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immunohistochemistry and may contain somatic mutations in PIK3CA identifying activation of the phosphoinositide 3-kinase (PI3K)-AKT pathway.8,10 These mutations have not been described in IPMN and highlight the molecularly distinct nature of ITPN. Somatic mutations of KRAS and GNAS are seen more frequently in IPMN than ITPN.8,10 Our case showed cytological features in keeping with the two previous cases of ITPN reported from endoscopic ultrasound guided fine needle aspirate (EUS-FNA) smears, such as complex branched cellular groups with enlarged nuclei, variably sized nucleoli, granular debris within tubular lumens and the absence of mucin.11,12 While differentiation from other lesions such as IPMN may be challenging, the presence of thick mucin and well-formed papillae favour an IPMN. Analysis of cell block preparations and immunohistochemistry may be helpful in these cases. Few published reports exist of ITPN with an associated invasive carcinoma1,2 and the biological behaviour of these lesions is not clear. The present case confirms that the tubulopapillary growth pattern typical of this neoplasm is retained in the locally invasive component. Furthermore, our case also shows retention of the classical architecture and cytological features in metastatic deposits in peri-pancreatic lymph nodes, rectal wall and liver. When encountering an intra-abdominal neoplasm exhibiting a fairly monotonous tubular and tubulopapillary pattern it is important to consider the diagnosis of ITPN, particularly in the setting of a co-existing pancreatic tumour. The relatively slow progression of disease in our case is consistent with observations of other investigators. In the largest series published to date, only 3 of 10 cases of ITPN showed associated invasive carcinoma, and survival times up to 7 years following diagnosis are documented even in patients with metastatic disease.1,2 This is in marked contrast to the dismal prognosis of conventional pancreatic ductal adenocarcinoma.3 The intramural location of the rectal metastasis in our patient raises the possibility of transcoelemic spread. In conclusion, ITPN is a recently recognised diagnostic entity with characteristic morphology, immunophenotype and molecular aberrations. Identification of this rare neoplasm is important given the significantly more favourable prognosis compared to invasive pancreatic ductal adenocarcinoma, both in terms of overall survival and the relatively indolent clinical course observed in the few reported instances of ITPN with associated invasive carcinoma. However, a few patients do die of disease and, as in this case, metastatic disease may develop. The presence of molecular aberrations in these tumours involving the PI3K-AKT pathway may provide potential therapeutic targets in future. Acknowledgements: We thank Dr Tina Selinger for assistance with the images. Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. Yasmin Matthews1,2 Catriona McKenzie1 Christopher Byrne3 James G. Kench1,4 1

Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, 2Douglass Hanly Moir Pathology, Macquaire Park, 3Department of Colorectal

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Surgery, Royal Prince Alfred Hospital, Camperdown, and Central Clinical School, University of Sydney, Camperdown, Sydney, NSW, Australia

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Contact Professor James Kench. E-mail: [email protected] 1. Yamaguchi H, Shimizu M, Ban S, et al. Intraductal tubulopapillary neoplasms of the pancreas distinct from pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 2009; 33: 1164–71. 2. Suda K, Hirai S, Matsumoto Y, et al. Variant of intraductal carcinoma (with scant mucin production) is of main pancreatic duct origin: a clinicopathological study of four patients. Am J Gastroenterol 1996; 91: 798–800. 3. Bosman FT, Carneiro F, Hruban RH, et al. WHO Classification of Tumours of the Digestive System. Lyon: IARC; 2010. 4. Jokoji R, Tsuji H, Tsujimoto M, et al. Intraductal tubulopapillary neoplasm of pancreas with stromal osseous and cartilaginous metaplasia; a case report. Pathol Int 2012; 62: 339–43. 5. Tajiri T, Tate G, Kunimura T, et al. Histologic and immunohistochemical comparison of intraductal tubular carcinoma, intraductal papillary-mucinous carcinoma, and ductal adenocarcinoma of the pancreas. Pancreas 2004; 29: 116–22. 6. Del Chiaro M, Pozzi Mucelli R, Bloomberg J, et al. Is intraductal tubulopapillary neoplasia a new entity in the spectrum of familial pancreatic cancer syndrome? Familial Cancer 2014; 13: 227–9. 7. Cooper CL, O’Toole SA, Kench JG. Classification, morphology and molecular pathology of premalignant lesions of the pancreas. Pathology 2013; 45: 286–304. 8. Yamaguchi H, Kuboki Y, Hatori T, et al. The discrete nature and distinguishing molecular features of pancreatic intraductal tubulopapillary neoplasms and intraductal papillary mucinous neoplasms of the gastric type, pyloric gland variant. J Pathol 2013; 231: 335–41. 9. Green KB, Sharma S. The pancreatic duct and its arteriovenous relationship. Am J Surg Pathol 2004; 28: 613–20. 10. Yamaguchi H, Kuboki Y, Hatori T, et al. Somatic mutations in PIK3CA and activation of AKT in intraductal tubulopapillary neoplasms of the pancreas. Am J Surg Pathol 2011; 35: 1812–7. 11. Aslan DL, Jessurun J, Gulbahce HE, et al. Endoscopic ultrasound-guided fine needle aspiration features of a pancreatic neoplasm with predominantly intraductal growth and prominent tubular cytomorphology: intraductal tubular carcinoma of the pancreas? Diagn Cytopathol 2008; 36: 833–9. 12. Guan H, Gurda G, Marie Lennon A, et al. Intraductal tubulopapillary neoplasm of the pancreas on fine needle aspiration: case report with differential diagnosis. Diagn Cytopathol 2014; 42: 156–60.

DOI: 10.1097/PAT.0000000000000228

Purpuric exanthem caused by Ross River virus infection Sir, The Ross River virus (RRV) is a species of the genus Alphavirus, of the family Togaviridae. It is endemic to Australia and New Guinea, and is the aetiological agent of the syndrome known as epidemic polyarthritis. It is the most common arbovirus infection in Australia, with national annual incidence rates of between 14 and 50 per 100,000 population.1–3 Large macropods such as wallabies are thought to be a significant vertebrate reservoir host, although other animals may also play a role, particularly in urban centres.4 Most human infections occur in people aged between 20 and 60 years, and can result in a number of symptoms, with the most common being fever, arthralgia, myalgia and rash. At least half of patients experience a debilitating polyarthritis, which may last for 6–12 months with a persisting lethargy.3 Serious complications, such as encephalitis, have been reported5 but seem to be rare, and while there is an early report of a death in

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Pathology (2015), 47(2), February

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association with viral infection,6 this is an exceedingly rare event. Approximately 50% of infected people develop a rash, which may be the sole manifestation of the disease. The rash is predominantly located on the limbs and the trunk, but may also be seen on the face, scalp or acral sites. Typically the exanthem is maculopapular in appearance, although in some cases it may be vesicular or, as demonstrated in this case, purpuric.1,4 The histological features of the RRV-associated rash are not well described, with the literature being limited to a single report in 1983.1 We have recently encountered a biopsy from a patient with proven RRV infection, and we present our histological findings herein. The patient was a 60-year-old female residing in the southwestern portion of Western Australia. This area of the country has been associated with several reported outbreaks of the disease.3 Prior to her presentation she had been in good health, and there was no history of recent travel. She developed generalised arthralgia, muscle cramps and lethargy for several months, and presented to her general practitioner after the appearance of purpuric lesions on her back, legs and palms. An indirect fluorescent antibody test (IFA) was positive for RRV IgM, allowing a presumptive diagnosis of RRV infection in the setting of an appropriate clinical presentation. Serology for other viral infections such as measles and rubella was negative. ANA and anti SSA/Ro were negative and no cryoglobulins were identified. As part of the diagnostic workup a 4 mm punch biopsy of skin was performed on an area of the rash from the left foot (Fig. 1). Microscopy revealed acral skin incorporating an area of lichenoid interface inflammatory change, with accompanying vacuolar damage to the basal layer of the epidermis. Underlying these changes was a perivascular inflammatory infiltrate within the superficial dermis, which was predominantly lymphohistiocytic in nature. There was prominent extravasation of erythrocytes into the dermis and focally into the lower reaches of the epidermis. No fibrinoid change was present around dermal blood vessels, and no haemosiderin deposition was identified, either with routine haemotoxylin and eosin or Perl’s Prussian blue reaction. There were no significant inflammatory changes in the deeper portions of the biopsy. The findings presented here represent the second report describing the histological features of an RRV-associated rash. The previous report, authored by Fraser and colleagues, described the features of two cases: one example of a typical maculopapular rash, and one example of a purpuric eruption.1

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Both cases showed a perivascular infiltrate of leucocytes (predominantly T lymphocytes and cells of the monocytic lineage), with the additional features of extravasated erythrocytes in the purpuric example. Our observations were similar, with the additional finding in our case of a prominent lichenoid interface reaction pattern. Fraser et al. identified RRV antigen in the perivascular tissues of the maculopapular rash, but not in the purpuric example, and saw no viral particles on ultrastructural examination.1 They reasoned that the virally infected cells had been cleared, and that the subsequent extravasation of erythrocytes may reflect damage to the vessel wall via the cytotoxic inflammatory reaction, rather than lodgement of viral particles or antigen. With the exception of the three major families of DNA viruses (Poxviridae, Herpesviridae and Papovaviridae) most cutaneous viral exanthems (including those associated with the Togaviridae) are histologically non-specific. Features typically seen in these cases include a superficial and perivascular chronic inflammatory infiltrate, mild epidermal spongiosis, occasional apoptotic keratinocytes and on occasions extravasation of red blood cells.7 These changes can also be seen in other conditions, particularly drug reactions, and part of the difficulty lies in the fact that there is little information regarding the spectrum and/or severity of changes which are acceptable for a viral aetiology.8 The findings described by both Fraser et al.1 and us are indeed relatively non-specific, and it would be difficult to exclude a purpuric drug reaction on histology alone. In addition, the possibility of a condition within the spectrum of pigmented purpuric dermatoses (PPD) might also be considered. This term encompasses a number of conditions, including Schamberg disease, Majocchi purpura, Gougerot–Blum purpura, lichen aureus and eczematoid purpura of Doucas and Kapetanakis. These conditions share the histological features of superficial lymphocytic infiltration with erythrocyte extravasation and haemosiderin deposition.9 While the absence of haemosiderin may help in this differential diagnosis, it is conceivable that in early lesions of PPD this feature may be absent.8 Vasculitic processes such as Henoch–Scho¨nlein purpura have been described as being of a similar clinical appearance to the purpuric rash of RRV,1 however histologically the abscence of fibrinoid change around the walls of dermal postcapillary venules would argue against this diagnosis. In conclusion, we have described the histological features of a purpuric rash occurring in the setting of RRV infection. The findings can be summarised as a lichenoid interface inflammatory reaction pattern, with a superficial and perivascular

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Fig. 1 (A) Low power view of the lesion, showing a superficial and perivascular inflammatory infiltrate within a fairly localised region of the dermis (H&E, scale bar ¼ 0.5 mm). (B) Higher power view showing details of the inflammatory process. The infiltrate is predominantly lymphohistiocytic in nature, with basal vacuolar degeneration consistent with a lichenoid interface reaction pattern. In addition there are numerous extravasated erythrocytes (H&E, scale bar ¼ 50 mm).

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lymphohistiocytic infiltrate and extravasation of erythrocytes. These changes are similar to the only other previously reported example, although the lichenoid interface reaction was not described in that case. The changes are relatively non-specific, and correlation with the clinical scenario and serological findings may be required for a definitive diagnosis. This case serves to expand the literature on the histological features of RRVinduced cutaneous manifestations, and also reminds pathologists of another potential cause for a purpuric rash in Australia. Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. Benjamin Allanson1 Nathan Tobias Harvey1,2 Peter John Beaton3 Benjamin Andrew Wood1,2 1

Department of Anatomical Pathology, PathWest, QEII Medical Centre, Nedlands, 2School of Pathology and Laboratory Medicine, The University of Western, Australia, Crawley, and 3John Parry Medical Centre, Narrogin, WA, Australia Contact Dr Nathan Harvey. E-mail: [email protected] 1. Fraser JR, Ratnamohan VM, Dowling JP, et al. The exanthem of Ross River virus infection: histology, location of virus antigen and nature of inflammatory infiltrate. J Clin Pathol 1983; 36: 1256–63. 2. Mylonas AD, Brown AM, Carthew TL, et al. Natural history of Ross River virus-induced epidemic polyarthritis. Med J Aust 2002; 177: 356–60. 3. Russell RC. Ross River virus: ecology and distribution. Annu Rev Entomol 2002; 47: 1–31. 4. Harley D, Sleigh A, Ritchie S. Ross River virus transmission, infection,;1; and disease: a cross-disciplinary review. Clin Microbiol Rev 2001; 14: 909–32. 5. Lucas RE, Qiao M. A case of encephalitis in central Australia due to Ross River virus? Aust NZ J Med 1999; 29: 268–70. 6. Scrimgeour EM. Suspected Ross River virus encephalitis in Papua New Guinea. Aust NZ J Med 1999; 29: 559. 7. Weedon D. Weedon’s Skin Pathology. 3rd ed London: Elsevier Health Sciences, 2009. 8. Leboit PE. What don’t we know, and when did we know that we didn’t know it? Am J Dermatopathology 2006; 28: 89–90. 9. Crowson AN, Magro CM, Zahorchak R. Atypical pigmentary purpura: a clinical, histopathologic, and genotypic study. Hum Pathol 1999; 30: 1004–12.

DOI: 10.1097/PAT.0000000000000222

Use of immunohistochemistry for SSTR2A to support a diagnosis of phosphaturic mesenchymal tumour Sir, Tumour induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic syndrome associated with tumours which secrete phosphaturic hormones, usually fibroblast growth factor 23 (FGF23), and therefore present with secondary osteomalacia.1 Historically the causative tumours of TIO were considered a diverse group, however in 2004 Folpe et al.2 proposed that the majority of cases actually represented a unique class of tumour which they termed ‘phosphaturic mesenchymal tumour mixed connective tissue variant’, now

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commonly shortened to ‘phosphaturic mesenchymal tumour’ (PMT). Although the histological features of PMT are distinct, the morphology can be subtle and difficult to distinguish from other tumour types particularly in small biopsies. Furthermore the concept of non-phosphaturic PMTs (that is tumours which are morphologically PMT but in which there is no evidence of phosphate wasting), further clouds the differential diagnosis.2 One approach to confirming the diagnosis of PMT is to demonstrate production of FGF23 by immunohistochemistry or RT-PCR (summarised by Houang et al.3). However neither technique is widely available. Furthermore, whilst up to 94% of PMTs associated with osteomalacia and 75% of PMTs not associated with osteomalacia will be shown to produce FGF23 by these techniques,4 FGF23 mRNA has also been found in up to 44% of otherwise typical aneurysmal bone cysts and 29% of chondromyxoid fibromas not associated with osteomalacia.5 That is, FGF23 immunohistochemistry and RT-PCR appear to be highly sensitive but not specific. In 2013 Houang et al.3 reported that immunohistochemistry for the somatostatin receptor 2A (SSTR2A) was highly sensitive for the diagnosis of PMT, being positive in 15 of 15 PMTs with typical morphology and confirmed phosphate wasting. Although not specific (SSTR2A expression was found in occasional synovial sarcomas, haemangiomas, aneurysmal bone cysts and osteosarcomas), SSTR2A showed stronger and more diffuse expression than FGF23. Therefore, it was proposed that SSTR2A expression could be used to confirm a diagnosis of PMT if FGF23 immunohistochemistry or RT-PCR was unavailable or apparently negative due to focal expression. We present a case of morphologically typical PMT which was negative for FGF23 by immunohistochemistry but demonstrated positive staining for somatostatin receptor 2A (SSTR2A) which was useful to definitively confirm the diagnosis. A 12-year-old female, who was well other than for occasional migraines, presented with a painless mass on the buccal aspect of the left mandible. Imaging (CT and MRI) demonstrated an intra- and extra-osseous component with cortical breach. She was not known to be suffering from osteomalacia, and serum FGF23 and phosphate were not measured prior to surgery. The tumour underwent excision biopsy and was submitted for pathological assessment as a single 19 mm tissue fragment. The tumour was composed of plump spindled cells in a somewhat myxoid and hyalinised stroma (Fig. 1A). Of note, in areas there were prominent haemangiopericytomatous vessels (Fig. 1B) and a peculiar ‘grungy’ calcification (Fig. 1C,D), both of which have been reported as characteristic of PMT.2–4 After synovial sarcoma was excluded with negative RT-PCR studies for SYT/SSX1 and SYT/SSX2, the possibility of PMT was considered. Immunohistochemistry for FGF23 using previously published methods3 was negative. However RT-PCR for FGF23 expression was positive and, although there was some uncertainty given the relatively low specificity of RTPCR,5 a diagnosis of PMT was favoured. The patient underwent further investigation. Serum calcium and phosphate (measured 15 days after surgery) were normal. FDG-PET performed 7 days post-operatively demonstrated increased uptake at the site of surgery attributed to granulation tissue. MRI performed 12 days after surgery demonstrated mass effect and oedema at the operative site along with an 11 mm lesion thought to be either residual tumour or post-operative reactive change.

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Purpuric exanthem caused by Ross River virus infection.

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