An 85-year-old man presented with a history of odynophagia since March 2015. He was a chronic smoker but did not drink alcohol. He had a medical history of hypertension, diabetes mellitus, and gout. He was first seen by us in April 2015. At the first presentation, physical examination revealed an irregular 3-cm ulcerative mass arising from the left tonsil (Fig 1). The rest of his oral cavity was otherwise normal and there was no cervical lymphadenopathy. Carcinoma of the left tonsil was suspected. Computed tomographic (CT) scan of the head and neck disclosed a non-specific soft tissue thickening and mucosal contrast enhancement at the left side of the oropharynx. Transoral punch biopsy of the left tonsillar mass was performed. Histopathology revealed no evidence of malignancy with heavy stromal infiltration by neutrophils, lymphocytes, and plasma cells plus focal microabscess formation. No granuloma or fungal elements were seen.

Subsequent upper gastrointestinal endoscopy was performed and disclosed the left tonsillar mass with no other abnormalities within the hypopharynx, oesophagus, or stomach. Because of the progressive odynophagia, a nasogastric feeding tube was inserted; as there was no improvement and the diagnosis was still elusive, left tonsillectomy was performed on the same day and was uneventful.

Histopathological examination of the left tonsil showed lymphoid tissue with preserved architecture present beneath the stratified squamous epithelium. Hyperplastic lymphoid follicles with germinal centre surrounded by mantle cells were present. Plasma cells were seen at the interfollicular area. There were no malignant cells. Immunostaining revealed more than 90% of plasma cells per high-power field with an immunoglobulin (Ig) G4:IgG ratio of more than 40% (Fig 2). The final diagnosis was IgG4-related disease of the left tonsil.

The patient refused workup with positron emission tomography–CT scan but clinically there was no feature of systemic IgG4-related disease so steroids were not prescribed. His odynophagia gradually improved and he could tolerate oral feeding with congee. The feeding nasogastric tube was removed. Unfortunately, the patient had a depressive mood and general debility. He eventually died of pneumonia in September 2015.

Immunoglobulin G4–related disease is a fibroinflammatory condition often associated with elevated serum IgG4 level.1 It is a multi-organ entity that encompasses various conditions formerly considered to be unrelated, single-organ diseases.2 It is notorious for its resemblance to malignant disease such as carcinoma of the pancreas. It is a source of undue anxiety for both patients and clinicians as the diagnosis may be difficult if the index of clinical suspicion for IgG4-related disease is low. Systemic symptoms (asthenia, weight loss, or fever) may occur in a minority of patients. The disease can affect the pancreas (autoimmune pancreatitis with abdominal pain), biliary tree (sclerosing cholangitis with jaundice), salivary glands or lacrimal gland (parotid, submandibular and lacrimal gland enlargement), lymph nodes, kidneys (tubulointerstitial nephritis with renal failure), and retroperitoneum (ureteric stricture).2

Measuring the serum IgG4 level is useful to establish the diagnosis of this uncommon disease3 and may avoid unnecessary diagnostic surgery. Although serum IgG4 level was initially thought to be a key diagnostic feature of IgG4-related disease, more recent evidence has devalued the significance of a raised level. The key to diagnosis is immunohistochemical demonstration of tissue infiltration by IgG4-bearing plasma cells and morphological evidence of lymphoplasmacytic infiltrates, storiform fibrosis, and obliterative phlebitis.2 Serum IgG4 assay was not done as this investigation was not available at our hospital. Nonetheless the diagnosis of IgG4-related disease of tonsil in this patient was obvious based on the histopathological examination with IgG4 immunostains.

Umehara et al4 proposed a set of criteria for the diagnosis of IgG4-related disease designed to be used irrespective of the specific organ involvement. The criteria are (1) serum IgG4 concentration of >135 mg/dL and (2) >10 IgG-positive plasma cells demonstrated per high-power field, of which >40% are IgG4-positive cells. Nevertheless the sensitivity is low for the diagnosis of autoimmune pancreatitis based on these criteria.

Of note, IgG4-related disease can manifest at the head and neck region. Kuttner’s tumour of the submandibular gland has been well reported and often masquerades as carcinoma.5 Nonetheless IgG4-related disease within the oral cavity is very rare. To the best of our knowledge, only one case of simultaneous IgG4-related lesions affecting the left border of the tongue and right tonsil has been reported in the literature.6 This patient presented with an elevated and nodular mass devoid of surface ulceration, associated with a generalised skin rash. The oral and cutaneous lesions gradually resolved after therapy with steroid.6 In contrast, our patient had an ulcerative mass without any skin rash. Both cases were initially suspected to be squamous cell carcinoma because of the alarming clinical features.

Steroid remains the mainstay of treatment for IgG4-related disease. It should be started early in order to prevent tissue fibrosis and thus irreversible organ damage, except in cases of asymptomatic disease of the submandibular gland or lymph node.7 Radiological abnormalities often vanish following the commencement of steroid therapy. Unfortunately, disease relapse is not uncommon after steroid therapy is tapered. There is no evidence to support the effectiveness of adding conventional steroid-sparing agents (eg azathioprine, methotrexate, or cyclophosphamide) to sustain remission for IgG4-related disease.7 Although remission can be achieved in more than 80% of patients with induction steroid therapy, some clinicians support the use of maintenance steroid at 5 mg or 2.5 mg daily for a durable response. However, disease may flare in a quarter of patients despite maintenance therapy. Moreover, the optimal duration for maintenance treatment is uncertain and the morbidity associated with steroid, although in low dose, is not negligible. Fortunately, repeated induction therapy with steroid for disease relapse is normally effective.7

In summary, IgG4-related disease can involve the tonsils and masquerade as tonsil carcinoma. Clinicians should consider IgG4-related disease as one of the differential diagnoses for a suspicious tonsillar mass. Early diagnosis of tonsillar mass with biopsy is essential to exclude tonsil carcinoma and to allow prompt steroid treatment for IgG4-related disease of tonsil which is curable.

1. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012;25:1181-92. Crossref

2. Stone JH, Brito-Zerón P, Bosch X, Ramos-Casals M. Diagnostic approach to the complexity of IgG4-related disease. Mayo Clin Proc 2015;90:927-39. Crossref

3. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 2001;344:732-8. Crossref

4. Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol 2012;22:21-30. Crossref

5. Chow TL, Chan TT, Choi CY, Lam SH. Kuttner’s tumour (chronic sclerosing sialadenitis) of the submandibular gland: a clinical perspective. Hong Kong Med J 2008;14:46-9.

6. Khurram SA, Fernando M, Smith AT, Hunter KD. IgG4-related sclerosing disease clinically mimicking oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol 2013;115:e48-e51. Crossref

7. Khosroshahi A, Wallace ZS, Crowe JL, et al. International consensus guidance statement on the management and treatment of IgG4-related disease. Arthritis Rheumatol 2015;67:1688-99. Crossref

A 37-year-old Chinese woman was admitted to the First Affiliated Hospital, College of Medicine, Zhejiang University, China in July 2009 with pain in the upper back and hip for 9 months. She denied any chronic medication or illness. Her serum calcium level was 2.73 mmol/L (reference range [RR], 2.08-2.60 mmol/L), phosphorus 0.68 mmol/L (RR, 0.81-1.62 mmol/L), alkaline phosphatase 366 IU/L (RR, 30-115 IU/L), and intact parathyroid hormone (iPTH) 1154 pg/mL (RR, 12-65 pg/mL). T-score and Z-score for femoral bone mineral density were -2.7 and -2.8, respectively. Cervical computed tomography (CT) scan and thyroid, parathyroid, and abdominal (including pancreas, adrenals) ultrasonography were unremarkable. Anterior planar technetium (^99mTc) sestamibi (MIBI) scintigraphy images of the neck and chest showed a focal shadow with intense tracer uptake in the superior thorax at 15 minutes (Fig a) and 120 minutes (Fig b) following injection of ^99mTc-MIBI. Thoracic CT revealed a contrast-enhanced nodule with soft tissue density of 2.9 x 1.3 cm in the anterior mediastinum (Fig c). Thoracic and abdominal CT showed a brown tumour in the right omoplate, the fourth posterior left rib, and iliac bone (Figs d and e).

A mid-sternal thoracotomy was performed. A dark red mass of 4 x 2.4 x 1 cm was found in the thymus isthmus and resected. The mediastinal mass was covered with a thin fibrous capsule and on section showed a greyish cut surface. Histology confirmed the presence of ectopic parathyroid adenoma composed predominantly of oxyphil cells arranged in acinar pattern. Serum calcium level was 2.18 mmol/L and iPTH 17.2 pg/mL 16 hours after surgery. Hypocalcaemia (serum calcium, 1.68 mmol/L) and hungry bone syndrome occurred 3 days after surgery and gradually improved over a week with calcium carbonate and calcitriol supplementation that was started after surgery and continued thereafter. Serum calcium and iPTH remained normal after 5 years’ follow-up.

A diagnosis of primary hyperparathyroidism in a symptomatic patient is made in the presence of hypercalcaemia, hypophosphataemia, and raised levels of alkaline phosphatase and iPTH,1 as demonstrated in our case. Primary hyperparathyroidism occurs in approximately 1% of the adult population, commonly due to solitary parathyroid adenomas (85%).1 Primary hyperparathyroidism due to ectopic parathyroid adenomas can pose diagnostic and management challenges, especially when imaging studies provide limited sensitivity.2

The embryological origin of the parathyroid glands is the endoderm of the third and fourth pharyngeal pouches, from where these glands migrate to their usual position behind the thyroid gland. It is well known that parathyroid glands can be found in aberrant locations, mainly in the thyroid parenchyma or in the mediastinum.3 The high incidence of ectopic inferior parathyroid glands has been attributed to abnormal migration during embryogenesis. Since parathyroid glands lack capsular fixation, an ectopic parathyroid gland may also develop from a gland that is initially present in a normal anatomic position but which enlarges and is displaced to an ectopic location where there is little resistance.

Ultrasonography is commonly used to locate enlarged parathyroid glands due to its convenience and low cost. Its ability to detect abnormalities, however, depends on the experience and skill of the operator so sensitivity in the localisation of enlarged parathyroid glands varies greatly (44%-87%).2 Ectopic parathyroid adenomas may be detected with MIBI at a sensitivity level almost identical to that of orthotopic adenomas. Focal increased activity separated from the lower pole of the thyroid on MIBI images gives a high probability for locating ectopic parathyroid adenoma in the thymus. Of note, ^99mTc-MIBI is a non-specific tracer that is taken up by mitochondria so any mitochondria-rich cells may show uptake. Mitochondrial density in an adenoma is also a major factor that can cause prolonged retention of ^99mTc. This is evidenced by the number of mitochondrion in lesions detected by scintigraphy that is significantly higher than in those that are missed, with the highest ratio of mitochondria per cell found in oxyphil cells. The typical pattern in a parathyroid adenoma demonstrates a prolonged retention of ^99mTc-MIBI in the adenoma with rapid washout of the tracer from normal thyroid tissue. The degree of MIBI uptake in parathyroid adenomas has been reportedly correlated with the size of gland and the cytological composition (greater uptake seen in adenomas with dominance of oxyphil cells over chief cells).2

Of note, CT may further contribute to the identification of ectopic parathyroids and the differential diagnosis from other lesions. In our cases, the parathyroid glands were not located by ultrasonography although a combination of MIBI scintigraphy and CT imaging accurately localised the tumour in the anterior mediastinum. This highlights the usefulness of combining multiple imaging techniques to locate an ectopic active parathyroid gland. These combinations are cost-effective, and considered an approach to routine preoperative localisation of ectopic parathyroid adenomas, especially in cases with a negative MIBI scan.4

Hungry bone syndrome refers to the rapid, profound, and prolonged hypocalcaemia associated with hypophosphataemia following parathyroidectomy as a result of extensive remineralisation.5 Various risk factors of hungry bone syndrome include older age, large parathyroid adenoma, overt bone disease, and vitamin D deficiency. Consequently, transient hypocalcaemia is frequently encountered postoperatively; the presence of mild hypocalcaemia provides reassurance that the hyperactive adenomatous gland has been successfully removed.

For any hypercalcaemia and high level of PTH without parathyroid adenoma in the neck, physicians should remain alert and continue to search for ectopic locations using a combination of imaging techniques. The mediastinum must be cautiously explored since it is a very common location for ectopic parathyroid adenoma. The combination of several imaging techniques has an incremental effect on the localisation of ectopic parathyroid adenomas compared with use of either one technique alone.

1. AACE/AAES Task Force on Primary Hyperparathyroidism. The American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Pract 2005;11:49-54. Crossref

2. Haber RS, Kim CK, Inabnet WB. Ultrasonography for preoperative localization of enlarged parathyroid glands in primary hyperparathyroidism: comparison with (99m) technetium sestamibi scintigraphy. Clin Endocrinol (Oxf) 2002;57:241-9. Crossref

3. Noussios G, Anagnostis P, Natsis K. Ectopic parathyroid glands and their anatomical, clinical and surgical implications. Exp Clin Endocrinol Diabetes 2012;120:604-10. Crossref

4. Elaraj DM, Sippel RS, Lindsay S, et al. Are additional localization studies and referral indicated for patients with primary hyperparathyroidism who have negative sestamibi scan results? Arch Surg 2010;145:578-81. Crossref

5. Witteveen JE, van Thiel S, Romijn JA, Hamdy NA. Hungry bone syndrome: still a challenge in the post-operative management of primary hyperparathyroidism: a systematic review of the literature. Eur J Endocrinol 2013;168:R45-53. Crossref

In March 2011, a 47-year-old Chinese woman who enjoyed good past health presented to a local general out-patient clinic in Hong Kong with a 2-week history of a mildly painful cord-like structure stretching from the inferior part of the left breast to the umbilicus level (Fig). She had worked as a dishwasher 3 months prior to the appearance of the lesion, a job that required her to carry stacks of heavy dishes. There was no recent trauma or surgery of the breast and no family history of breast cancer. Physical examination revealed a 15-cm long by 0.5-cm wide erythematous subcutaneous cord-like lesion stretching from the inferior part of the left breast down along the anterolateral chest wall to the umbilicus level. The lesion was firm and mildly tender. It was adherent to the skin, but was slightly movable over the deeper tissues. Examination of the breasts showed no asymmetry or skin changes. Palpation of the right breast was normal. There was, however, mild lumpiness over the outer upper quadrant of the left breast although no definite breast lump found. The nipples were normal with no discharge. There were no palpable axillary or regional lymph nodes.

The patient was diagnosed with Mondor’s disease with involvement of the thoracoepigastric vein. The course of the disease was explained and the patient was advised to avoid repetitive strain of the chest wall. Paracetamol was prescribed for symptomatic relief. She was referred to the Surgical Specialist Outpatient Clinic (SOPC) for further evaluation of left breast lumpiness. The cord in this patient disappeared spontaneously after approximately 5 weeks. Clinical assessment at the SOPC in May 2011 did not identify any palpable breast lump. Routine mammogram was later performed in August 2012 and revealed a 2-cm ill-defined high-density speculated lesion in the outer-upper quadrant of the left breast. Supplementary ultrasonography was also performed and revealed an ill-defined irregular hypoechoic lesion measuring 0.7 x 0.6 x 1.65 cm. The patient was followed up in the SOPC 2 weeks later and the lesion was also clinically palpable. Core biopsy confirmed invasive ductal carcinoma. Left modified radical mastectomy was performed with metastatic invasive ductal carcinoma and axillary lymph node involvement confirmed (stage pT1cpN1). The patient was also treated with adjuvant chemotherapy.

Mondor’s disease is an uncommon clinical condition of thrombophlebitis of the subcutaneous veins of the anterolateral thoracoabdominal wall. The most commonly affected vessels are the thoracoepigastric, lateral thoracic, and superior epigastric veins.1 It is characterised by sudden onset of one or more subcutaneous palpable and visible cord(s) over the mammary area, chest wall, or epigastrium.

Mondor’s disease occurs most commonly in middle-aged patients, and is more common in women than in men (ratio 3:1).2 The involved subcutaneous veins will initially turn red and tender and subsequently become a painless and tough fibrous band. Pathologically, the first stage is due to infiltration of inflammatory cells resulting in obliterative thrombophlebitis of the affected veins, causing redness and tenderness. In the second stage, connective tissues proliferate in the vessels with consequent formation of the fibrous band.1 Recanalisation of the veins occurs later and the fibrous band will disappear within several weeks.3

It is thought to be a very uncommon disease although the true incidence is unknown as it is self-limiting and patients may not seek medical attention. The diagnosis can usually be made based on clinical history and typical physical findings. Biopsy is not essential.

The aetiology of Mondor’s disease is still unclear. In many cases it is idiopathic, although it has also been linked with recent breast surgery, local trauma, excessive physical activity with muscle strain, an inflammatory process, infections, and mammary pathology including mastitis or abscess.2 Association with breast cancer has also been reported. Catana et al4 studied 63 cases of Mondor’s disease of whom eight (12.7%) had associated breast cancer. The authors suggested that mammography should be performed in patients with Mondor’s disease even when physical examination was normal. A retrospective review in 2011 identified five cases of Mondor’s disease of the breast; none of which was associated with breast cancer.5 Nonetheless, the authors advised thorough evaluation of the breast to exclude an underlying breast cancer. In our patient, the correlation with an occult carcinoma of the breast could not be confirmed since there was a time delay between the presentation of Mondor’s disease and the diagnosis of breast carcinoma. Moreover, the patient’s recent strenuous job with repetitive straining of the chest wall muscle might have been a predisposing factor.

Since Mondor’s disease is self-limiting, symptomatic treatment is suggested. General advice includes rest, local application of heat, and better breast support. Oral non-steroidal anti-inflammatory drugs provide effective symptomatic relief.2

In summary, Mondor’s disease is a condition that is rarely encountered in primary care. Recognising this condition is important as it can avoid unnecessary investigations and referral for diagnosis. Although the association of underlying breast cancer with Mondor’s disease has not been confirmed, family physicians should be aware of the possibility and conduct a thorough evaluation including clinical examination and imaging of the breast to exclude its presence in patients diagnosed with Mondor’s disease.

1. Alvarez-Garrido H, Garrido-Ríos AA, Sanz-Muñoz C, Miranda-Romero A. Mondor’s disease. Clin Exp Dermatol 2009;34:753-6. Crossref

2. Mayor M, Burón I, de Mora JC, et al. Mondor’s disease. Int J Dermatol 2000;39:922-5. Crossref

3. Ichinose A, Fukunaga A, Terashi H, et al. Objective recognition of vascular lesions in Mondor’s disease by immunohistochemistry. J Eur Acad Dermatol Venereol 2008;22:168-73.

4. Catana S, Zurrida S, Veronesi P, Galimberti V, Bono A, Pluchinotta A. Mondor’s disease and breast cancer. Cancer 1992;69:2267-70. Crossref

5. Salemis NS, Merkouris S, Kimpouri K. Mondor’s disease of the breast. A retrospective review. Breast Dis 2011;33:103-7. Crossref

An 18-year-old girl was admitted to the Aga Khan Hospital, Pakistan in April 2014 with progressively worsening shortness of breath, orthopnoea, malaise, and low-grade fever for 3 years, and generalised body swelling for 6 months. She had no significant medical history or trauma.

On physical examination she was a medium-built girl with a heart rate of 120 beats/min, raised jugular venous pressure, and bilateral pedal pitting oedema. Chest auscultation revealed muffled heart sounds with bilateral basilar lung crepitations. The chest X-ray showed wide mediastinum with clear lung markings.

The computed tomographic (CT) scan showed a conglomerate undefined mass in the anterior, middle, and posterior mediastinum encasing the entire heart and great vessels with most marked extension in the retrocardiac area (Fig 1). The echo showed a large echo-dense mass compressing the heart with invasion into the left atrium (LA), obliterating most of the LA cavity.

Video-assisted thoracoscopic surgery was performed and the mass biopsied for histopathological examination. The histopathology showed fibrosis and chronic granulomatous inflammation with fungal hyphae on periodic acid–Schiff staining (Fig 2). The fungal cultures grew Aspergillus flavus.

A diagnosis of invasive mediastinal aspergillosis was made and the patient was started on oral itraconazole 100 mg twice a day. She showed a remarkable recovery in her symptomatology in the first 6 weeks of follow-up.

Aspergillosis refers to a variety of diseases caused by several species of Aspergillus organisms that are abundant in the environment and recognition of which has increased over recent years. There are three main categories in general: saprophytic aspergilloma, allergic bronchopulmonary aspergillosis, and invasive aspergillosis. The term ‘invasive aspergillosis’ is generally used to imply a histopathologically demonstrated invasion of tissues by these spores. It represents an important cause of morbidity and mortality, particularly among immunocompromised patients, occurring mostly in those with haematological malignancies who are undergoing chemotherapy and organ transplantation with concomitant immunosuppressive therapy. Extension of invasive pulmonary aspergillosis to the mediastinum has been reported only rarely.1 Our case is an immunocompetent patient with extensive mediastinal aspergillosis who presented with dyspnoea and symptoms of cardiac tamponade.

Invasive aspergillosis varies in severity and clinical course, depending upon the affected organ and the host. It is caused by many Aspergillus groups; however the most common is the Aspergillus fumigatus group. These groups live in soil, and derive nutrients from dead plants and animal matter. It has been further subdivided in recent years to angioinvasive and airway-invasive aspergillosis. Invasive aspergillosis is a major cause of morbidity and mortality in immunosuppressed patients.2

The form that Aspergillus lung disease takes is heavily dependent on the immune response of the patient.3 Indolent forms of locally invasive aspergillosis in the form of chronic necrotising or semi-invasive aspergillosis in apparently immunocompetent individuals are now recognised.

Invasive aspergillosis is a result of three factors: (1) suppression of the immune response due to debilitating disease or therapy; (2) glucocorticoid therapy with consequent diminished inflammatory response and disruption of the normal flora by antimicrobial agents4; and (3) local implantation of the fungus. The disease is well known in immunocompromised individuals but has also been described in healthy individuals. Patients with a compromised immune system, specifically with neutropenia, are susceptible to acute airway-invasive and angioinvasive aspergillosis in the absence of pre-existing lung pathology.

There have been a few cases described in which patients were immunocompetent. Orr et al5 documented two patients with normal host defences in whom postmortem examination revealed death due to disseminated aspergillosis (one patient had a history of coronary heart disease, the other acute renal failure following gangrenous appendicitis). Our patient was otherwise healthy as confirmed by the normal haematological studies.

The usual pathogenesis of invasive aspergillosis is by dissemination from a primary site, such as the lungs or the paranasal sinuses, or by contiguous spread.6 In this particular patient, the chest X-ray and CT scan of the chest were clear without a primary lesion. It was therefore postulated that inhalation of the fungal spores with immediate mediastinal invasion resulted in the implantation of a high concentration of aspergillus spores around the heart. This was followed by chronic infiltration around the pericardium and extension into the heart.

This idea was supported by the histopathology report of granulomatous tissue fibrosis, indicating a long-standing process, and in keeping with the history of worsening shortness of breath for 3 years. Our case showed an undefined mass in the anterior, middle, and posterior mediastinum extending into the LA. The effects of the mass could explain all of the patient’s symptoms, namely worsening dyspnoea and cardiac tamponade symptoms.

In conclusion, this case highlights that there is usually a long dormant period before the clinical manifestation of aspergillosis, clinically and radiologically the disease may be suggestive of a malignant process, and contamination with aspergillus should be considered from all possible aspects, particularly in healthy individuals.

1. Shakoor MT, Ayub S, Ayub Z, Mahmood F. Fulminant invasive aspergillosis of the mediastinum in an immunocompetent host: a case report. J Med Case Rep 2012;6:311. Crossref

2. Al-Alawi A, Ryan CF, Flint JD, Müller NL. Aspergillus-related lung disease. Can Respir J 2005;12:377-87. Crossref

3. Gefter WB. The spectrum of pulmonary aspergillosis. J Thorac Imaging 1992;7:56-74. Crossref

4. Mashimoto H, Suyama N, Araki J, et al. A case of mediastinitis and bilateral pyothorax, following acute epiglottitis with concurrent Aspergillus infection [in Japanese]. Kansenshogaku Zasshi 1992;66:648-52. Crossref

5. Orr DP, Myerowitz RL, Dubois PJ. Patho-radiologic correlation of invasive pulmonary aspergillosis in the compromised host. Cancer 1978;41:2028-39. Crossref

6. Hendrix WC, Arruda LK, Platts-Mills TA, Haworth CS, Jabour R, Ward GW Jr. Aspergillus epidural abscess and cord compression in a patient with aspergilloma and empyema. Survival and response to high dose systemic amphotericin therapy. Am Rev Respir Dis 1992;145:1483-6. Crossref

A 23-year-old female was admitted for fever, cough, and right pleuritic pain in January 2015. Chest X-ray revealed right pleural effusion. Subsequent computed tomography of the thorax demonstrated necrotising pneumonitis in the right lower lobe, with large right empyema and multiple left lung centrilobular nodules suspicious of tuberculosis (Fig 1a). On admission, haemoglobin level was only 84 g/L. Oesophagogastroduodenoscopy (OGD) found a linear deep oesophageal ulceration with suspected fistula opening (Fig 1b), biopsy of which yielded Mycobacterium tuberculosis. Gastrografin swallow confirmed contrast leakage at the lower oesophagus with fistulation to the right hemithorax (Fig 1c), suggesting the occurrence of tuberculous oesophagopleural fistula (OPF) and resulting empyema.

Prompt chest drainage and systemic antibiotics were initiated, targeting the polymicrobial and smear positive tuberculous tissue samples. Subsequent therapeutic OGD with endoscopic stenting was performed. The patient was placed in the left lateral decubitus position and sedated. The linear ulcer at 24 to 32 cm from incisor, with 5-mm fistula opening at 24 cm was visualised. Submucosal lipiodol injection under fluoroscopy marked the margins of the fistulated ulcer, and the most distal end of the linear ulcer (Fig 2a).

A 12-cm 22-Fr retrievable, fully covered, self-expandable metallic stent (SEMS) with an over-the-wire distal delivery stent deployment system (Taewoong Medical, South Korea) was selected. The shoulders of the stent were placed across the fistula opening, being deployed over the guidewire (Fig 2b and 2c). All positions were confirmed by fluoroscopy and the proximal stent secured with two endoclips at 12 and 6 o’clock position.

The patient tolerated the procedure well. She was put on total parenteral nutrition for 2 weeks, then resumed enteral feeding via a nasoduodenal tube inserted during a separate OGD session. Decortication was later performed to clear the empyema cavity (Fig 1d). Follow-up OGD at 8 weeks demonstrated no stent migration and stent was removed uneventfully by pulling on the purse-string suture with endoscopic forceps. Check endoscopy confirmed complete healing of the ulcer by scarring (Fig 1e). The retrieved fully covered SEMS was intact and without tissue ingrowth (Fig 1f).

Recovery of the patient was satisfactory. She achieved complete resolution of sepsis and tolerated an oral diet after stent removal. Follow-up computed tomography of the thorax in May 2015 showed minimal thoracic collection and no lung consolidation.

Oesophageal stenting has significantly matured since its inception. In unresectable malignant obstruction, SEMS has become the standard of care, with high technical success (83%-100%) in positioning and effective dysphagia palliation (80%-95%).1 Emerging roles are also seen in benign conditions like anastomotic leaks or perforations, with promising 81.4% and 86% success in defect closure, respectively.2 Success is nonetheless variable in treating benign strictures and refractory oesophageal variceal bleeding.1 In malignant oesophagorespiratory fistulae (ORF), 80% of cases achieve complete healing with SEMS.3 Little is known about the efficacy in benign ORF, OPF in particular, due to the clinical rarity and inherent heterogeneity.

Oesophagorespiratory fistulae is an uncommon entity comprising all pathological connections between the oesophagus and airway. Malignant oesophageal, lung, or mediastinal tumours are the most common causes. Fistulation occurs secondary to tumour invasion or inflammation post-radiotherapy, laser, chemotherapy or stenting. Benign ORF is rare, with major causes being trauma and infection.4 Regarding fistula subtypes, only 3% to 11% represent oesophagopulmonary fistula or OPF that communicate peripherally. The rest are either oesophagotracheal (52%-57%) or oesophagobronchial (37%-40%) in location.5 It is easy to understand why few reports exist of OPF and its treatment.

In general, OPF has a similar aetiology to ORF. Malignancies aside, it is a well-recognised complication in 0.2% to 1% of pneumonectomies. Other traumatic causes include endoscopic sclerotherapy, gunshot wound, and foreign body ingestion.5 Infective causes range from tuberculosis to mycotic disease, also candidiasis in immunocompromised individuals. Other reported cases include Crohn’s disease, perforated Barrett’s ulcer, and ruptured diverticulum.6 7 8 Like postsurgical leaks and perforations, OPF is a sinister condition associated with high morbidity and mortality.2 3 Significant mediastinal and pleural contamination, polymicrobial sepsis and abscesses often ensue, warranting multiple drainage procedures and surgery, as well as intensive life support.

Oesophagopleural fistula rarely heals spontaneously. Principles of management include drainage of collection, exclusion of fistulation, aggressive antimicrobials, and lastly, intensive nutritional and organ support. Established abscesses persist despite spillage control by stenting, hence necessitating drainage procedures.9 Pleural drainage is possible via tube thoracostomy or image-guided pigtail catheter insertion. Yet if multiloculated collections exist, open or thoracoscopic drainage is preferred since it permits septa breakdown under direct vision, thorough irrigation, and placement of a drain in an ideal position.10 Early use of broad-spectrum intravenous antibiotics with aerobic and anaerobic coverage is equally important. Fistula exclusion may be operative, fluoroscopic, or endoscopic. Traditional surgical approaches involve either primary suturing or segmental oesophagectomy, but are complex and associated with high morbidity (30%-50%) and mortality (10%).11 Bypass and muscle flap buttressing are newer operations possible for the debilitated.12 13 Embolisation with vascular plug and coils under fluoroscopy has been reported in one article. Endoscopic fibrin glue application represents a viable option in small-calibre fistulae. Limited reports also exist for other endoscopic measures like argon plasma or electrocoagulation, suturing, or clipping devices.11

Our patient represented a promising candidate for oesophageal stenting. Initially performed with rigid plastic tubes, development has evolved to SEMS with easier insertion and less migration. Most commonly made of nitinol, SEMS exhibits great flexibility and radial force to maintain patency and position. They come uncovered, partially, or fully covered, with a plastic or silicon membrane. Fully covered SEMS is the stent-of-choice in managing fistulae, since the covering is vital for leakage prevention and easy retrievability.1 Most published studies suggest stent placement immediately after leakage confirmation to minimise mediastinal contamination.3 Insertion is via upper endoscopy under sedation, with the patient in a left lateral or prone position to minimise aspiration. Stent size is chosen according to oesophageal diameter and defect size. The proximal and distal ends of the lesion are identified endoscopically, marked by radiopaque dye, then a guidewire advanced over the defect, stent positioned across and deployed over-the-wire, all under endoscopic and fluoroscopic guidance. Potential stent shrinkage or migration is counteracted by allowing 4-6 cm proximal and distal coverage.1 10 A feeding tube is routinely inserted for prompt enteral nutrition. No data are available for optimal timing of when to resume an enteral diet, but in oesophageal leaks, Rajan et al10 demonstrated fitness on day 2 following stent placement. Oral intake is not encouraged though due to potential peristalsis-inducing stent migration and hence leakage. No conclusive timing for stent removal exists, with studies in general reporting intervals of 4 to 6 weeks or 6 to 8 weeks.10 In our case, stent removal at 8 weeks was without difficulty, with no tissue ingrowth or stent disintegration.

Only one review of SEMS placement in oesophageal fistulae exists. It is reported that 64.7% clinical success was achieved in defect closure, which is significantly lower than the over 80% rates in malignant ORF, perforations, and post-surgical leaks.2 3 Detailed scrutiny of the seven studies pooled, however, revealed that aortoesophageal and oesophagoatrial fistulae were also included.13 These conditions present with life-threatening torrential haemorrhage, and are undoubtedly different in terms of pathogenesis and survival to the majority of ORF where sepsis is the main issue. Moreover, fistulae subtype or location was mostly not reported, and if present, mostly oesophagotracheal. Significant heterogeneity exists. Only one of 24 fistulae was identified as OPF. It is questionable how applicable the data are.

Specific literature is lacking. Our case report aside, Kang et al4 represent the only article reporting endoscopic SEMS for OPF as far as we are aware. Successful technical and clinical outcomes were achieved in both studies. To take this further, considering the similarities in terms of pleural or mediastinal sepsis and treatment goals in minimising further contamination, we believe it is reasonable to extrapolate the success in managing perforations and postsurgical leaks to ORF.

Potential SEMS-related complications include retrosternal pain, oesophageal perforation, bronchoesophageal fistulae, stent migration, obstruction, or fracture. Migration of the stent contributes to clinical failure, and appears to be a particularly troubling issue for fully covered SEMS, with 10% to 25% occurrence in covered stents and 2% to 5% in uncovered.1 It is also more frequent in placements for fistulae (33.3%) compared with benign strictures (15.8%).14 Appropriate stent size and length reduce the risk of migration, balancing the larger radial force to oppose migration against the risk of pressure necrosis. To counteract migration, some stents come with flared proximal ends.3 Endoscopic clip application of the proximal stent end to the oesophageal wall has also been reported to be an effective strategy.15 Such technological advances may further improve outcomes.

Our case represents the first in local medical literature to report SEMS use in benign OPF. With the global trend towards minimally invasive therapies, we expect a paradigm shift towards effective novel techniques such as endoscopic stenting or repair. In this patient with tuberculous fistulae, we favoured stenting over any endoscopic suturing or clipping to avoid the tension exhibited in inflamed tissue.

1. Kang HW, Kim SG. Upper gastrointestinal stent insertion in malignant and benign disorders. Clin Endosc 2015;48:187-93. Crossref

2. van Halsema EE, van Hooft JE. Clinical outcomes of self-expandable stent placement for benign esophageal diseases: a pooled analysis of the literature. World J Gastrointest Endosc 2015;7:135-53. Crossref

3. Mangiavillano B, Pagano N, Arena M, et al. Role of stenting in gastrointestinal benign and malignant diseases. World J Gastrointest Endosc 2015;7:460-80.

4. Kang GH, Yoon BY, Kim BH, et al. A case of spontaneous esophagopleural fistula successfully treated by endoscopic stent insertion. Clin Endosc 2013;46:91-4. Crossref

5. Shin JH, Kim JH, Song HY. Interventional management of esophagorespiratory fistula. Korean J Radiol 2010;11:133-40. Crossref

6. Albuquerque A, Ramalho R, Macedo G. Multiple esophagopleural and esophagobronchial fistulas in a patient with Crohn’s disease. Endoscopy 2012;44 Suppl 2:E114-5. Crossref

7. Andersson R, Nilsson S. Perforated Barrett’s ulcer with esophago-pleural fistula. A case report. Acta Chir Scand 1985;151:495-6.

8. Agarwal V, Singh SK, Siddiqi MS, Joshi LM, Tandon S. Esophagopleural fistula following spontaneous rupture of traction diverticulum. Asian Cardiovasc Thorac Ann 2003;11:344-5. Crossref

9. Kim KR, Shin JH, Song HY, et al. Palliative treatment of malignant esophagopulmonary fistulas with covered expandable metallic stents. AJR Am J Roentgenol 2009;193:W278-82. Crossref

10. Rajan PS, Bansal S, Balaji NS, et al. Role of endoscopic stents and selective minimal access drainage in oesophageal leaks: feasibility and outcome. Surg Endosc 2014;28:2368-73. Crossref

11. Koo JH, Park KB, Choo SW, Kim K, Do YS. Embolization of postsurgical esophagopleural fistula with AMPLATZER vascular plug, coils, and Histoacryl glue. J Vasc Interv Radiol 2010;21:1905-10. Crossref

12. Kim JJ, Park JK, Moon SW, Park K. A new surgical technique for spontaneous esophagopleural fistula after pneumonectomy: cervical esophagogastrostomy via presternal and subcutaneous route, using a thoracic esophageal mucosal stripping. Thorac Cardiovasc Surg 2013;61:496-8. Crossref

13. David EA, Kim MP, Blackmon SH. Esophageal salvage with removable covered self-expanding metal stents in the setting of intrathoracic esophageal leakage. Am J Surg 2011;202:796-801. Crossref

14. Buscaglia JM, Ho S, Sethi A, et al. Fully covered self-expandable metal stents for benign esophageal disease: a multicenter retrospective case series of 31 patients. Gastrointest Endosc 2011;74:207-11. Crossref

15. Park SY, Park CH, Cho SB, et al. The usefulness of clip application in preventing migration of self-expandable metal stents in patients with malignant gastrointestinal obstruction [in Korean]. Korean J Gastroenterol 2007;49:4-9.