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Capnocytophaga canimorsus in a postsplenectomy patient
ABSTRACTS
The ovaries are common sites for intra-abdominal metastasis. About 6% of ovarian cancers found at laparotomy are secondary tumours from other sites.1 However, metastatic transitional cell carcinoma (TCC) involving the ovary from the urinary bladder or elsewhere within the urinary tract is extremely rare. Primary TCC accounts for 1–2% of all ovarian tumours.2 TCC of the ovary is a recently recognised subtype of ovarian surface epithelial-stromal cancer. Microscopically, metastatic urothelial carcinoma of ovary is very similar to a primary ovarian TCC. The presence of a component of benign or borderline Brenner tumour confirms an ovarian primary.3 The distinction between metastatic TCC of urothelial origin and a borderline or malignant Brenner tumour and a primary ovarian TCC can be difficult or sometimes impossible. We present a case of ovarian metastasis from urothelial carcinoma of the bladder. The patient developed bilateral bulky ovarian metastases 7 years after the diagnosis of the primary bladder tumour. The history of primary tumour was not available initially. We favoured metastatic ovarian tumours for the following reasons: (a) definite histological evidence of a primary bladder tumour, (b) bilateral ovarian involvement, and (c) lack of residual Brenner tumour. Although rare, possibility of metastasis from urothelial carcinoma should be considered as a differential diagnosis in cases of transitional cell carcinoma of ovary. Relevant clinical information is vital for accurate diagnosis. Careful histological and histochemical analysis may help to differentiate between the two. References
S97
Breast tissue and lactational breast tissue are not commonly seen within dermoid cysts. Only three cases have been reported in the literature, all occurring in pregnant women. The response of the breast tissue to the endogenous systemic hormones in pregnancy illustrates the potential functional capability of the differentiated tissue found within dermoid cysts. EPITHELIAL MISPLACEMENT IN THE GASTROINTESTINAL TRACT: A DIAGNOSTIC PITFALL REVISITED IN A PATIENT WITH PEUTZ JEGHER’S SYNDROME Y. L. Tang, C. Y.P Chau, W. M. Yap, K. L. Chuah Department of Pathology, Tan Tock Seng Hospital, Singapore
1. Petru E, Pickel H, Heydarfadai M, et al. Nongenital cancers metastatic to the ovary. Gynecol Oncol 1992; 44: 83–6. 2. Young RH, Scully RE. Urothelial and ovarian carcinomas of identical cell types: problems in interpretation. A report of three cases and review of the literature. Int J Gynecol Pathol 1988; 7: 197–211. 3. Eichhorn JH, Young RH. Transitional cell carcinoma of the ovary: a morphologic study of 100 cases with emphasis on differential diagnosis. Am J Surg Pathol 2004; 28: 453–63. 4. Logani S, Oliva E, Amin MB, et al. Immunoprofile of ovarian tumors with putative transitional cell (urothelial) differentiation using novel urothelial markers: histogenetic and diagnostic implications. Am J Surg Pathol 2003; 27: 1434–41.
Epithelial misplacement or ‘pseudoinvasion’ is a known phenomenon occurring in the gastrointestinal tract that may potentially result in the misdiagnosis of a malignancy, particularly to the uninitiated. Recent papers indicated that similar diagnostic dilemmas occur in the breast and thyroid tissues, usually following a biopsy procedure. In the gastrointestinal tract, the epithelial displacement is thought to result from herniation of the mucosa through defects of the muscularis mucosae and propria secondary to trauma from medical procedures or due to the inherent peristaltic action. We detail an instance where epithelial misplacement in a hamartomatous polyp in the ileum affecting a 17-year-old Malay man with Peutz-Jeghers syndrome raised the concern for malignancy. The patient had undergone a subtotal colectomy with extended ileal resection following intussusception. The resected specimen revealed multiple hamartomatous polyps in the small bowel and caecum. On histology, one polyp disclosed the presence of mucosa and mucinous pools in the adipose tissue of the serosal layer which abut the peritoneal surface, mimicking an adenocarcinoma with mucinous features. The criteria and immunohistochemical stains acting as adjuncts for separating ‘pseudoinvasion’ occurring in the various types of gastrointestinal polyp including those with dysplasia from an adenocarcinoma are presented.
LACTATIONAL METAPLASIA IN A DERMOID CYST: CASE REPORT AND REVIEW OF THE LITERATURE
CAPNOCYTOPHAGA CANIMORSUS IN A POSTSPLENECTOMY PATIENT
Katrina Tang, Leonardo Santos Department of Anatomical Pathology, SSWAPS Liverpool, NSW, Australia
Hui Sien Tay, Alan E. Mills Department of Anatomical Pathology, Bendigo Health Pathology Services, Bendigo, Vic, Australia
A 30-year-old primigravid woman underwent an emergency caesarean section for delivery of twins at 34 weeks gestation, with an incidental intra-operative finding of a 70 mm right ovarian cyst and a 45 mm left ovarian cyst. Both cysts contained abundant hair and oily sebaceous material. Microscopic examination confirmed both ovarian cysts were dermoid cysts (mature cystic teratomas) composed of skin with adnexal structures, adipose tissue, cartilage, glial tissue, thyroid and gastrointestinal glands. In addition, the right dermoid cyst showed a focus of glandular tissue resembling lactational breast tissue. PASD highlighted the intraluminal secretions, while the glandular epithelium stained positively with CK7 and 34bE12. A surrounding layer of myoepithelial cells was seen with p63 and CD10. Ultrastructurally, abundant secretory material was apparent. The organelle-rich acinar cells contained lipid droplets and a few electron-dense secretory granules. Myoepithelial cells were flattened and attenuated.
Capnocytophaga canimorsus, formally known as Dysgonic fermenter 2 (DF-2), is a commensal bacteria of dog and cat saliva. It can be transmitted to humans by bite, scratch, or mere exposure to animals by licking. It is a Gram negative rod that typically causes septicaemia and disseminated intravascular coagulopathy. Dermatological lesions and gangrene are common. The reported mortality rate is up to 30%. Most of the patients affected have compromised immunity, secondary to splenectomy or alcoholism. However, in one of the review articles, up to 40% of septicaemia occurred in patients with no predisposing factors. We described a 60-year-old female who presented with septicaemia secondary to Capnocytophaga canimorsus, following a minor bite by a dog. Her medical history included splenectomy for idiopathic thrombocytopenic purpura 24 years ago, with normal blood count since the splenectomy. The diagnosis was strongly suspected on peripheral blood film, which was later confirmed on blood cultures. Despite maximal therapy and surgical intervention, the patient succumbed
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited. Copyright
S98
PATHOLOGY 2012 ABSTRACT SUPPLEMENT
to the infection. In view of the severity of this infection, clinicians should be aware of the possibility of Capnocytophaga canimorsus infection in the management of animal bites, especially in patients with predisposing factors. TRUE NEUROMA OF THE APPENDIX: A CASE REPORT AND LITERATURE REVIEW Hui Sien Tay1, Alan E. Mills1 Department of Anatomical Pathology, Bendigo Health Pathology Services, Bendigo, Vic, Australia The differential diagnosis of stromal tumours of the appendix includes leiomyoma, gastrointestinal stromal tumour and neurogenic lesions. Terminology of neurogenic tumours is confusing in the literature. The term ‘neuroma’ of the appendix includes the common obliterative fibrosis of the appendix. However, true neuroma of the appendix occurring as a circumscribed nodular tumour, like all appendiceal stroma tumours is extremely uncommon. We report a true neuroma of appendix in a healthy 3 year old boy, who presented with symptoms of appendicitis. BRAF MUTATION DETECTION IN HAIRY CELL LEUKAEMIA FROM ARCHIVAL HAEMATOLYMPHOID SPECIMEN Carla Thomas1, Benhur Amanuel1, Jill Finlayson2, Fabienne G. Iacopetta1, Dominic V. Spagnolo1, Wendy N. Erber2,3 1 Department of Anatomical Pathology, 2Department of Haematology, PathWest Laboratory Medicine, Nedlands, and 3School of Pathology and Laboratory Medicine, The University of Western Australia, Nedlands, WA Australia Introduction: Hairy cell leukaemia (HCL) is a rare, indolent chronic B-cell leukaemia accounting for approximately 2% of all adult leukaemias. The recent association of the V600E BRAF mutation in HCL makes it a valuable molecular diagnostic marker. Objective: To compare the ability of Sanger sequencing (SS), fluorescent single-strand conformational analysis (F-SSCA) and high resolution melting (HRM) analysis to detect BRAF mutations in HCL with DNA extracted predominantly from archival material. Methodology: 20 cases of HCL consisting of four archival Romanovsky stained air-dried peripheral blood and bone marrow aspirate smears, 12 mercury fixed decalcified bone marrow trephine biopsies, three formalin fixed, paraffin embedded (FFPE) splenectomy samples and one fresh peripheral blood sample were reviewed. DNA was amplified by PCR and BRAF mutation status determined by the three methods above. Results: V600E mutation was identified in 95%, 87% and 76% of HCL cases by F-SSCA, HRM and SS, respectively. In one HCL case, in addition to the V600E mutation, a K601T mutation was identified. One of the Romanowsky stained samples was negative for mutation by all three methods. Three mercury fixed cases were negative for mutation by sequencing but positive for the mutation using F-SSCA and HRM. This discrepancy could be due to mutations below the limit of sensitivity of SS. Conclusion: DNA from archival slide scrapings, mercury-fixed and FFPE tissue can be used to identify BRAF mutations with high sensitivity especially using HRM/F-SSCA. The V600E mutation can be used as a supplementary molecular marker to aid in the diagnosis of HCL. The presence of the mutation may provide a target for therapy.
Pathology (2012), 44(S1)
MONITORING PERFORMANCE OF EXTERNAL QUALITY CONTROL Vanessa Thomson RCPA Quality Assurance Programs, Sydney, NSW, Australia Aim: In 2010 the Royal College of Pathologists of Australasia Quality Assurance Programs (RCPA QAP), received Quality Use of Pathology Program funding to determine if regular external quality assurance that laboratories perform could be used to identify unacceptable performance earlier than the usual 3 year NATA accreditation cycle, to help minimise risk to patients. Method: Criteria for unacceptable performance have been established to identify laboratories that maybe underperforming in external quality assurance (EQA). New frameworks have also been developed that outline the process of actions to be taken by the RCPA QAP when participant results and IVDs fall outside levels of acceptable performance. The frameworks proactively notify participants or manufacturers or their sponsors to assist them early. Results: When unacceptable performance is identified, according to the set criteria, a letter will be sent to the participant outlining the result(s) falling outside the criteria for acceptable performance and offer assistance to review the QAP results. Persisting unacceptable performance will be referred to a Committee for review and results referred to the National Association of Testing Authorities (NATA) or Therapuetic Goods Administration (TGA) for follow-up. Conclusion: The RCPA QAP has established a performance monitoring system using the EQA results. The early warning system will identify laboratories of concern and assist them to obtain their accreditation. Conflict of interest statement: This research was supported by the Department of Health and Ageing. The Department had no role in analysing the data or preparing the abstract. NUT MIDLINE CARCINOMA OF THE UPPER AERODIGESTIVE TRACT Clinton Turner, Jessica Matich, Chris van Vliet LabPlus, Auckland City Hospital, Auckland, New Zealand NUT (nuclear protein in testis) midline carcinoma (NMC) is a rare highly aggressive tumour characterised by chromosomal rearrangements of NUT on 15q14. Initially described in paediatric and adolescent populations, NMC is now known to occur over a wide age range. In adults, a common site of occurrence is the upper aerodigestive tract. We describe the case of a 54-year-old male presenting with 3 months of epistaxis. Examination revealed a mass in the right middle meatus. Biopsy showed a small round blue cell tumour without differentiating histological features. Immunohistochemically, the tumour was positive for cytokeratins (MNF116, HMWCK, CK7, CK5), p63, CD99 and CD34. FISH studies for Ewing/PNET and synovial sarcoma translocations were negative. FISH analysis confirmed the presence of the BRD4-NUT rearrangement typical of NMC. The patient underwent craniofacial resection and post-operative radiotherapy. Follow-up to date has shown no recurrence. NMC is not commonly included in the differential diagnosis of upper aerodigestive tract carcinomas. However, NMC should be considered in any poorly differentiated carcinoma of the upper aerodigestive tract, particularly those coexpressing cytokeratin and CD34. FISH testing for the characteristic translocation confirms the diagnosis. Aggressive therapy has
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited. Copyright
The ovaries are common sites for intra-abdominal metastasis. About 6% of ovarian cancers found at laparotomy are secondary tumours from other sites.1 However, metastatic transitional cell carcinoma (TCC) involving the ovary from the urinary bladder or elsewhere within the urinary tract is extremely rare. Primary TCC accounts for 1–2% of all ovarian tumours.2 TCC of the ovary is a recently recognised subtype of ovarian surface epithelial-stromal cancer. Microscopically, metastatic urothelial carcinoma of ovary is very similar to a primary ovarian TCC. The presence of a component of benign or borderline Brenner tumour confirms an ovarian primary.3 The distinction between metastatic TCC of urothelial origin and a borderline or malignant Brenner tumour and a primary ovarian TCC can be difficult or sometimes impossible. We present a case of ovarian metastasis from urothelial carcinoma of the bladder. The patient developed bilateral bulky ovarian metastases 7 years after the diagnosis of the primary bladder tumour. The history of primary tumour was not available initially. We favoured metastatic ovarian tumours for the following reasons: (a) definite histological evidence of a primary bladder tumour, (b) bilateral ovarian involvement, and (c) lack of residual Brenner tumour. Although rare, possibility of metastasis from urothelial carcinoma should be considered as a differential diagnosis in cases of transitional cell carcinoma of ovary. Relevant clinical information is vital for accurate diagnosis. Careful histological and histochemical analysis may help to differentiate between the two. References
S97
Breast tissue and lactational breast tissue are not commonly seen within dermoid cysts. Only three cases have been reported in the literature, all occurring in pregnant women. The response of the breast tissue to the endogenous systemic hormones in pregnancy illustrates the potential functional capability of the differentiated tissue found within dermoid cysts. EPITHELIAL MISPLACEMENT IN THE GASTROINTESTINAL TRACT: A DIAGNOSTIC PITFALL REVISITED IN A PATIENT WITH PEUTZ JEGHER’S SYNDROME Y. L. Tang, C. Y.P Chau, W. M. Yap, K. L. Chuah Department of Pathology, Tan Tock Seng Hospital, Singapore
1. Petru E, Pickel H, Heydarfadai M, et al. Nongenital cancers metastatic to the ovary. Gynecol Oncol 1992; 44: 83–6. 2. Young RH, Scully RE. Urothelial and ovarian carcinomas of identical cell types: problems in interpretation. A report of three cases and review of the literature. Int J Gynecol Pathol 1988; 7: 197–211. 3. Eichhorn JH, Young RH. Transitional cell carcinoma of the ovary: a morphologic study of 100 cases with emphasis on differential diagnosis. Am J Surg Pathol 2004; 28: 453–63. 4. Logani S, Oliva E, Amin MB, et al. Immunoprofile of ovarian tumors with putative transitional cell (urothelial) differentiation using novel urothelial markers: histogenetic and diagnostic implications. Am J Surg Pathol 2003; 27: 1434–41.
Epithelial misplacement or ‘pseudoinvasion’ is a known phenomenon occurring in the gastrointestinal tract that may potentially result in the misdiagnosis of a malignancy, particularly to the uninitiated. Recent papers indicated that similar diagnostic dilemmas occur in the breast and thyroid tissues, usually following a biopsy procedure. In the gastrointestinal tract, the epithelial displacement is thought to result from herniation of the mucosa through defects of the muscularis mucosae and propria secondary to trauma from medical procedures or due to the inherent peristaltic action. We detail an instance where epithelial misplacement in a hamartomatous polyp in the ileum affecting a 17-year-old Malay man with Peutz-Jeghers syndrome raised the concern for malignancy. The patient had undergone a subtotal colectomy with extended ileal resection following intussusception. The resected specimen revealed multiple hamartomatous polyps in the small bowel and caecum. On histology, one polyp disclosed the presence of mucosa and mucinous pools in the adipose tissue of the serosal layer which abut the peritoneal surface, mimicking an adenocarcinoma with mucinous features. The criteria and immunohistochemical stains acting as adjuncts for separating ‘pseudoinvasion’ occurring in the various types of gastrointestinal polyp including those with dysplasia from an adenocarcinoma are presented.
LACTATIONAL METAPLASIA IN A DERMOID CYST: CASE REPORT AND REVIEW OF THE LITERATURE
CAPNOCYTOPHAGA CANIMORSUS IN A POSTSPLENECTOMY PATIENT
Katrina Tang, Leonardo Santos Department of Anatomical Pathology, SSWAPS Liverpool, NSW, Australia
Hui Sien Tay, Alan E. Mills Department of Anatomical Pathology, Bendigo Health Pathology Services, Bendigo, Vic, Australia
A 30-year-old primigravid woman underwent an emergency caesarean section for delivery of twins at 34 weeks gestation, with an incidental intra-operative finding of a 70 mm right ovarian cyst and a 45 mm left ovarian cyst. Both cysts contained abundant hair and oily sebaceous material. Microscopic examination confirmed both ovarian cysts were dermoid cysts (mature cystic teratomas) composed of skin with adnexal structures, adipose tissue, cartilage, glial tissue, thyroid and gastrointestinal glands. In addition, the right dermoid cyst showed a focus of glandular tissue resembling lactational breast tissue. PASD highlighted the intraluminal secretions, while the glandular epithelium stained positively with CK7 and 34bE12. A surrounding layer of myoepithelial cells was seen with p63 and CD10. Ultrastructurally, abundant secretory material was apparent. The organelle-rich acinar cells contained lipid droplets and a few electron-dense secretory granules. Myoepithelial cells were flattened and attenuated.
Capnocytophaga canimorsus, formally known as Dysgonic fermenter 2 (DF-2), is a commensal bacteria of dog and cat saliva. It can be transmitted to humans by bite, scratch, or mere exposure to animals by licking. It is a Gram negative rod that typically causes septicaemia and disseminated intravascular coagulopathy. Dermatological lesions and gangrene are common. The reported mortality rate is up to 30%. Most of the patients affected have compromised immunity, secondary to splenectomy or alcoholism. However, in one of the review articles, up to 40% of septicaemia occurred in patients with no predisposing factors. We described a 60-year-old female who presented with septicaemia secondary to Capnocytophaga canimorsus, following a minor bite by a dog. Her medical history included splenectomy for idiopathic thrombocytopenic purpura 24 years ago, with normal blood count since the splenectomy. The diagnosis was strongly suspected on peripheral blood film, which was later confirmed on blood cultures. Despite maximal therapy and surgical intervention, the patient succumbed
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited. Copyright
S98
PATHOLOGY 2012 ABSTRACT SUPPLEMENT
to the infection. In view of the severity of this infection, clinicians should be aware of the possibility of Capnocytophaga canimorsus infection in the management of animal bites, especially in patients with predisposing factors. TRUE NEUROMA OF THE APPENDIX: A CASE REPORT AND LITERATURE REVIEW Hui Sien Tay1, Alan E. Mills1 Department of Anatomical Pathology, Bendigo Health Pathology Services, Bendigo, Vic, Australia The differential diagnosis of stromal tumours of the appendix includes leiomyoma, gastrointestinal stromal tumour and neurogenic lesions. Terminology of neurogenic tumours is confusing in the literature. The term ‘neuroma’ of the appendix includes the common obliterative fibrosis of the appendix. However, true neuroma of the appendix occurring as a circumscribed nodular tumour, like all appendiceal stroma tumours is extremely uncommon. We report a true neuroma of appendix in a healthy 3 year old boy, who presented with symptoms of appendicitis. BRAF MUTATION DETECTION IN HAIRY CELL LEUKAEMIA FROM ARCHIVAL HAEMATOLYMPHOID SPECIMEN Carla Thomas1, Benhur Amanuel1, Jill Finlayson2, Fabienne G. Iacopetta1, Dominic V. Spagnolo1, Wendy N. Erber2,3 1 Department of Anatomical Pathology, 2Department of Haematology, PathWest Laboratory Medicine, Nedlands, and 3School of Pathology and Laboratory Medicine, The University of Western Australia, Nedlands, WA Australia Introduction: Hairy cell leukaemia (HCL) is a rare, indolent chronic B-cell leukaemia accounting for approximately 2% of all adult leukaemias. The recent association of the V600E BRAF mutation in HCL makes it a valuable molecular diagnostic marker. Objective: To compare the ability of Sanger sequencing (SS), fluorescent single-strand conformational analysis (F-SSCA) and high resolution melting (HRM) analysis to detect BRAF mutations in HCL with DNA extracted predominantly from archival material. Methodology: 20 cases of HCL consisting of four archival Romanovsky stained air-dried peripheral blood and bone marrow aspirate smears, 12 mercury fixed decalcified bone marrow trephine biopsies, three formalin fixed, paraffin embedded (FFPE) splenectomy samples and one fresh peripheral blood sample were reviewed. DNA was amplified by PCR and BRAF mutation status determined by the three methods above. Results: V600E mutation was identified in 95%, 87% and 76% of HCL cases by F-SSCA, HRM and SS, respectively. In one HCL case, in addition to the V600E mutation, a K601T mutation was identified. One of the Romanowsky stained samples was negative for mutation by all three methods. Three mercury fixed cases were negative for mutation by sequencing but positive for the mutation using F-SSCA and HRM. This discrepancy could be due to mutations below the limit of sensitivity of SS. Conclusion: DNA from archival slide scrapings, mercury-fixed and FFPE tissue can be used to identify BRAF mutations with high sensitivity especially using HRM/F-SSCA. The V600E mutation can be used as a supplementary molecular marker to aid in the diagnosis of HCL. The presence of the mutation may provide a target for therapy.
Pathology (2012), 44(S1)
MONITORING PERFORMANCE OF EXTERNAL QUALITY CONTROL Vanessa Thomson RCPA Quality Assurance Programs, Sydney, NSW, Australia Aim: In 2010 the Royal College of Pathologists of Australasia Quality Assurance Programs (RCPA QAP), received Quality Use of Pathology Program funding to determine if regular external quality assurance that laboratories perform could be used to identify unacceptable performance earlier than the usual 3 year NATA accreditation cycle, to help minimise risk to patients. Method: Criteria for unacceptable performance have been established to identify laboratories that maybe underperforming in external quality assurance (EQA). New frameworks have also been developed that outline the process of actions to be taken by the RCPA QAP when participant results and IVDs fall outside levels of acceptable performance. The frameworks proactively notify participants or manufacturers or their sponsors to assist them early. Results: When unacceptable performance is identified, according to the set criteria, a letter will be sent to the participant outlining the result(s) falling outside the criteria for acceptable performance and offer assistance to review the QAP results. Persisting unacceptable performance will be referred to a Committee for review and results referred to the National Association of Testing Authorities (NATA) or Therapuetic Goods Administration (TGA) for follow-up. Conclusion: The RCPA QAP has established a performance monitoring system using the EQA results. The early warning system will identify laboratories of concern and assist them to obtain their accreditation. Conflict of interest statement: This research was supported by the Department of Health and Ageing. The Department had no role in analysing the data or preparing the abstract. NUT MIDLINE CARCINOMA OF THE UPPER AERODIGESTIVE TRACT Clinton Turner, Jessica Matich, Chris van Vliet LabPlus, Auckland City Hospital, Auckland, New Zealand NUT (nuclear protein in testis) midline carcinoma (NMC) is a rare highly aggressive tumour characterised by chromosomal rearrangements of NUT on 15q14. Initially described in paediatric and adolescent populations, NMC is now known to occur over a wide age range. In adults, a common site of occurrence is the upper aerodigestive tract. We describe the case of a 54-year-old male presenting with 3 months of epistaxis. Examination revealed a mass in the right middle meatus. Biopsy showed a small round blue cell tumour without differentiating histological features. Immunohistochemically, the tumour was positive for cytokeratins (MNF116, HMWCK, CK7, CK5), p63, CD99 and CD34. FISH studies for Ewing/PNET and synovial sarcoma translocations were negative. FISH analysis confirmed the presence of the BRD4-NUT rearrangement typical of NMC. The patient underwent craniofacial resection and post-operative radiotherapy. Follow-up to date has shown no recurrence. NMC is not commonly included in the differential diagnosis of upper aerodigestive tract carcinomas. However, NMC should be considered in any poorly differentiated carcinoma of the upper aerodigestive tract, particularly those coexpressing cytokeratin and CD34. FISH testing for the characteristic translocation confirms the diagnosis. Aggressive therapy has
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited. Copyright