Triple-hit high-grade B-cell lymphoma presenting with ovarian torsion

Abstract

We report a case of a previously healthy woman in her early 70s who presented with 2 weeks of episodic abdominal pain and significant weight loss. Imaging of her abdomen revealed acute right ovarian torsion associated with bilateral ovarian enlargement and an indeterminant pelvic mass. An urgent laparoscopic bilateral oophorectomy was performed with pathological results consistent with triple-hit high-grade B-cell lymphoma. She was successfully treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab, intrathecal methotrexate and venetoclax with complete remission after three cycles. Ovarian lymphoma is a rare entity and its genetic features have not been well described. We performed a literature review, describe the current knowledge regarding ovarian lymphoma and its therapeutic implication in the genomic age.

Background

Adnexal masses in elderly women are a concerning finding given the high frequency of an underlying neoplasm. Non-malignant adnexal masses are less common in postmenopausal women. Malignancies may arise as primary lesions from the ovaries, fallopian tubes, uterus, omentum or peritoneum or they may represent a distant metastasis (most commonly breast or gastrointestinal origin (Krukenberg tumour)). Primary ovarian lymphoma is a rare cause of ovarian mass due to the lack of a traditional lymphatic system in this location.¹ It has been hypothesised that primary ovarian lymphoma may originate from lymphocytes in the ovaries (including in corpus luteum), lymphocytes in surrounding blood vessels or from an abnormal deposit of lymphocytes related to autoimmune disease.² Despite advancement in imaging technology, most ovarian masses in postmenopausal women still warrant an exploratory laparotomy for complete surgical staging. Ovarian lymphoma represents a problematic differential diagnosis in this context as they can respond to systemic chemotherapy without surgical intervention. As such, the decision to proceed with surgery requires careful consideration particularly in the setting of bilateral ovarian masses. Adnexal masses can lead to complications such as haemorrhage, rupture or torsion. Ovarian torsion is a gynaecological emergency and usually warrants urgent to emergency laparoscopic exploration regardless of the underlying aetiology of the mass.

Case presentation

A 72-year-old previously healthy woman presented with episodic abdominal pain. Her first episode occurred 2 weeks prior to presentation after a heavy meal. She described the pain as non-radiating ‘stomach’ pain that subsided after a few hours. The next morning, she woke up with a similar but less painful episode that also spontaneously subsided after a few hours. On the day of presentation, she experienced excruciating 10/10 pain that worsened with movement. This was associated with mild nausea without vomiting. She also reported 20-pound weight loss over the past 6 months that she had attributed to her low sugar diet. She denied other associated gastrointestinal or genitourinary symptoms including change in bowel movement, change in urinary habits or pain with urination. She was postmenopausal and denied vaginal bleeding. Her medical history was remarkable for mild asthma, diverticulitis in 2014 and resected basal cell carcinoma. She also had a cholecystectomy. She took Lipitor, vitamin D3a multivitamin and an albuterol inhaler. Family history was notable for prostate cancer in her father. She occasionally drank alcohol in social settings but denied any use of tobacco or marijuana products.

On physical examination her vital signs were stable but she appeared to be in pain. She was not pale or jaundiced. Cardiovascular and respiratory examinations were within normal limits. Abdominal examination revealed mild tenderness in the right lower quadrant with deep palpation without hepatosplenomegaly or peritoneal signs. No mass was appreciated. No cervical or inguinal lymphadenopathy was appreciated.

Investigations

Her initial laboratory findings included complete blood count, basic metabolic panel, liver function test, erythrocyte sedimentation rate, C reactive protein, all within normal limits. Her CEA, CA-125, uric acid and lactate dehydrogenase were also within normal limits. A CT scan of her abdomen/pelvis showed a midline enhancing mass that was separate from the uterus but inconclusive for an ovary or pedunculated fibroids (figure 1A, B). The study was also notable for right adnexal fluid and para-aortic lymphadenopathy of up to 1.5 cm. Her pelvic ultrasound revealed a midline soft tissue 6.9×4.5 cm mass without demonstratable flow, a left ovary with normal flow, as well as a separate right adnexal hypoechoic mass. The radiographer was unable to visualise a distinct right ovary (figure 1C, D). Pelvic MRI revealed a non-enhancing T2 dark mass measuring 8.3×6.5×5.9 cm posterior to the uterus, extending to the right adnexa, thought to represent a torsed, enlarged ovary. The left ovary was enlarged, measuring 3.3×2.0×2.3 cm, with homogenous T2 hyperintensity, concerning for lymphomatous involvement (figure 1E–G).

Figure 1.

Abdominal imagines prior to surgery. (A) Coronal CT of the abdomen with intravenous contrast showed para-aortic lymphadenopathy (circle) measuring up to 1.5 cm. (B) Axial CT of the abdomen with intravenous contrast showed a left adnexal mass (arrow) which may represent an abnormal left ovary or a soft tissue mass (asterisk) or possibly contiguous with the uterus representing a pedunculated fibroid (U). (C, D) Transvaginal pelvic ultrasound confirmed the left ovary (arrow) was separated from the midline pelvic soft tissue lesion (asterisk) and had minimal doppler flow. (E–G) Coronal view of abdominal MRI with T2, T1 and T1 postcontrast, respectively, showed a 3.3×2.0×2.3 cm homogeneously enhancing T2 hyperintense ovary in the left adnexa (arrow) as well as a non-enhancing 8.3×6.5×5.9 cm mass within the midline of the pelvis extending towards the right lateral pelvis likely arising from the right ovary (asterisk) concerning for torsion given the enlargement lack of enhancement.

She was diagnosed with right ovarian torsion and underwent a laparoscopic bilateral salpingo-oophorectomy with peritoneal washing. The intraoperative finding revealed a torsed right ovarian and fallopian tube with marked oedema and necrosis. This was detorsed and removed. The left ovary was enlarged and solid appearing with a normal appearing left fallopian tube. These were subsequently removed.

Differential diagnosis

The patient presentation of acute on subacute abdominal pain associated with weight loss, a large indeterminant pelvic mass abutting the uterus and bilateral ovarian masses complicated by unilateral torsion was concerning for malignant neoplasm. The bilateral involvement and a normal CA-125 level made the differential diagnoses of the most common primary ovarian neoplasms—epithelial neoplasm, germ cell tumour or sex cord-stromal tumour—less likely. Other differential considerations included distal metastasis from a secondary site such as endometrial, breast or gastrointestinal tract. This was thought to be less likely given her normal endometrial thickness on CT scan, absence of breast mass or masses in her gastrointestinal tract on imaging. Locoregional spread of sarcoma or primary peritoneal carcinoma were possible. However, the indeterminant mass was only abutting the uterus and did not actually originate from it. Benign lesions such as leiomyoma were also considered however patient did not have any significant premenopausal or perimenopausal problems which made this less likely. the less common primary ovarian lymphoma was also within the differential, given limited lymphadenopathy. Lymphomatous involvement of the ovaries can present with bilateral ovarian mass at any age, fitting this patient’s presentation. However, the rarity of primary lymphoma of the ovary made the diagnosis less likely.

Additional investigation

The surgical specimens were sent for pathological examination and molecular analysis. On inspection, the right ovarian and fallopian associated with gross haematoma. H&E stain slides showed multiple fragments of tissue consistent with ovary associated with haemorrhage and oedema. Abundance atypical, malignant-appearing, discohesive cells with medium size nuclei, coarse chromatin and minimal cytoplasm were present in both the left and right ovaries (figure 2A). Abundant necrosis was noted. Immunohistochemistry (IHC) revealed diffuse positivity for CD20, CD10 and increased Ki67 staining (~90% of cells) supporting a diagnosis of B-cell lymphoma (figure 2B). Additional IHC stains showed >40% expression of MYC and >50% expression of BCL2 (figure 2C, D). Stains for CD23, cyclin D1, CD30, MUM1, TdT, EBV, keratin AE1/AE3, S100 and calretinin were negative. Fluorescence in situ hybridisation confirmed MYC rearrangement (not involving IGH), IGH/BCL2 rearrangement and BCL6 rearrangement (figure 3). These findings supported the diagnosis of triple-hit high-grade B-cell lymphoma involving bilateral ovaries.

Figure 2.

Pathohistological slides of the right ovary and fallopian tube. (A) Atypical cells with medium-sized nuclei, coarse chromatin and minimal cytoplasm, arranged in a discohesive pattern, consistent with high-grade B-cell lymphoma on a background of haemorrhage and oedema suggestive of torsion (H&E, ×400). (B–D) Immunohistochemical stains including B-cell marker CD20 (×200), MYC (×400) and BCL-2 (×400), respectively, all with diffuse positive staining.

Figure 3.

Fluorescence in situ hybridisation. Vyvis break-apart probe for BCL6 on chromosome 3 and MYC on chromosome 6 and translocation probed for IGH and BCL2 on chromosome 14 and 18 and MYC and IGH (and the pericentrometric region of chromosome 8) were used. Signal patterns represent MYC rearrangement (with a gene other than IGH), BCL6 rearrangement and IGH/BCL2 rearrangement consistent with ‘triple’ hit lymphoma.

Staging Positron Emission Tomography - Computed topograph (PET-CT) demonstrated marked flurodeoxyglucose (FDG) uptake, greater than liver (SUV max 13.4), in the previously indeterminant right adnexal mass which likely represent a pelvic adenopathy, consistent with lymphoma (figure 4A–C). The spleen demonstrated more avid FDG uptake than the liver (figure 4D–F). Increased activity was also seen in the paraaortic lymph nodes (figure 4G). Lumbar puncture showed two nucleated cells/μL with 85% lymphocytes, 15% monocytes and 0 red blood cell. Subsequent workup of bone marrow biopsy did not show lymphomatous involvement. These findings highlight that the disease was relatively confined to the pelvic region, consistent with primary ovarian lymphoma with metastatic spread.

Figure 4.

Positron Emission Tomography - Computed topography (PET-CT) after bilateral salpingo-oophorectomy. (A) Axial view of the pelvic demonstrating a soft tissue density mass (arrow). (B, C) Corresponding axial view with attenuation correction and axial fused imaging demonstrating the soft tissue mass with avid increased in flurodeoxyglucose (FDG) and metabolic activity (SUV of 13.4). (D) Non-contrast axial view of the spleen (arrowhead). (E, F) Corresponding attenuated correction and axial view fused imaging of the spleen with diffusely increased FDG avidity with SUV of 1.97, greater than the liver. (G) Coronal view with maximum intensity projection showing peri-aortic and mesenteric lymphadenopathy with SUV max of 1.9 (circle) and a soft tissue density mass in the pelvis (arrow).

Overall, the patient was diagnosed with triple-hit high-grade B-cell lymphoma with Ann Arbor staging of intravenous involving bilateral ovaries along with diffuse pelvic and splenic involvement without central nervous system (CNS) involvement. Her performance status was grade as Eastern Cooperative Oncology group (ECOG) of 0 and Karnofsky performance status of 90% with an international prognostic index of 3.

Treatment, outcome and follow-up

She was started on six cycles of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) and intrathecal methotrexate with granulocyte colony stimulating factor. The patient also received three dose of MYC/BCL2 inhibitor, venetoclax, as part of a randomised controlled trial (NCT03984448). She was randomised to Arm B with Venetoclax and received venetoclax 600 mg daily for 5 days during cycles 2, 3 and 4. This was timed at day 4–8 of her cycle 2 and subsequently on day 1–5 for her 3 and 4 of her DA-EPOCH-R regimen. Tumour lysis lab was checked 12, 24 hours and 7 days after the first dose of vetenoclax. She experienced alopecia, loss of appetite, nausea, acid reflux, voice hoarseness and peripheral neuropathy from the chemotherapy regimen. Her absolute neutrophil count nadir was 580/μL on one occasion without signs of infection. She did not show any clinical or laboratory signs of tumour lysis. Her peripheral neuropathy was deemed grade I, however, her hoarseness was due to vocal cord paralysis and may be related to grade II motor neuropathy. Given these side effects, the vincristine dose was reduced by 25% after the fourth cycle. Her appetite and voice hoarseness improved at treatment completion. She had persistent peripheral neuropathy and residual acid reflux symptoms that were controlled with a proton pump inhibitor and an H2 inhibitor.

Overall, she tolerated the treatment well. PET/CT follow-up after three cycles showed complete resolution of the soft tissue mass and reduction in the size of lymphadenopathy. At treatment completion she had complete resolution of her lymphadenopathy with Deauville score of 1.

Discussion

We presented a case of triple-hit B-cell lymphoma presenting as ovarian torsion associated with an adjacent pelvic mass of unknown origin. It can be difficult to discern whether an ovarian lymphoma is primary or secondary as the ovary is also a common site of secondary lymphoma spread. Fox et al proposed diagnostic criteria in 1988 where the lymphoma has to be clinically confined to the ovary and absent in the blood or bone marrow.³ Primary ovarian lymphoma (POL) can still be considered if the spread has occurred in immediately adjacent tissue or local pelvic lymph nodes.³ Although this patient had lymphomatous involvement of pelvic and para-aortic lymph nodes and spleen as demonstrated by the PET-CT, it is still reasonable to consider this case a late presentation of a primary ovarian lymphoma with subsequent spread, given the chronicity of her symptoms and lack of prior imaging.

POL can present at any age, with the youngest case report at 2 years old and the mean age of presentation 42 years of age.⁴ Typical presenting symptoms include abdominal mass associated with pain or discomfort and ‘B’ symptoms of fatigue, night sweats and unintentional weight loss.^5–7 Bilateral ovarian masses are more common than a unilateral mass at presentation. Symptoms of local spread are less common but can lead to vaginal bleeding, constipation, bowel obstruction, ascites or pleural effusion. Our patient is of a more advanced age but did have typical symptoms of ovarian lymphoma. However, it is important to note that these symptoms are non-specific and similar to those experienced as a result of other types of pelvic masses.

Prior reports of primary ovarian lymphoma date back before the genomic era and limited data are available regarding their genomic aberrations. Given the combined rarity of both POL and double-hit B-cell lymphoma, there has only been one other case report of primary ovarian lymphoma with double-hit status.⁸ Khattar et al report a targeted capture sequencing with up to 4800 genes of primary ovarian lymphoma in two paediatric patients.⁹ Genomic mutation in 18 loci were identified including key drivers mutation in EZH2, HLA-A, MYD88, CREBBP and NOTCH1 where EZH2 and MYC88 are uniquely mutated in each case. Extra-nodal non-Hodgkin lymphoma (NHL) in privileged immune sites such as primary CNS and testicular lymphoma may exhibit similar genomic profiles as an ovarian lymphoma.¹⁰ Indeed, HLA-A and DDX11, common mutated genes unique to primary testicular lymphoma were also found to be mutated in both of these POL cases.¹⁰ Further studies are needed to characterised the contribution of these mutations in cancer progression and their therapeutic implications.

Diffuse large B-cell lymphoma is the most common histological type of POL followed by Burkitt lymphoma.^{5 11} Assessing MYC status, BCL2 and/or BCL6 translocation and MYC/BCL2 protein expression by IHC have now become a standard of care.¹² Tumours expressing both MYC and BCL-2 by IHC are termed ‘double expressor’ high-grade lymphoma, and those with proven genetic aberrations are termed ‘double-hit’ high-grade lymphoma. Cytogenetic identification of MYC rearrangement, BCL2 and BCL6 translocation are termed ‘triple-hit’ lymphoma. Double-hit/triple-hit lymphoma (DHL/THL) account for less than 15% of B-cell lymphoma and are now classified as a distinct entity from diffuse large B-cell lymphoma.¹³ They are more aggressive, share similar characteristics with Burkitt lymphoma and are more resistant to standard R-CHOP therapy.^14–16 More intense upfront chemotherapy regimens such as hyper-CVAD, EPOCH-R or CODIX-M/R-IVAC are preferred. Among these EPOCH-R in particular have been shown to have more favourable outcome in a meta-analysis of retrospective studies and a prospective clinical trial.^{17 18} The role of consolidation therapy with haematopoietic stem cell transplantation (h-SCT) remains controversial. So far, a small retrospective did not show any significant benefit of consolidated h-SCT along with chemotherapy. DHL/THL also carries a significantly higher risk of CNS relapse and CNS prophylaxis with methotrexate is warranted regardless of CNS-International Prognostic Index (CNS-IPI) score.¹⁹

Given the aggressive nature of this lymphoma, clinical trials are underway to test the utility of novel therapeutics such as small-molecular inhibitors targeting myc or B-cell lymphoma 2 (Bcl-2) signalling pathway, checkpoint inhibitors, chimeric antigen T-cell therapy and bromodomain inhibitors.^{20 21} This patient was enrolled in a phase II/III randomised, controlled clinical trial of Bcl-2 inhibitor venetoclax²² (NCT03984448) and randomised to the treatment arm. Bcl-2 inhibitor such as venetoclax and navitoclax is an emerging class of medication used in haematological malignancy and has been approved for relapsed chronic lymphocytic leukaemia, acute myeloid leukaemia, relapsed myeloma and relapsed follicular, mantle cell and diffuse large B-cell lymphoma.²³ Bcl-2 inhibitor can be highly effect and used as a monotherapy in certain malignancy. It is difficult to speculate the extend of venetoclax contribution to her remission. However, given the genetic alteration seen and potency seen in other haematological malignancy, venetoclax may contribute to her remission. Overall, given the aggressiveness of THL, patients should be considered for a clinical trial participation upfront.

Radical surgical intervention is generally not indicated. However, given the challenge surrounding definitive diagnosis of ovarian tumour without tissue sample, patients usually received surgical resection with recognition of lymphoma after the fact, as happened in our case. A key additional and distinguishing factor for this particular patient was evidence of ovarian torsion, making surgery a necessary intervention.

Patient’s perspective.

The first symptom I had was a bad stomach ache that occurred soon after I had eaten a lunch the was heavier than I normally ate. It lasted for a couple of hours and was pretty uncomfortable. Then it went away, and I attributed it to overeating. Then, a few days later, I woke up with a stomach ache that wasn’t as severe as the previous one and didn’t last as long. After it subsided, I didn’t give it much thought. Then, almost exactly 2 weeks after my first stomach ache, I stood up after watching the News and felt a sharp, really severe pain in my lower right side. As I moved around, the pain got worse and very shortly afterwards, I asked my husband to drive me to the ER, because I knew something was definitely wrong. The only other indication that I had was a loss of 20 pounds over the previous 6 months. During that timeframe, I had changed my diet somewhat to reduce the amount of added sugar that I was eating in hopes of lowering my glucose levels. It seemed unusual to lose that much weight in response to the fairly minor changes I had made, and I had resolved to bring it up with my PCP at my next annual physical which had been scheduled for the next month. When I was admitted to the ER, the admitting doctor said that he was pretty convinced by the level and location of pain that it was kidney stones. Over the next couple of days, I saw both internists and OB/GYN, as it still wasn’t clear what was causing my pain. Finally, after multiple CT scans, multiple MRIs, and a pelvic ultrasound, the conclusion was that the cause of my pain was torsion in my right ovary. There also appeared to be a small mass on the left side and a larger mass behind my uterus. Prior to surgery, the surgeon explained that, via laparoscopic surgery, she would be removing both ovaries and would be able to take a closer look and a biopsy of the adnexal mass.

The diagnosis came in two stages. The first stage (high-grade B-cell lymphoma) was conveyed by my surgeon when I went to my post-operation check-up. I was very surprised because before leaving the hospital after surgery, the attending OB/GYN doctor said that he was quite certain that the mass was not cancerous based of its appearance and location. At the appointment, the surgeon said that she was surprised as well. When she told me that this type of cancer is treatable with a high likelihood of cure, I felt somewhat better. She referred me to a haematology/oncology doctor who said the same thing, so I again was reassured. I then had a PET C/T scan which showed that the cancer was a stage I or II. My haematology/oncology doctor reviewed the treatment plan which was 4 sessions of R-CHOP chemotherapy administered as an outpatient. While I was frightened of having cancer, I felt that the treatment plan was manageable and had every chance of success.

The second stage of the diagnosis came several days before I was to start my first R-CHOP infusion. The haematology/oncology doctor called to say that she had just received additional data from the pathology report, and it indicated that I had triple-hit lymphoma. When she explained that this meant the cancer was both aggressive and more resistant to traditional chemotherapy treatments, I was horrified. She also explained that I could no longer receive treatment as an outpatient; that I would need to go to a different hospital; and that I needed go there right away to meet my new team of doctors and begin treatment. At this point all my previous feelings of optimism and reassurance of a cure had disappeared, and I felt like I was in a state of shock as I sent emails to my siblings and close friends to tell them of the change in diagnosis and that I was leaving for the hospital right away.

The first round of chemo was pretty scary. Before actually getting started with the chemo, I had my first lumbar puncture which was terrifying to anticipate but not really so bad to experience. Being attached to an IV 24/7 for 4 days wasn’t pleasant, but, other than some mild nausea and loss of appetite, it wasn’t too bad. After the first round of chemo, I knew what to expect and so the remaining five rounds were pretty straightforward. The side effects during the 2 weeks after each session were not always the same each time. Sometimes I had nausea, mouth sores, and digestive problems, either constipation or diarrhoea, and sometimes I didn’t. My voice became very hoarse after the second round and stayed that way until the sixth when it started to improve. The tingling/numbness in my fingers and toes started in the second round and continues still. My taste buds were affected so that things that I normally enjoyed (eg, coffee), I couldn’t stand to eat/drink. My hair started to fall out early on until I was left with peach fuzz which has yet to grow in. Overall, I tolerated the chemo well so the dosage strength didn’t need to be adjusted except for the vincristine which was lowered in the last few rounds to see if my neuropathy and hoarseness would improve.

I was enthused about participating in the clinical trial. There didn’t appear to be any significant additional side effects, and the drug had been used with other types of cancer with positive results. When I learned that I’d been randomly chosen to receive the venetoclax, I was delighted. Unfortunately, the trial was halted due to some participants’ coming down with severe infections. By that time, I had received three full doses of venetoclax with no side effects beyond what was expected from EPOCH-R. I’m thankful for whatever good it may have done me.

My husband was my biggest supporter the entire time. While we were learning about my type of cancer and treatment, he accompanied me to doctors’ appointments (when allowed) and helped me articulate my questions and concerns. He also visited me every day while I was in the hospital receiving chemo treatments. Since we were practicing self-quarantine and social distancing due to COVID-19, I wasn’t able to be with my family or friends, but we communicated frequently by email and Zoom calls which made me feel not so isolated. Also, my local family and our next door neighbours frequently delivered home-made dinners and desserts, many of which I wasn’t able to eat due to a lack of appetite, but they kept my husband well fed.

Also, I feel extremely fortunate to have had access to wonderful doctors and nurses. The team of doctors communicated quickly and clearly with one another from the outset, and that may have saved my life, given how aggressive my cancer was. The EPOCH-R regimen that was chosen resulted in my being in regression halfway through the six cycles. The RNs and NPs who undertook most of my care while hospitalised were caring, sympathetic, efficient and effective. I don’t think I would have tolerated the chemo as well as I did without them.

Learning points.

• Triple hit B-cell lymphoma (THL) can present as bilateral ovarian tumour with torsion particularly in the setting of normal CA-125 level.

• THL are associated with worse response to R-CHOP and warrant more aggressive upfront regimen including central nervous system prophylaxis.

• Patient will THL should be considered for a clinical trial participation upfront.