Identifying ataxia‐telangiectasia in cancer patients: Novel insights from an interesting case and review of literature

Abstract Timely genetic testing leading to early diagnosis of A‐T is crucial due to its plethora of implications on clinical management, particularly in those who develop malignancies. Thus, clinicians have to be astute in identifying diagnostic clues of A‐T.


| INTRODUCTION
Ataxia-telangiectasia (A-T), a rare hereditary cancer syndrome, can present with a myriad of clinical manifestations. Here, we described a case whose diagnosis of A-T was missed till a second malignancy was confirmed. We aim to highlight diagnostic clues of A-T and discussed important considerations in management of malignancies in A-T.
Ataxia-telangiectasia (A-T) (OMIM #208900) is a rare autosomal recessive disorder resulting from biallelic pathogenic variants in the Ataxia-Telangiectasia mutated (ATM) gene (OMIM *607585). Classically, it is characterized by progressive cerebellar ataxia, cutaneous telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity. [1][2][3] However, variant A-T may have a myriad of presentations. The ATM gene encodes a serine/threonine protein kinase which plays a crucial role in the repair of DNA double-stranded breaks [1][2][3][4][5] and when impaired leads to carcinogenesis. Studies estimate lifetime cancer risks of 25%-40% 4-6 of both solid and hematological malignancies. 2,4,[7][8][9][10] Here, we report a patient with sensorimotor polyneuropathy, metachronous T-cell prolymphocytic leukemia (T-PLL), and cervical carcinosarcoma who was eventually diagnosed with A-T to highlight clinical pearls and important management considerations for clinicians. A 34-year-old Chinese woman presented with urinary incontinence, intermittent abdominal discomfort, and menorrhagia. On physical examination, a necrotic bleeding vaginal mass was noted. Computed tomography (CT) of the abdomen and pelvis revealed a cervical lesion and right ovarian lesion measuring 8 × 7 cm and 9 × 6 cm, respectively Figure 1. Medical history was significant for possible cerebral palsy that was recently revised to possible Charcot-Marie-Tooth disease when she presented with progressively worsening weakness, with nerve conduction study and electromyography showing diffused sensorimotor axonal polyneuropathy. She was diagnosed with CD4/CD8 double-positive T-PLL Figure 2A with complex cytogenetics at age 31 after an incidental finding of leucocytosis. Bone marrow cytogenetics then showed an abnormal mosaic female chromosome analysis with a normal cell line and one with numerical and structural abnormalities. However, there were no deletions or missense variants involving the ATM locus 11q23, which is present in up to 65% of all cases of T-PLL. [11][12][13] She was placed on expectant management given absence of cytopenia nor rapidly increasing lymphocytosis, B symptoms, lymphadenopathy, or end organ involvement, as per T-PLL International Study Group (TPLL-ISG) guidelines. 14 Moreover, given her comorbidities and functional status, she was a poor candidate for most cytotoxic treatments targeting T-PLL or bone marrow transplant. Other comorbidities included type 2 diabetes mellitus, multiple ophthalmological issues and persistently raised alphafetoprotein (AFP) with mild transaminitis since age 29 for which investigations were unyielding.

| CASE REPORT
Tumor markers were normal apart from baseline elevated AFP: CEA 1.5 ug/L, CA 125 23.6 u/ml, Beta-hCG < 0.6U/l, AFP 153 ug/L. Cervical biopsy showed squamous cell carcinoma (SCC) while right ovarian biopsy showed adenocarcinoma with focal mucinous differentiation. Our multidisciplinary consensus was that of at least FIGO stage IIB cervical SCC with a synchronous primary ovarian mucinous adenocarcinoma. Initial recommendation was made for definitive treatment with neoadjuvant chemotherapy followed by chemo-radiotherapy for her cervical SCC and sequential debulking surgery for her ovarian adenocarcinoma. She received 2 cycles of paclitaxel (175 mg/m 2 ) and carboplatin (AUC 5) at 3 weekly intervals but did not achieve adequate control of her symptoms of pain and per vagina bleeding. After restaging scans showed local progression of the ovarian mass, she underwent palliative open radical hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic lymphadenectomy. Histology revealed cervical carcinosarcoma with heterologous (cartilaginous) differentiation, predominantly comprised of adenosquamous carcinoma with focal neuroendocrine differentiation, admixed with a minor sarcomatous component. There was bilateral parametrium, upper vagina, lower uterine segment, and pelvic lymph node involvement. Histology of the right ovarian lesion revealed adenosquamous carcinoma, favoring metastasis from the cervical tumor as both had similar histology and immunoprofile Figure 2B.
In view of multiple primary cancers at a young age and uncertain underlying neurological condition, she was referred for genetic assessment upon her cervical cancer diagnosis. Born at term, independently ambulant and fully functional initially, she subsequently had difficulty walking and learning around age 9 and became wheelchair bound since age 23 Figure 3. Interview with patient's caregiver revealed that she was thought to have cerebral palsy, and her initial clinicians did not consider a diagnosis of A-T. Unfortunately, specific details regarding her neurological deterioration and the workup then were not available as she was seen in a different institution. There was no family history of consanguinity nor developmental issues. Her father, a nonsmoker, died from lung cancer at age 47. Her paternal grandfather, a smoker, also died from lung cancer in his 30s while her paternal grandmother died from uterine cancer in her 30-40s Figure 4. Saliva collected for germline clinical multi-gene panel testing using next-generation sequencing revealed two pathogenic variants in ATM (NM_000051.3): c. 2304_2305insTT (p.Glu769Leufs*9) and c. 9023G > A (p.Arg3008His). Cytogenetic testing performed on patient's blood revealed an increase in both spontaneous and Gamma-Ray induced chromosome breakage, confirming the diagnosis of ataxia-telangiectasia. Clinical examination did not reveal any cutaneous telangiectasia, although a broad face with coarse eyebrows and a few café-au-lait spots were noted. Subsequent testing revealed low IgG and IgA levels with gross pan-cerebellar atrophy on magnetic resonance imaging of the brain in keeping with A-T. In view of her A-T diagnosis, it was recommended to avoid radiation therapy in subsequent treatment. A postoperative CT revealed a new right lung nodule and a hepatic lesion likely representing metastases. Her diagnosis was revised to FIGO stage IVB cervical carcinosarcoma and she received a further 2 cycles of palliative chemotherapy with etoposide (300 mg/m 2 ) and cisplatin (100 mg/m 2 ), with a 50% dose reduction in view of a diagnosis of A-T. Her disease progressed 3 months later, and she was placed on best supportive care prior to her demise shortly after.

| DISCUSSION
This case highlights the potential for missed or delayed A-T diagnoses, especially in cases of variant A-T, and provides an impetus for clinicians to be aware of suggestive signs to facilitate earlier diagnosis. The first clue of our patient's A-T diagnosis was the regressive loss of developmental milestones from age 9. Second, the early-onset T-PLL concurs with A-T patients having a predisposition to T-cell as opposed to B-cell tumors 12 and at a significantly younger age of 20-30s 4,10,12,15,16 compared to a median age of 69 in patients without A-T. 10 Third, multiple primary cancers in patients with A-T are not uncommon, with incidence ranging from 4% to 15%. 8,17,18 Of note, solid tumors mainly present in F I G U R E 2 A, Mature-looking T-PLL lymphocyte with cytoplasmic blebs in peripheral blood film. B, Histology slides showing (i) Cervical adenosquamous carcinoma with complex glandular proliferation, papillae, and scattered keratinizing squamous whorls, (ii) Focal malignant cartilaginous nodules associated with cervical adenocarcinoma, (iii) Anastomosing cords of cells punctuated by small tubules, demonstrating cytoplasmic reactivity for synaptophysin on immunostain, and (iv) Ovarian metastasis with similar looking adenosquamous carcinoma with foci of keratinization (*) and some cells containing cytoplasmic mucin ( ) adulthood, with majority being breast, liver, gastric, thyroid, and esophageal carcinomas Appendix 1. 2,4,7 Finally, diabetes mellitus and particularly the raised AFP of unknown cause were also consistent with A-T. [19][20][21] A range of phenotypes have been described in individuals with A-T Table 1. Patients with variant A-T have residual ATM kinase activity and thus a milder clinical course than classic A-T. 22,23 Variant A-T may present with extrapyramidal signs instead of cerebellar ataxia, milder neurological symptoms, and no lung disease or immunodeficiency. Although residual ATM kinase activity is protective against childhood tumors, variant A-T are still at increased risk of developing cancers 22,23 especially solid malignancies given their longer lifespan compared to classic A-T whose average life expectancy is approximately 25 years 24, emphasizing the importance of timely genetic testing in this group who may present atypically. Although ATM kinase activity was not tested, based on clinical presentation, our patient is likely to have variant A-T. Furthermore, residual ATM kinase activity has been demonstrated in another patient with the c. 9023G > A (p.Arg3008His) variant. 23 In comparison, A-T heterozygotes often have a normal clinical phenotype. Although epidemiological studies report increased incidence of malignancies in blood relatives of A-T patients [25][26][27][28][29] only the risk of breast cancer has been consistently shown to be raised, with lifetime risk of approximately 38%. 29 Female relatives who are A-T heterozygotes should thus be offered surveillance with yearly mammography starting from age 40. 30 To our knowledge, this is the first clinical report of an association between A-T and cervical cancer though it has been reported in relatives of A-T patients who are obligate heterozygous carriers of ATM variants. 9,27,28,31 The association between somatic alterations in ATM and risk of cervical cancer have also been reported. 32,33 Despite our patient's strong family history of young lung cancers, this has not been prominently reported in clinical literature on A-T. Interestingly, up to 40% of lung adenocarcinomas have been reported to lack ATM protein expression due to somatic alterations. 34 ATM rs189037, rs664677, and rs664143 gene polymorphisms have also been reported as risk factors for lung cancer. 35 These ATM variants deserve further study with regards to their association with lung cancer, particularly in Asians where there is a higher incidence of adenocarcinomas in nonsmokers.
While radiation-induced toxicities including death and secondary malignancies 5,36 are well established in A-T, evidence is lacking for chemotherapy. Certain chemotherapeutic agents have been shown to have increased toxicities Appendix 2, whereas agents such as prednisone, 6-mercaptopurine, asparaginase, and daunorubicin have been shown to be tolerable at normal doses. 37 There are currently no consensus guidelines with regard to dosing of chemotherapy in A-T. Various approaches tried in multiple hematological and solid cancers are summarized in Table 2. Inferences that can be drawn are limited by the heterogeneity of primary malignancies reported over an extended time course whereby the standard dose/regime may have evolved. [37][38][39][40] In general, the most common strategy employed across studies is a 50% dose reduction of the standard regime. Some gradually up titrated the dose as tolerated while taking care to limit doses of certain agents, such as methotrexate and cyclophosphamide. Durable complete remissions have been successfully achieved with modified dose chemotherapy regimens. [41][42][43][44][45][46][47][48][49] The largest of these studies by Schoenaker et al 39 demonstrated no significant difference in remission rates for patients with T-cell acute lymphoblastic leukemia receiving modified dose chemotherapy. Studies to better describe safety and efficacy of chemotherapeutic regimes in A-T patients are needed. Ultimately, the decision regarding treatment regime and dosage should be a discussion among all managing healthcare professionals, patient and their family, and individualized based on patient's underlying comorbidities, functional status, and treatment goals.
T A B L E 1 Differences in features between classic A-T, variant A-T and ATM heterozygotes 22,23,29,53

T A B L E 2 (Continued)
Given significant considerations in the management of malignancies, early diagnosis of A-T, prior to that of malignancy should there be, is of critical importance. Although there are no guidelines for cancer screening in A-T, early diagnosis and hence knowledge of the underlying genetic disorder will allow patients/families to be cognizant of symptoms and prompt clinicians to do the necessary screening and workup, hopefully enabling detection of malignancy, if any, at a more favorable stage. Additionally, allogeneic hematopoietic stem cell transplantation has been shown to correct immunodeficiency and potentially retard deterioration of neurological function in case reports 50,51 which may be considered in selected cases. Regardless, early diagnosis of A-T also allows for earlier introduction to a multidisciplinary care team, 7,52 with the aim to reduce associated morbidities, such as reducing contractures and maintaining functional activity, improving airway clearance, reducing aspiration risk, appropriate treatment of infections especially if recurrent, earlier detection and management of endocrinopathies, ultimately improving quality of life.

| CONCLUSION
There is a need to improve the general genetic literacy of all clinicians. Ataxia-telangiectasia is one of the important hereditary cancer syndromes that clinicians should not only be aware of, but also be astute in identifying the diagnostic clues. Any co-occurrence of neurodevelopmental diagnosis must trigger a consideration for timely genetic testing. Also, AFP should be measured to rule out A-T in children and patients with progressive neurological decline. Early diagnosis is critical as it may significantly alter management, treatment approach in individuals diagnosed with cancer and allow for interventions that may potentially reduce associated morbidities.

ACKNOWLEDGMENTS
We would like to thank our patient for consenting to the publication of the case report. We would also like to express our gratitude to the Lee foundation for their generous donations to the Lee Kong Chian NCCS Cancer Genetics Service fund that help subsidize the cost of testing for many of our patients.