JORRP is a rare disease which is typically diagnosed in early childhood. It is thought to be caused by the HPV types 6 and 11, which may have been vertically transmitted to the child at birth. It usually affects the larynx, but up to 5% of the patients show involvement of trachea and bronchi and 1% of patients develop manifestations within the lung parenchyma [1, 2]. Rarely spontaneous carcinomatous transformation occurs , but distant metastases do not develop . We here describe a 19-year-old male patient with an aggressive form of JORRP that required numerous interventions after diagnosis. Scattered papillomas were found in the trachea, bronchi, and both lungs. In multiple locations, bilateral malignant transformation into well-differentiated squamous cell carcinomas had occurred. HPV11 was detected in laryngeal biopsies at high viral load, suggestive of an on-going productive infection. Moreover, HPV11 was detected in autopsy material of the pulmonary squamous cell carcinomas, the left atrial papilloma, the left atrial thrombus, and the thromboembolic material. The same HPV type was isolated and cloned from the laryngeal biopsy. Sequencing of the patient’s HPV11 isolate showed that it is 99% identical to the HPV11 reference nucleotide sequence . It revealed 15 mutations previously observed in an HPV11 isolate from a squamous cell carcinoma of the penis [15, 16].
HPV infections usually remain localised and viral particles are not shed into the blood stream. Interestingly however, high viral genome copy numbers were detected in the plasma fraction of the patient’s blood, but not in the cellular fraction demonstrating that the viral genomes were not cell associated. The increased number of viral genomes detected within the plasma as compared to the whole blood (Table 2) is explained by the exclusion of the HPV-negative cellular fraction, which ultimately led to a concentration of the remaining plasma fraction. In connection with the high viral load within the serum, our patient presented high antibody titres against the viral structural protein L1. The antibody titre measured in the 2007 sample (Table 2) is one of the highest ever seen in our laboratory, which usually processes samples from patients vaccinated with the quadrivalent vaccine against HPV6, 11, 16 and 18. Interestingly, no antibodies against the oncoproteins E6 and E7 were detected. A similar immune response against the structural proteins of the virus is typically induced by HPV vaccines or by viral particles entering the blood stream, however, we were not able to show the presence of viral particles within the patient’s plasma. As HPV infections usually remain localised and viral particles are not shed into the blood stream, we hypothesise that a potential angioinvasion of the lung squamous cell carcinoma may have provided a way which enabled viral DNA to enter the blood stream. On another note, it is possible that the high HPV DNA levels originate from necrotic cells or thrombi shed from the endocardial lesion and/or respiratory tumors. In a study from Maloney et al., only 20% of the patients show detectable antibody levels . Interestingly, those three reported patients also had the highest levels of HPV11 viral load and the highest average numbers of annual surgical procedures. HPV DNA has previously been detected within blood cells of healthy individuals  and in the plasma of HIV-1 patients  and women with cervical cancer [20, 21]. However, none of these studies examined the immune response.
From the history of our patient it appears that the spread of the HPV infection was not contained by high antibody titres directed against L1. Alternatively, spread of infection might have occurred at a very early stage especially considering that multiple surgical interventions might have increased the risk for tracheal and pulmonary involvement. Viral DNA could therefore have persisted for a considerable time before disease progression and we speculate that a high antibody titre might reflect an increase in disease progression and an elevation of productive infection within existing papillomas.Post mortem examination revealed that descending tracheobronchial respiratory papillomas had undergone squamous metaplasia and subsequent malignant transformation into well-differentiated squamous cell carcinomas. Based on the structural and cytological similarity, including cytological atypia of the tracheobronchial, pulmonary and atrial papillomatous lesions, we conclude that all, especially the latter lesion, were HPV-induced. More importantly, these papillomatous lesions were the source for the recurrent thromboembolic events (Figure 1F) that had led to two episodes of Leriche’s syndrome and to multiple ischemic infractions in various organs, including spleen, kidneys, lower extremities, brain, and heart.
On the basis of the detection of HPV11 DNA in the atrial papilloma, we demonstrated the presence of a very rare endocardial papilloma . To our knowledge this is the first report of an HPV-induced endocardial papilloma as the source of fatal thromboembolic complications during the course of canalicular disseminating HPV11-associated longstanding JORRP disease with malignant transformation into well-differentiated squamous cell carcinoma. In addition, this case is remarkable considering the high levels of viral DNA detected within the patient’s serum and the high immune response directed against the viral structural surface protein L1. A humoral immune response against structural proteins is outmost uncommon in RRP patients and may in our case be explained by the presence of productive papilloma tissue. In summary, we here reported a severe case of JORRP hallmarked by HPV11 DNAemia and very high L1-antibody titres. Furthermore, our unusual and unexpected finding of the extent of malignant transformation and the discovery of a very rare fatal endocardial lesion highlight the unpredictability of JORRP and the complexity of its clinical management.
Ethics and consent
Ethical approval for the Cidofovir inhalation therapy was obtained from the Ethics Committee of the University Hospital Tuebingen. Written informed consent for the inhalation therapy and the publication of this case report and accompanying images and data was obtained from the patient and his next of kin. A copy of the written consent is available for review by the Editor of this journal. All methodology reported in this paper served for the sole purpose of diagnostics.