lead to myelination in the vestibular area of CN VIII¹ (see figure). They occur with equal frequency on the superior and inferior branches of the vestibular nerve and originate only rarely at the cochlear portion of the eighth cranial nerve. Vestibular schwannomas represent approximately 8% to 10% of brain tumors and 80% to 90% of tumors in the cere­bellopontine angle in adults.² Tumors are distributed evenly across genders, but the majority of diagnosed patients are white.³

Most likely because of improvements in diagnostic technology, the incidence of vestibular schwannoma has increased over the past 30 years. One British research team predicts that one in 1,000 persons will receive a diagnosis of vestibular schwannoma in their lifetime.⁴ These tumors are most commonly diagnosed in people ages 30 to 60, with a median age of 55.⁵

A relationship has been demonstrated between neurofibromatosis type 2 (NF2), an autosomal-dominant disease, and the development of vestibular schwannomas.^6,7 NF2 has a birth prevalence of one in about 25,000 persons,^4,8 and those who inherit the responsible gene inevitably develop vestibular schwannomas.⁹ Patients with a confirmed diagnosis of vestibular schwannoma should be screened by a geneticist for the NF2 gene; although the tumors are benign, they can cause compression of the vestibular nerve, leading to deafness and balance disorders.¹⁰ Schwannomas of the spinal nerves can also occur in persons with NF2.¹¹ Compression of the spinal nerves in these patients can lead to significant morbidity and a shortened average life span.¹⁰

NF2 is diagnosed using the following criteria:

1) Bilateral vestibular schwan­nomas

2) Diagnosis of a family member with either NF2 or unilateral vestibular schwannoma, and

3) Juvenile posterior subscapular lens opacities.^9,12,13

Because schwannomas grow slowly, the vestibular system can adapt to the slow destruction of CN VIII. For this reason, patients typically present with unilateral deafness or hearing impairment rather than dizziness.¹¹ Many patients also present with tinnitus and/or vertigo.^14,15

Some vestibular tumors remain stable or even regress; others progress, in some cases causing life-threatening complications.¹⁶ An extremely rare complication of a vestibular schwannoma was reported in one patient: an intratumoral hemorrhage that led to acute neurologic deterioration and death.¹⁷

Since the case patient underwent immediate surgical intervention, it appears she was experiencing significant involvement and it was likely anticipated that without surgical intervention, clinical progression would occur. Her young age could be considered a risk factor for a faster-growing neuroma.¹⁸

Clinical Presentation and Diagnosis
Primary care clinicians commonly see patients with complaints of dizziness, lightheadedness, faintness, or a sensation of spinning or tilting. Vestibular schwannoma should be considered in the differential diagnosis of the patient who presents with these complaints, as well as tinnitus or hearing loss.⁹ The patient with vestibular schwannoma may also have a history of headache, unsteady gait, facial pain, and numbness.¹⁹ A partial differential diagnosis is listed in the table^20,21). The astute clinician will systematically rule out many of these conditions, since certain other features that may be present (eg, rapid onset, vomiting, fever) do not typically occur in the patient with vestibular schwannoma.

Because the symptoms typically associated with vestibular schwannoma are likely to occur bilaterally in patients with other conditions, unilateral symptoms should alert the clinician to investigate further. The patterns and growth rates of vestibular schwannomas are highly variable and currently unpredictable¹⁸ (according to Fortnum et al,¹⁴ at least 50% of tumors do not grow within several years after diagnosis); thus, no clear predictors of tumor growth have been identified to assist in the evaluation of an affected patient,¹⁶ although faster tumor growth rates have been reported in young patients, and Baser et al¹⁸ have called for additional research involving younger persons with vestibular schwannomas.

Standard testing is audiometry followed by MRI, which is considered the most effective means to confirm a diagnosis of vestibular schwannoma.^5,14,22

Treatment for Vestibular Schwannoma
Treatment, whether with surgery or radiation, is associated with significant morbidity and possibly decreased quality of life.¹⁶ Therefore, distinguishing patients whose tumors will grow and pose a threat to them from those whose tumors are likely to remain stable is central to appropriate management.²³

Treatment modalities are considered based on tumor size, growth, presence or absence of tinnitus, and the patient’s preferences and life expectancy.²³ In most cases, decision making is complex and should be customized to meet the patient’s individual circumstances. Patients with similar clinical scenarios have been reported to opt for different treatment choices.²⁴

Four treatment options are currently available for patients with vestibular schwannoma:

Serial observation with periodic MRI studies. Since vestibular schwannomas are benign and slow-growing, conservative manage­ment can be a reasonable option, particularly if the patient is elderly, the tumor is small, and/or little hearing loss has taken place. However, use of observation is associated with a risk for progressive and permanent hearing loss.² Between 15% and 50% of patients who opt for serial observation will undergo subsequent surgical intervention, particularly in cases involving worsening tinnitus, balance problems, or hearing loss.^23-25

Chemotherapy. Agents including bevacizumab (a humanized monoclonal antibody against vascular endothelial growth factor)^8,26,27 and erlotinib (an epidermal growth factor receptor inhibitor) may delay progression or even facilitate regression of vestibular schwannomas.²⁸ Hearing improvement has also been reported in patients with NF2 who were treated with bevacizumab⁸; research is ongoing.²⁶

Fractionated radiotherapy. Hearing may be preserved in 60% to 95% of patients, depending on levels of dosing to the cochlea, but 3% to 7% of patients will need further treatment.^29-31 Radiation treatment is a likely choice in patients with tumors measuring 2.0 cm or less. Larger tumors are considered a surgical disease, and directed radiotherapy may be administered postoperatively (as in the case patient) for residual portions of the tumor.¹⁶

Microsurgery. Compared with other treatment modalities, the emphasis of microsurgery is on removing tumors (particularly larger tumors) rather than controlling their growth.²⁹ The three common approaches are retrosigmoid, middle fossa, or translabyrinthine.^32-34 Preservation of hearing is reportedly better following retrosigmoid or middle fossa microsurgery, compared with a translabyrinthine procedure (because in the latter, the tumor cannot be exposed without damage to the inner ear).^32,35

With any such surgery, risks include cranial nerve damage, leakage of cerebrospinal fluid, and infection.^29,32 Postsurgically, about half of patients report frequent headaches, which are persistent in about half of these cases.^36-38 Another concern is preservation of the facial nerves, with a risk for temporary facial weakness or dysfunction.^3,24,39 Less than 2% of patients who undergo microsurgery require additional treatment.²⁹

Stereotactic radiosurgery. These procedures, which are performed using the Gamma Knife,^® the CyberKnife, or the linear accelerator,^29,40,41 are considered appropriate for patients with smaller tumors and those who are not candidates for conventional surgery.¹ Trigeminal neuropathy, injury to the facial nerves, and hydrocephaly are reported complications of Gamma Knife radiosurgery, but improvements in these technologies are ongoing.^1,2,40

Patient Outcomes
The outcome in a patient with vestibular schwannoma depends on the treatment administered, but prolonged follow-up is typically necessary. For patients being managed through observation, annual brain scans are recommended for 10 years, with subsequent scans every three to five years if no tumor growth is seen. For patients who have had surgery, annual brain scans are advised for the successive eight to 10 years, with decreasing frequency if no tumor remains. In patients who undergo radiation, annual scans are recommended for 10 years, then every two years if no tumor growth is detected.³⁶

Psychosocial experiences vary widely among patients who have undergone treatment for vestibular schwannomas. Some are unable to perform necessary or recreational activities, and others must retire early from work.⁴² Others, however, have minimal disruption in their lives and enjoy a good quality of life. The most difficult consequence of vestibular schwannoma and its treatment, according to patients, is the associated hearing loss.^8,19

THE CASE PATIENT
The 22-year-old patient in this case had an atypical presentation of vestibular schwannoma. Although she did present with vertigo, she also complained of headache, nausea, and photophobia—which are rarely reported in investigations of these tumors. She was also younger than the typical patient and did not report tinnitus.

The case patient reportedly underwent surgery and subsequent radiation to treat the remaining portion of her tumor. She suspended her attendance at the college and, as of this writing, has not re-enrolled. She was lost to follow-up.

CONCLUSION
For the primary care provider, diagnostic challenges require great clinical acumen. Vertigo, headache, hearing loss, and tinnitus are all symptoms seen in the primary care setting; when they occur together, the clinician should be alerted to investigate further. A high level of suspicion is appropriate when a patient complains of longstanding auditory symptoms, with or without headache. Unilateral hearing loss is a common symptom in patients with vestibular schwannomas, although some may present with facial weakness or pain, imbalance, and/or vertigo.

In addition to the history and physical exam, experts recommend that audiometry and MRI be considered, particularly if hearing loss is unilateral. Genetic screening for NF2 should be performed if vestibular schwannoma is found on MRI. Referral to a neurologist, a neurosurgeon, or an otolaryngologist is appropriate.

REFERENCES
1. Arthurs BJ, Lamoreaux WT, Giddings NA, et al. Gamma Knife radiosurgery for vestibular schwannoma: case report and review of the literature. World J Surg Oncol. 2009 Dec 18;7:100.

2. Mohammed TA, Ahuja MS, Ju SS, Thomas J. Normal pressure hydrocephalus after Gamma Knife radiosurgery for vestibular schwannoma. J Postgrad Med. 2010;56(3):213-215.

3. Gal TJ, Shinn J, Huang B. Current epidemiology and management trends in acoustic neuroma. Otolaryngol Head Neck Surg. 2010;142(5):677-681.

4. Evans DG, Moran A, King A, et al. Incidence of vestibular schwannoma and neurofibromatosis 2 in the North West of England over a 10-year period: higher incidence than previously thought. Otol Neurotol. 2005;26(1):93-97.

5. Haynes D. Acoustic neuroma diagnosis and treatment options. Hearing Health. 2009;25(3):32. www.drf.org/magazine/36/Summer+2009+Issue/article/272. Accessed May 16, 2011.

6. Sobel RA. Vestibular (acoustic) schwannomas: histologic features in neurofibromatosis 2 and in unilateral cases. J Neuropathol Exp Neurol. 1993;52(2):106-113.

7. Evans DG, Huson SM, Donnai D, et al. A clinical study of type 2 neurofibromatosis. Q J Med. 1992;84(304):603-618.

8. Plotkin SR, Stemmer-Rachamimov AO, Barker FG 2nd, et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med. 2009;361(4):358-367.

9. Evans DGR, Sainio M, Baser E. Neurofibromatosis type 2. J Med Genet. 2000:37(11):897-904.

10. Gusella JF, Ramesh V, MacCollin M, Jacoby LB. Neurofibromatosis 2: loss of Merlin’s protective spell. Curr Opin Genet Dev. 1996;6(1):87-92.

11. Sagar SM, Israel MA. Ch 374. Primary and metastatic tumors of the nervous system. In: Kasper DL, Braunwald E, Fauci AS, et al. Harrison’s Principles of Internal Medicine. 17th ed. New York, NY: McGraw-Hill Companies, Inc; 2008:2601-2610.

12. Evans DGR. Neurofibromatosis 2 [bilateral acoustic neurofibromatosis, central neurofibromatosis, NF2, neurofibromatosis type II]. Genet Med. 2009;11(9):599-610.

13. Arya R, Sahu JK, Kabra M. Neurofibromatosis type II (Wishart type). J Pediatr Neurol. 2009;7(3): 333-335.

14. Fortnum H, O’Neill C, Taylor R, et al. The role of magnetic resonance imaging in the identification of suspected acoustic neuroma: a systematic review of clinical and cost effectiveness and natural history. Health Technol Assess. 2009;13(18):iii-iv, ix-xi, 1-154.

15. Forton GE, Cremers CW, Offeciers EE. Acoustic neuroma ingrowth in the cochlear nerve: does it influence the clinical presentation? Ann Otol Rhinol Laryngol. 2004;113(7):582-586.

16. Nikolopoulos TP, Fortnum H, O’Donoghue G, Baguley D. Acoustic neuroma growth: a systematic review of the evidence. Otol Neurotol. 2010;31(3):478-485.

17. Yates CW, Weinberg M, Packer MJ, Jacob A. Fatal case of tumor-associated hemorrhage in a large vestibular schwannoma. Ann Otol Rhinol Laryngol. 2010;119(6):402-405.

18. Baser ME, Mautner VF, Parry DM, Evans DGR. Methodological issues in longitudinal studies; vestibular schwannoma growth rates in neurofibromatosis 2. J Med Genet. 2005;42(12):903-906.

19. Brooker J, Burney S, Fletcher J, Dally M. A qualitative exploration of quality of life among individuals diagnosed with an acoustic neuroma. Br J Health Psychol. 2009;14(pt 3):563-578.

20. Strupp M, Brandt T. Diagnosis and treatment of vertigo and dizziness. Dtsch Arzetbl Int. 2008;105(10):173-180.

21. Kerber KA. Dizziness and vertigo. In: Andreoli TE, Griggs RC, Benjamin I , Wing EJ, eds. Andreoli and Carpenter’s Cecil Essentials of Medicine. 8th ed. Philadelphia, PA: Elsevier Inc; 2010:1104-1105.

22. Gimsing S. Vestibular schwannoma: when to look for it? J Laryngol Otol. 2010;124(3):258-264.

23. Agrawal Y, Clark JH, Limb CJ, et al. Predictors of vestibular schwannoma growth and clinical implications. Otol Neurotol. 2010;31(5):807-812.

24. Cheung SW, Aranda D, Driscoll CLW, Parsa AT. Mapping clinical outcomes expectations to treatment decisions: an application to vestibular schwannoma management. Otol Neurotol. 2010;31(2):284-293.

25. Myrseth E, Pedersen PH, Møller P, Lund-Johansen M. Treatment of vestibular schwannomas: why, when and how? Acta Neurochir (Wien). 2007;149(7):647-660.

26. Sidney Kimmel Comprehensive Cancer Center, Massachusetts General Hospital, National Cancer Institute. Bevacizumab for symptomatic vestibular schwannoma in neurofibromatosis type 2 (NF2). http://clinicaltrials.gov/ct2/show/NCT01207687. Accessed May 16, 2011.

27. Mautner VF, Nguyen R, Kutta H, et al. Bevacizumab induces regression of vestibular schwannomas in patients with neurofibromatosis type 2. Neuro Oncol. 2010;12(1):14-18.

28. Plotkin SR, Halpin C, McKenna MJ, et al. Erlotinib for progressive vestibular schwannoma in neurofibromatosis 2 patients. Otol Neurotol. 2010;31(7):1135-1143.

29. Arthurs BJ, Fairbanks RK, Demakas JJ, et al. A review of treatment modalities for vestibular schwannoma. Neurosurg Rev. 2011 Feb 9; [Epub ahead of print].

30. Andrews DW, Werner-Wasik M, Den RB, et al. Toward dose optimization for fractionated stereotactic radiotherapy for acoustic neuromas: comparison of two dose cohorts. Int J Radiat Oncol Biol Phys. 2009;74(2):419-426.

31. Thomas C, Di Maio S, Ma R, et al. Hearing preservation following fractionated stereotactic radiotherapy for vestibular schwannomas: prognostic implications of cochlear dose. J Neurosurg. 2007;107(5):917-926.

32. Samii M, Gerganov V, Samii A. Improved preservation of hearing and facial nerve function in vestibular schwannoma surgery via the retrosigmoid approach in a series of 200 patients. J Neuro­surg. 2006;105(4):527-535.

33. Shiobara R, Ohira T, Inoue Y, et al. Extended middle cranial fossa approach for vestibular schwannoma: technical note and surgical results of 896 operations. Prog Neurol Surg. 2008;21:65-72.

34. Schmerber S, Palombi O, Boubagra K, et al. Long-term control of vestibular schwannoma after a translabyrinthine complete removal. Neurosurgery. 2005;57(4):693-698.

35. Phillips DJ, Kobylarz EJ, De Peralta ET, et al. Predictive factors of hearing preservation after surgical resection of small vestibular schwannomas. Otol Neurotol. 2010;31(9):1463-1468.

36. Park JK, Black MP, Vernick DM, Ramakrishna N. Vestibular schwannoma (acoustic neuroma) (2010). www.uptodate.com/contents/vestibular-schwannoma-acoustic-neuroma. Accessed May 16, 2011.

37. Schankin CJ, Gall C, Straube A. Headache syndromes after acoustic neuroma surgery and their implications for quality of life. Cephalalgia. 2009;29(7):760-761.

38. Ryzenman JM, Pensak ML, Tew JM Jr. Headache: a quality of life analysis in a cohort of 1,657 patients undergoing acoustic neuroma surgery: results from the Acoustic Neuroma Association. Laryngoscope. 2005;115(4):703-711.

39. Sriskandan N, Connor SE. The role of radiology in the diagnosis and management of vestibular schwannoma. Clin Radiol. 2010;66(4):357-365.

40. Yang I, Sughrue ME, Han SJ, et al. Facial nerve preservation after vestibular schwannoma Gamma Knife surgery. J Neurooncol. 2009;93(1): 41-48.

41. Unger F, Dominikus K, Haselsberger K. Stereotactic radiosurgery and fractionated stereotactic radiotherapy of acoustic neuromas [in German]. HNO. 2011;59(1):31-37.

42. Tos T, Caye-Thomasen P, Stangerup SE, et al. Long-term socio-economic impact of vestibular schwannoma for patients under observation and after surgery. J Laryngol Otol. 2003;117(12):955-964.

A 22-year-old student was brought in to a college student health center in a wheelchair by campus safety personnel. She appeared drowsy and was crying softly. She complained of a severe headache and said she was “tired of going through this all the time.” The woman said she had seen spots and become dizzy, then had gotten “the worst headache of my life” while sitting in class. She rated the headache pain at 8 on a 10-point scale and also complained of nausea and photophobia.

The history revealed dizziness that made her “feel as if I’m tipping over” and similar headaches during the previous year. The patient said she had seen “a few doctors” for her symptoms, but that they “could never find anything.” The headaches usually occurred on the left side of her head, lasted hours to days, and were only partially relieved with acetaminophen. The patient could not remember whether she had eaten breakfast and was unsure of what day it was. She described herself as frustrated and began to weep again.

She was currently under the care of a psychologist but seemed uncertain why; she said that she was sexually active and used condoms. She had undergone an appendectomy at age 12. She denied taking any medications besides acetaminophen. She denied smoking or drug use, history of migraine headaches, vision or hearing changes, facial weakness, depression, or anxiety. Her family history included a grandfather with diabetes and hypertension and an uncle with heart disease. The family history was negative for migraine or psychiatric illness.

Because of the patient’s weakness, she was assisted onto the examination table by a nurse. Physical exam revealed a pale, slightly sweaty, overweight, tearful young woman who was slow to respond. Her blood pressure was measured at 134/104 mm Hg; pulse, 100 beats/min; respirations, 14 breaths/min; and temperature, 97.0ºF. Point-of-care testing of blood glucose was 91 mg/dL, and hemoglobin was measured at 12.3 g/dL. The ophthalmologic exam was positive for photophobia and revealed slightly disconjugate gaze with horizontal nystagmus during testing of cranial nerves (CN) III, IV, and VI. The otoscopic exam revealed a slightly injected right tympanic membrane, and there were no apparent hearing deficits.

The neurologic exam showed patellar and brachial deep tendon reflexes equal, grips weak and equal, and the pupillary response intact. The patient was able to stand without assistance, although her gait was slightly unsteady. Because the patient was of college age, the clinician ruled out meningitis by negative Kernig’s and Brudzinski’s signs and absence of fever. Subarachnoid hemorrhage was also a concern when the patient mentioned the “worst headache of my life,” indicating the need for emergent imaging.

The patient’s presentation, it was felt, warranted a 911 call. The emergency medical team arrived, and its members began to question the patient. Discrepancies in the patient’s history during the paramedics’ reexamination led them to question whether an emergency department (ED) visit was necessary, but at the clinician’s insistence, they agreed to transport the student to the ED.

The following day, the student health center clinician was contacted by a member of the hospital ED staff with an update on the patient’s status. Shortly after her arrival at the hospital, she underwent MRI and was diagnosed with a vestibular schwannoma. She had surgery that same evening, during which the surgeon removed most of the tumor. Although the ED staff was not at liberty to provide more complete information, they did inform the clinician that the patient would require radiation for the remainder of the tumor.

DISCUSSION
Vestibular schwannoma is also known as acoustic schwannoma, acoustic neuroma, acoustic neurinoma, or vestibular neurilemmoma. These tumors arise from perineural elements of Schwann cells, which commonly form and lead to myelination in the vestibular area of CN VIII¹ (see figure). They occur with equal frequency on the superior and inferior branches of the vestibular nerve and originate only rarely at the cochlear portion of the eighth cranial nerve. Vestibular schwannomas represent approximately 8% to 10% of brain tumors and 80% to 90% of tumors in the cere­bellopontine angle in adults.² Tumors are distributed evenly across genders, but the majority of diagnosed patients are white.³

Most likely because of improvements in diagnostic technology, the incidence of vestibular schwannoma has increased over the past 30 years. One British research team predicts that one in 1,000 persons will receive a diagnosis of vestibular schwannoma in their lifetime.⁴ These tumors are most commonly diagnosed in people ages 30 to 60, with a median age of 55.⁵

A relationship has been demonstrated between neurofibromatosis type 2 (NF2), an autosomal-dominant disease, and the development of vestibular schwannomas.^6,7 NF2 has a birth prevalence of one in about 25,000 persons,^4,8 and those who inherit the responsible gene inevitably develop vestibular schwannomas.⁹ Patients with a confirmed diagnosis of vestibular schwannoma should be screened by a geneticist for the NF2 gene; although the tumors are benign, they can cause compression of the vestibular nerve, leading to deafness and balance disorders.¹⁰ Schwannomas of the spinal nerves can also occur in persons with NF2.¹¹ Compression of the spinal nerves in these patients can lead to significant morbidity and a shortened average life span.¹⁰

NF2 is diagnosed using the following criteria:

1) Bilateral vestibular schwan­nomas

2) Diagnosis of a family member with either NF2 or unilateral vestibular schwannoma, and

3) Juvenile posterior subscapular lens opacities.^9,12,13

Because schwannomas grow slowly, the vestibular system can adapt to the slow destruction of CN VIII. For this reason, patients typically present with unilateral deafness or hearing impairment rather than dizziness.¹¹ Many patients also present with tinnitus and/or vertigo.^14,15

Some vestibular tumors remain stable or even regress; others progress, in some cases causing life-threatening complications.¹⁶ An extremely rare complication of a vestibular schwannoma was reported in one patient: an intratumoral hemorrhage that led to acute neurologic deterioration and death.¹⁷

Since the case patient underwent immediate surgical intervention, it appears she was experiencing significant involvement and it was likely anticipated that without surgical intervention, clinical progression would occur. Her young age could be considered a risk factor for a faster-growing neuroma.¹⁸

Clinical Presentation and Diagnosis
Primary care clinicians commonly see patients with complaints of dizziness, lightheadedness, faintness, or a sensation of spinning or tilting. Vestibular schwannoma should be considered in the differential diagnosis of the patient who presents with these complaints, as well as tinnitus or hearing loss.⁹ The patient with vestibular schwannoma may also have a history of headache, unsteady gait, facial pain, and numbness.¹⁹ A partial differential diagnosis is listed in the table^20,21). The astute clinician will systematically rule out many of these conditions, since certain other features that may be present (eg, rapid onset, vomiting, fever) do not typically occur in the patient with vestibular schwannoma.

Because the symptoms typically associated with vestibular schwannoma are likely to occur bilaterally in patients with other conditions, unilateral symptoms should alert the clinician to investigate further. The patterns and growth rates of vestibular schwannomas are highly variable and currently unpredictable¹⁸ (according to Fortnum et al,¹⁴ at least 50% of tumors do not grow within several years after diagnosis); thus, no clear predictors of tumor growth have been identified to assist in the evaluation of an affected patient,¹⁶ although faster tumor growth rates have been reported in young patients, and Baser et al¹⁸ have called for additional research involving younger persons with vestibular schwannomas.

Standard testing is audiometry followed by MRI, which is considered the most effective means to confirm a diagnosis of vestibular schwannoma.^5,14,22

Treatment for Vestibular Schwannoma
Treatment, whether with surgery or radiation, is associated with significant morbidity and possibly decreased quality of life.¹⁶ Therefore, distinguishing patients whose tumors will grow and pose a threat to them from those whose tumors are likely to remain stable is central to appropriate management.²³

Treatment modalities are considered based on tumor size, growth, presence or absence of tinnitus, and the patient’s preferences and life expectancy.²³ In most cases, decision making is complex and should be customized to meet the patient’s individual circumstances. Patients with similar clinical scenarios have been reported to opt for different treatment choices.²⁴

Four treatment options are currently available for patients with vestibular schwannoma:

Serial observation with periodic MRI studies. Since vestibular schwannomas are benign and slow-growing, conservative manage­ment can be a reasonable option, particularly if the patient is elderly, the tumor is small, and/or little hearing loss has taken place. However, use of observation is associated with a risk for progressive and permanent hearing loss.² Between 15% and 50% of patients who opt for serial observation will undergo subsequent surgical intervention, particularly in cases involving worsening tinnitus, balance problems, or hearing loss.^23-25

Chemotherapy. Agents including bevacizumab (a humanized monoclonal antibody against vascular endothelial growth factor)^8,26,27 and erlotinib (an epidermal growth factor receptor inhibitor) may delay progression or even facilitate regression of vestibular schwannomas.²⁸ Hearing improvement has also been reported in patients with NF2 who were treated with bevacizumab⁸; research is ongoing.²⁶

Fractionated radiotherapy. Hearing may be preserved in 60% to 95% of patients, depending on levels of dosing to the cochlea, but 3% to 7% of patients will need further treatment.^29-31 Radiation treatment is a likely choice in patients with tumors measuring 2.0 cm or less. Larger tumors are considered a surgical disease, and directed radiotherapy may be administered postoperatively (as in the case patient) for residual portions of the tumor.¹⁶

Microsurgery. Compared with other treatment modalities, the emphasis of microsurgery is on removing tumors (particularly larger tumors) rather than controlling their growth.²⁹ The three common approaches are retrosigmoid, middle fossa, or translabyrinthine.^32-34 Preservation of hearing is reportedly better following retrosigmoid or middle fossa microsurgery, compared with a translabyrinthine procedure (because in the latter, the tumor cannot be exposed without damage to the inner ear).^32,35

With any such surgery, risks include cranial nerve damage, leakage of cerebrospinal fluid, and infection.^29,32 Postsurgically, about half of patients report frequent headaches, which are persistent in about half of these cases.^36-38 Another concern is preservation of the facial nerves, with a risk for temporary facial weakness or dysfunction.^3,24,39 Less than 2% of patients who undergo microsurgery require additional treatment.²⁹

Stereotactic radiosurgery. These procedures, which are performed using the Gamma Knife,^® the CyberKnife, or the linear accelerator,^29,40,41 are considered appropriate for patients with smaller tumors and those who are not candidates for conventional surgery.¹ Trigeminal neuropathy, injury to the facial nerves, and hydrocephaly are reported complications of Gamma Knife radiosurgery, but improvements in these technologies are ongoing.^1,2,40

Patient Outcomes
The outcome in a patient with vestibular schwannoma depends on the treatment administered, but prolonged follow-up is typically necessary. For patients being managed through observation, annual brain scans are recommended for 10 years, with subsequent scans every three to five years if no tumor growth is seen. For patients who have had surgery, annual brain scans are advised for the successive eight to 10 years, with decreasing frequency if no tumor remains. In patients who undergo radiation, annual scans are recommended for 10 years, then every two years if no tumor growth is detected.³⁶

Psychosocial experiences vary widely among patients who have undergone treatment for vestibular schwannomas. Some are unable to perform necessary or recreational activities, and others must retire early from work.⁴² Others, however, have minimal disruption in their lives and enjoy a good quality of life. The most difficult consequence of vestibular schwannoma and its treatment, according to patients, is the associated hearing loss.^8,19

THE CASE PATIENT
The 22-year-old patient in this case had an atypical presentation of vestibular schwannoma. Although she did present with vertigo, she also complained of headache, nausea, and photophobia—which are rarely reported in investigations of these tumors. She was also younger than the typical patient and did not report tinnitus.

The case patient reportedly underwent surgery and subsequent radiation to treat the remaining portion of her tumor. She suspended her attendance at the college and, as of this writing, has not re-enrolled. She was lost to follow-up.

CONCLUSION
For the primary care provider, diagnostic challenges require great clinical acumen. Vertigo, headache, hearing loss, and tinnitus are all symptoms seen in the primary care setting; when they occur together, the clinician should be alerted to investigate further. A high level of suspicion is appropriate when a patient complains of longstanding auditory symptoms, with or without headache. Unilateral hearing loss is a common symptom in patients with vestibular schwannomas, although some may present with facial weakness or pain, imbalance, and/or vertigo.

In addition to the history and physical exam, experts recommend that audiometry and MRI be considered, particularly if hearing loss is unilateral. Genetic screening for NF2 should be performed if vestibular schwannoma is found on MRI. Referral to a neurologist, a neurosurgeon, or an otolaryngologist is appropriate.

REFERENCES
1. Arthurs BJ, Lamoreaux WT, Giddings NA, et al. Gamma Knife radiosurgery for vestibular schwannoma: case report and review of the literature. World J Surg Oncol. 2009 Dec 18;7:100.

2. Mohammed TA, Ahuja MS, Ju SS, Thomas J. Normal pressure hydrocephalus after Gamma Knife radiosurgery for vestibular schwannoma. J Postgrad Med. 2010;56(3):213-215.

3. Gal TJ, Shinn J, Huang B. Current epidemiology and management trends in acoustic neuroma. Otolaryngol Head Neck Surg. 2010;142(5):677-681.

4. Evans DG, Moran A, King A, et al. Incidence of vestibular schwannoma and neurofibromatosis 2 in the North West of England over a 10-year period: higher incidence than previously thought. Otol Neurotol. 2005;26(1):93-97.

5. Haynes D. Acoustic neuroma diagnosis and treatment options. Hearing Health. 2009;25(3):32. www.drf.org/magazine/36/Summer+2009+Issue/article/272. Accessed May 16, 2011.

6. Sobel RA. Vestibular (acoustic) schwannomas: histologic features in neurofibromatosis 2 and in unilateral cases. J Neuropathol Exp Neurol. 1993;52(2):106-113.

7. Evans DG, Huson SM, Donnai D, et al. A clinical study of type 2 neurofibromatosis. Q J Med. 1992;84(304):603-618.

8. Plotkin SR, Stemmer-Rachamimov AO, Barker FG 2nd, et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med. 2009;361(4):358-367.

9. Evans DGR, Sainio M, Baser E. Neurofibromatosis type 2. J Med Genet. 2000:37(11):897-904.

10. Gusella JF, Ramesh V, MacCollin M, Jacoby LB. Neurofibromatosis 2: loss of Merlin’s protective spell. Curr Opin Genet Dev. 1996;6(1):87-92.

11. Sagar SM, Israel MA. Ch 374. Primary and metastatic tumors of the nervous system. In: Kasper DL, Braunwald E, Fauci AS, et al. Harrison’s Principles of Internal Medicine. 17th ed. New York, NY: McGraw-Hill Companies, Inc; 2008:2601-2610.

12. Evans DGR. Neurofibromatosis 2 [bilateral acoustic neurofibromatosis, central neurofibromatosis, NF2, neurofibromatosis type II]. Genet Med. 2009;11(9):599-610.

13. Arya R, Sahu JK, Kabra M. Neurofibromatosis type II (Wishart type). J Pediatr Neurol. 2009;7(3): 333-335.

14. Fortnum H, O’Neill C, Taylor R, et al. The role of magnetic resonance imaging in the identification of suspected acoustic neuroma: a systematic review of clinical and cost effectiveness and natural history. Health Technol Assess. 2009;13(18):iii-iv, ix-xi, 1-154.

15. Forton GE, Cremers CW, Offeciers EE. Acoustic neuroma ingrowth in the cochlear nerve: does it influence the clinical presentation? Ann Otol Rhinol Laryngol. 2004;113(7):582-586.

16. Nikolopoulos TP, Fortnum H, O’Donoghue G, Baguley D. Acoustic neuroma growth: a systematic review of the evidence. Otol Neurotol. 2010;31(3):478-485.

17. Yates CW, Weinberg M, Packer MJ, Jacob A. Fatal case of tumor-associated hemorrhage in a large vestibular schwannoma. Ann Otol Rhinol Laryngol. 2010;119(6):402-405.

18. Baser ME, Mautner VF, Parry DM, Evans DGR. Methodological issues in longitudinal studies; vestibular schwannoma growth rates in neurofibromatosis 2. J Med Genet. 2005;42(12):903-906.

19. Brooker J, Burney S, Fletcher J, Dally M. A qualitative exploration of quality of life among individuals diagnosed with an acoustic neuroma. Br J Health Psychol. 2009;14(pt 3):563-578.

20. Strupp M, Brandt T. Diagnosis and treatment of vertigo and dizziness. Dtsch Arzetbl Int. 2008;105(10):173-180.

21. Kerber KA. Dizziness and vertigo. In: Andreoli TE, Griggs RC, Benjamin I , Wing EJ, eds. Andreoli and Carpenter’s Cecil Essentials of Medicine. 8th ed. Philadelphia, PA: Elsevier Inc; 2010:1104-1105.

22. Gimsing S. Vestibular schwannoma: when to look for it? J Laryngol Otol. 2010;124(3):258-264.

23. Agrawal Y, Clark JH, Limb CJ, et al. Predictors of vestibular schwannoma growth and clinical implications. Otol Neurotol. 2010;31(5):807-812.

24. Cheung SW, Aranda D, Driscoll CLW, Parsa AT. Mapping clinical outcomes expectations to treatment decisions: an application to vestibular schwannoma management. Otol Neurotol. 2010;31(2):284-293.

25. Myrseth E, Pedersen PH, Møller P, Lund-Johansen M. Treatment of vestibular schwannomas: why, when and how? Acta Neurochir (Wien). 2007;149(7):647-660.

26. Sidney Kimmel Comprehensive Cancer Center, Massachusetts General Hospital, National Cancer Institute. Bevacizumab for symptomatic vestibular schwannoma in neurofibromatosis type 2 (NF2). http://clinicaltrials.gov/ct2/show/NCT01207687. Accessed May 16, 2011.

27. Mautner VF, Nguyen R, Kutta H, et al. Bevacizumab induces regression of vestibular schwannomas in patients with neurofibromatosis type 2. Neuro Oncol. 2010;12(1):14-18.

28. Plotkin SR, Halpin C, McKenna MJ, et al. Erlotinib for progressive vestibular schwannoma in neurofibromatosis 2 patients. Otol Neurotol. 2010;31(7):1135-1143.

29. Arthurs BJ, Fairbanks RK, Demakas JJ, et al. A review of treatment modalities for vestibular schwannoma. Neurosurg Rev. 2011 Feb 9; [Epub ahead of print].

30. Andrews DW, Werner-Wasik M, Den RB, et al. Toward dose optimization for fractionated stereotactic radiotherapy for acoustic neuromas: comparison of two dose cohorts. Int J Radiat Oncol Biol Phys. 2009;74(2):419-426.

31. Thomas C, Di Maio S, Ma R, et al. Hearing preservation following fractionated stereotactic radiotherapy for vestibular schwannomas: prognostic implications of cochlear dose. J Neurosurg. 2007;107(5):917-926.

32. Samii M, Gerganov V, Samii A. Improved preservation of hearing and facial nerve function in vestibular schwannoma surgery via the retrosigmoid approach in a series of 200 patients. J Neuro­surg. 2006;105(4):527-535.

33. Shiobara R, Ohira T, Inoue Y, et al. Extended middle cranial fossa approach for vestibular schwannoma: technical note and surgical results of 896 operations. Prog Neurol Surg. 2008;21:65-72.

34. Schmerber S, Palombi O, Boubagra K, et al. Long-term control of vestibular schwannoma after a translabyrinthine complete removal. Neurosurgery. 2005;57(4):693-698.

35. Phillips DJ, Kobylarz EJ, De Peralta ET, et al. Predictive factors of hearing preservation after surgical resection of small vestibular schwannomas. Otol Neurotol. 2010;31(9):1463-1468.

36. Park JK, Black MP, Vernick DM, Ramakrishna N. Vestibular schwannoma (acoustic neuroma) (2010). www.uptodate.com/contents/vestibular-schwannoma-acoustic-neuroma. Accessed May 16, 2011.

37. Schankin CJ, Gall C, Straube A. Headache syndromes after acoustic neuroma surgery and their implications for quality of life. Cephalalgia. 2009;29(7):760-761.

38. Ryzenman JM, Pensak ML, Tew JM Jr. Headache: a quality of life analysis in a cohort of 1,657 patients undergoing acoustic neuroma surgery: results from the Acoustic Neuroma Association. Laryngoscope. 2005;115(4):703-711.

39. Sriskandan N, Connor SE. The role of radiology in the diagnosis and management of vestibular schwannoma. Clin Radiol. 2010;66(4):357-365.

40. Yang I, Sughrue ME, Han SJ, et al. Facial nerve preservation after vestibular schwannoma Gamma Knife surgery. J Neurooncol. 2009;93(1): 41-48.

41. Unger F, Dominikus K, Haselsberger K. Stereotactic radiosurgery and fractionated stereotactic radiotherapy of acoustic neuromas [in German]. HNO. 2011;59(1):31-37.

42. Tos T, Caye-Thomasen P, Stangerup SE, et al. Long-term socio-economic impact of vestibular schwannoma for patients under observation and after surgery. J Laryngol Otol. 2003;117(12):955-964.

This issue includes a Priority Update from the Research Literature (PURL) that evaluates the results of 2 studies concerning PSA screening.^1,2 No sooner had this PURL been completed than The New England Journal of Medicine (NEJM) published the results of a randomized controlled trial of radical prostatectomy vs watchful waiting in early prostate cancer,^3- accompanied by an editorial titled, “Effective treatment for early-stage prostate cancer—possible, necessary, or both?”⁴ Meanwhile, we await the results of 2 trials being touted as definitive: the Prostate cancer Intervention Versus Observation Trial (PIVOT)⁵ and the Prostate testing for cancer and Treatment (ProtecT) trial.⁶

Keeping up with this area of practice is beginning to feel like a full-time job.

But I am going to go out on a limb here and suggest that, until we have fundamentally changed strategies for targeted case finding or early intervention (think genomic and proteomic markers), it is time to stop this screening nonsense. The facts speak for themselves: A trial of 182,000 patients finds in a post hoc analysis of a very narrow population that death can be averted in one of 723 individuals who are screened.² What about the complications associated with diagnosis, work-up, and treatment?

It is time for urologists and primary care physicians to tell patients that PSA screening is unlikely to benefit them.

Some of you will suggest that we counsel patients about PSA testing to facilitate informed decision-making. But do we advise patients to play the lottery or try futile therapies?

The only men who stand to get even a small benefit from PSA screening are those in excellent health, and it is pretty darn hard to improve on that. I urge all of us to stop offering routine PSA testing and, when asked, to advise against this risky intervention.

This issue includes a Priority Update from the Research Literature (PURL) that evaluates the results of 2 studies concerning PSA screening.^1,2 No sooner had this PURL been completed than The New England Journal of Medicine (NEJM) published the results of a randomized controlled trial of radical prostatectomy vs watchful waiting in early prostate cancer,^3- accompanied by an editorial titled, “Effective treatment for early-stage prostate cancer—possible, necessary, or both?”⁴ Meanwhile, we await the results of 2 trials being touted as definitive: the Prostate cancer Intervention Versus Observation Trial (PIVOT)⁵ and the Prostate testing for cancer and Treatment (ProtecT) trial.⁶

Keeping up with this area of practice is beginning to feel like a full-time job.

But I am going to go out on a limb here and suggest that, until we have fundamentally changed strategies for targeted case finding or early intervention (think genomic and proteomic markers), it is time to stop this screening nonsense. The facts speak for themselves: A trial of 182,000 patients finds in a post hoc analysis of a very narrow population that death can be averted in one of 723 individuals who are screened.² What about the complications associated with diagnosis, work-up, and treatment?

It is time for urologists and primary care physicians to tell patients that PSA screening is unlikely to benefit them.

Some of you will suggest that we counsel patients about PSA testing to facilitate informed decision-making. But do we advise patients to play the lottery or try futile therapies?

The only men who stand to get even a small benefit from PSA screening are those in excellent health, and it is pretty darn hard to improve on that. I urge all of us to stop offering routine PSA testing and, when asked, to advise against this risky intervention.

This issue includes a Priority Update from the Research Literature (PURL) that evaluates the results of 2 studies concerning PSA screening.^1,2 No sooner had this PURL been completed than The New England Journal of Medicine (NEJM) published the results of a randomized controlled trial of radical prostatectomy vs watchful waiting in early prostate cancer,^3- accompanied by an editorial titled, “Effective treatment for early-stage prostate cancer—possible, necessary, or both?”⁴ Meanwhile, we await the results of 2 trials being touted as definitive: the Prostate cancer Intervention Versus Observation Trial (PIVOT)⁵ and the Prostate testing for cancer and Treatment (ProtecT) trial.⁶

Keeping up with this area of practice is beginning to feel like a full-time job.

But I am going to go out on a limb here and suggest that, until we have fundamentally changed strategies for targeted case finding or early intervention (think genomic and proteomic markers), it is time to stop this screening nonsense. The facts speak for themselves: A trial of 182,000 patients finds in a post hoc analysis of a very narrow population that death can be averted in one of 723 individuals who are screened.² What about the complications associated with diagnosis, work-up, and treatment?

It is time for urologists and primary care physicians to tell patients that PSA screening is unlikely to benefit them.

Some of you will suggest that we counsel patients about PSA testing to facilitate informed decision-making. But do we advise patients to play the lottery or try futile therapies?

The only men who stand to get even a small benefit from PSA screening are those in excellent health, and it is pretty darn hard to improve on that. I urge all of us to stop offering routine PSA testing and, when asked, to advise against this risky intervention.

ILLUSTRATIVE CASES

A 65-year-old obese man with high blood pressure comes in for a complete physical and asks if he should have the “blood test for cancer.” He had a normal prostate specific antigen (PSA) the last time he was tested, but that was 10 years ago. What should you tell him?

A 55-year-old man schedules a routine check-up and requests a PSA test. His last test, at age 50, was normal. The patient has no known medical problems and no family history of prostate cancer, and he exercises regularly and doesn’t smoke. How should you respond to his request for a PSA test?

Prostate cancer is the second leading cause of cancer deaths among men in the United States, after lung cancer. One in 6 American men will be diagnosed with prostate cancer; for about 3% of them, the cancer will be fatal.^3,4

Widespread testing without evidence of efficacy
The PSA test was approved by the US Food and Drug Administration (FDA) in 1986.⁵ Its potential to detect early prostate cancer in the hope of decreasing morbidity and mortality led to widespread PSA screening in the 1990s, before data on the efficacy of routine screening existed.

By 2002, only one low-quality RCT that compared screening with no screening had been published. The investigators concluded that screening resulted in lower mortality rates, but a subsequent (and superior) intention-to-treat analysis showed no mortality benefit.⁶ Two large RCTs, both published in 2009, reported conflicting results.^7,8

The European Randomized Study of Screening for Prostate Cancer (ERSPC) enrolled 182,000 men ages 50 to 74 years and randomized them to either PSA screening every 4 years or no screening. Prostate cancer-specific mortality was 20% lower for those in the screening group compared with the no-screening group; however, the absolute risk reduction was only 0.71 deaths per 1000 men.⁷

The US Prostate, Lung, Colorectal, Ovarian Cancer (PLCO) Screening Trial randomized 77,000 men ages 55 to 74 years to either annual PSA and digital rectal examination (DRE) screening or usual care. After 7 years of follow-up, no significant difference was found in prostate cancer deaths or all-cause mortality in the screening group vs the control group. It is important to note, however, that 52% of the men in the control group had ≥1 PSA screening during the study period, which decreased the researchers’ ability to fully assess the benefits of screening.⁸

PSA’s limitations and potential harmful effects
The PSA test’s significant limitations and potentially harmful effects counter the potential benefits of screening. About 75% of positive tests are false positives, which are associated with psychological harm in some men for up to a year after the test.⁶ In addition, diagnostic testing and treatment for what may be nonlife-threatening prostate cancer can cause harm, including erectile dysfunction (ED), urinary incontinence, bowel dysfunction, and death. Rates of ED and incontinence 18 months after radical prostatectomy are an estimated 59.9% and 8.4%, respectively.⁹

Do the benefits of PSA testing outweigh the harms—and for which men? The meta-analysis and post hoc analysis detailed in this PURL help clear up the controversy.

STUDY SUMMARY: Widespread screening doesn’t save lives

Djulbegovic et al examined 6 RCTs, including the ERSPC and PLCO studies described earlier, that compared screening for prostate cancer (PSA with or without DRE) with no screening or usual care.¹ Together, the studies included nearly 390,000 men ages 45 to 80 years, and had 4 to 15 years of follow-up. The results showed that routine screening for prostate cancer had no statistically significant effect on all-cause mortality (relative risk [RR]=0.99; 95% confidence interval [CI], 0.97-1.01), death from prostate cancer (RR=0.88; 95% CI, 0.71-1.09), or diagnosis of stage III or IV prostate cancer (RR=0.94; 95% CI, 0.85-1.04). Routine screening did, however, increase the probability of being diagnosed with prostate cancer at any stage, especially at stage I. For every 1000 men screened, on average, 20 more cases of prostate cancer were diagnosed.

Healthy men may benefit from screening
Crawford et al conducted a post hoc analysis of the PLCO trial, which had found no benefit to annual PSA testing and serial DRE compared with usual care for the general population.² Their analysis compared the mortality benefits (both prostate cancer–specific and overall) of annual PSA screening for healthy men with no or minimal comorbidities vs the mortality benefits for men with any risk factor for the 2 leading causes of death: cancer and cardiovascular disease.

Annual PSA testing yielded more diagnoses of prostate cancer in both healthy and at-risk men. Deaths from prostate cancer were infrequent in both groups, occurring in 0.22% (164/73,378) of all participants.

Men with ≥1 risk factor had similar prostate cancer–specific deaths with both yearly screening and usual care (62 vs 42 deaths, adjusted hazard ratio [AHR]=1.43; 95% CI, 0.96-2.11); their prostate cancer–specific mortality rate was 0.27% (95% CI, 0.21-0.34) and 0.19% (95% CI, 0.14-0.25), respectively.

However, healthy men younger than 75 years had fewer prostate cancer–specific deaths with annual PSA screenings (22 vs 38; AHR=0.56; 95% CI, 0.33-0.95; P=.03). Specifically, the prostate cancer mortality rate was 0.17% (95% CI, 0.11-0.25) in the group that received screening vs 0.31% (95% CI, 0.22-0.42) in the usual care group. Thus, the absolute risk reduction for prostate cancer-specific mortality in men without comorbidities who received yearly screening instead of usual care was 0.14% (0.31% vs 0.17%, P=.03), with a number needed to screen of 723 to prevent one death from prostate cancer. There was a non-significant reduction in all-cause mortality in the intervention group vs the control group (AHR=0.93; 95% CI, 0.86-1.02; P=.11).

WHAT’S NEW: At best, screening has a small benefit

These trials indicate that only a small group of men will potentially benefit from PSA screening. Prior to this meta-analysis, a Cochrane review published in 2006 had concluded that there was insufficient evidence to support or refute the routine use of mass screening for prostate can-cer.¹⁰ The meta-analysis by Djulbegovic et al, which included 4 additional trials, 2 of them large, found no benefit of PSA screening in reducing mortality from prostate cancer for the general population.¹

Annual screening does appear to provide a small reduction in prostate cancer deaths but no significant reduction in all-cause mortality in men younger than age 75 who have no risk factors for cancer or cardiovascular disease.

CAVEATS: Study limitations, some unknowns

These studies did not address whether certain groups at higher risk of developing prostate cancer, such as African American men and those with a family history of prostate cancer, would benefit from PSA screening. In addition, both of the studies detailed in this PURL had substantive weaknesses.

Methodological limitations of the studies in the meta-analysis included the lack of intention-to-treat analysis and allocation concealment, which favors finding a benefit for the screening arm, and PSA screening in the nonscreening arm, which biases the results toward not finding a screening benefit that might exist. Despite these weaknesses, this meta-analysis brings together the best available evidence of the value of screening for prostate cancer.

In addition, there was no quantitative assessment of complication rates included in the meta-analysis. None of the 6 trials collected data on the effect of screening or treatment on participants’ quality of life.

In the post hoc study showing a benefit for screening healthy men, the decrease in prostate cancer deaths was small in magnitude, did not have an impact on all-cause mortality, and was of marginal statistical significance. Although the data came from the largest multicenter study to date of prostate cancer screening, the results of a post hoc analysis of a single trial should be interpreted with caution. The study was initially designed to test the effect of screening on a general population. Whenever a study deviates from the original hypothesis to evaluate a subset of the study population, the investigators increase the risk of finding a difference where none exists. Thus, it is possible that the findings of benefit for healthy men may not truly be present.

What’s more, the risk factors identified by the authors could be interpreted as arbitrary. They included diverticulosis, which is not known to increase the likelihood of cancer or heart disease, as a risk factor. By the same token, smoking—a known risk factor for both cancer and cardiovascular disease—was not addressed. Finally, potential harms associated with false-positive tests and prostate cancer treatment were not addressed in these studies.

CHALLENGES TO IMPLEMENTATION: Old habits die hard

Clinicians have recommended PSA screening for men >50 years, and men have requested such screening, for more than 2 decades. Physicians often opt to order a PSA test rather than to take the time to explain potential harms and benefits and listen to the patient’s thoughts and feelings about the value of screening. In addition, physicians who believe the lack of benefit from screening does not apply to their patients will continue to order the PSA test. (See “The perils of PSA screening”.)

Patients may opt to continue to be screened although they have developed a risk factor for cardiovascular disease. Also, a decision not to screen directly contradicts the recommendation of the American Urological Association, which calls for annual PSA testing for asymptomatic men with a life expectancy >10 years starting at 40 years of age.¹¹

Shared decision-making
The US Preventive Services Task Force (USPSTF) provides a basis for shared decision-making between physicians and patients concerning prostate cancer screening. The USPSTF states that there is insufficient evidence to recommend for or against prostate cancer screening for the general male population younger than age 75 and recommends against screening men age 75 and older or those with a life expectancy of less than 10 years.¹²

Decisions regarding PSA screening should be shared and documented for all men between the ages of 50 and 75 years. Advise patients with risk factors that the evidence shows little value and possible harm from screening. Tell healthier men that PSA testing appears to offer a small benefit, at best.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources; the grant is a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASES

A 65-year-old obese man with high blood pressure comes in for a complete physical and asks if he should have the “blood test for cancer.” He had a normal prostate specific antigen (PSA) the last time he was tested, but that was 10 years ago. What should you tell him?

A 55-year-old man schedules a routine check-up and requests a PSA test. His last test, at age 50, was normal. The patient has no known medical problems and no family history of prostate cancer, and he exercises regularly and doesn’t smoke. How should you respond to his request for a PSA test?

Prostate cancer is the second leading cause of cancer deaths among men in the United States, after lung cancer. One in 6 American men will be diagnosed with prostate cancer; for about 3% of them, the cancer will be fatal.^3,4

Widespread testing without evidence of efficacy
The PSA test was approved by the US Food and Drug Administration (FDA) in 1986.⁵ Its potential to detect early prostate cancer in the hope of decreasing morbidity and mortality led to widespread PSA screening in the 1990s, before data on the efficacy of routine screening existed.

By 2002, only one low-quality RCT that compared screening with no screening had been published. The investigators concluded that screening resulted in lower mortality rates, but a subsequent (and superior) intention-to-treat analysis showed no mortality benefit.⁶ Two large RCTs, both published in 2009, reported conflicting results.^7,8

The European Randomized Study of Screening for Prostate Cancer (ERSPC) enrolled 182,000 men ages 50 to 74 years and randomized them to either PSA screening every 4 years or no screening. Prostate cancer-specific mortality was 20% lower for those in the screening group compared with the no-screening group; however, the absolute risk reduction was only 0.71 deaths per 1000 men.⁷

The US Prostate, Lung, Colorectal, Ovarian Cancer (PLCO) Screening Trial randomized 77,000 men ages 55 to 74 years to either annual PSA and digital rectal examination (DRE) screening or usual care. After 7 years of follow-up, no significant difference was found in prostate cancer deaths or all-cause mortality in the screening group vs the control group. It is important to note, however, that 52% of the men in the control group had ≥1 PSA screening during the study period, which decreased the researchers’ ability to fully assess the benefits of screening.⁸

PSA’s limitations and potential harmful effects
The PSA test’s significant limitations and potentially harmful effects counter the potential benefits of screening. About 75% of positive tests are false positives, which are associated with psychological harm in some men for up to a year after the test.⁶ In addition, diagnostic testing and treatment for what may be nonlife-threatening prostate cancer can cause harm, including erectile dysfunction (ED), urinary incontinence, bowel dysfunction, and death. Rates of ED and incontinence 18 months after radical prostatectomy are an estimated 59.9% and 8.4%, respectively.⁹

Do the benefits of PSA testing outweigh the harms—and for which men? The meta-analysis and post hoc analysis detailed in this PURL help clear up the controversy.

STUDY SUMMARY: Widespread screening doesn’t save lives

Djulbegovic et al examined 6 RCTs, including the ERSPC and PLCO studies described earlier, that compared screening for prostate cancer (PSA with or without DRE) with no screening or usual care.¹ Together, the studies included nearly 390,000 men ages 45 to 80 years, and had 4 to 15 years of follow-up. The results showed that routine screening for prostate cancer had no statistically significant effect on all-cause mortality (relative risk [RR]=0.99; 95% confidence interval [CI], 0.97-1.01), death from prostate cancer (RR=0.88; 95% CI, 0.71-1.09), or diagnosis of stage III or IV prostate cancer (RR=0.94; 95% CI, 0.85-1.04). Routine screening did, however, increase the probability of being diagnosed with prostate cancer at any stage, especially at stage I. For every 1000 men screened, on average, 20 more cases of prostate cancer were diagnosed.

Healthy men may benefit from screening
Crawford et al conducted a post hoc analysis of the PLCO trial, which had found no benefit to annual PSA testing and serial DRE compared with usual care for the general population.² Their analysis compared the mortality benefits (both prostate cancer–specific and overall) of annual PSA screening for healthy men with no or minimal comorbidities vs the mortality benefits for men with any risk factor for the 2 leading causes of death: cancer and cardiovascular disease.

Annual PSA testing yielded more diagnoses of prostate cancer in both healthy and at-risk men. Deaths from prostate cancer were infrequent in both groups, occurring in 0.22% (164/73,378) of all participants.

Men with ≥1 risk factor had similar prostate cancer–specific deaths with both yearly screening and usual care (62 vs 42 deaths, adjusted hazard ratio [AHR]=1.43; 95% CI, 0.96-2.11); their prostate cancer–specific mortality rate was 0.27% (95% CI, 0.21-0.34) and 0.19% (95% CI, 0.14-0.25), respectively.

However, healthy men younger than 75 years had fewer prostate cancer–specific deaths with annual PSA screenings (22 vs 38; AHR=0.56; 95% CI, 0.33-0.95; P=.03). Specifically, the prostate cancer mortality rate was 0.17% (95% CI, 0.11-0.25) in the group that received screening vs 0.31% (95% CI, 0.22-0.42) in the usual care group. Thus, the absolute risk reduction for prostate cancer-specific mortality in men without comorbidities who received yearly screening instead of usual care was 0.14% (0.31% vs 0.17%, P=.03), with a number needed to screen of 723 to prevent one death from prostate cancer. There was a non-significant reduction in all-cause mortality in the intervention group vs the control group (AHR=0.93; 95% CI, 0.86-1.02; P=.11).

WHAT’S NEW: At best, screening has a small benefit

These trials indicate that only a small group of men will potentially benefit from PSA screening. Prior to this meta-analysis, a Cochrane review published in 2006 had concluded that there was insufficient evidence to support or refute the routine use of mass screening for prostate can-cer.¹⁰ The meta-analysis by Djulbegovic et al, which included 4 additional trials, 2 of them large, found no benefit of PSA screening in reducing mortality from prostate cancer for the general population.¹

Annual screening does appear to provide a small reduction in prostate cancer deaths but no significant reduction in all-cause mortality in men younger than age 75 who have no risk factors for cancer or cardiovascular disease.

CAVEATS: Study limitations, some unknowns

These studies did not address whether certain groups at higher risk of developing prostate cancer, such as African American men and those with a family history of prostate cancer, would benefit from PSA screening. In addition, both of the studies detailed in this PURL had substantive weaknesses.

Methodological limitations of the studies in the meta-analysis included the lack of intention-to-treat analysis and allocation concealment, which favors finding a benefit for the screening arm, and PSA screening in the nonscreening arm, which biases the results toward not finding a screening benefit that might exist. Despite these weaknesses, this meta-analysis brings together the best available evidence of the value of screening for prostate cancer.

In addition, there was no quantitative assessment of complication rates included in the meta-analysis. None of the 6 trials collected data on the effect of screening or treatment on participants’ quality of life.

In the post hoc study showing a benefit for screening healthy men, the decrease in prostate cancer deaths was small in magnitude, did not have an impact on all-cause mortality, and was of marginal statistical significance. Although the data came from the largest multicenter study to date of prostate cancer screening, the results of a post hoc analysis of a single trial should be interpreted with caution. The study was initially designed to test the effect of screening on a general population. Whenever a study deviates from the original hypothesis to evaluate a subset of the study population, the investigators increase the risk of finding a difference where none exists. Thus, it is possible that the findings of benefit for healthy men may not truly be present.

What’s more, the risk factors identified by the authors could be interpreted as arbitrary. They included diverticulosis, which is not known to increase the likelihood of cancer or heart disease, as a risk factor. By the same token, smoking—a known risk factor for both cancer and cardiovascular disease—was not addressed. Finally, potential harms associated with false-positive tests and prostate cancer treatment were not addressed in these studies.

CHALLENGES TO IMPLEMENTATION: Old habits die hard

Clinicians have recommended PSA screening for men >50 years, and men have requested such screening, for more than 2 decades. Physicians often opt to order a PSA test rather than to take the time to explain potential harms and benefits and listen to the patient’s thoughts and feelings about the value of screening. In addition, physicians who believe the lack of benefit from screening does not apply to their patients will continue to order the PSA test. (See “The perils of PSA screening”.)

Patients may opt to continue to be screened although they have developed a risk factor for cardiovascular disease. Also, a decision not to screen directly contradicts the recommendation of the American Urological Association, which calls for annual PSA testing for asymptomatic men with a life expectancy >10 years starting at 40 years of age.¹¹

Shared decision-making
The US Preventive Services Task Force (USPSTF) provides a basis for shared decision-making between physicians and patients concerning prostate cancer screening. The USPSTF states that there is insufficient evidence to recommend for or against prostate cancer screening for the general male population younger than age 75 and recommends against screening men age 75 and older or those with a life expectancy of less than 10 years.¹²

Decisions regarding PSA screening should be shared and documented for all men between the ages of 50 and 75 years. Advise patients with risk factors that the evidence shows little value and possible harm from screening. Tell healthier men that PSA testing appears to offer a small benefit, at best.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources; the grant is a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASES

A 65-year-old obese man with high blood pressure comes in for a complete physical and asks if he should have the “blood test for cancer.” He had a normal prostate specific antigen (PSA) the last time he was tested, but that was 10 years ago. What should you tell him?

A 55-year-old man schedules a routine check-up and requests a PSA test. His last test, at age 50, was normal. The patient has no known medical problems and no family history of prostate cancer, and he exercises regularly and doesn’t smoke. How should you respond to his request for a PSA test?

Prostate cancer is the second leading cause of cancer deaths among men in the United States, after lung cancer. One in 6 American men will be diagnosed with prostate cancer; for about 3% of them, the cancer will be fatal.^3,4

Widespread testing without evidence of efficacy
The PSA test was approved by the US Food and Drug Administration (FDA) in 1986.⁵ Its potential to detect early prostate cancer in the hope of decreasing morbidity and mortality led to widespread PSA screening in the 1990s, before data on the efficacy of routine screening existed.

By 2002, only one low-quality RCT that compared screening with no screening had been published. The investigators concluded that screening resulted in lower mortality rates, but a subsequent (and superior) intention-to-treat analysis showed no mortality benefit.⁶ Two large RCTs, both published in 2009, reported conflicting results.^7,8

The European Randomized Study of Screening for Prostate Cancer (ERSPC) enrolled 182,000 men ages 50 to 74 years and randomized them to either PSA screening every 4 years or no screening. Prostate cancer-specific mortality was 20% lower for those in the screening group compared with the no-screening group; however, the absolute risk reduction was only 0.71 deaths per 1000 men.⁷

The US Prostate, Lung, Colorectal, Ovarian Cancer (PLCO) Screening Trial randomized 77,000 men ages 55 to 74 years to either annual PSA and digital rectal examination (DRE) screening or usual care. After 7 years of follow-up, no significant difference was found in prostate cancer deaths or all-cause mortality in the screening group vs the control group. It is important to note, however, that 52% of the men in the control group had ≥1 PSA screening during the study period, which decreased the researchers’ ability to fully assess the benefits of screening.⁸

PSA’s limitations and potential harmful effects
The PSA test’s significant limitations and potentially harmful effects counter the potential benefits of screening. About 75% of positive tests are false positives, which are associated with psychological harm in some men for up to a year after the test.⁶ In addition, diagnostic testing and treatment for what may be nonlife-threatening prostate cancer can cause harm, including erectile dysfunction (ED), urinary incontinence, bowel dysfunction, and death. Rates of ED and incontinence 18 months after radical prostatectomy are an estimated 59.9% and 8.4%, respectively.⁹

Do the benefits of PSA testing outweigh the harms—and for which men? The meta-analysis and post hoc analysis detailed in this PURL help clear up the controversy.

STUDY SUMMARY: Widespread screening doesn’t save lives

Djulbegovic et al examined 6 RCTs, including the ERSPC and PLCO studies described earlier, that compared screening for prostate cancer (PSA with or without DRE) with no screening or usual care.¹ Together, the studies included nearly 390,000 men ages 45 to 80 years, and had 4 to 15 years of follow-up. The results showed that routine screening for prostate cancer had no statistically significant effect on all-cause mortality (relative risk [RR]=0.99; 95% confidence interval [CI], 0.97-1.01), death from prostate cancer (RR=0.88; 95% CI, 0.71-1.09), or diagnosis of stage III or IV prostate cancer (RR=0.94; 95% CI, 0.85-1.04). Routine screening did, however, increase the probability of being diagnosed with prostate cancer at any stage, especially at stage I. For every 1000 men screened, on average, 20 more cases of prostate cancer were diagnosed.

Healthy men may benefit from screening
Crawford et al conducted a post hoc analysis of the PLCO trial, which had found no benefit to annual PSA testing and serial DRE compared with usual care for the general population.² Their analysis compared the mortality benefits (both prostate cancer–specific and overall) of annual PSA screening for healthy men with no or minimal comorbidities vs the mortality benefits for men with any risk factor for the 2 leading causes of death: cancer and cardiovascular disease.

Annual PSA testing yielded more diagnoses of prostate cancer in both healthy and at-risk men. Deaths from prostate cancer were infrequent in both groups, occurring in 0.22% (164/73,378) of all participants.

Men with ≥1 risk factor had similar prostate cancer–specific deaths with both yearly screening and usual care (62 vs 42 deaths, adjusted hazard ratio [AHR]=1.43; 95% CI, 0.96-2.11); their prostate cancer–specific mortality rate was 0.27% (95% CI, 0.21-0.34) and 0.19% (95% CI, 0.14-0.25), respectively.

However, healthy men younger than 75 years had fewer prostate cancer–specific deaths with annual PSA screenings (22 vs 38; AHR=0.56; 95% CI, 0.33-0.95; P=.03). Specifically, the prostate cancer mortality rate was 0.17% (95% CI, 0.11-0.25) in the group that received screening vs 0.31% (95% CI, 0.22-0.42) in the usual care group. Thus, the absolute risk reduction for prostate cancer-specific mortality in men without comorbidities who received yearly screening instead of usual care was 0.14% (0.31% vs 0.17%, P=.03), with a number needed to screen of 723 to prevent one death from prostate cancer. There was a non-significant reduction in all-cause mortality in the intervention group vs the control group (AHR=0.93; 95% CI, 0.86-1.02; P=.11).

WHAT’S NEW: At best, screening has a small benefit

These trials indicate that only a small group of men will potentially benefit from PSA screening. Prior to this meta-analysis, a Cochrane review published in 2006 had concluded that there was insufficient evidence to support or refute the routine use of mass screening for prostate can-cer.¹⁰ The meta-analysis by Djulbegovic et al, which included 4 additional trials, 2 of them large, found no benefit of PSA screening in reducing mortality from prostate cancer for the general population.¹

Annual screening does appear to provide a small reduction in prostate cancer deaths but no significant reduction in all-cause mortality in men younger than age 75 who have no risk factors for cancer or cardiovascular disease.

CAVEATS: Study limitations, some unknowns

These studies did not address whether certain groups at higher risk of developing prostate cancer, such as African American men and those with a family history of prostate cancer, would benefit from PSA screening. In addition, both of the studies detailed in this PURL had substantive weaknesses.

Methodological limitations of the studies in the meta-analysis included the lack of intention-to-treat analysis and allocation concealment, which favors finding a benefit for the screening arm, and PSA screening in the nonscreening arm, which biases the results toward not finding a screening benefit that might exist. Despite these weaknesses, this meta-analysis brings together the best available evidence of the value of screening for prostate cancer.

In addition, there was no quantitative assessment of complication rates included in the meta-analysis. None of the 6 trials collected data on the effect of screening or treatment on participants’ quality of life.

In the post hoc study showing a benefit for screening healthy men, the decrease in prostate cancer deaths was small in magnitude, did not have an impact on all-cause mortality, and was of marginal statistical significance. Although the data came from the largest multicenter study to date of prostate cancer screening, the results of a post hoc analysis of a single trial should be interpreted with caution. The study was initially designed to test the effect of screening on a general population. Whenever a study deviates from the original hypothesis to evaluate a subset of the study population, the investigators increase the risk of finding a difference where none exists. Thus, it is possible that the findings of benefit for healthy men may not truly be present.

What’s more, the risk factors identified by the authors could be interpreted as arbitrary. They included diverticulosis, which is not known to increase the likelihood of cancer or heart disease, as a risk factor. By the same token, smoking—a known risk factor for both cancer and cardiovascular disease—was not addressed. Finally, potential harms associated with false-positive tests and prostate cancer treatment were not addressed in these studies.

CHALLENGES TO IMPLEMENTATION: Old habits die hard

Clinicians have recommended PSA screening for men >50 years, and men have requested such screening, for more than 2 decades. Physicians often opt to order a PSA test rather than to take the time to explain potential harms and benefits and listen to the patient’s thoughts and feelings about the value of screening. In addition, physicians who believe the lack of benefit from screening does not apply to their patients will continue to order the PSA test. (See “The perils of PSA screening”.)

Patients may opt to continue to be screened although they have developed a risk factor for cardiovascular disease. Also, a decision not to screen directly contradicts the recommendation of the American Urological Association, which calls for annual PSA testing for asymptomatic men with a life expectancy >10 years starting at 40 years of age.¹¹

Shared decision-making
The US Preventive Services Task Force (USPSTF) provides a basis for shared decision-making between physicians and patients concerning prostate cancer screening. The USPSTF states that there is insufficient evidence to recommend for or against prostate cancer screening for the general male population younger than age 75 and recommends against screening men age 75 and older or those with a life expectancy of less than 10 years.¹²

Decisions regarding PSA screening should be shared and documented for all men between the ages of 50 and 75 years. Advise patients with risk factors that the evidence shows little value and possible harm from screening. Tell healthier men that PSA testing appears to offer a small benefit, at best.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources; the grant is a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.