Case 10-2018: an 84-Year-Old Man with Painless Unilateral Testicular Swelling

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Case Records of the Massachusetts General Hospital

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Case 10-2018: An 84-Year-Old Man with Painless Unilateral Testicular Swelling

Ryan W. Thompson, M.D., HeiShun Yu, M.D., Douglas M. Dahl, M.D., Rocio M. Hurtado, M.D., and Dipti P. Sajed, M.D., Ph.D.

Presentation of Case

Dr. Michael S. Abers (Medicine): An 84-year-old man was evaluated at this hospital From the Departments of Medicine (R.W.T.), because of painless right testicular swelling. Radiology (H.Y.), Urology (D.M.D.), and Pathology (D.P.S.), Massachusetts Gen‑ The patient had been in his usual state of health until 6 weeks before this eral Hospital, and the Departments of evaluation, when he noted while showering that the right testicle was approxi- Medicine (R.W.T., R.M.H.), Radiology mately 3 times larger than the left testicle. The testicle was soft and nontender on (H.Y.), Urology (D.M.D.), and Pathology (D.P.S.), Harvard Medical School — both palpation, and the enlargement had not been present the previous day. in Boston. The next day, the patient was evaluated at a local urgent care clinic. He re- N Engl J Med 2018;378:1233-40. ported no trauma, heavy lifting, recent sexual intercourse, testicular or scrotal DOI: 10.1056/NEJMcpc1712224 pain, abdominal or back pain, skin changes or rash, obstructive urinary symp- Copyright © 2018 Massachusetts Medical Society. toms, hematuria or dysuria, or discharge. He had no constitutional symptoms, such as fever, night sweats, or weight loss. On examination, the right testicle had a large, soft, mobile posterior mass; the left testicle was normal. A presumptive diagnosis of a hydrocele was made, and the patient was advised to use scrotal support and, if pain occurred, to take nonsteroidal antiinflammatory drugs. Tes- ticular ultrasonography was scheduled for the following day. Dr. HeiShun Yu: The next day, ultrasonography (Fig. 1) revealed marked asymmetric enlargement and hypervascularity of the right testicle. A hypoechoic region in the mediastinum testis was most likely related to edema due to infection or inflammation. The epididymis was also enlarged and hypervascular. An associated complex hydrocele, with septations and internal debris, was present on the right side. These findings were compatible with right epididymo-orchitis. The left testicle had normal echotexture and no focal lesion. There was an incidental left varicocele. Dr. Abers: A 10-day course of oral levofloxacin was prescribed. Six weeks later, at a follow-up visit with his primary care physician, the patient reported persistent testicular swelling. He noted that there had been a mild decrease in the swelling after he had completed the levofloxacin course but that the testicle continued to

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A B

C D

Figure 1. Initial Ultrasound Images. A transverse ultrasound image of the scrotum shows asymmetric enlargement and edema of the right testicle (Panel A, arrow), and a corresponding color Doppler image shows asymmetric hypervascularity of the right testicle (Panel B, arrow). A sagittal ultrasound image of the right hemiscrotum shows enlargement of the right epididymis (Panel C, arrow), and a corresponding color Doppler image shows diffuse hypervascularity of the right testicle and epididymis (Panel D).

enlarge thereafter, causing inconvenience owing of age. He was a retired health care professional; to its bulk and the pressure in the right groin, he reported that he had had at least one negative which made it difficult for him to sit and to flex tuberculin skin test in the past. More than 40 his upper leg. There were no additional symp- years earlier, he had smoked cigarettes for 5 years; toms, such as pain or fever. he did not consume alcohol or use illicit drugs. The patient had long-standing benign pros- He had traveled to Canada, Western Europe, and tatic hypertrophy with associated nocturia, as the Caribbean in the past. His mother had died well as Raynaud’s phenomenon, mild normo- in her 70s after a stroke, his father had lived cytic anemia, peptic ulcer disease, colonic diver- beyond 90 years of age, a brother had prostatic ticulosis, hypercholesterolemia, hearing loss, and hypertrophy, and a sister had multiple sclerosis. cataracts. An episode of syncope had occurred There was no family history of cancer. after exercise on a hot and humid day 3 years On examination, the patient appeared well. The earlier, and he had undergone left inguinal herni- temperature was 36.3°C, the heart rate 54 beats orrhaphy with mesh placement 13 years earlier. per minute, the blood pressure 119/64 mm Hg, Medications were aspirin, omeprazole, tamsulo- and the oxygen saturation 98% while he was sin, finasteride, nifedipine as needed for symp- breathing ambient air. The weight was 72.3 kg, toms of Raynaud’s phenomenon, and pravastatin. and the body-mass index (the weight in kilograms The patient had no known allergies. He per- divided by the square of the height in meters) formed aerobic exercise daily. He was married, 28.3. A firm, nontender right scrotal mass (7 cm had no children, and had immigrated to the in diameter) was located in the posterior region, United States from Turkey when he was 20 years protruding superiorly to the external inguinal

1234 n engl j med 378;13 nejm.org March 29, 2018 The New England Journal of Medicine Downloaded from nejm.org by MARK LITWIN on April 10, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved. Case Records of the Massachusetts General Hospital ring. The mass transmitted light on transillumi- of testicular loss due to torsion or systemic nation. The scrotal skin was normal, with no spread of infection, they are unlikely diagnoses erythema or peau d’orange (orange peel) changes. in this case, given the patient’s gradual onset The left testicle had changes consistent with a of symptoms and the absence of pain on pre- varicocele. The prostate was small and benign sentation. on palpation. There was no inguinal lymphade- nopathy. The remainder of the examination was Hernia and Hydrocele normal. Urinalysis showed yellow, clear urine, Common causes of painless testicular enlarge- with a specific gravity of 1.011 (reference range, ment in elderly men include hydrocele, varico- 1.001 to 1.035), a pH of 6.0 (reference range, 5.0 cele, and inguinoscrotal hernia. Assessment for to 9.0), and no evidence of leukocyte esterase or a hernia can easily be performed on physical occult blood. A culture of the urine was sterile. examination. Although this patient had previ- Dr. Yu: Repeat testicular ultrasonography (Fig. 2) ously undergone a left inguinal hernia repair, a revealed further enlargement of the right testi- hernia on the right side was a consideration. cle. The right testicular volume was approximate- However, the transmission of light on transillu- ly 33 ml; it had been approximately 19 ml on an mination rendered a diagnosis of inguinoscrotal image obtained 6 weeks earlier. The hypoechoic hernia unlikely and confirmed the presence of region in the right mediastinum testis had in- fluid inside the scrotum, a finding consistent creased in size. The right testicular parenchyma with a hydrocele. Therefore, hydrocele was the and epididymis remained hypervascular. Multi- leading consideration on the patient’s initial ex- ple new nonspecific hypoechoic areas were scattered throughout the remaining testicular parenchyma. The left testicle was normal. A Dr. Abers: A diagnostic procedure was performed.

Differential Diagnosis Dr. Ryan W. Thompson: This 84-year-old man presented with a 6-week history of painless swelling of the right testicle. In formulating a differential diagnosis, the two key considerations are establishing the most worrisome or “can’t miss” diagnoses and establishing the most likely diag- B nostic possibilities according to age and epidemiologic and other features of the patient’s presentation. In an 84-year-old man with unilateral testicular swelling, with a solid testicular mass in the absence of systemic inflammatory symptoms that would be suggestive of acute infection, my initial impression is cancer. In fact, such a clinical presentation in an older man would be considered cancer until proven otherwise. Figure 2. Additional Ultrasound Images. Two additional considerations in narrowing Repeat ultrasonography was performed approximately the differential diagnosis are the degree of pain 6 weeks after the first ultrasound examination, at the and the pace of onset. Causes of testicular en- time of the current evaluation. A transverse ultrasound largement that develop suddenly and often in- image of the scrotum shows persistent asymmetric en‑ largement of the right testicle and worsening edema in volve considerable pain include testicular torsion the mediastinum testis (Panel A, arrow), and a corre‑ and acute testicular infections, such as epididy- sponding color Doppler image shows persistent hyper‑ mitis and orchitis. Although these diagnoses fall vascularity of the right testicle (Panel B, arrow). into the “can’t miss” category because of the risk

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amination at the urgent care clinic. Although a this case, pseudolymphoma should be consid- hydrocele was indeed seen on subsequent tes- ered as a diagnosis of exclusion, only when all ticular ultrasonography, the fluid contained sep- other plausible diagnoses have been ruled out. tations and internal debris, which were indica- tive of a more complex process that probably Genitourinary Sarcoidosis involved inflammation. Genitourinary sarcoidosis can have a gradual onset and can involve the testes, epididymis, and Inflammation any other scrotal structure. In most case reports The patient’s ultrasound images also showed of genitourinary sarcoidosis, the affected pa- hypervascularity of the right testicle and epi- tients were 20-to-40-year-old men of African didymis, a finding suggestive of an inflamma- descent.8-10 Because of these epidemiologic fac- tory process. Infection was initially thought to tors, sarcoidosis is low on the list of possible be present and levofloxacin was prescribed, but diagnoses for this patient. the absence of tenderness and of other symptoms of infection raises concerns about a more Genitourinary Tuberculosis subacute and invasive process that perhaps caused Could this patient have genitourinary tuberculo- obstruction of drainage or of flow through the sis? He was originally from Turkey, a region in mediastinum testis. Although the patient had a which tuberculosis is endemic, but he had not mild decrease in testicular swelling after the lived there for more than 60 years. It is possible course of levofloxacin, he did not have complete that he had been exposed to tuberculosis in the improvement while he was receiving the drug, United States, but as a health care worker, he which argues against an acute bacterial infec- had presumably undergone a tuberculin skin test tion as the cause of his condition. more than once. Although genitourinary tuberculosis is rare, some reports suggest that it ac- Cancer counts for a small percentage of cases of extra- Could this patient have testicular cancer? The pulmonary tuberculosis11; middle-aged men are most common cause of testicular tumors in pa- most commonly affected.12 In most patients with tients older than 60 years of age is primary tes- genitourinary tuberculosis, symptoms typically ticular lymphoma.1-3 Overall, primary testicular develop gradually and a scrotal lump is usually lymphoma is rare, accounting for only 1 to 2% of present for more than 3 months. A testicular non-Hodgkin’s lymphomas and only 1 to 9% of mass due to tuberculosis may be either painful all primary testicular tumors.1,4,5 The most com- or painless on examination.12 Urine cultures and mon presenting feature of primary testicular acid-fast staining for mycobacteria can be posi- lymphoma is painless enlargement of the testi- tive, but the sensitivity of staining is low and cle, similar to that seen in this patient. At the cultures can take several weeks to show a posi- time of diagnosis, constitutional symptoms are tive result.13,14 Nucleic acid testing has become a uncommon and an accompanying hydrocele is useful clinical diagnostic test for genitourinary present in approximately 40% of patients.3 Com- tuberculosis because of its more favorable test mon findings on imaging include hypervascu- characteristics and fast turnaround time.15 Geni- larity and hypoechogenicity or hyperechogenicity tourinary tuberculosis typically develops after of involved tissue.6 Other testicular tumors — disseminated disease.12 Patients often (but not including germ-cell tumors (e.g., seminoma), always) present with systemic inflammatory rhabdomyosarcoma, and stromal tumors (e.g., symptoms, such as fever, night sweats, anorexia, Leydig-cell, granulosa-cell, and Sertoli-cell tu- and weight loss. In this case, it is notable that mors) — are even more rare.7 In this patient, it the patient had some improvement after taking would be reasonable to check serum tumor levofloxacin, an antibacterial agent with possible markers, since germ-cell tumors can produce antituberculous activity. increases in levels of alpha-fetoprotein and beta subunit of human chorionic gonadotropin. In ad- Narrowing the Differential Diagnosis dition, pseudolymphoma is a rare, benign condi- The differential diagnosis in this case can be tion that mimics lymphoma and can be mani- reasonably narrowed to tuberculosis and cancer. fested by scrotal or testicular enlargement. In In elderly men presenting with a relatively pain-

1236 n engl j med 378;13 nejm.org March 29, 2018 The New England Journal of Medicine Downloaded from nejm.org by MARK LITWIN on April 10, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved. Case Records of the Massachusetts General Hospital less, firm testicular mass and no systemic symp- leukocytosis, or other evidence of an infectious toms that would suggest infection, cancer would process. Thus, testicular lymphoma could not be be the most common diagnosis. However, in this ruled out, and the patient consented to and sub- case, the absence of a discrete mass on imaging sequently underwent right orchiectomy. makes the diagnosis of cancer unlikely. Given that the imaging studies do not sup- Clinical Diagnosis port a diagnosis of cancer, the most likely diagnosis in this patient is genitourinary tuberculo- Testicular lymphoma. sis. The small, scattered hypoechoic lesions that were noted on imaging could be consistent with Dr. Ryan W. Thompson’s tuberculosis. The fact that the testicular symp- Diagnosis toms improved with levofloxacin is also suggestive of tuberculosis. Patients with renal tubercu- Genitourinary tuberculosis. losis classically have “sterile pyuria”; in this case, the absence of white cells in the urine makes Pathological Discussion renal tuberculosis unlikely, but the negative urine culture does not rule out the possibility of Dr. Dipti P. Sajed: Evaluation of the right orchiec- testicular tuberculosis. tomy specimen revealed an ill-defined tannish- Several features of this patient’s presentation yellow mass (3.6 cm in greatest dimension) do not fit perfectly with a diagnosis of tubercu- punctuated by small yellow nodules that involved losis. First, the painless testicular enlargement both the testicle and the epididymis (Fig. 3A). is somewhat unusual, since most patients with Results of histologic examination mirrored the genitourinary tuberculosis present with at least gross appearance, with well-formed granulomas some pain. Second, he had no urinary or sys- in a nodular pattern that were confluent in some temic inflammatory symptoms. Finally, he had areas and discrete in others (Fig. 3B). The nod- been a health care worker and reported having ules were apparent in both the testicular paren- had at least one negative tuberculin skin test. chyma, in a predominantly interstitial pattern, Although the presence of pain, systemic symp- and the epididymis. The granulomas contained toms, and a positive tuberculin skin test would numerous epithelioid histiocytes with a rim of support the diagnosis of tuberculosis, their ab- lymphocytes surrounding a central area of ne- sence does not rule out this diagnosis. I suspect crosis (Fig. 3C). In formulating the differential that this patient had genitourinary tuberculosis diagnosis of a granulomatous process of the and that the diagnostic procedure was a right testicle, there are two important considerations. orchiectomy. First, the presence of necrotizing granulomatous Dr. David M. Dudzinski (Medicine): Dr. Dahl, inflammation most commonly suggests an in- what was your clinical impression when you fectious cause, such as tuberculous or nontuber- evaluated this patient? culous mycobacteria, brucella species, Treponema Dr. Douglas M. Dahl: Because the abrupt onset pallidum, blastomyces species, or other bacteria of right testicular enlargement would be most or fungi.16 Second, a granulomatous process in a consistent with bacterial epididymitis and reac- primarily interstitial location is most likely due tive hydrocele, I thought it was unusual that the to infection; on rare occasions, it is due to sar- patient did not have fever, pain, or a clinically coidosis of the testicle, which very rarely causes significant response to a fluoroquinolone anti- necrosis and is generally a diagnosis of exclu- biotic agent. Thus, his presentation raised con- sion. In contrast, nonspecific (idiopathic) granu- cerns about testicular lymphoma, which is the lomatous orchitis, which is one of the most cancer that is most likely to cause a testicular common forms of non-neoplastic testicular mass in an elderly man. I obtained a pelvic mag- enlargement, has a predominantly intratubular netic resonance imaging study, which did not pattern17; in addition, it does not cause necrosis show any findings in the genitalia or pelvis that or well-formed granulomas. Taken together, the were consistent with lymphoma or other can- features of this case indicated that infection was cers. The hydrocele persisted unabated. The pa- a likely cause of the granulomatous inflamma- tient had no systemic inflammatory symptoms, tion and warranted further investigation. A his-

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A B

C D

Figure 3. Right Orchiectomy Specimen. A photograph of the orchiectomy specimen (Panel A) shows an ill‑defined, tannish‑yellow nodular mass in the testi‑ cle (arrows) and epididymis (arrowheads). A hematoxylin and eosin stain of the mass (Panel B) shows well‑formed granulomas in a nodular pattern that are confluent in some areas (arrows) and discrete in others (arrowhead). At high magnification (Panel C), the granulomas contain palisading epithelioid histiocytes (arrows) with a rim of lym‑ phocytes (arrowheads) surrounding a central area of amorphous necrotic debris. A Ziehl–Neelsen stain (Panel D) shows a few acid‑fast bacilli (arrows) in the necrotic areas of the granulomas.

tochemical stain for acid-fast organisms was infection was our top consideration, but there performed and revealed a few acid-fast bacilli in are other nontuberculous mycobacterial infec- areas of necrosis (Fig. 3D). The final anatomical tions, including some that grow rapidly and diagnosis is therefore mycobacterial epididymo- some that grow slowly. There were no overt clues orchitis, with further classification contingent on or risk factors for M. leprae or M. bovis infection; microbiologic studies. M. bovis infection causes an orchitis that is classically associated with the administration of Discussion of Management bacille Calmette–Guérin in the context of therapy for transitional-cell bladder cancer. Dr. Rocio M. Hurtado: Our clinical approach to this It was critically important to obtain microbio- patient’s treatment was first focused on making logic confirmation of M. tuberculosis in order to a definitive microbiologic diagnosis. Although the choose an effective drug regimen and to rule out differential diagnosis of mycobacterial epididymo- the presence of drug resistance, given the rising orchitis is small, the diagnosis has management- rates of drug resistance throughout the world. related implications. Mycobacterium tuberculosis However, the strain in this patient had most

1238 n engl j med 378;13 nejm.org March 29, 2018 The New England Journal of Medicine Downloaded from nejm.org by MARK LITWIN on April 10, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved. Case Records of the Massachusetts General Hospital likely been acquired several decades earlier. The definitively established, although the standard patient’s older age increased the likelihood of course for tuberculosis is 6 months. Given this hepatotoxicity from standard antituberculosis patient’s clinical presentation, the surgical de therapy. Therefore, the performance of antimi- bulking of the primary reservoir by means of crobial susceptibility testing was key in selecting orchiectomy, his ability to receive first-line drugs the most appropriate alternative regimens in the (isoniazid and rifampin, with documented ther- event that drug toxicity were to develop. Because apeutic levels during treatment), and the objec- fluoroquinolones are often included in regimens tive evidence of culture conversion during treat- for patients with hepatotoxicity, it was also im- ment, we elected to treat him for 9 months. He had portant to rule out fluoroquinolone resistance in no evidence of relapse at 1 year after treatment. this patient, who had previous exposure to this The patient recovered during the weeks after class of drugs. surgery and the initiation of treatment. He had Unfortunately, the determination of a micro- complete resolution of his symptoms. biologic diagnosis in this patient was hampered A Physician: If the urine cultures had been by the fact that mycobacterial infection had not performed before surgery, confirming the micro- been previously suspected and therefore no tis- biologic diagnosis, would orchiectomy have been sue specimen was available for culture. Since necessary? tuberculosis is a systemic disease and more than Dr. Dahl: Even though the active infectious pro- 50% of patients with genitourinary tuberculosis cess could be controlled in this case, the hydro- have renal involvement (suggesting local spread cele would still have needed to be surgically in addition to the postulated hematogenous corrected, since it was causing the most discom- spread in other forms of tuberculosis),18 we per- fort — making swimming and exercise difficult formed mycobacterial cultures of the urine, in- — and may or may not have resolved. If it was cluding three 50-ml urine samples obtained going to resolve, it would have taken a very long during the first morning void and one sample time. From a practical point of view, there was obtained after prostatic massage. We pursued no reason not to perform an orchiectomy. this line of investigation even in the absence of Dr. Hasan Bazari (Medicine): Why were you able clinically significant abnormal urinary sediment, to reinitiate antimycobacterial therapy without since up to 15% of patients with genitourinary further toxicity? tuberculosis have bland urinary sediment.19 This Dr. Hurtado: Many drug reactions are idiosyn- patient was also evaluated for other sites of cratic, and a proportion of patients who have potential concomitant pulmonary or extrapulmo- toxic effects from medications can do well when nary involvement. Ultimately, all four mycobac- the drugs are reintroduced. Given this patient’s terial cultures of the urine grew M. tuberculosis. age, we chose not to rechallenge him with pyra- The patient began first-line therapy for drug- zinamide because we wanted to decrease the susceptible tuberculosis with isoniazid, rifampin, overall burden of hepatotoxicity, especially since ethambutol, and pyrazinamide with pyridoxine. we already knew that the organism was drug- Clinically significant hepatotoxicity developed susceptible. Instead, we elected to treat him with- after 2 weeks of therapy, which prompted dis- out pyrazinamide for longer than the standard continuation of all medications for 2 weeks, treatment period. followed by reintroduction of isoniazid and eth- Dr. Dudzinski: Did the fact that he had some ambutol first and then rifampin. The drugs were improvement with the levofloxacin have an effect administered without further toxic effects. Fol- on therapeutic decision making? low-up cultures of urine obtained at 2 months Dr. Hurtado: Unfortunately, up to one third of of treatment and at the end of treatment were patients with urinary tuberculosis may have con- sterile. Results of drug susceptibility testing comitant bacterial pathogens, so this feature confirmed a fully drug-susceptible organism. alone cannot be used in decision making. It is Ethambutol was discontinued, and the patient true, however, that widespread fluoroquinolone completed 9 months of therapy with isoniazid use, especially in Asia, remains a concern, since plus rifampin and pyridoxine. a growing body of literature documents rising Of note, the recommended length of treat- rates of primary resistance to fluoroquinolones ment for genitourinary tuberculosis has not been among patients with tuberculosis.

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Final Diagnosis This case was presented at the Medical Case Conference. No potential conflict of interest relevant to this article was reported. Mycobacterial epididymo-orchitis due to Myco- Disclosure forms provided by the authors are available with bacterium tuberculosis. the full text of this article at NEJM.org.

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