ABSTRACTS

Diagnosis of Li-Fraumeni syndrome just in time to prevent iatrogenic secondary cancer

A 40-year old patient presented with a lump in the left breast which prompted her to seek medical attention. There was a positive family history for different cancers. MRI mammae showed two lesions highly suspicious of cancer, one identified as an invasive ductal adenocarcinoma (IDA), the second as a ductal carcinoma in situ (DCIS). Biopsy of a visible axillary lymph node was positive for IDA. ER and PR were highly positive, with HER2-negativity. Tumor marker CA15.3 was normal. CT-scan thorax/abdomen and bone scintigraphy showed no evidence of distant metastases.

She underwent left radical mastectomy + axillary lymph node dissection. Microscopic evaluation of the surgical specimen revealed a moderately differentiated IDA (T=1.6cm) and DCIS (T=8.5cm) and one out of nine positive lymph nodes (pT1cpN1acM0).

Adjuvant chemotherapy (4 cycles dose dense epirubicin-cyclophosphamide followed by 12x weekly paclitaxel), radiotherapy on left chest wall/lymph nodes and hormonal treatment were scheduled.

After the last paclitaxel, genetic testing revealed Li-Fraumeni syndrome (LFS), just before initiation of irradiation. LFS is characterized clinically by the appearance of tumors in multiple organs generally at an early age. This autosomal dominantly inherited condition is caused by germline mutations of the tumor suppressor gene TP53. Lifetime breast cancer risk is 49% by age 60. Because of a higher radiosensitivity in LFS with 40% risk of radiation-induced second cancer (mostly soft tissue sarcoma), radiotherapy was abruptly cancelled. She was subsequently started on combination endocrine therapy triptorelin + letrozole for 5 years.

She is currently undergoing intensive cancer surveillance (e.g. full body MRI, endoscopy) as per recently revised guidelines (= modified Toronto protocol), because riskof cancer development isstrikingly high in LFS. If a strict adherence can be maintained, the overall survival outlook is promising. The demonstration of a TP53 mutation in our patient means that her first-degree relatives also have a 50% risk of being carrier of the mutation. They are eligible for presymptomatic screening from newborn age.

Patient will undergo a risk reducing contralateral mastectomy with reconstruction in the near future. Also handling with the psychosocial aspects of individuals and families with LFS is a challenge for a multidisciplinary team.

One in a million

Introduction

A malignant pheochromocytoma is a rare neuroendocrine tumour with an incidence of less than 1/million/year, often diagnosed in a late stage because of the atypical and indolent presentation and the lack of biochemical, morphological, genetic or histological predictors of malignancy.

Case-report

We report a case of a 71-year-old woman with a mass in the right adrenal gland on abdominal ultrasound, performed for vague abdominal complaints. Computed tomography (CT) of abdomen and chest further differentiated the mass as having characteristics of malignancy and revealed multiple lesions in both lungs. A 24-hour urinary collection showed elevated metanephrines. A 68 gallium-DOTANOC-PET/CT-scan and 18F-FDG PET/CT-scan confirmed the suspicion of a malignant pheochromocytoma with lung metastases. The patient was treated by replacing the beta-blocker by an alpha-blocker to block the adrenergic spells. The adrenal tumour was resected, preceded by an embolization of the supplying arteries to prevent a catecholamine storm. Histology revealed large tumour with central necrosis and a fibrous capsule, capsular invasion was present. There were nests containing polygonal cells with large, hyperchromatic nuclei. There was a strong expression of antibodies against chromogranin and synaptophysin; S100 and vimentin staining were negative. The Pheochromocytoma of the Adrenal gland Scaled (PASS) Score was 3 (1 point for capsular invasion, 2 points for central necrosis). The metastases were monitored 3 months after the first evaluation with CT, which showed stable disease. A meta-iodobenzylguanidine scan (MIBG) didn’t show any uptake.

Conclusion

In a malignant pheochromocytoma, the degree of malignancy can only be determined by imaging. Additional imaging should be chosen with care, especially because standard 18F-FDG PET/CT has a lower sensitivity for detecting metastases than 68 gallium-DOTANOC-PET/CT. MIBG-capture is not always present in pheochromocytoma, which excludes MIBG therapy in progressive disease. Beta-blockers in monotherapy should be avoided because it could cause a hypertensive crisis caused by an alpha-1 mediated vasoconstriction. The cornerstone of treatment is resection, preferably of the primary tumour and all metastatic lesions. Our patient has inoperable lung metastases. In case of progressive disease, treatment options are peptide receptor radionuclide therapy (PRRT) and chemotherapy. Further follow-up is scheduled.

Immune checkpoint inhibitor and kidney transplantation

A 50 years old kidney transplant recipient was diagnosed with spinal cell carcinoma.

He started hemodialysis (1981) for FSGS and he underwent a 3rd renal transplantation in 2013, the other two grafts being lost for chronic rejection. Immunosuppression was progressively diminished for relapsing spinal cell carcinomas since 2013. mTOR-inhibitors were not tolerated by the patient.

In March 2018, the patient developed a lesion suspected of spinal cell carcinoma in the right pre-auricular region that infiltrated the parotid gland and the temporomandibular joint. The 26.04.2018 a right parotidectomy, lymphoadenectomy and resection of external auditory canal were performed. Histology showed pT3N0 epidermoid cell carcinoma. Radiotherapy was started without any beneficial effect on the tumor with PET-CT and MRI showing several osteolytic lesions and meningeal involvement. First line chemotherapy with Cisplatine and 5FU was given with no effect. Anti -PD1 treatment was, then, given as rescue therapy.

This challenging case reflects the difficulties we faced in order to decide the treatment options: if chemotherapy is administered nephrotoxic drugs (such as cisplatine) are mandatory while novel treatment modalities such as immunotherapy may jeopardize the graft viability since immunosuppression is modulated by liberating the PD1-pathway.

The use of immune checkpoint inhibitor in patients with solid organ allografts is relatively unknown but mechanism of action suggests an increased risk of rejection; the literature is poor and contain only a limited number of reported cases.

The recommendations in using checkpoint inhibitors in cancer treatment support immunosuppression minimization in order to enhance the action of these drugs. This, ad to use of cytotoxic T lymphocyte stimulation, is associated in the majority of cases to cell-mediated/humoral rejection. (1)(2)

Our patient is included in a study to benefit from an off label PD-1 inhibitor Cemiplimab. The adverse events of this molecule are similar to other PD-1 inhibitor. (3) We supposed that the risk of rejection is high, but that the neoplastic disease needed an innovative treatment since previous treatments failed.

This case illustrates the complexity to choose a treatment that may improve the survival of a cancer transplanted patient but involve high probability of major events such as transplant rejection.

Repeated auto-immune hemolysis elicited by immunotherapy

Case Report

A 68-year-old man with a B-CLL in remission 1y after chemo-immunotherapy (FC-R), presented with a fast-growing malignant melanoma on his scalp. Due to fast spread therapy with pembrolizumab was initiated.

The patient presented 3 weeks after the first dose with clear pallor, complaints of fatigue, vertigo and orthostatic hypotension. A thorough history and examination could not identify any bleedings.

Blood tests confirmed the presence of anemia with a hemoglobin (Hb) of 5.4 g/dl. Leukocyte (6900/mm³) and thrombocyte (162000/m³) count were normal. Additional lab investigations showed haptoglobin below the measurable values (<0.08g/l), markedly raised LDH (1336U/I) and bilirubin (3.3mg/dl total and 2.3 mg/dl indirect). Both direct and indirect Coombs tests were positive and aspecific warm auto-antibodies were found. The likely diagnosis of an AIHA caused by pembrolizumab was made. Although B-CLL itself can cause auto-immune hemolytic anemia (AIHA), there were no signs of reactivation of the B-CLL. Nonetheless, it was considered an import underlying risk factor.

On the other hand, an apparent low reticulocyte count was seen, pointing out an red blood cell aplasia. The patient received high dose corticosteroids, blood transfusions and IV immunoglobulins. Slowly the reticulocyte count began to rise, followed by a raise in hemoglobin.

Due to progression of the melanoma and lack of other therapeutic options, a second cycle of pembrolizumab was administered. However, this second dose was immediately followed by AIHA, this time without aplasia. In addition to immunoglobulins and corticosteroids, rituximab was associated to the treatment, followed again by hematological improvement.

In light of this repeated hemolytic anemia other therapeutic options were sought. Unfortunately, the patient developed serious infectious complications and died before an alternative treatment could be completed.

Discussion

We presented a case of immunotherapy- induced auto-immune hemolytic anemia. Although rare, it has been previously described (1–10). Our case differs from those earlier published as our patient had a prior history of B-CLL as a underlying risk factor of the AIHA.

An unusual complete remission of a diffuse metastatic squamous cell cutaneous carcinoma with an EGFR-TKI

Cutaneous squamous cell carcinoma is a malignant tumour of the epidermis which reproduces the appearance of keratinising cells. In frequency terms it is the second most common tumour among malignant cutaneous neoplasias.

For patients with disease not amenable to curative intent therapy, treatment options are limited to platinum-based chemotherapy regimens and more recently to the anti-PD1 immune checkpoint inhibitor.

Erlotinib is a receptor tyrosine Kinase inhibitor, which acts on the epidermal growth factor receptor(EGFR) and produces long-lasting responses with palliative benefit and relatively low toxicity, especially in patients with activating EGFR mutation

Hereby we describe the case of a 61-year-old patient diagnosed with a squamous cell carcinoma of the lower limbs, of the keratoacanthoma type, treated successively by surgical excision, isotretinoin acid, topical imiquimod and topical 5-FU without significant response. He then was started on Erlotinib 150mg od and has been in complete remission since > 3 years, knowing that his tumour does not harbour any significant mutation.

Urethral carcinoma: A rare disease but yet no clear guideline for treatment

Female urethral carcinoma is among the rarest types of neoplasia of the genitourinary tract and corresponds to 0.003% of all malignant neoplasias occurring in the female urogenital tract. Of the urethral cancers, 70% are squamous cell, 20% are transitional cell, and 10% are adenocarcinoma. Primary urethral adenocarcinoma in women is a rare malignancy of unclear origin.

We present the case of a 69-year-old woman diagnosed in 2015 with an adenocarcinoma of the urethra (pT4N0R1L0Pn1), treated by cystectomy and hysterectomy, adnexectomy and lymphadenectomy followed by radiotherapy. One year later, a PET-CT scan showed micro-nodules in the lungs and a biopsy confirmed the diagnosis of disseminated adenocarcinoma from the urethra. The patient was discussed by our multidisciplinary oncology treatment team and we decided to treat the patient with carboplatin and taxol. A CT scan after three courses of treatment revealed a partial response. It is not clear whether the patient would have benefited from adjuvant chemotherapy since the tumour extent was large.

This is an extremely rare case with no clear guidelines regarding treatment. Options for treatment of female urethral carcinoma include surgery, radiation therapy and chemotherapy, alone or in combination. Treatment has tended toward a multimodality approach in recent years. For advanced female urethral cancer, a combination of chemotherapy, radiation therapy and surgery is recommended for optimal local and distant disease control.

Autoimmune Thrombocytopenia: Another Toxicity Induced by Immunotherapy

Metastatic urothelial bladder carcinoma is an incurable disease. For years, the therapeutic options were limited to platinum based chemotherapy with modest efficacy. Considering the large mutational burden in bladder cancer, immunotherapy became a standard of care in the second line and in the front line when patients are unfit for platinum based regimen. Thus, oncologists are dealing with new side effects and toxicities.

We report the case of a 66-year-old male patient, smoker, diagnosed with urothelial bladder cancer, with initial metastases to the lungs, retroperitoneal and mediastinal lymphadenopathies. He received a first-line chemotherapy consisting of cisplatin and gemcitabine. After 3 cycles, the evaluation showed a partial response. The response was maintained after 6 cycles and a decision of therapeutic pause was taken. Three months later, the follow-up imaging revealed pulmonary and nodal progression. Immunotherapy was initiated with a checkpoint inhibitor. Partial response was obtained after 3 cycles with good clinical and biological tolerance. After the fourth cycle, he developed an isolated grade I thrombocytopenia that worsened to grade III, before the administration of the sixth cycle. CT-scan confirmed the persistence of partial response. Immunotherapy was put on hold. A bone scan excluded bone metastases. Bone marrow aspirate and biopsy were in favor of a peripheral origin of thrombocytopenia without any dysplasia or infiltration by metastatic cells. After completing the viral and autoimmune work-up, the diagnosis of autoimmunethrombocytopenia secondary to immunotherapy was made. The patient received the same regimen administered for idiopathic thrombocytopenic purpura based on dexamethasone 40 mg daily for 4 days. Platelet count began to recover with normalization after one week. Immunotherapy was discontinued. Six months later, the disease progressed with interval appearance of new liver metastases. A third line chemotherapy was administered without any response. The patient’s clinical condition deteriorated and he died as a result of progression of the metastatic disease. Autoimmune thrombocytopenia has been rarely reported as an autoimmune disorder related to immunotherapy. Clinicians must exclude all other causes of thrombocytopenia before validating this diagnosis. Its management is extrapolated from that of idiopathic thrombocytopenic purpura.