Case Report

Delay in Diagnosis of Testicular Cancer in a Patient with Down Syndrome: a Case Report and Review of Current Literature

Colby Sharlin1, Yazan Al Hasan2, Justin Hoskin2, Emma Weatherford3, Jeffrey F Wang3, Earle Collum2, Richard Trepeta2, John Anwar2, Deepti Boddupali2 and Jue Wang1,2,4,*

1Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, USA
2St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, USA
3Baylor University, Waco, USA
4Genitourinary Oncology Section, University of Arizona Cancer Center at Dignity Health St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, USA

Received date: 17 July 2017; Accepted date: 26 Sep 2017; Published date: 04 Oct 2017.

*Corresponding author: Jue Wang, University of Arizona Cancer Center at Dignity Health St. Joseph’s, Phoenix, Arizona, USA, Tel: +1 602-406-8222; E-mail: jue.wang@dignityhealth.org
Abstract

Feelings of embarrassment or fear may contribute to delay in the diagnosis of genitourinary tumors, with subsequent increase in morbidity and mortality. We report a delayed diagnosis of testicular cancer in a 29-year-oldmale with Down syndrome (DS) who presented with complaints of recurrent lower abdominal and back pain of six months, without telling his family that his symptoms are related to a large left testicular mass. He underwent a left radical inguinal orchiectomy and a histopathological examination of the mass showed a mixed germ cell tumor with non-seminomatous components predominantly consisting of yolk sac tumor (70%) and a smaller component of embryonal carcinoma (30%). We review the literature on testicular cancer in patients with DS and discuss the challenges in diagnosis and treatment of these patients. We identify missed opportunities contributing to the delayed diagnosis. We emphasize the need for improved knowledge of how to communicate with affected individuals, as well as thorough physical examination in these patients to avoid delayed diagnosis.

Keywords: Testicular cancer; Germ cell tumors (GCTs); Delayed diagnosis; Pulmonary metastases; Down syndrome; Trisomy chromosome 21; Physical examination; Chemotherapy

Introduction

Testicular cancers (TC) are rare in the general population, accounting for 1% of all human malignancy, but affect mainly young adults between the ages of 15 to 35 years [1]. Testicular cancers are often revealed as a painless nodule with swelling of the scrotum [2]. TC shows excellent cure rates based on their chemo sensitivity - especially to cisplatin-based chemotherapy - careful staging at diagnosis, adequate early treatment based on multidisciplinary approach, and strict follow-up and salvage therapies [3,4,5]. Delay in diagnosis of a testicular cancer may result in an advanced stage of disease at diagnosis, which may affect disease free and overall survival [6]. Down syndrome (DS), also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21 [7]. Patients with DS have a particular tumor profile with approximately 10 to 20 fold higher risk for developing acute lymphoblastic leukemia and acute myeloid leukemia (AML), as compared with non-DS individuals, although they do not have a uniformly increased risk of developing solid tumors [7]. Recently the association of testicular tumors and Down’s syndrome has been documented [8]. Care providers for individuals with DS are confronted with obstacles in communication, assessment, diagnosis, treatment and follow-up [7,8]. The presentations of testicular cancer are similar to that of general population [2,8]. However, intellectually-disabled patients, and especially those with DS have greater difficulty in describing pain or physical symptoms [8,9]. These patients may also be reluctant to reveal their symptoms because of feelings of embarrassment or fear [10]. This report describes a case of delayed diagnosis in a 29-year-old male with DS who presented with complaints of recurrent lower abdominal and back pain because of a vast left testicular mass. We discuss the challenges in diagnosis and treatment of testicular cancer in individuals with DS.

Case Report

A 29 year-old male with DS and past medical history of hypothyroidism was brought to the Emergency Department (ED) after his mother discovered left testicular enlargement. He was seen at his primary care physician’s office one hour prior to ED visit for complaints of abdominal pain and lower back pain for six months. The findings from his primary care physician was “unremarkable” and he was sent to home. The patient showed his mother his swollen scrotum after they arrived home. Upon further questioning, the patient’s family found that he was too embarrassed to tell his primary care physician and hoped his doctor would find it himself through examination. Unfortunately his physician did not examine his genitourinary system. The patient was subsequently taken to the Emergency Department, where ultrasound revealed a heterogeneous well-vascularized 8.1 x 5.8 x 6.7 cm mass in the left testicle. Laboratory tests revealed an elevated alpha-fetoprotein (AFP) at16,871.24 ng/ml, elevated lactate dehydrogenase (LDH) of 636 Units/L, and betahCG of 6 Int Unit/L. CT Abdomen and Pelvis with IV Contrast showed large complex left testicular mass as previously identified on ultrasound (Figure 1). CT Chest showed more than 20 pulmonary metastases with the largest in the right lower lobe measuring 24 x 23 mm (Figure 2). The patient underwent a left radical inguinal orchiectomy. Three days following orchiectomy, tumor markers were redrawn and were found to be reduced at: AFP 4,149.82 ng/mL, Beta-hCG 1 IU/L, LDH 230 U/L. A Magnetic resonance imaging (MRI) of the lumbar spine was unremarkable. After a detailed discussion with the family and consent of the parents and sister, the patient was treated with Bleomycin, Etoposide, and Cisplatin (BEP) for 4 cycles for his stage IIIB disease (T2, N0, M1a, S2). Post-chemotherapy laboratory showed normalization of all tumor markers. The patient remains doing well during the follow-up period.

Figure 1: A Computed tomography (CT)of Pelvis showing large complex left testicular mass
Figure 2: Computed tomography (CT) of Chest showing largest pulmonary metastasis measuring approximately 24 x 23 mm
Pathological Findings

Examination of surgical specimens from orchiectomy revealed that the testicle and epididymis were largely replaced by a predominantly solid pink-tan to red-brown diffusely hemorrhagic mass with focal cystic components exuding a yellow gelatinous substance. Further immune histo chemical staining showed evidence of a mixed germ cell tumor with non-seminomatous components predominantly consisting of yolk sac tumor (70%) and a smaller component of embryonal carcinoma (30%). The neoplastic cells were positive for pancytokeratin, D2-40, and CAM 5.2. “Additionally, cytoplasmic staining with CD117 antibody.” Some epithelial areas were positive for CD30. The tumor was positive for AFP and scattered staining with glypican 3. There was lympho vascular invasion, but no invasion of the spermatic cord (Figure 3).

Figure 3: Pathology slides obtained from left testicle. Clockwise: (1) Hematoxylin & Eosin stain, 500 micron field showing infiltration by tumor cells. (2) Hematoxylin & Eosin stain, 100 micron field, demonstrating poorly differentiated regions. (3) AFP stain, 200 micron field. AFP+ is found is non-seminoma testicular cancers, particularly with yolk sac tumors. (4) CD30 stain, 400 micron field. CD30+ is associated with embryonal carcinoma
Literature Review

We searched published literature for germ cell tumors (GCTs) in patients with Down syndrome. In our literature review of germ cell tumors in patients with DS, we identified 43 cases of testicular GCTs [11- 32]. Of the 43 testicular GCTs cases, seminomas were most common with 29 cases, and there were only seven identified cases of mixed GCTs. The present case represents the 44th case of testicular GCTs and eighth known case of mixed testicular GCTs in a patient with DS, thus an exceedingly rare association. The demographic, pathologic features, treatment and outcome of the published cases of GCTs in male Down syndrome patients are reviewed in table 1. The median age at presentation was 30 years for patients with seminomas (range 2-50 years) and 22 years for patients with nonseminomas (range 2-50 years). In most cases, cancer was diagnosed following the discovering of swelling by care provider or found incidentally (either painless or painful) in the region of the testes, although abdominal pain was a symptom in a few cases. Nearly all patients (93%) underwent orchiectomy. In addition, one patient was treated with partial resection of his tumor, which had grown too large for further surgical treatment. In addition, 22 patients (51%) received chemotherapy and eight (19%) received radiotherapy. Twenty-nine patients (67%) recovered fully, showing no evidence of disease at the last point of follow-up. Two (7%) died during chemotherapy: one due to aspiration pneumonia and one due to cardio respiratory distress. Three (5%) died of progression of the cancer, and two (5%) died of other causes.

Discussion

The association between DS and GCTs, particularly testicular GCTs, is now being established [8,9]. Previous investigation conducted in Sweden and Denmark of 4872 individuals found that individuals with DS had an increased risk of incident leukemia and elevated risks of testicular and liver malignancies [18]. Several investigations have attempted to identify the prevalence of DS amongst those presenting with testicular cancer. One such study identified prevalence at 0.5% [33] and another estimated it at 0.9% [34]. One explanation for the association between DS and testicular cancer was postulated by a research team in the Netherlands, which found a significant delay in the maturation of germ cells in patients with Trisomy 21 during the fetal period. This delay, they suggest, could result in germ cells remaining in a vulnerable state for a prolonged period of time [35]. Interestingly, studies utilizing comparative genomic hybridization found

Reference

Authors

Age

Discovery

Symptoms

Histology

Stage

Location

AFP

b-hCG

Orchiectomy

Chemotherapy

Radiotherapy

Outcome

Follow-up (months)

11

Aguilar-Ponce, et al.

22

Caregiver

scrotal swelling

Seminoma

I

B

Normal

 

Y

N

Y

NED

105

12

Braun, et al.

19

Caregiver

scrotal swelling

Seminoma

IIA

R

Normal

Normal

Y

N

N

NED

9

13

Dada, et al.

2

 

scrotal swelling

Seminoma

I

L

 

 

Y

N

N

N/A

N/A

14

Dieckmann, et al.

29

Caregiver

scrotal swelling

Seminoma

I

L

Normal

Normal

Y

Y

N

NED

12

14

Dieckmann, et al.

32

 

scrotal swelling

Seminoma

I

L

 

Elevated

Y

N

Y

NED

96

14

Dieckmann, et al.

32

Incidental

scrotal swelling

Seminoma

I

R

Normal

Normal

Y

N

N

NED

12

14

Dieckmann, et al.

35

Incidental

scrotal swelling

Seminoma

I

L

Normal

Normal

Y

N

Y

NS

N/A

15

Hafeez, et al.

37

 

scrotal swelling

Seminoma

IIC

L

 

 

Y

Y

N

NED

48

15

Hafeez, et al.

50

 

 

Seminoma

IIC

L

 

 

Y

Y

N

NED

96

15

Hafeez, et al.

39

Incidental

scrotal swelling

Seminoma

III

L

Normal

Elevated

Y

Y

N

NED

48

15

Hafeez, et al.

48

Caregiver

scrotal swelling

Seminoma

I

L

 

 

Y

Y

N

NED

36

15

Hafeez, et al.

38

 

Painful, scrotal swelling

Seminoma

I

R

 

 

Y

N

Y

NED

36

14

Hafeez, et al.

40

 

 

Seminoma

I

R

 

 

Y

Y

N

NED

48

15

Hafeez, et al.

21

 

 

Seminoma

I

B

 

 

Y

Y

N

N/A

34.5

16

Hayashi, et al.

40

 

scrotal swelling

Seminoma

IIB

R

 

 

Y

N

Y

N/A

N/A

17

HsiungStripp, et al.

43

Incidental

scrotal swelling

Seminoma

IIB

L

 

 

Y

N

Y

NED

4

17

HsiungStripp, et al.

39

 

scrotal swelling

Seminoma

IIB

R

 

 

Y

N

Y

DOC

9

17

HsiungStripp, et al.

32

Self

Discomfort and swelling of R flank

Seminoma

IIC

R

Normal

Normal

Y

Y

N

NED

N/A

18

Ichiyanagi and Sasagawa

30

 

scrotal swelling

Seminoma

I

R

Normal

Normal

Y

N

N

NED

8

19

Kamidono, et al.

41

Caregiver

scrotal swelling

Seminoma

III

R

Normal

Normal

Y

Y

N

DOD

1.25

20

Miki, et al.

42

Incidental

scrotal swelling

Seminoma

IIB

L

Normal

Normal

Y

N

N

DOD

24

21

Na, et al.

19

Incidental

Painful scrotal swelling with hard mass in R inguinal area

Seminoma

I

R

Normal

Normal

Y

N

N

NED

1

22

Sasagawa

35

 

scrotal swelling

Seminoma

I

R

Normal

Normal

Y

N

N

N/A

N/A

23

Satgé, et al [1]

14

 

 

Seminoma

I

R

 

 

Y

N

Y

DOC

 

24

Satgé, et al [2]

28

 

scrotal swelling

Seminoma

I

L

Normal

Normal

Y

Y

N

DOT

N/A

25

Sleijfer, et al.

30

Incidental

Abdominal discomfort

Seminoma

IIC

L

Normal

Elevated

Y

Y

N

NED

60

26

Suzuki, et al.

33

 

scrotal swelling

Seminoma

I

L

Normal

Normal

Y

N

N

NED

48

27

Villaneuva, et al.

29

 

scrotal swelling

Seminoma

I

L

 

 

Y

N

N

NED

38

11

Aguilar-Ponce, et al.

22

 

scrotal swelling

Seminoma

I

L

 

 

Y

N

N

NED

50

26

Dexeus

17

 

 

EC

II

 

 

 

Y

Y

N

DOT

N/A

27

Hashimoto

17

 

scrotal swelling

EC

III

R

Elevated

Normal

Y

Y

N

NED

24

21

Satgé, et al, [2]

23

 

Painful scrotal swelling

EC

I

R

Normal

Normal

Y

Y

N

NED

120

24

Satgé, et al. [1]

19

 

 

EC

I

R

 

 

Y

N

N

NED

300

25

Villaneuva

19

 

scrotal swelling

EC

III

L

Elevated

 

Y

Y

N

NED

22

11

Aguilar-Ponce, et al.

23

Caregiver

scrotal swelling

Teratoma, EC, YST, and choriocarcinoma

III

L

Elevated

Elevated

Y

Y

N

NED

53

26

Dexeus

35

 

 

Teratoma, EC, and seminoma

II

 

 

 

Y

Y

N

NED

36

29

Almouhissen, et al.

22

 

scrotal swelling

YST 

III

L

Elevated

Elevated

Y

Y

N

N/A

N/A

15

Hafeez, et al.

33

Incidental

scrotal swelling

 EC, YST, teratoma

IIB

B

Normal

Elevated

Y

Y

Y

NED

96

30

Kuroda, et al.

20

Self

scrotal swelling

YST and EC

III

L

Elevated

Elevated

Y

Y

N

NED

7

31

Martin, et al.

50

Caregiver

R groin lump

Seminoma, teratoma, seminoma

I

B

Elevated

Normal

Y

Y

N

N/A

0

32

Oosterhuis, et al.

23

 

 

YST and teratoma

I

R

Elevated

Normal

Y

N

N

NED

55

22

Satgé, et al. [1]

2

 

 

YST and EC

IIA

R

 

 

Y

N

N

NED

48

11

Aguilar-Ponce, et al.

23

Incidental

Acute abdominal pain

N/A

III

L

Normal

Normal

Y

Y

N

DOD

12

Table 1: Summary of demographic data, pathological features, treatment, and outcomes of 43 published cases of testicular cancer in patients with Down syndrome identified in current literature

EC: Embryonal Carcinoma; YST: Yolk Sack Tumor, R: Right; L: Left; B: Bilateral; Y: Yes; N: No.
NED: No Evidence of Disease; DOD: Dieof Comorbid Condition; DOD: Die of Disease; DOT: Die of Therapy;N/A: Not Available

gains of chromosome 21 in seven of eleven primary testicular GCTs, among other chromosomal gains [36]. This finding also supports the link between testicular germ cell tumors and DS. The care of persons with DS and cancer presents a challenge to caregivers and clinicians at all stages, from prevention to screening, detection, diagnosis, treatment, and follow-up [8- 10]. The presentation of testicular cancer is similar to that of nondisabled persons: painless nodule and a swelling of the scrotum. Due to intellectual disability, persons with DS may not convey their symptoms and pain, often leading to delayed diagnosis and potentially worse outcome. Patients may be fearful of physical examination and may therefore mask their symptoms as long as possible. Additionally, families of these patients do not necessarily have specific knowledge of cancer risk in persons with DS. In our literature review (Table 1), 9% patients the symptoms was initially found by care provider, incidental discovery was noted in 12% cases. 26 (51%) patients were diagnosed as stage I, 14 (33%) as stage II, and 7 (16%) as stage III.

The cure rate for testicular cancer is exceptionally good. More than 96% of men with early stage testicular cancer will be completely cured [3, 4]. However, delay in the diagnosis of testicular cancer is associated with greater morbidity and poorer prognosis [7]. If the tumor is diagnosed at stage 1, treatment is easier and less toxic than if the tumor has spread to other parts of the body. Studies investigating patient and doctor delay in testicular cancer diagnosis and factors associated with delay suggest that the most important risk for longer patient delay was embarrassment and lower education [37,38]. Studies examining the optimization of management of testicular cancer in individuals with DS are lacking [10] and there are no specific guidelines. Multiple factors contribute to the delay in diagnosis in our case. The patient in our report had been complaining of vague abdominal pain and back pain for six months. Apparently he was too embarrassed to tell his parents about his testicular mass. He also did not tell his primary care physician about his concerns, but hoped his doctor would find it himself through examination. Unfortunately his physician did not examine his external genitalia. Individuals with DS may have learning difficulties, behavioral problems, and multiple comorbidities that have the potential to make standard treatment more difficult. Although the general principles for treating germ cell tumor are applied to individuals with DS, treating a testicular cancer is much more difficult in individuals with DS as compared with nondisabled persons for several reasons. First, many patients with DS have delayed diagnosis of cancer, as discussed above. When tumors are discovered at a late stage they are usually treated with more intense therapeutic regimens that have more side effects. Second, persons with DS have difficulties in understanding the illness and treatment. Third, comorbidities linked to DS in these patients can limit the use of certain chemotherapy agents. Chemotherapy may need to be modified or adapted because of comorbidities and pre-existing organ dysfunction. Nonetheless, 90% patients were successfully treated using standard chemotherapy, illustrating the potential to cure in testicular cancer patients with DS. Patients with testicular cancer and Down syndrome have complex medical and psychological needs. Their intellectual disability should not preclude curative treatment. At the University of Arizona Cancer Center (UACC) at Dignity Health St. Joseph’s hospital, we implement a Testicular Cancer Awareness Program to educate clinicians, DS patients, and their caregivers

Conclusion

Inadequacies of physical examination by primary care physician and challenge in communication likely contributed to missed or delayed diagnosis. Primary care physicians should take note of the possible connection that exists between those with Down syndrome and the development of germ cell tumors. In order to avoid delay in diagnosis, we propose that clinicians should closely attend to the patient presentation and complaints, as well as reports by caregivers. Above all, a timely and complete physical examination and appropriate referral are needed to ensure early diagnosis and best outcomes.

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