A 26-year-old woman presented to the emergency department of Queen Mary Hospital in August 2014 with fever and right otorrhea following extraction of her right lower third molar 5 days previously. Physical examination revealed right buccal swelling, limited mouth opening, and pus-like discharge in the right external auditory canal (EAC) exacerbated by mastication. There was no hearing loss or facial nerve palsy. Otoscopy revealed granulation tissue and pus arising from the anterior wall of the inner right EAC.

Contrast-enhanced computed tomography scan showed a right parapharyngeal rim enhancing collection (Fig 1) tracking into the right temporomandibular fossa. Enhancing soft tissue was seen at the inner one-third of the right EAC. A bony defect was present at its anterior wall, compatible with a persistent foramen tympanicum (also known as foramen of Huschke), allowing communication between the EAC and the temporomandibular fossa (Fig 2). Overall findings were compatible with right parapharyngeal abscess discharging via a persistent foramen tympanicum into the right EAC.

The patient was treated with a course of antibiotics in view of her stable condition and lack of airway compromise. The patient responded clinically and repeat computed tomography scan 1 week after initial presentation showed complete resolution of the right parapharyngeal abscess and enhancing soft tissue within the right EAC. Subsequent bacterial culture of the right ear discharge yielded Streptococcus anginosus, a common cause of oral infection.

Parapharyngeal abscesses are deep cervical infections with potential serious complications such as shock, mediastinitis, jugular vein thrombosis, upper airway obstruction, and death. Tonsillitis and odontogenic infection are the most common aetiologies. The clinical presentation typically involves fever, neck pain, odynophagia, neck oedema, and upper airway obstruction.1

Otorrhea is typically caused by external or middle ear pathologies such as otitis. Otorrhoea as a presenting symptom for a neck abscess is highly unusual. In our literature review, only two cases were found. Biron et al2 described a patient with a submandibular abscess that tracked into the ipsilateral external auditory meatus via the parapharyngeal and masticator spaces. Pepato et al3 reported a case of lower third molar infection presenting as purulent ear discharge, with persistent foramen tympanicum found in a follow-up cone-beam computed tomography study. The route of spread was postulated to be either via the Santorini fissures (the tiny defects in the anterior wall of the cartilaginous EAC) or via a persistent foramen tympanicum.

Persistent foramen tympanicum, first described by Emil Huschke in 1844, represents a failure of ossification of the tympanic part of the temporal bone and normally occurs from birth with completion by age 5 years. The foramen is located at the anteroinferior aspect of the EAC, just posterior to the temporomandibular joint. Incidence is quoted from 4.6% to 22.7% based on radiological and cadaveric studies.4

The majority of individuals with the foramen are asymptomatic although various complications have been reported. Most are benign, such as salivation from the ear during mastication and spontaneous herniation of the temporomandibular joint into the EAC leading to otalgia and tinnitus. Iatrogenic middle ear injury is possible when the foramen is inadvertently traversed during temporomandibular joint arthroscopy.5 It is possible that the lack of bony integrity reduces mechanical resistance to pathological processes, such as the spreading of parapharyngeal abscess in our case. Parotid pleomorphic adenomas have also been reported to herniate through the foramen to present as an EAC mass.

To the best of our knowledge, this is the first case to provide direct radiological evidence of persistent foramen tympanicum as a route for drainage leading to masticatory otorrhoea. It is important for doctors to be aware of the clinical presentation to permit diagnosis and subsequent treatment.

All authors contributed to the concept, image acquisition, image and data interpretation, manuscript drafting, and critical revision for important intellectual content. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

The authors have no conflicts of interest to disclose.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Patient consent was obtained for the purpose of this case study.

1. Brito TP, Hazboun IM, Fernandes FL, et al. Deep neck abscesses: study of 101 cases. Braz J Otorhinolaryngol 2017;83:341-8. Crossref

2. Biron A, Halperin D, Sichel JY, Eliashar R. Deep neck abscess of dental origin draining through the external ear canal. Otolaryngol Head Neck Surg 2005;133:166-7. Crossref

3. Pepato AO, Yamaji MA, Sverzut CE, Trivellato AE. Lower third molar infection with purulent discharge through the external auditory meatus. Case report and review of literature. Int J Oral Maxillofac Surg 2012;41:380-3. Crossref

4. Akbulut N, Kursun S, Aksoy S, Kurt H, Orhan K. Evaluation of foramen tympanicum using cone-beam computed tomography in orthodontic malocclusions. J Craniofac Surg 2014;25:e105-9. Crossref

5. Nakasato T, Nakayama T, Kikuchi K et al. Spontaneous temporomandibular joint herniation into the external auditory canal through a persistent foramen tympanicum (Huschke): radiographic features. J Comput Assist Tomogr 2013;37:111-3. Crossref

Hashimoto’s encephalopathy (HE), also termed as steroid responsive encephalopathy associated with autoimmune thyroiditis, is a rare and highly variable clinical spectrum. The clinical presentation includes seizures, stroke-like episodes, cognitive decline, neuropsychiatric symptoms, and myoclonus.1 We report a rare and unusual case of HE in which there was a partial response to steroid therapy.

A 76-year-old man was admitted to the Department of Neurology of the Near East University Hospital, Cyprus, in October 2016 with the chief complaint of myoclonic jerks and walking difficulty for the past 6 weeks. The patient’s family had observed no significant cognitive or behavioural change. He did not experience any seizure. His medical history included hypertension and diabetes. On neurological examination he was alert and fully oriented. Motor weakness was noted at the left lower extremity with Babinski sign. He had myoclonus in all limbs and bilateral postural tremor, which was predominantly left sided. Magnetic resonance imaging (MRI) scan of the brain revealed widespread T2 hyperintensities mainly in the juxtacortical areas (Fig 1). Blood studies including complete blood count and electrolyte count; liver, renal and thyroid function tests; tumour markers; and paraneoplastic antibody analysis (anti-Hu, -Yo, -Ri, -Ma, -CV2) were all normal. Vasculitis markers including antinuclear antibodies, anti-ds DNA, anticardiolipin immunoglobulin (Ig) M, IgG antibodies, antiphosphatidylserine IgM, IgG antibodies, perinuclear antineutrophil cytoplasmic antibodies, cytoplasmic antineutrophil cytoplasmic antibodies, anti-La and anti-Ro antibodies, and rheumatoid factor were within normal limits. He tested negative for human immunodeficiency virus. His cognitive status worsened during his first week of hospitalisation and he rapidly developed delusions and aggressive behaviour. He was not able to cooperate with the neurocognitive assessment. Electroencephalogram showed 5 to 6 Hz diffuse slow-wave activity without any epileptiform discharge (Fig 2). Cerebrospinal fluid (CSF) analysis showed a very high protein content (1.95 g/L). The CSF/serum glucose ratio was normal. Cerebrospinal fluid investigation and culture was negative, excluding central nervous system infection. Whole-body positron emission tomography was performed to exclude paraneoplastic processes and the result was normal. Consequently, steroid-responsive encephalopathy and associated autoimmune thyroiditis was suspected, and antithyroglobulin antibody (anti-TG-Ab) and antithyroperoxidase antibody (anti-TPO-Ab) levels were studied. Serum level of both was increased (431 IU/mL and 40 IU/mL respectively). He was not taking any medication (eg, lithium, amiodarone, etc) that could account for the positivity of thyroid antibodies. Thyroid ultrasonography did not show any pathological findings. Intravenous pulse steroid treatment (IVPS, methylprednisolone 1 g/day) was started. Myoclonus resolved on the fourth day of treatment. Because the cognitive status of the patient was not adequately changed, IVPS was extended to 10 days. A partial response was obtained in cognition and Mini-Mental State Examination score was 11/30 after IVPS. Another electroencephalogram showed mild improvement. Consequently, oral methylprednisolone was continued at a dosage of 1 mg/kg/day. Afterwards, intravenous Ig treatment was given at a dose of 0.4 g/kg for 5 days. No additional improvement was seen. Lumbar puncture and thyroid autoantibody testing were repeated. The anti-TPO-Ab and anti-TG-Ab levels were normalised, and CSF was acellular at that time and protein content decreased (1.45 g/L). Azathioprine 100 mg/day was gradually added to his treatment. The patient was discharged from the hospital with oral steroid and azathioprine treatment. His neurological status was stable. He died 3 months later due to a lung infection.

The clinical findings, CSF analysis, and MRI of our patient were compatible with HE. The challenging conditions we faced were the lack of prominent cognitive or psychiatric change at the beginning and normal thyroid functions. The differential diagnosis included vasculitis, paraneoplastic limbic encephalitis, and Creutzfeldt-Jakob disease (CJD). The MRI was very helpful for differential diagnosis. The pattern of isolated cortical hyperintensity with concomitant combined cortical and deep grey matter (basal ganglia) hyperintensity on fluid attenuation inversion recovery along with restricted diffusion can differentiate CJD from other rapidly progressive dementias with a high sensitivity and specificity.2 Because the consecutive diffusion-weighted images of the patient were not compatible with CJD, 14-3-3 assay in the CSF was not studied. In addition, it is not specific for CJD and its positivity is also reported in HE.3 The laboratory and imaging findings were not compatible with limbic encephalitis. We assessed his objective clinical recovery (dramatic disappearance of myoclonus and partial cognitive-behavioural improvement) following pulse steroid therapy. Response to treatment may also exclude the diagnosis of CJD.

The pathophysiology of HE is not well understood. Autoimmune cerebral vasculitis and antibody-mediated neuronal reaction are the most accepted mechanisms. Most patients are euthyroid at the time of diagnosis.4 Antithyroperoxidase antibody is known as a positive predictor of responsiveness to steroid therapy and higher titres are associated with a more favourable outcome.5 Most cases in the literature treated with steroids make a complete recovery.5 Since it is a rare condition, the optimum treatment for steroid-resistant cases is unknown. Response to intravenous Ig or plasmapheresis treatments in steroid non-responsive cases has also been reported.5 Despite the normalisation of anti-TPO-Ab and anti-TG-Ab levels and somewhat improved inflammatory findings of CSF after treatment, we observed a complete response in myoclonus and only a partial improvement in cognition in our patient. This supports the hypothesis that thyroid autoantibodies are not the only pathogenic mechanism in HE. Other causes, the role of the thyroid gland, and other antibodies should be clarified by future studies.

Concept or design: B Kaymakamzade, S Ertugrul Mut.
Acquisition of data: H Özkayalar, A Eker, S Ertugrul Mut.
Analysis or interpretation of data: B Kaymakamzade.
Drafting of the manuscript: All authors.
Critical revision for important intellectual content: S Ertugrul Mut, B Kaymakamzade.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

We thank Dr Mustafa Canatan and Dr Fehim Türktan for their contribution to the editing of the manuscript.

All authors have disclosed no conflicts of interest.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

This study was conducted in accordance with the principles outlined in the Declaration of Helsinki. The patient provided written informed consent.

1. Mocellin R, Walterfang M, Velakoulis D. Hashimoto’s encephalopathy: epidemiology, pathogenesis and management. CNS Drugs 2007;21:799-811. Crossref

2. Vitali P, Maccagnano E, Caverzasi E, et al. Diffusion-weighted MRI hyperintensity patterns differentiate CJD from other rapid dementias. Neurology 2011;76:1711-9. Crossref

3. Hernández Echebarría LE, Saiz A, et al. Detection of 14-3-3 protein in the CSF of a patient with Hashimoto’s encephalopathy. Neurology 2000;54:1539-40. Crossref

4. Oide T, Tokuda T, Yazaki M, et al. Anti-neuronal autoantibody in Hashimoto’s encephalopathy: neuropathological, immunohistochemical, and biochemical analysis of two patients. J Neurol Sci 2004;217:7-12. Crossref

5. Litmeier S, Prüss H, Witsch E, Witsch J. Initial serum thyroid peroxidase antibodies and long-term outcomes in SREAT. Acta Neurol Scand 2016;134:452-7. Crossref

A 46-year-old man presented to the Department of Orthopaedics and Traumatology, Pamela Youde Nethersole Eastern Hospital in February 2004 with a 3-month history of self-detected left thigh mass. It was of spontaneous onset with no history of trauma, associated pain, weakness, or numbness. The patient had full range of movement and no lymphadenopathy was noted. Magnetic resonance imaging (MRI) [Fig 1] revealed a large area of infiltrative soft-tissue thickening at the medial aspect of the left distal thigh and involved the subcutaneous layer. The lesion measured 8.4 × 3.4 × 11.2 cm (anteroposterior × transverse × longitudinal) and was characterised by T1-weighted (T1W) hypointense to isointense and T2-weighted (T2W) fat-suppressed hyperintense signals with internal heterogeneity. Internal foci of hypointensity in the T2W fat-suppressed images were noted. An internal reticular pattern of septal thickening was also found. There was enhancement after gadolinium contrast administration. The margin of the lesion was well delineated from the underlying vastus medialis and sartorius muscles with no features of muscular invasion or destruction. The knee joint was unremarkable and bone marrow signal was normal. The neurovascular bundle was also intact. Overall features were non-specific for either inflammatory or neoplastic pathology.

Microscopic examination of an incisional biopsy over the left vastus medialis with a wedge of skin and subcutaneous tissue revealed infiltrate in the subcutis and to a lesser extent the deep dermis. The infiltrate consisted of lymphocytes and a low number of plasma cells. Immunohistochemical stains showed mainly T-cells and some B-cells. Occasional areas with aggregates of paler histiocytic cells were present and suggested granuloma formation. Stains for acid-fast bacilli and fungus were negative. The paler histiocytic cells were S100-positive and showed lymphophagocytosis (Fig 2). Molecular study by polymerase chain reaction showed no clonal T-cell proliferation. The overall features were suggestive of Rosai-Dorfman disease (RDD).

Radical excision of the lesion was performed subsequently and included the epimysium of the gracilis, sartorius and aponeurosis of the vastus medialis. The excision margin in the radial excision of the lesion was 2 cm. Microscopic examination revealed that the mass in the subcutis was composed of nodules or aggregates of lymphohistiocytic cells separated by areas of fibrosis. The cellular aggregates were composed of dark areas with plasma cells and lymphocytes and pale areas with clusters of histiocytes. The histiocytes showed round vesicular nuclei, distinct nucleoli, and abundant foamy cytoplasm with presence of emperipolesis (phagocytosis of plasma cells and lymphocytes). The histiocytes showed positive immunostaining for S100. Special stains for acid-fast bacilli and fungus were again negative. The overall features were consistent with RDD. The resection margins were unremarkable. The patient recovered well postoperatively.

Eight years after the operation, the patient detected a nodular swelling over the inferior margin of the surgical site. Serial MRI showed a static nodular T1W hypointense, and T2W isointense to mildly hyperintense soft-tissue lesion with contrast enhancement, measuring approximately 8 mm in diameter (Fig 3). Features could represent postoperative change or tumour recurrence. The patient was otherwise asymptomatic and he opted for follow-up scans to monitor the lesion instead of surgical excision.

Rosai-Dorfman disease is also known as sinus histiocytosis with massive lymphadenopathy and was first described by Rosai and Dorfman in 1969.1 It is a rare non-malignant histiocytic proliferative disorder. Although the disease may develop at any age, it is more common in young adults with a mean age of onset of 20 years and a slight male predominance (1.4:1).2 3

The aetiology of RDD is unknown, although previous studies have attempted to relate RDD to infectious agents including Epstein-Barr virus, human herpesvirus 6, herpes simplex virus, Brucella, Klebsiella rhinoscleromatis, and Nocardia.4 The disease involves a wide distribution and can affect a multitude of organ systems, including nodal involvement and extranodal involvement. The majority of patients present with painless massive cervical lymphadenopathy. Most patients have a complete and spontaneous remission, but some may experience recurrent or persistent albeit stable lymphadenopathy. In rare cases, the disease may follow an aggressive course and be fatal.

Pure cutaneous RDD is a distinct clinical entity that has an older age of onset (median 43.5 years) and a male-to-female ratio of 1:2.3 In contrast to systemic RDD that is commonly seen in blacks and rarely reported in Asians, most patients with purely cutaneous RDD are Asians or whites. The lesion remains localised to the skin even after long-term follow-up.5

Histologically, RDD is characterised by sheets of large pale histiocytes with large, round, vesicular nuclei. Phagocytosis of lymphoid cells or neutrophils by histiocytes may be found (“emperipolesis”). Immunohistochemical stains are useful when diagnosing RDD and the most consistent and reliable phenotype for RDD is S100 positive and CD1a negative.

Relative to the wide disease spectrum, there are variable radiographic features. Although no specific imaging characteristics allow differentiation of lymphadenopathy in RDD from the myriad other disease processes, massive painless bilateral cervical lymph node enlargement, particularly when it occurs in children and adolescents, should prompt consideration of RDD as a differential diagnosis. Nodal involvement may be evidenced as lymphadenopathy. In computed tomography scan of the sinuses and brain, polypoid masses, mucosal thickening, soft-tissue lesion of the paranasal sinuses or nasal cavity with or without associated osseous erosion can be seen. Features of brain involvement include a hyperattenuating meningeal-based mass showing contrast enhancement or parenchymal oedema surrounding the lesion. In MRI of the sinuses and brain, sinus lesions may also demonstrate hypointensity on T2W images. Meningeal-based mass lesions may demonstrate T1W isointensity to grey matter, T2W hyperintensity to grey matter and homogeneous contrast enhancement.6 Gallium scanning may show increased uptake and increased metabolism with fluorodeoxyglucose positron emission tomography. The differential diagnosis is broad and includes infectious (granulomatous) disease, Wegener’s granulomatosis, other histiocytosis, Hodgkin’s and non-Hodgkin’s lymphoma, and fibroinflammatory lesions. In general, RDD does not show bone or soft-tissue destruction as in cases of Wegener’s granulomatosis and T-cell lymphoma.

Rosai-Dorfman disease usually follows a benign and self-limiting course with treatment largely targeted at controlling local manifestations. Surgical options may be warranted for symptomatic control.

All authors contributed to the concept or design, acquisition of data, analysis or interpretation of data, drafting of the manuscript, and critical revision for important intellectual content. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

This study was conducted in accordance with the Declaration of Helsinki. The patient provided written informed consent.

1. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. A newly recognized benign clinical pathologic entity. Arch Pathol 1969;87:63-70.

2. Annessi G, Giannetti A. Purely cutaneous Rosai-Dorfman disease. Br J Dermatol 1996;134:749-53. Crossref

3. Brenn T, Calonje E, Granter SR, et al. Cutaneous Rosai-Dorfman disease is a distinct clinical entity. Am J Dermatopathol 2002;24:385-91. Crossref

4. Lu CI, Kuo TT, Wong WR, Hong HS. Clinical and histopathologic spectrum of cutaneous Rosai-Dorfman disease in Taiwan. J Am Acad Dermatol 2004;51:931-9. Crossref

5. Farooq U, Chacon A, Vincek V, Elgart GW. Purely cutaneous Rosai-Dorfman disease with immunohistochemistry. Indian J Dermatol 2013;58:447-50. Crossref

6. Symss NP, Cugati G, Vasudevan MC, Ramamurthi R, Pande A. Intracranial Rosai Dorfman disease: report of three cases and literature review. Asian J Neurosurg 2010;5:19-30.

Solitary lung nodules of <3 cm in diameter within the lung parenchyma and with no other abnormalities are often picked up incidentally during routine radiographic imaging. The incidence of cancer for such nodules has been estimated to be 10% to 70%. Management strategy depends on the clinical probability of cancer; nodule size, features, and growth rate ascertained by radiology; and the surgical risk to the patient. We report a case of such a nodule revealed by radiology and suspicious for malignancy. Subsequent excision and pathological examination revealed unexpected findings.

The index patient was a 61-year-old Chinese man from Northern China with history of laryngeal cancer treated successfully by local surgery and radiotherapy 6 years prior to present admission. Routine chest computed tomography (CT) scan revealed a peripheral lung nodule 9 mm in diameter in the right lower lobe. Follow-up CT scan 1 year later revealed minimal increase in size to 10 mm and the patient was referred to the Department of Thoracic Surgery, University of Hong Kong–Shenzhen Hospital in November 2015 for further treatment. The patient was a former chronic smoker for more than 10 years (10 cigarettes/day) but had stopped smoking upon diagnosis of laryngeal cancer.

Physical examination of the patient was unremarkable. High-resolution CT scan confirmed the presence of a peripheral lung nodule in his right lower lobe lateral-basal segment that was suspicious for malignancy. It measured 12 mm in diameter and had a spiculated border with a central cavity (Fig a). Another high-density 2-mm nodule was present in the right upper lobe subpleural region associated with apical fibrosis. There was pleural thickening and mildly increased peripheral lung markings in bilateral lower lobes. The peribronchiolar and hilar lymph nodes were not enlarged. After further examination and assessment of the surgical risk, video-assisted thoracoscopy was decided, with patient consent.

During video-assisted thoracoscopy, wedge excision of the nodule was done. Intra-operative frozen section consultation revealed a 10-mm papillary glandular tumour 8 mm away from the pleura. There was profuse mucin production and intra-alveolar extension suspicious for mucinous adenocarcinoma. Right lower lobectomy was subsequently performed, and the patient had an uneventful recovery. Microscopic examination of formalin-fixed paraffin-embedded sections from the nodule showed an arborising papillary tumour (Fig b) surrounded by intra-alveolar mucin. There was extension along the alveolar lining at its periphery (Fig b, inset) simulating ‘lepidic spread’ of adenocarcinoma. The papillary structures (Fig c and d) consisted of fibrous cores covered by single to multiple layers of mucin-secreting and ciliated (Fig d, inset) columnar cells and basal cells. There was focal tumour necrosis, rare mitoses, and mild nuclear atypia. Mucin and inflammatory cells filled the central cystic space. Origin from a dilated terminal bronchiole could be traced (Fig e). A batch of immunohistochemical studies showed CK7+/CK20- tumour cells mostly negative for thyroid transcription factor-1 except at the periphery, suggestive of residual alveolar lining cells. Monoclonal carcinoembryonic antigen highlighted the mucinous cells and p63 stained the basal cells. Proliferative index by Ki67 was low (5%). The overall picture was consistent with ciliated muconodular papillary tumour (CMNPT) of the lung. Examination of the lobectomy specimen showed focal peribronchiolar fibrosis compatible with the effect of smoking.1 These foci often contained peribronchiolar metaplasia featuring ciliated and mucinous columnar cells (Fig f) occasionally forming small papillae (Fig f, inset). The 2-mm lesion in the right upper lobe was a fibrotic nodule. The patient was well 1 year after surgery.

The term CMNPT of the lung was first used by Ishikawa in 2002 to describe a 1.5-cm peripheral lung nodule consisting of ciliated columnar cells, mucous cells and basal cells with papillary architecture. It was considered benign in view of indolent behaviour and bland-looking cells. Further reports by Ishikawa2 and others3 4 5 6 7 of similar tumours under various names (eg, solitary peripheral ciliated glandular papillomas, peripheral pulmonary papillary/glandular neoplasms with ciliated cells) supported this group of tumours as a specific entity that has not been included in the 2015 World Health Organization Classification of Lung Tumours.8 We searched the literature and reviewed 12 reports of 33 such tumours (online supplementary Appendix). Controversy exists whether CMNPT should be considered a benign tumour, a well-differentiated adenocarcinoma (in view of frequent intra-alveolar extension), or a spectrum of entities with possible progression. The consistent small size, slow growth rate, and lack of recurrence or metastasis after surgery support the benign nature of this tumour. Differentiation from mucinous adenocarcinoma is difficult for pathologists, especially during intra-operative frozen section, owing to the profuse mucin production and lepidic growth pattern. High-power examination revealing tripartite cell differentiation and lack of significant atypia in a clinically slow-growing lung nodule should raise suspicion of CMNPT. Wedge excision with clear margin is the treatment of choice. Our findings concur with a previous report3 of tumour origin from the terminal bronchiole. The finding of co-existing peribronchiolar metaplasia with similar cell components as CMNPT in the rest of the lung is unique. This suggests progression of disease from smoking-induced metaplasia to neoplasia during the pathogenesis. Although chronic smoking was noted in most male patients with CMNPT (14 out of 16 with smoking history specified in the online supplementary Appendix), co-existing peribronchiolar metaplasia was only briefly mentioned in one report,4 probably owing to limited sampling in wedge excision for most tumours. Molecular analysis for BRAF or EGFR mutations was not done in our case, because there was no therapeutic indication. Studies of CMNPT by Chuang et al5 and Lau et al6 yielded no KRAS or EGFR mutation. In contrast, Kamata et al7 reported mutations involving EGFR, BRAF, PTEN11, CTNNB1, IDH1, and TP53 in Asian patients and Liu et al4 reported mutations involving BRAF and AKT1 in one non-Asian patient. Because CMNPT is commonly reported in patients from East Asia, more reports are expected when awareness of this entity is raised among pathologists in this region. The pathogenesis, molecular characteristics, and natural behaviour of CMNPT can be better defined when more data are available.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Concept or design: FMF Cheung.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: FMF Cheung.
Critical revision for important intellectual content: All authors.

The authors would like to thank Dr Siu-wah Pang for contributing to the diagnosis of this tumour.

All authors have disclosed no conflicts of interest.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

This study was approved by the Ethics Committee of the University of Hong Kong–Shenzhen Hospital as original work with no infringement of personal privacy. The requirement for patient consent was waived by the Ethics Committee.

1. Katzenstein AL, Mukhopadhyay S, Zanardi C, Dexter E. Clinically occult interstitial fibrosis in smokers: classification and significance of a surprisingly common finding in lobectomy specimens. Hum Pathol 2010;41:316-25. Crossref

2. Ishikawa M, Sumitomo S, Imamura N, et al. Ciliated muconodular papillary tumor of the lung: report of five cases. J Surg Case Rep 2016;2016.pii:rjw144. Crossref

3. Aida S, Ohara I, Shimazaki H, et al. Solitary peripheral ciliated glandular papillomas of the lung: a report of 3 cases. Am J Surg Pathol 2008;32:1489-94. Crossref

4. Liu L, Aesif SW, Kipp BR, et al. Ciliated muconodular papillary tumors of the lung can occur in Western patients and show mutations in BRAF and AKT1. Am J Surg Pathol 2016;40:1631-6. Crossref

5. Chuang HW, Liao JB, Chang HC, Wang JS, Lin SL, Hsieh PP. Ciliated muconodular papillary tumor of the lung: a newly defined peripheral pulmonary tumor with conspicuous mucin pool mimicking colloid adenocarcinoma: a case report and review of literature. Pathol Int 2014;64:352-7. Crossref

6. Lau KW, Aubry MC, Tan GS, Lim CH, Takano AM. Ciliated muconodular papillary tumor: a solitary peripheral lung nodule in a teenage girl. Hum Pathol 2016;49:22-6. Crossref

7. Kamata T, Sunami K, Yoshida A, et al. Frequent BRAF or EGFR mutations in ciliated muconodular papillary tumors of the lung. J Thorac Oncol 2016;11:261-5. Crossref

8. Travis WD, Brambilla E, Burke AP, et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: International Agency for Research on Cancer; 2015.

Intrauterine insemination (IUI) is a fertility treatment that involves injection of a processed semen sample into the uterus via a transvaginal catheter after the cervix has been swabbed clean. Sterile instruments are used to reduce the risk of infection.

Historically, Candida glabrata has been considered a relatively non-pathogenic saprophyte of the normal flora of healthy individuals, rarely causing serious infections in humans. Contrary to the more common vaginal coloniser Candida albicans, C glabrata is unable to penetrate intact fetal membranes in vitro.1 This explains the rarity of C glabrata chorioamnionitis although it is a common vaginal coloniser found in up to 8% of pregnant women.1

The present study describes a rare case of C glabrata chorioamnionitis and fungaemia in a pregnancy following IUI.

A 32-year-old healthy primigravida with a trichorionic-triamniotic triplet pregnancy conceived by IUI presented in December 2011 to Queen Mary Hospital, Hong Kong at 16 weeks’ gestation with leaking of liquor. Physical examination and ultrasonography confirmed rupture of membranes of one of the triplets. The patient was initially treated with oral erythromycin but 2 days later she developed a fever of 39℃. Empirical intravenous broad-spectrum antibiotics were given for presumptive bacterial chorioamnionitis. In view of the poor prognosis at such an early gestation and the risk of maternal sepsis, medical abortion with misoprostol was considered appropriate. Complete abortion was achieved and the patient’s fever subsided the next day.

Two days after abortion, blood culture and vaginal swab test results revealed the presence of C glabrata. Intravenous anidulafungin 200 mg stat, then 100 mg every 24 hours was prescribed. The patient remained well and was discharged from the hospital after 2 weeks of antifungal treatment. Results from a second blood culture taken 3 days after abortion were negative.

In view of the rarity of fungaemia in immunocompetent hosts, testing for human immunodeficiency virus antibodies, lymphocyte subset and dihydrorhodamine reduction test was performed. All results were normal. Histological examination of the three placentae showed polymorph infiltration and presence of fungal spores, confirming acute fungal chorioamnionitis.

To the best of our knowledge, this is the first report of C glabrata chorioamnionitis and fungaemia in a pregnancy following IUI. A search of the literature revealed 18 articles reporting 22 cases of C glabrata chorioamnionitis (online supplementary Appendix 1). Fifteen of the reported cases were associated with in-vitro fertilisation (IVF) and four with a foreign body (intrauterine contraceptive device or cervical cerclage). The growing number of reports may be partly due to improved diagnostic methods, but the increasing use of assisted reproductive technologies also appears to be an important factor. Contamination of the embryo by infected semen or the mother’s cervicovaginal Candida during transvaginal oocyte harvest, or direct inoculation of C glabrata into the uterus during embryo transfer are possible aetiological mechanisms.2 The only two reported cases of the rare Candida lusitaniae chorioamnionitis in the literature were also associated with IVF (online supplementary Appendix 2), further supporting the hypothesis.

Most of the reported cases were associated with preterm labour or preterm premature rupture of membranes (PPROM); therefore, it is also possible that intrauterine C glabrata infection was a result of ascending infection after PPROM and preterm labour, since assisted reproductive technologies are associated with multiple pregnancy, preterm labour, and PPROM. However, PPROM and preterm labour occur in about 6% of births and there have been only 23 reported cases (including the current report) of C glabrata chorioamnionitis. Sixteen of the 23 reported cases were associated with IVF and IUI. We conclude that C glabrata chorioamnionitis is more likely due to inoculation of the fungus into the uterus during IVF and IUI procedures, rather than a result of preterm labour and PPROM. The present case supports this hypothesis.

Although maternal outcome was good in the published cases, this fungal chorioamnionitis was often associated with poor fetal outcome. Only 30% (7 of 23 cases, including the present case) of the published affected pregnancies had any neonatal survival as they usually presented with PPROM or preterm labour in the second or early third trimester.

There are no guidelines for screening for vaginitis before assisted reproductive procedures. If asymptomatic C glabrata or other fungal colonisation is identified, there is no consensus on whether treatment should be given. One case of a successful IVF pregnancy following eradication of C glabrata by topical boric acid treatment had been preceded by an IVF pregnancy that ended in C glabrata sepsis and fetal loss.3 The authors suggested routine vaginal culture for yeast and treatment of positive culture results prior to embryo transfer, and commented that such an inexpensive test adds little to the overall costs and procedures associated with IVF.3 On the contrary, some authors suggest that a comprehensive screening programme may not be justified given the rarity of invasive disease despite widespread use of IVF and the relatively high rates of C glabrata carriage among pregnant women.2 The true incidence of C glabrata chorioamnionitis is unknown because it is likely to be underdiagnosed due to the difficulty in laboratory diagnosis.2 Treatment cost-effectiveness cannot be estimated, but the number needed to treat to prevent one C glabrata–related adverse outcome is likely to be large in view of the relatively high carrier rate and the rarity of C glabrata chorioamnionitis. Further research is needed to evaluate the cost-effectiveness of such a screen-and-treat programme before it can be recommended. In addition, there have been reports of emergence of antifungal resistance. If all asymptomatic carriers are treated prior to embryo transfer, emergence of drug resistance will become a concern. Similarly, whether it is worth screening men for any asymptomatic carriage is uncertain.

The possibility of C glabrata chorioamnionitis should be considered in pregnant women who develop chorioamnionitis after conceiving with assisted reproductive techniques. The reporting of this potentially devastating condition should be encouraged so as to improve our knowledge about its incidence, risk factors, pathogenesis, and management. Further research is needed to determine the incidence of fungal infection–related adverse outcomes and the cost-effectiveness of a screen-and-treat approach prior to assisted reproduction.

All authors contributed to the concept of the paper. SSF Yung, MMC Cheng, and PWS Ma contributed to the acquisition, analysis, and interpretation of data. SSF Yung drafted the article.

All authors have disclosed no conflicts of interest. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity. This paper was presented as a poster in the 25th Asian & Oceanic Congress of Obstetrics and Gynaecology (AOCOG), Hong Kong, on 15-18 June 2017.

1. Ganer Herman H, Mevorach Zussman N, Krajden Haratz K, Bar J, Sagiv R. Candida glabrata chorioamnionitis following in vitro fertilization: review of the literature. Gynecol Obstet Invest 2015;80:145-7. Crossref

2. Jackel D, Lai K. Candida glabrata sepsis associated with chorioamnionitis in an in vitro fertilization pregnancy: case report and review. Clin Infect Dis 2013;56:555-8. Crossref

3. Asemota OA, Nyirjesy P, Fox R, Sobel JD. Candida glabrata complicating in vitro pregnancy: successful management of subsequent pregnancy. Fertil Steril 2011;95:803.e1-2. Crossref