We present a 65 year old man who presented with a three year history of right testicular swelling and weight loss.
Authors: Deivasikamani Ramanujam Venkatachala1, Elaine MacDuff 2, Karen Smith 3 , Mike Jane3, Ed Kalkman1, Martin Russel1, Ashita Waterston1 ,Jeff White1.
1. The Beatson West of Scotland Cancer Centre, Glasgow.
2. Western Infirmary, Glasgow.
3. Glasgow Royal Infirmary, Glasgow.
Corresponding Author: Deivasikamani Ramanujam Venkatachala, The Beatson West of Scotland Cancer Centre, Glasgow. E-mail: [email protected]
Testicular germ cell tumours are the most common cancer of young men. They respond well to treatment, with anticipated cure rates of over 90%. Late recurrences two years after initial treatment are uncommon; and very late recurrences beyond five years of initial treatment are rare. However they are reported in Non Seminomatous Germ Cell Tumour (NSGCT).
Malignant teratoma is a type of NSGCT characterized by the presence of undifferentiated elements and the potential for distant metastasis. Bony involvement in malignant teratoma is rare, and isolated bone involvement is very rare.
Tumour markers are helpful in identifying early recurrence in malignant teratoma, emphasising the need for serial measurements and longer follow up. 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) scanning plays an important role in identifying the site of recurrence in marker only recurrence in malignant teratoma.
Late recurrences in malignant teratoma arise from differentiated elements. They are best treated by surgery, aiming for complete resection to achieve cure .Management of iliac bone metastasis is complex and involves input from various specialities in a multidisciplinary team setting. Chemotherapy and radiotherapy help to palliate symptoms and improve quality of life.
We present a 65 year old man who presented with a three year history of right testicular swelling and weight loss. Further investigations revealed malignant teratoma with multiple pulmonary nodules and no other metastases. His tumour markers were raised with a Human Chorionic Gonadotropin (HCG) of 1253 mIU/ml. He had an intermediate risk tumour in the International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic classification.
He was treated with orchidectomy and four cycles of BEP (Bleomycin, Etoposide and Platinum) chemotherapy with a good response. He achieved remission with complete resolution of the pulmonary nodules and his tumour markers normalised. A follow up CT scan did not show any evidence of residual disease to warrant post chemotherapy surgery. The left iliac bone was slightly prominent, suggestive of Paget’s disease. He was asymptomatic and was followed up regularly in the Germ Cell Cinic.
Seven years later his alpha fetoprotein (AFP) level increased gradually, and remained between 8 and 37ku/l. (Figure 1).
Figure 1. Alpha fetoprotein (AFP) level increased gradually
He was clinically well without any symptoms. He had various scans during this period including a FDG- PET/CT scan which showed no evidence of recurrence. However, the left iliac bone appeared irregular with a trabecular pattern and was metabolically inactive. The bone changes were similar to the appearances on CT scan at the time of presentation. It was concluded that this was either fibrous dysplasia or Paget’s Disease following discussions in the multi disciplinary meeting.
Six months later his AFP increased to 100ku/l. Further imaging with FDG- PET/ CT scanning showed a metabolically active lesion in the tail of the pancreas as well as the left iliac bone. He was clinically well without any symptoms. He was discussed in the multi disciplinary meeting. The bone appearances in the iliac bone remained unchanged on the CT scan except being metabolically active, and he was asymptomatic. The abnormal activity in the iliac bone was again concluded as being secondary to either fibrous dysplasia or Paget’s Disease. A pancreatic biopsy was planned to exclude recurrence in the pancreas.
Meanwhile the patient developed hip pain and his AFP progressively increased to 6,000ku/l. Further FDG -PET/CT scan showed persistent activity in the iliac bone (Figure 2 &3) along with a soft tissue mass, and the pancreatic lesion disappeared.
Figure 2. FDG -PET/CT scan
Subsequently he had biopsy of the left iliac bone which confirmed metastatic teratoma of yolk sac tumour with atypical glandular and papillary growth pattern. (Figure 4 &5)
At this stage he was considered for radical surgery. As the teratoma was diffusely infiltrating the iliac bone and the sacrum, it was thought that radical surgery even with a hind quarter amputation would not achieve clear margins and would result in considerable disability. He was treated with radical radiotherapy and received 50 Gy in 25 fractions to the iliac bone and pelvis. He had good clinical response and his AFP reduced to 2162 ku/l.
However in the next six months his hip pain worsened and the AFP progressively increased to 26100 ku/l. At this stage further treatment options were discussed and he had less radical surgical curettage and cementoplasty of the iliac bone. Following this he had a good clinical response, his pain improved significantly and his AFP dropped to 6100 ku/l.
Within three months his hip pain worsened and his AFP progressively increased to 11,100 ku/l. He was treated with six courses of palliative Gemcitabine and Oxaliplatin chemotherapy. He had a good clinical and metabolic response and his AFP dropped to 26 ku/l.
Within two months of completing chemotherapy his AFP progressively increased to 650 ku/l. He had two courses of Cisplatin and Etoposide with some response but this was discontinued due to myelotoxicity.
He was considered for experimental treatment but was not eligible for any current studies. He currently remains well and active with symptomatic treatment alone and enjoys a good quality of life.
Patients with germ cell tumours respond well to treatment. Patients who remain in remission for more than two years following initial treatment are considered to be cured.  Most recurrences occur within two years of treatment; late recurrences beyond two years of initial therapy are uncommon.
Very late recurrences beyond five years are rare and occur in Non Seminomatous Germ Cell Tumour; with a 1% annual risk of recurrence between five and ten years. The commonest sites of late relapse are abdominal (in the paraaortic, and retroperitoneal regions), and occur in about 50 % of the patients. [2, 4] Positive tumour markers at presentation and the presence of differentiated elements in the tumour after chemotherapy are important predictive factors of late recurrence. 
Clinically detectable bone metastasis occurs in 3% of patients with metastatic germ cell tumour at presentation . The incidence of late bone metastasis varies between 3- and 9% [6, 7] and isolated late bone recurrence is very rare, seen in 1% of the patients.  The bones of the trunk, especially the lumbar spine are commonly involved as described in historical autopsy series [8, 9] and pelvic bone involvement is very rare.
Long term follow up beyond five years is vital in patients with NSGCT presenting with positive tumour markers and advanced stage at diagnosis. Follow up usually involves clinical assessment, chest radiographs and measurement of tumour markers.
Serial measurement of tumour markers is useful in diagnosing late recurrences as they are elevated in greater than 50% of the recurrences.  Elevated tumour markers are one of the earliest and sole indicators of recurrence as seen in our patient.  FDG-PET /CT scan is valuable in localising the site of recurrence in patients with marker only relapse. 
Most of the late recurrences in NSGCT after initial chemotherapy are believed to arise from residual differentiated teratoma elements. Late recurrences with yolk sac differentiation reveal atypical glandular and papillary growth pattern.  They have a different natural history characterized by slow growth, secretion of AFP, chemo resistance and poor prognosis. [3, 11]
Surgery plays the most important role in the management of late recurrence. [2, 4] Complete resection of viable tumour increases the chance of cure. However with incomplete resection the recurrence rate is higher. Chemotherapy and radiotherapy helps in palliating symptoms and thereby improves quality of life.
Isolated bone metastasis in Non Seminomatous Germ Cell Tumour is very rare. Management of iliac bone disease is complex and should involve a multi disciplinary team approach.
Prolonged follow up beyond five years with measurement of tumour markers is important, especially for those presenting with positive tumour markers and advanced stage at presentation.
FDG-PET/ CT scan plays a vital role in localising relapse site in marker only recurrences.
Late recurrences have a different natural history. Surgery plays the most important role in the management of late recurrence.
Chemotherapy and radiotherapy help in palliating symptoms and thereby improve quality of life.
1, Einhom LH-: Testicular cancer as a model for a curable neoplasm: The Richard and Hilda Rosenthal Foundation Award Lecture. Cancer Res. 1981; 41:3275-3280.
2, Baniel J, Foster RS, Gonin R ,Messemer JE,Donohue JP, Einhom LH. Late relapse of testicular cancer. J Clin Oncol.1995; 13(5): 1170–1176.
3, Gerl A, Clemm C, Schmeller N, Hentrich M, Lamerz R, Wilmanns W. Late relapse of germ cell tumors after cisplatin-based chemotherapy. Ann Oncol. 1997; 8:41–47.
4, Shahidi M, Norman AR, Dearnaley DP, Nicholls J, Horwich A, Huddart RA. Late Recurrence in 1263 Men with Testicular Germ Cell Tumors. Cancer. 2002; 95:520-530.
5, Oldenburg J, Alfsen GC, Waehre H, Fossa SD. Late recurrences of germ cell malignancies: a population-based experience of over three decades. Br J Cancer.2006; 94:820-827.
6, Hitchins RN ,Philip PA, Wignall B, et al. Bone disease in testicular and extragonadal germ cell tumours. Br. J. Cancer.1988; 58:793-796.
7, Flechon A, Culine S, Theodore C, Droz JP. Pattern of Relapse after First Line Treatment of Advanced Stage Germ-Cell Tumors. European Urology. 2005; 48: 957–964.
8, Dixon FJ and Moore RA. Testicular tumours – A clinicopathologic study. Cancer. 1953; 6(3): 427- 454.
9, Mostofi FK .Testicular tumours – Epidemiologic, etiologic, and pathologic features. Cancer. 1973; 32(5), 1186 – 1201.
10, Hain SF, O’Doherty MJ, Timothy AR, Leslie MD, Harper PG and Huddart RA. Br J Cancer.2000; 83(7): 863-869.
11, Michael H, Lucia J, Foster RS, and Ulbright TM, American Journal of Surgical Pathology.2000; 24(2): 257–273.
Date added to bjui.org: 15/03/2012