Revisiting anti-Hu paraneoplastic autoimmunity: phenotypic characterization and cancer diagnosis

Abstract

Anti-Hu are the most frequent antibodies in paraneoplastic neurological syndromes, mainly associated with an often limited stage small cell lung cancer. The clinical presentation is pleomorphic, frequently multifocal. Although the predominant phenotypes are well characterized, how different neurological syndromes associate is unclear. Likewise, no specific study assessed the performance of new-generation CT and PET scanners for cancer screening in these patients. Herein, we aimed to describe the clinical pattern and cancer screening in a retrospective cohort of 466 patients with anti-Hu autoimmunity from the French Reference Centre on Paraneoplastic Neurological Syndromes registry. Clinical presentation, cancer screening and diagnosis were analysed. Among the 466 patients, 220 (54%) had multifocal neurological involvement. A hierarchical cluster analysis grouped the patients into (i) mainly limbic encephalitis, (ii) predominantly peripheral neuropathy and (iii) broad involvement of the nervous system (mixed group). Compared with limbic encephalitis and mixed groups, patients in the neuropathy group more frequently had a chronic onset of symptoms (29 versus 13 and 17%), elevated CSF proteins (83 versus 47 and 67%) and died from cancer progression (67 versus 15 and 28%; all P < 0.05). No significant difference in overall survival was observed between groups. Dysautonomia and brainstem signs were associated with a higher risk of death from the neurological cause; cancer diagnosis was the main predictor of all-cause death, especially when diagnosed within 2 years from clinical onset (all P < 0.05). Three hundred and forty-nine (75%) patients had cancer: in 295 (84%) neurological symptoms preceded tumour diagnosis, being lung cancer in 262 (89%), thereof small cell lung cancer in 227 (87%). First CT scan revealed lung cancer in 205/241 (85%), and PET scan shortened the interval to diagnosis when the initial CT scan was negative [7 months (1-66) in 27 patients versus 14 months (2-45) in 6; P < 0.001]. Although cancer diagnosis mostly occurred within 2 years from clinical onset, 13/295 (4%) patients exceeded that threshold. Conversely, 33 patients (7%) were 'cancer-free' after 2 years of follow-up. However, 13/33 (39%) had initial suspicious imaging findings that spontaneously regressed. In conclusion, although anti-Hu autoimmunity clinical presentation is mostly multifocal, we observed patients with a predominant limbic syndrome or isolated sensory neuropathy. Early implementation of PET scan shortens the interval to cancer diagnosis, which was the strongest predictor of death, especially if diagnosed ≤2 years from clinical onset. As cancer was diagnosed >2 years after clinical onset in few patients, screening should be extended up to 5 years. In addition, tumour regression was suspected in a substantial proportion of 'cancer-free' patients.

Keywords: ANNA-1; anti-tumour immune response; cancer regression; clinical outcome; paraneoplastic autoimmunity.

Graphical Abstract

Figure 1

Clinical spectrum and survival in anti-Hu PNS patients. (A) Heatmap and hierarchical clustering of anti-Hu PNS patients taking into account the specific involvement of the nervous system. (B) Kaplan–Meier curves. Tick marks indicate censored patients, and comparison was made using the Log-rank test. Abs, antibodies; ALS, amyotrophic lateral sclerosis; LEMS, Lambert–Eaton Myasthenic syndrome.

Figure 2

Variables associated with outcome. (A) Forest plot of Cox regression analysis assessing the association of different specific nervous system involvement with dying from neurological cause. (B) Forest plot of multiple logistic regression analysis evaluating the adjusted effect of potential predictive variables to explain a mRS strictly less than four at the last visit. (C) Cox regression analysis using the same model reported by Graus et al. to identify predictors of all-cause mortality in patients presenting with PNS symptoms (n = 412/466, 88%). As the assumption of hazards proportionality was not satisfied by this model, we conducted a stratified model according to the putative variable (mRS at diagnosis), and the hypothesis of no interaction was verified. *Confirmed cancer or evidence of it upon screening. Abs, antibodies; LEMS, Lambert–Eaton myasthenic syndrome; mRS, modified Rankin score; N, number.

Figure 3

Survival according to the diagnosis of cancer and its timing. (A) Kaplan–Meier curves. Tick marks indicate censored patients, and comparison made using the Log-rank test. (B) Three-, 5- and 10-year survival rates table. *Of these, n = 13 patients were subsequently diagnosed with cancer and n = 33 remained ‘cancer-free’ during the entire follow-up. CI, confidence interval.

Figure 4

Cancer screening workflow. Screening techniques in patients with paraneoplastic symptoms predating the diagnosis of cancer. ^aIn both patients, the following PET scan was positive, 26 and 8 months after the first screening. ^bOne patient was diagnosed directly by bronchoscopy, the other 5/6 had a subsequent positive CT scan. ^cThese cancers included n = 4 of unknown origin (one undifferentiated adenocarcinoma, one small cell from pelvis adenopathy conglomerate, one neuroendocrine undifferentiated from liver metastasis and one neuroendocrine inguinal mass), n = 3 neuroblastoma, n = 2 prostate (one adenocarcinoma and one small cell), n = 2 breast carcinoma, n = 1 urothelial bladder cancer, n = 1 renal cell cancer, n = 1 thymoma, n = 1 small cell thymus, n = 1 small cell hypopharynx and n = 1 neuroendocrine tumour of the ileum. ^dThis patient had a neuroendocrine undifferentiated cancer of the rectum. ^eThese cancers included n = 3 diagnosed in subsequent CT scan (one breast cancer, one Hodgkin lymphoma, one ganglioneuroblastoma); n = 2 diagnosed on subsequent PET scan (one prostate adenocarcinoma, one chronic lymphocytic leukaemia), n = 1 bladder cancer by cystoscopy, n = 1 breast cancer on MRI and n = 1 prostate epithelioma found due to elevated prostate-specific antigen. ^fThese cancers included n = 1 prostate adenocarcinoma found due to elevated prostate-specific antigen, n = 1 biopsy of lymph node found in physical examination revealing an undifferentiated adenocarcinoma suggestive of prostatic origin, n = 1 urothelial bladder cancer in cystoscopy, n = 1 neuroblastoma in thorax MRI and n = 1 poor differentiated adenocarcinoma in sigmoidoscopy. ^gThese cancers included n = 1 breast cancer found on mammography and ultrasound, and n = 1 urothelial bladder cancer on cystoscopy (haematuria).

Figure 5

Regression of mediastinal lymphadenopathies and lung nodule in a patient with anti-Hu PNS. A woman in her 50s, current smoker, subacutely developed a clinical picture compatible with limbic encephalitis leading to the detection of anti-Hu antibodies. The first cancer screening, performed 4 months after clinical onset, found strongly hypermetabolic para-tracheal, precarinal and superior right hilar lymphadenopathies (Ai–Aii) and a weak hypermetabolism (Aiii) in a superior right lung nodule of 6 mm diameter (Aiv). The result of a biopsy performed 2 months later was inconclusive. Subsequent screening, performed 7 months after clinical onset, found an almost complete regression of mediastinal hypermetabolic lymphadenopathies and the lung nodule (Bi–Biv). Subsequent screening performed 14 and 25 months after clinical onset were completely normal (Ci–Div).