High grade non-germinal centre-like diffuse large B-cell lymphoma double expressor presenting as a hydrocoele

Abstract

A 72-year-old man was referred to our urology outpatient department with a left hemi-scrotal swelling increasing in size over a matter of weeks, initially suspicious for a left hydrocoele. Initial investigation with ultrasound (US) identified a heterogenous enlargement of the left testis and epididymis with a soft tissue mass extending through the inguinal canal. Subsequent CT detected this soft tissue mass to extend along the left gonadal vein to the level of the left renal vein. A biopsy of the retroperitoneal mass confirmed a diagnosis of diffuse large B-cell lymphoma. Immunohistochemical staining further categorised this lymphoma as double expressor but not double hit.

Through multidisciplinary team involvement the patient was treated with combination steroids and chemotherapy. Given the scrotal involvement this was considered a sanctuary site for chemotherapy therefore the patient also received radiotherapy to the scrotum. He recovered well following his treatment. This case highlights how early specialist referral can identify rare variants of disease. Essential preoperative imaging with US prior to treating a presumed hydrocoele prevented inappropriate surgical excision. A multidisciplinary team approach improved the patient’s outcome and is hoped to have improved his chances of recurrence-free survival.

Background

Testicular lymphoma is rare accounting for less than 5% of all testicular neoplasms, but the incidence increases with age.¹ Testicular lymphoma is the most common testicular neoplasm in men over 60 years.¹ Overall, less than one-third of lymphomas are primary extranodal, of which just 2% arise from the testis.² Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma (25% of cases), with a male predominance and a median age of presentation of 64 years.³ New biological subsets termed double hit lymphoma (DHL) and double expressor lymphoma (DEL), relating to identification of concurrent MYC and BCL2 deregulation, have identified patients with a more aggressive form of lymphoma often refractory to standard chemotherapy.⁴ DHL is rare and accounts for just 5%–7% of all DLBCL, with DEL accounting for 20%–30%. DEL is associated with an inferior overall survival (HR 2.52) and progression-free survival (HR 2.45).⁵

We report the case of a septuagenarian presenting with a painless scrotal swelling, who through collaborative investigation and management achieved early diagnosis and treatment of a stage 2aE high grade DLBCL. A multidisciplinary approach was required involving urology, radiology, medical oncology, haematology, radiation oncology, neurosurgery, neurology, cardiology, interventional radiology, pathology, clinical nurse specialists, physiotherapy and occupational therapy were essential to deliver this patient’s treatment. This case presents a rare form of lymphoma and highlights how a broad clinical suspicion for all patients being reviewed in the outpatient setting is required.

Preoperative work-up is essential for appropriate patient care and early involvement of a multidisciplinary team provides the best possible patient care. This report describes the management of a patient with a common urological presentation which leads to the early diagnosis and treatment of a rare form on non-Hodgkin’s lymphoma.

Case presentation

A 72-year-old man was referred to our urology outpatient department with a painless left hemi-scrotal swelling increasing in size over a few weeks, initially suspicious for a left hydrocoele. His history was significant for ischaemic heart disease with previous coronary artery bypass grafting and type 2 diabetes mellitus. On examination there was left hemi-scrotal swelling approximately 6 cm in size and an ultrasound (US) was arranged routinely. He did not complain of any fever, night sweats or weight loss. His Eastern Cooperative Oncology Group (ECOG) performance status was 0.

Investigations

His baseline full blood count and biochemistry were unremarkable. Testicular tumour markers were performed identifying a normal α-fetoprotein of 2.9 µg/L, a normal β-hCG of 2 U/L, and an elevated lactate dehydrogenase of 665 U/L.

US of the scrotum identified a grossly enlarged left testis measuring 5.6×5.9 cm with heterogeneous echotexture and diffuse areas of low echogenicity within which it appeared to demonstrate excess vascularity, a small left hydrocoele was present, with abnormal thickening of the left epididymis, and a soft tissue abnormality extending into the spermatic cord and left inguinal canal (figure 1).

Figure 1.

Ultrasound left testis with arrow identifying heterogeneous echotexture.

A CT of the thorax, abdomen and pelvis identified abnormal soft tissue extending along the left spermatic cord and into the retroperitoneum along the line of the gonadal vein to the level of the left renal vein which is patent. There was encasement of the left ureter with resultant hydronephrosis. No lymphadenopathy, solid organ abnormality or destructive bony abnormalities identified (figure 2).

Figure 2.

CT with arrow identifying left retroperitoneal mass.

A PET/CT was performed showing extensive fluorodeoxyglucose (FDG)-avid disease extending from the left retroperitoneal region along the left testicular vessels to left hemi-scrotum (figure 3).

Figure 3.

Positron emission tomography with arrow identifying increased metabolic activity in the left retroperitoneum.

A CT-guided retroperitoneal biopsy was performed by the interventional radiology department. The biopsy demonstrated an atypical cellular infiltrate with necrosis, condensation of viable cells around some vascular structures and abundant apoptosis. The tumour cells were pleomorphic, medium to large in size, containing variable amounts of cytoplasm with identifiable nucleoli (figure 4). Immunohistochemical analysis identified the lesional cells to be positive for CD45 and the B-cell marker CD20, and negative for CD5, cyclinD1 and EBER. BCL6 and MUM1 were positive, and CD10 negative, allowing classification as non-germinal centre-like by the Hans algorithm. The Ki67 proliferation index was greater than 90%, and there was double expression of both BCL2 and c-MYC protein. Florescence in situ hybridisation (FISH) studies showed no evidence of a MYC gene rearrangement, excluding DHL. Bone marrow biopsy was negative for lymphomatous involvement. Cerebrospinal fluid cytology did not demonstrate malignant cells.

Figure 4.

Retroperitoneal biopsy. H&E, 400 x. The malignant cells are large, with irregular nuclear contours, coarse chromatin and prominent nucleoli. There is abundant apoptotic debris and mitoses are readily identified.

The final diagnosis was DLBCL, non-germinal centre-like, with a double-expressor phenotype.

Differential diagnosis

The patient was initially referred with concerns for an enlarging left scrotal swelling presumed to be a hydrocoele. Clinical examination was consistent with this initial diagnosis and the swelling transilluminated. Despite this clinical diagnosis further investigation with US was arranged prior to any surgical intervention. Initial imaging with US demonstrated heterogeneity of the testis with areas of hypervascularity. The possibility of orchitis was excluded as the patient had not had any recent symptoms in keeping with infective orchitis. A primary testicular neoplasm was added to the list of differentials, however, given the patient’s age a seminomatous or non-seminomatous germ cell tumour was thought to be less likely. A diagnosis of non-germ cell tumour was thought more likely. US also identified that the soft tissue mass extended through the inguinal canal and offered further differential diagnoses of an indirect inguinal hernia vs a neoplastic process. Subsequent CT and PET confirmed the diagnosis of a neoplasm extending along the left retroperitoneal space. With the assistance of CT-guided biopsy, a final diagnosis of DLBCL was confirmed.

Treatment

The patient was referred urgently to the haematology service for further treatment. Given his left sided hydronephrosis there was discussion regarding the need for ureteric stent placement to decompress the left renal collecting system. The advice from the haematology service was that the steroid would act quite effectively in reducing the tumour burden around the left ureter and a stent would be unlikely to be required. Given the initial suspicion of DHL and the considerable time taken for molecular testing results, as well as his ECOG 0 status, he was treated initially with rituximab, etoposide, prednisolone, vincristine, cyclophosphamide and doxorubicin hydrochloride (R-EPOCH) with intrathecal prophylaxis with methotrexate. He was de-escalated to rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisolone (R-CHOP) due to neutropenic sepsis. Due to ongoing concerns regarding neutropenia, he was further de-escalated to R-mini-CHOP. A US following his initial treatment was performed to assess for resolution of the previously noted left hydronephrosis, which had completely resolved (figure 5). He developed atrial fibrillation with echocardiographic evidence of cardiomyopathy during his treatment and his doxorubicin was switched to liposomal doxorubicin to reduce the risk of cardiac toxicity. He developed a lower limb deep vein thrombosis (DVT) and was commenced on therapeutic anticoagulation. Due to a persistent post-lumbar puncture headache, a cerebral magnetic resonance image (MRI) was performed identifying incidental bilateral subdural haemorrhages (SDH), likely subacute or chronic. Involvement of neurosurgery and neurology was required; however, no intervention was necessary. His anticoagulation for his DVT was ceased during this time and he had an inferior vena cava filter placed by interventional radiology. He subsequently restarted therapeutic anticoagulation given follow-up imaging showed reduction in the bilateral SDH. Physiotherapy and occupational therapy were heavily involved in his recovery given his multiple hospital admissions.

Figure 5.

Post-treatment positron emission tomography showing resolution of the previously identified left retroperitoneal fluorodeoxyglucose-avid mass.

The scrotal swelling reduced following his systemic treatment. Given the scrotum is a sanctuary site for chemotherapy he was referred for radiotherapy to the scrotum. He received 30 Gy in 15 fractions. He suffered some minor temporary skin changes over the scrotum but otherwise the treatment was well tolerated.

Outcome and follow-up

At 1 year following his initial diagnosis and 6 months after completing his systemic therapy there was no metabolically active evidence of lymphoma relapse based on PET and no measurable recurrence on CT imaging (figure 5). He has recovered well following his systemic chemotherapy and adjuvant radiotherapy.

Discussion

Although the testes have been well documented as a common site of origin for extranodal lymphoma, there is a paucity of literature identifying the rarer DEL subtype of DLBCL originating from the testes. Overall, less than one-third of lymphomas are primary extranodal, of which just 2% arise from the testis.^{2 6} Incidence increases with age and in those over 60 years it is the most common malignancy of the testis.² A retrospective analysis of 106 extranodal DLBCL biopsies identified 21 samples with testicular tumour origin, of which just one sample demonstrated DHL.⁷

The incidence of DLBCL in Europe is 3.8/100,000/year, increasing considerably with age.⁸ Risk factors include a family history of lymphoma, autoimmune disease, HIV infection, hepatitis C virus seropositivity and obesity.⁹ A biopsy is essential in diagnosis and is assessed in several ways; histological or cytological evaluation assesses cellular morphology; immunophenotyping using flow cytometry or immunohistochemistry allows detailed subclassification; cytogenetic studies using conventional karyotype or FISH identifies chromosomal abnormalities; and molecular analysis by PCR, DNA sequencing or gene expression studies identifies mutations and gene rearrangements, gain or loss of certain genes.^{7 10}

A comprehensive work-up is essential for planning of treatment and should include clinical examination, performance status, assessment of B symptoms (fever, night sweats, weight loss), a full blood count, LDH and uric acid as screening for blood borne viruses.¹¹ The gold standard for imaging is PET/CT as increased metabolic activity can be identified as FDG-avid, which may direct focused adjuvant therapies, particularly in sanctuary sites for chemotherapy (central nervous system and testis).^{7 11} This allows for staging based on the Ann Arbour classification, escalating based on number of nodal regions involved, involvement of nodes based on the diaphragm or involvement of extranodal tissue.¹² Based on these investigations in 1993 the international prognostic index (IPI) was created and validated, estimating 3-year overall survival based on five risk factors including age >60 years, elevated serum LDH, stage 3–4 disease, performance status 2–4 or more than one extranodal site.¹³

Chemotherapy and steroids remain the mainstay of treatment with differing regimes based on the patients IPI, age and other co-morbidities that might increase the risk of toxicity.¹⁴ Generally, between six and eight cycles of combination chemotherapy such as R-EPOCH, R-CHOP or R-mini-CHOP are recommended with or without adjuvant radiotherapy if there is presence of bulky disease.¹⁵ Adjuvant radiotherapy is also used, as in this present case, for sanctuary sites for chemotherapy such as central nervous system and testis. Response to treatment is measured using PET/CT to identify any remaining metabolically active disease.¹⁶ There is no evidence to support any further follow-up imaging if post-treatment PET/CT is negative as it has been identified that patients who are 2 years post-treatment and remain event-free have an overall survival identical to the general population.¹⁷

Our case demonstrates a rare form of extranodal DLBCL with a typically aggressive course, identified at an early stage and through a multidisciplinary team approach the patient is disease free just 1 year after initial presentation. A broad index of suspicion is required for all patients being reviewed in all outpatient department settings. With further developments in recent years using molecular analysis the cohort of higher risk patients such as those with DEL and DHL can be identified, and appropriate chemotherapy regimens initiated at an early stage.

Learning points.

• This case of an unusual presentation of an aggressive subtype of lymphoma should encourage the reader to adopt a broad differential diagnosis and to use the imaging modalities available to avoid diagnostic uncertainty. Essential preoperative imaging with ultrasound prior to treating a presumed hydrocoele prevented inappropriate surgical excision.

• The use of a multidisciplinary team approach is essential in treating all patients with a malignancy to deliver expedient and tailored patient care. The involvement of allied health professionals in the recovery of these patients post chemotherapy is fundamental.

• Discussion of a patient’s treatment at a multidisciplinary team meeting is essential to identify any adjuvant treatment that may be recommended by specialists in different fields.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).