Importance of early detection

The common sense importance of early detection and diagnosis of testicular cancer has been

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known for many years. Before the advent of curative therapy, this was one of the few ways (if not the only way) to prevent deaths in the usually young and otherwise healthy men who are affected. In the current era of effective chemotherapy, most (but not all) patients can be salvaged despite delays in diagnosis and, consequently, more advanced disease [2]. This salvage, however, generally requires much more extensive chemotherapy or surgery, and the potential morbidity of these more heroic efforts must not be underestimated. Expedient diagnosis of these neoplasms affords the opportunity to treat these patients at their earliest stage of disease and therefore to minimize long-term morbidity.

Despite this worthy goal of early diagnosis, pitfalls in the early and accurate diagnosis of testicular tumors are common. Delay in diagnosis of testicular cancer is well documented [2-30]. Table 1 illustrates that the mean delay (26 weeks) has varied little over the last 75 years from various series throughout the world. It is interesting that this approximate 5-month delay from initial symptoms to a surgical diagnosis has remained constant in these reports. Despite this consistency, some investigators have shown a trend toward a decreased delay in more recent years [2,12]. Dieckmann and colleagues [12] found that the number of patients in whom diagnosis was made improved within 2 weeks from 13.6% to 25.4% between 1969 to 1976 and 1982 to 1986. Similarly, Moul and colleagues [2] found that the mean symptomatic interval decreased from 22.7 to 16.4 weeks between the 1970 to 1974 and the 1985 to 1987 intervals. Conversely, Nikzas and colleagues [22] found no decrease in delay between 1980 and 1987 in 232 patients studied in Great Britain. Even if delay time has improved somewhat, in some series it remains a significant

Table 1

Delay in diagnosis of testicular cancer: review of the literature

Mean duration

Time period No. of

of symptoms

Study

of review

patients (wk)

Weissbach

1926-1973

182

40

et al [3]

Host and

1932-1953

289

33.6

Stokke [4]

Patton et al [5]

1940-1956

510

20

Thompson

1940-1960

178

87

et al [6]

Bosl et al [7]

1941-1978

335

12

Kurohara

1945-1965

196

25.4

et al [8]

Borski [9]

1953-1973

150

26.1

Seib et al [10]

1960-1973

50

20

Ware et al [11]

1965-1977

100

17.3

Dieckmann

1969-1986

156

24.3

et al [12]

Kulig [13]

1970-1979

27

24

Moul et al [2]

1970-1987

148

21.1

Leyh [14]

1971-1982

101

21.8

Kuhne et al [15]

1971-1982

50

30.5

Scher et al [16]

1972-1979

123

8

Fischer [17]

1973-1981

182

20

Heising [18]

1976-1981

1344

19.6

Jones and

1976-1982

121

19.8

Appleyard [19]

Thornhill

1980-1985

217

40

et al [20]

Chilvers et al [21] 1980-1986

257

16

Nikzas et al [22]

1980-1987

232

22

Total

4948

26

problem. Patients and health care providers may contribute to delay in diagnosis. Patient-mediated delays owing to ignorance, embarrassment, fear of cancer, or fear of emasculation are well known [23,28]. Dieckmann and colleagues [12] found that delay was related to educational level. College-educated men in whom both seminoma and nonseminoma were diagnosed were found to have shorter mean and median delays. The less informed or less educated patient may actually believe that a larger testicle makes a more virile man [23]. Patients who have testicular cancer may be more inclined than other cancer patients to delay or even refuse seeking medical attention or treatment [31]. Testicular cancer affects young and usually otherwise healthy men who may be unable to acknowledge the threat of fatal disease. Instead of seeking evaluation, they may hold fast to their normal routine as a denial mechanism termed the flight into health [32]. Furthermore, that testicular cancer involves the loss of an external sexual organ during a time in the patient's life when sexuality is very important is an added stressor [31]. Jones and Appleyard [19] point out that it is often the partner and not the patient himself who insists that medical attention be sought.

Physician-mediated delay most commonly results from the misdiagnosis of a testis tumor as an infection. Unfortunately for the clinician, the classic painless testicular mass or swelling is the presenting symptom in only approximately half of patients in whom testicular cancer ultimately is diagnosed (Table 2). Scrotal pain with or without a mass occurs in up to 50% of testicular cancer presentations and has been attributed to hemorrhage into the tumor [5,25,33].

This painful presentation is not uncommonly responsible for a false diagnosis of epididymitis. In one study of 335 testicular cancer patients, one third were treated initially with antibiotics or local treatments for presumed epididymitis, and most of these were delayed from appropriate orchiec-tomy for more than 2 weeks [7]. In another study of 133 men who had testicular cancer, 23 (17%) were treated initially for epididymitis [26]. Most were delayed for 2 or 3 months, and 5 patients were delayed from 6 to 22 months.

Because nonseminomas generally are considered a more rapidly growing neoplasm than seminomas, they may be more commonly associated with a painful presentation. Sandeman [24] found that 109 (47%) nonseminoma patients initially presented with pain, whereas only 102 (38%) seminoma patients had a similar presentation. Seminomas are usually a more indolent-growing neoplasm, and a painless mass or swelling is the most common presentation. It is the nonseminoma patient who might benefit the most from early diagnosis but who also may be more difficult to distinguish from a patient who has an inflammatory lesion.

In my prior practice at the Walter Reed Army Medical Center and now at Duke University, we frequently see young men who are prime candidates for testicular cancer or epididymitis. Our policy is to assume malignancy until proved otherwise. Urinalysis usually demonstrates pyuria when epididymitis is present and, in most cases, epididymal tenderness and swelling are distinguishable from the testis proper. When more severe orchitis or swelling is present and suspicion for tumor persists, a 1% lidocaine cord block can allow for a more meaningful examination. If we

Table 2

Presenting signs and symptoms of testicular tumors in various series

Percentage presenting

Table 2

Presenting signs and symptoms of testicular tumors in various series

Percentage presenting

Patton

Robson

Sandeman

Bosl

Dieckmann

Thornhill

Wishnow

Meffan

et al [5]

et al [33]

[24]

et al [7]

et al [12]

et al [20]

et al [27]

et al [30]

Signs and symptoms

(n = 491)

(n = 360)

(n = 502)

(n = 335)

(n = 180)

(n = 217)

(n = 154)

(n = 79)

Painless mass or swelling

NS

56.9

54

NS

51.2

32

57

43

Painful scrotum with or

NS

26.4

42

45

32.8

31

40

50

without mass or swelling

Incidental finding

5

4.3

4

NS

NS

23

NS

NS

Associated with trauma

7

13a

NS

11.2b

NS

10

NS

3

Symptoms and signs of

10

5.2

NS

10.7

6.3

19

NS

5

metastases

Gynecomastia or

NS

NS

NS

5

1.1

2

3

1.3

tenderness

Abbreviation: NS, not stated. a Hernia, traumatic orchitis, or torsion. b Trauma, hydrocele, or benign tumor.

Abbreviation: NS, not stated. a Hernia, traumatic orchitis, or torsion. b Trauma, hydrocele, or benign tumor.

still have any index of suspicion for a tumor, we proceed directly to scrotal sonography.

Serum tumor markers, such as b-human chorionic gonadotropin and a-fetoprotein, usually are also useful to obtain in this setting and are absolutely essential to obtain before orchiec-tomy. The differential diagnosis of testicular masses has been aided by cytologic examination of seminal fluid obtained by ejaculation or prostatic massage [34,35]; however, this is not in widespread clinical use. Even if the clinician is sure of a diagnosis of epididymitis or orchitis, it is still prudent to insist that the patient be seen in follow-up in 7 to 10 days after the inflammation has subsided to re-examine the testis for an occult neoplasm. This follow-up of presumed infection is crucial especially if the diagnosis of epididymitis is not certain.

In addition to presumed infection, trauma frequently may cloud an accurate and early diagnosis of testicular cancer. Stephen [25] cites trauma as ''a wolf in sheep's clothing'' with respect to complicating the diagnosis of testicular cancer. Up to 10% of testicular cancer patients initially receive a diagnosis of posttraumatic pain or swelling (see Table 2). It is presumed that the enlarged tumorous testis is more susceptible to trauma or that less significant trauma might more easily precipitate symptoms. Patton and colleagues [5] claim that the trauma is coincidental in attracting the patient's attention to an already existing lesion. Stephen [25] has described an interesting sign whereby the lack of sickening pain at the moment of injury, because of prior destruction or partial destruction of the testis from neoplasm, is an important point to elicit from the patient. The pitfall is a less-than-adequate evaluation for tumor in a patient presenting with trauma. One should be especially wary when the swelling or pain is out of proportion to what would be considered minor trauma, or vice versa. Again, in the setting of trauma, a high index of suspicion for tumor is necessary and scrotal sonography, exploration, or compulsive follow-up frequently is indicated.

Up to 19% of patients present with signs or symptoms of metastases (see Table 2). Back pain, abdominal mass, lymphadenopathy, and weight loss are the most prevalent constitutional symptoms. An additional 1% to 5% of patients present with gynecomastia or breast tenderness. The major pitfall in these presentations is to fail to examine the genitalia and so miss an obvious testicular tumor, and thereby delay, misdiagnose, or mistreat a metastatic germ cell cancer. Oliver [28] has stated that the most severe delays in diagnosis occur in patients undergoing investigation of symptoms that are subsequently shown to have been caused by metastases. Inappropriate laparot-omy in the case of an obvious testicular tumor remaining in situ is not rare [23]. Patients who have back pain have been subjected to osteopathic therapy while a testicular cancer went unsuspected [26]. Prout and Griffin [26] have even reported two patients being subjected to mastectomy for gynecomastia before any evaluation for testicular cancer. Surprising as this may be, we have also seen a patient who had bilateral subcutaneous mastectomy and soon thereafter received a diagnosis of obvious testicular cancer [36].

For seminoma patients, delay in diagnosis is not necessarily associated with more advanced disease or decreased survival. Many investigators have noted that seminomas can have a protracted indolent growth, and symptom duration does not correlate with disease stage [2,12,24]. Because of slow growth characteristics, stage I seminoma can be associated with very long symptomatic intervals. Moul and colleagues [2] found the mean symptomatic interval for stage I seminomas to be 39 weeks, whereas that for stage II disease ranged from 11 to 18.5 weeks. Dieckmann and colleagues [12] found that stage I patients had a 228-day mean delay in diagnosis, compared with 129 days for the stage II seminomas. Regarding survival and delay for seminoma patients, the longer period of delay has not been shown statistically to affect survival, although deaths from seminoma have been associated with very long delays [2].

For the nonseminoma patient, there is a clearer association between delay in diagnosis and advanced disease. Bosl and colleagues [7] found a median delay of 75, 101, and 134 days for stages I, II, and III testicular cancer, respectively (24% seminomas included). Thornhill and colleagues [20] noted that stage I patients had a mean duration of symptoms of 2.2 months, whereas stage II cases were delayed 4.7 months (stage III and IV were delayed 3.4 and 4.5 months, respectively). Chilvers and colleagues [21], reporting on 257 nonseminomatous germ cell tumor (NSGCT) patients seen between 1980 and 1986, found that of those who sought medical advice within 100 days of onset of symptoms, 54% had stage I tumors compared with 41% who delayed longer (P — .05 by c2 analysis). The Wishnow and colleagues [27] study of 154 NSGCT patients compared patients in whom tumor was diagnosed within 1 month (n — 65, group 1) to patients delayed longer than 1 month (n — 89, group 2). Sixty-two percent of group 1 presented with stage I disease compared with only 28% of group 2 (P<.001). Similarly, only 8% of group I patients had stage III disease, compared with 39% of group 2 patients (P<.001, c2). Moul and colleagues [2] found the mean symptomatic interval for stages I, IIA, and IIB nonseminomas to range between 8.5 and 9.7 weeks, whereas for stages IIC and III the delay was 26.4 weeks.

Increased delay has also traditionally been associated with decreased survival for nonsemi-noma patients. Sandeman [24] reported a progressively decreased 3-year disease-free interval as delay increased. Post and Belis [23] reported a 69% 3-year survival for patients in whom NSGCT was diagnosed within 3 months, versus a 47% survival if the delay was greater than 3 months. Prout and Griffin [26] noted a 0% crude death rate for men in whom diagnosis was made within 1 month, compared with a 27.6% death rate when delay was longer than 1 month. Oliver [28] found that the average delay was 2 months in patients who remained free of disease, 4 months in those who relapsed but were salvaged, and 7 months in those who died of drug-resistant disease. Thornhill and colleagues [20], studying 217 cases of testicular cancer in Ireland, found delay to be statistically associated with metastases, diminished prospects of cure, and mortality. The median duration of symptoms was 4 months in those who died of disease, compared with 2.5 months in those patients who were alive. Wish-now and colleagues [27] noted that only 1 of 65 patients in whom diagnosis was made within 1 month died of disease, whereas 11 of 89 (12.4%) delayed beyond 1 month died of testicular cancer (P — .0072, c2). In a study of 232 patients treated between 1980 and 1987, Nikzas and colleagues [22] found an 8% mortality in patients in whom tumor was diagnosed within 6 months, compared with 16% in those with a longer delay (P< .01).

Moul and colleagues [2] found that a delay greater than 16 weeks had a strong statistical adverse effect on survival for nonseminoma patients treated between 1970 and 1987. When these investigators separated patients treated during the more contemporary ''cisplatin era'' (1979-1987), the impact of delay on survival was attenuated and no longer was statistically significant. These authors concluded that effective chemotherapy salvages many patients who in the past would have been at a disadvantage as a consequence of delayed diagnosis. Other investigators also have found that delay in diagnosis does not necessarily influence survival for NSGCT patients in the contemporary era. In their study of 257 NSGCT patients between 1980 and 1986, Chilvers and colleagues [21] actually found an inverse relationship between delay and survival. Patients in whom diagnosis was made within 0 to 49 days had a lessened relapse-free survival compared with patients in whom diagnosis was made later (P<.05, log rank test for trend). The authors concluded that faster-growing, more aggressive tumors are more likely to produce symptoms leading to medical consultation. Similarly, Meffan and colleagues [30], in a small study of 79 patients (40 seminomas, 39 NSGCT) treated between 1976 and 1985 in New Zealand, found no relation between delay and prognosis. They concluded that all cases in their series were being diagnosed too late and that is why no association was seen.

Although contemporary chemotherapy may salvage most patients despite delay in diagnosis and more advanced disease, deaths still result from delay. Furthermore, effective chemotherapy may be a double-edged sword in that clinicians may become more lax in expediently caring for these patients and so delay may increase [27]. The potentially higher morbidity associated with the more intensive therapy that is required to salvage patients as a consequence of delay must not be underestimated. Efforts to decrease delay in diagnosis may be the most cost-effective method to improve further the survival of testicular cancer patients and to lessen treatment morbidity.

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