Pathology (April 2014) 46(3), pp. 240–266
CORRESPONDENCE High concordance rate of HER2 status assessed via silver in situ hybridisation (SISH) between core biopsy and excision specimens: a 4 year retrospective review from a single institution Sir, HER2 amplification occurs in about 15% of breast carcinomas and these tumours have an aggressive behaviour. Currently, there is no consensus as to whether HER2 in situ hybridisation (ISH) is best performed on core biopsy (CBx) or excision specimens. In our department, we prefer to perform testing on excision specimens partly because the initial Roche-funded HER2 testing program was largely limited to excision specimens. We present a 4 year experience of HER2 SISH testing on CBx of invasive breast carcinomas between 2008 and 2012 from the Department of Tissue Pathology and Diagnostic Oncology at Westmead Hospital, Sydney. The overall aim of the study was to assess the suitability of CBx for HER2 ISH testing and to determine the concordance rate between the CBx and the excision specimens. HER2 SISH testing was performed on a total of 194 breast CBx from 185 patients using either Inform HER2 SISH or INFORM HER2 dual SISH stains (Ventana, USA) in accordance with the protocol from Ventana. The reporting was based on the American Society of Clinical Oncology (ASCO) guidelines.1 A tumour was HER2 amplified if the HER2 copy was >6 on the single HER2 SISH probe, or if the HER2:Cep 17 ratio was >2.2. Negative tumours would have HER2 copy of A indicates that this mutation may have triggered the oncocytic phenotype, as a consequence of a feedback compensatory mechanism.2 Moreover, the mitochondrial damage caused by m.4561T>A may have contributed to hampering the tumourigenic potential conferred by the HPV
infection, a hypothesis that is in line with recent findings on the role of mtDNA mutations in tumour progression, but warrants further investigation to recognise whether the mitochondrial genetic hit was subsequent to the viral one. In order to investigate whether the m.4561T>A was a tumour specific event in the two hyperplasias, Sanger sequencing was performed on DNA extracted from the patient’s blood, hair and saliva. Analysis of the unaffected peritumoural tissue was not feasible since the hyperplasia occupied the whole parotid tissue (Fig. 1A,B). The mutation was not initially detected in any of the specimens (Fig. 2A). Nonetheless, due to the multi-copy nature of the mitochondrial genome, mtDNA mutations may be present at a low mutant load that goes undetected with Sanger sequencing. Low heteroplasmy mtDNA mutations have been detected in healthy germ-line tissue of patients with oncocytic tumours, and observed to shift to homoplasmy only in neoplastic cells,10 thus we decided to investigate this aspect in our case. A highly sensitive allele specific locked nucleic acid quantitative realtime PCR (ASLNAqRT-PCR)12 assay was performed, which allows detection of 1/1000 mutant molecules. ASLNAqRTPCR confirmed that the two hyperplasias both carried nearly homoplasmic m.4561T>A (Fig. 2C,D and Supplementary Fig. 4, http://links.lww.com/PAT/A14). Blood and hair DNA results showed wild-type mitochondrial genomes. Interestingly, the saliva specimen harboured the m.4561T>A at a low mutant load (2.6%) (Fig. 2D,E and Supplementary Figure 4, http://links.lww.com/PAT/A14), indicating that the mutation was neither germ-line nor tumour-specific, but likely occurred de novo during embryonic development in the cells from which
14 052
P1 12 052
10 052
P2 8 052
P1,P2
8 052
B
S
4 052
H
2 052
B,H 0 052
A
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
D
S
WT specific primer Ct
B ATP5B
C
NDUFB6
NDUFB8
Copy number
Mutant specific primer Ct
Copy number
Mutant load (%)
P1
16.42
98056
9.08
10534975
99.1
P2
16.08
118581
11.14
3758612
96.9
B
15.73
144208
n.d.
0
0.0
H
23.17
2253
n.d.
0
0.0
S
13.27
570449
22.19
14929
2.6
E
Fig. 2 Genetic and functional analysis of the m.4561T>A mutation. (A) MT-ND2 electropherograms showing m.4561T>A mutation (black arrow) in parotid hyperplasias (P1 and P2), but not in the blood (B), hair (H) or saliva (S) specimens. (B) Phylogenetic alignment showing a conserved region of MT-ND2 affected by m.4561T>A/(V31E). Phylogenetically conserved amino acids are labelled with an asterisk; the numbering corresponds to the H. sapiens amino acid sequence and the black arrow indicates the mutation site. (C) Immunohistochemical analysis of the right parotid hyperplasia showing lack of NDUFB8 staining. (D) Raw data output of the mutant specific LNAqRT-PCR performed on two parotid hyperplasias (P1 and P2), blood (B), hair (H) and saliva (S). Positive signal is observed in the two hyperplasias and in the patient’s saliva (S). (E) Detailed cycle threshold (ct) and copy number data presenting mutant load levels of the m.4561T>A.
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CORRESPONDENCE
the two parotids derived. The saliva specimen was collected 2 months after the last surgical resection, and contamination by hyperplastic cells may be ruled out. Although m.4561T>A was not tumour specific per se, it shifted to homoplasmy exclusively in the two hyperplasias suggesting common aetiopathogenesis of the two lesions, possibly due to an exceptionally premature disease onset, initiated in tissues from which the two parotids developed. This would explain why only the parotid tissue was affected. On the other hand, HPV infection might have been responsible for transmission of the proliferating potential from one parotid to the other, albeit it remains unexplained why such transmission would not be extended to other tissues. Taken together, this case brings attention to the existence of novel molecular markers of MNOH, namely mtDNA mutations and HPV infection. Here, their identification enabled us to clarify the unusual presentation of hyperplasias in two anatomically separate sites. Generally, such analysis may provide insight in aetiopathogenesis of other bilateral parotid lesions, particularly in the context of oncocytic phenotype development. Conflicts of interest and sources of funding: This work was supported by grant IG8810 from the Associazione Italiana Ricerca sul Cancro (AIRC), by grant DISCO TRIP from Fondazione Umberto Veronesi and by grant FIRB ‘Futuro in Ricerca’ TRANSMIT J31J10000040001 to GG; IK is supported by an AIRC triennial fellowship ‘Borromeo’. The authors state that there are no conflicts of interest to disclose. Ivana Kurelac1 Nunzio Cosimo Salfi2 Claudio Ceccarelli3 Federica Alessandrini3 Monica Cricca3 Umberto Caliceti4 Giuseppe Gasparre1 1
U. O. Genetica Medica, Dip. di Scienze Mediche e Chirurgiche, U. O. Anatomia e Istologia Patologica, 3Dipartimento di Medicina Clinica Diagnostica e Sperimentale, and 4U. O. Otorinolaringoiatria, Policlinico Universitario S. OrsolaMalpighi, Universita` di Bologna, Bologna, Italy 2
Contact Dr G. Gasparre. E-mail: [email protected] 1. Gregorie C. Salivary gland tumors: the parotid gland. In: Bagheri S, Bell B, Khan H, editors. Current Therapy In Oral and Maxillofacial Surgery. Missouri, MO: Elsevier Saunders, 2011; 450–460. 2. Gasparre G, Romeo G, Rugolo M, Porcelli AM. Learning from oncocytic tumors: Why choose inefficient mitochondria? Biochim Biophys Acta 2010; 1807: 633–42. 3. Chen S, Paul BC, Myssiorek D. An algorithm approach to diagnosing bilateral parotid enlargement. Otolaryngol Head Neck Surg 2013; 148: 732–9. 4. Ethunandan M, Pratt CA, Morrison A, Anand R, Macpherson DW, Wilson AW. Multiple synchronous and metachronous neoplasms of the parotid gland: the Chichester experience. Br J Oral Maxillofac Surg 2006; 44: 397– 401. 5. Ellis GL, Auclair P. Tumors of the Salivary Glands. Atlas of Tumor Pathology. Series 4. Washington, DC: AFIP and American Registry of Pathology, 2008.
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6. Kirdar S, Basak S, Odobasi O, Doger FK, Erpek G. Human papillomavirus in rare unilateral benign intranasal tumours. Rhinology 2009; 47: 349–53. 7. Vageli D, Sourvinos G, Ioannou M, Koukoulis GK, Spandidos DA. High-risk human papillomavirus (HPV) in parotid lesions. Int J Biol Markers 2007; 22: 239–44. 8. Iommarini L, Calvaruso MA, Kurelac I, Gasparre G, Porcelli AM. Complex I impairment in mitochondrial diseases and cancer: parallel roads leading to different outcomes. Int J Biochem Cell Biol 2012; 45: 47–63. 9. Ugalde C, Hinttala R, Timal S, et al. Mutated ND2 impairs mitochondrial complex I assembly and leads to Leigh syndrome. Mol Genet Metab 2007; 90: 10–4. 10. Gasparre G, Iommarini L, Porcelli AM, et al. An inherited mitochondrial DNA disruptive mutation shifts to homoplasmy in oncocytic tumor cells. Hum Mutat 2009; 30: 391–6. 11. Kurelac I, MacKay A, Lambros MB, et al. Somatic complex I disruptive mitochondrial DNA mutations are modifiers of tumorigenesis that correlate with low genomic instability in pituitary adenomas. Hum Mol Genet 2013; 22: 226–38. 12. Strand H, Ingebretsen OC, Nilssen O. Real-time detection and quantification of mitochondrial mutations with oligonucleotide primers containing locked nucleic acid. Clin Chim Acta 2008; 390: 126–33.
DOI: 10.1097/PAT.0000000000000079
Primary gastric synovial sarcoma Sir, Synovial sarcoma (SS) accounts for 5–10% of soft tissue sarcomas. It mostly occurs in young adults (15–40 years old), with a slight predominance in males. The most common locations are in the limbs, near the joints, which account more than 80% of new cases, the knee being the most affected joint.1,2 However, cases with unusual locations such as head, neck, skin, lungs, abdomen, mediastinum, retroperitoneum, kidneys, oral cavity and digestive tract,3 among others, have been described, representing approximately the remaining 10%. To date, only 14 gastric synovial sarcomas have been reported in the English literature. The site of occurrence of this neoplasm often determines the onset and development of symptoms. Neoplastic growth into the gastric cavity or on adjacent structures can be considerable before it starts causing discomfort, thus delaying the diagnosis.3,4 In its gastrointestinal location, SS presents similar microscopy characteristics to other locations. There are three classically defined microscopic variants: biphasic, monophasic and poorly differentiated.2 The origin of these tumour cells may correspond to a mesenchymal pluripotent cell, which could explain the development thereof in almost any anatomical location. A 44-year-old male, current smoker, with a previous diagnosis of ulcerative colitis, received discontinuous treatment with steroid drugs for 5 years. Symptoms initiated 5 months before admission, characterised by abdominal discomfort which exacerbated with prolonged fasting and post-prandial fullness, dizziness and weight loss of 2 kg in a month. A gastrosendoscopic examination was performed, where an ulcerated polypoid lesion was seen, extending from the subcardial region to the lesser curvature. Serological tumour markers were negative. The patient underwent a total gastrectomy. A polylobulated and solid mass, 15 10 9 cm, was found at the lesser curvature with a cut surface suggestive of fibrous tissue (Fig. 1A,B). Microscopic examination with
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CORRESPONDENCE
Pathology (2014), 46(3), April
10 high power fields (HPFs). The cells were organised in a solid, non-specific pattern and infiltrated the entire gastric wall (Fig. 1C,D). The immunohistochemical study showed widespread vimentin positivity, and focal cytokeratin AE1/ AE3 (AE1/AE3) and epithelial membrane antigen (EMA) positivity (Fig. 2A). CD34, CD117 (Fig. 2B), common muscle actin (CMA), desmin, S100 and Dog-1 staining were negative. The cell proliferation rate estimated with Ki-67 antibody was approximately 5%. Specific molecular analysis for gastrointestinal stromal tumour (GIST; PDGRF and KIT
Fig. 1 Gross and microscopic features of gastrectomy specimen. (A) Polylobulated yellowish mass, emerging from the lesser curvature. (B) Post-fixation cross-section showing the solid-fibre pattern of the neoplasm. Histological features of gastric SS: (C) spindle cell neoplasm, organised in fascicles, (D) with frequent atypical mitotic figures (H&E).
haematoxylin and eosin (H&E) revealed a lesion almost exclusively composed of spindle cells with elongated nuclei and well-defined cytoplasm with a mitotic rate of 11 per
Fig. 2 Immunohistochemistry and FISH. (A) EMA with focal positivity. (B) Negative CD117 in tumour cells. (C) Positive X;18 translocation confirmed by FISH break-apart probe: one separate red and green signal per nucleus indicating the presence of a (X;18) translocation.
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genes) was negative. The characteristic X;18 translocation of SS was detected by fluorescence in situ hybridisation (FISH; Fig. 2C). In 2000 Billings et al.5 first described two SS cases of primary gastric origin. Seven years later, Akhunji et al.6 presented a new case, and the following year Makhlouf et al.4 published the largest series, which included 10 patients. The latest published case belongs to Wang et al. (2012).7 The fact that the number of cases is so small poses limitations to any studies being performed (e.g., diagnostic tests, therapeutic targets), therefore the information provided by each new case of gastric SS is relevant to improve the understanding of the disease and its characteristics. A synopsis of the information available on gastric SS clinical-pathological features has been summarised in Table 1. The gastric body and fundus are the most common locations, with two cases (including ours) placed in the lesser curvature. The location and the large size of the tumour may have conditioned the early onset of symptoms (age below the expected average for an SS of the stomach). Three biphasic gastric SS have been reported.4–6 The rest (including ours) belong to the monophasic subclass, which poses a difficult differential diagnosis in this setting.7,8 The immunohistochemical studies of this neoplasm have been varied, although determination of expression of wide spectrum cytokeratin was a constant, obtaining positive results in all the reported cases. EMA was positive in all the cases as well. Additionally, CD117 and CD34 were negative in all the tumours in which they were carried out. This immunohistochemical profile is similar to that expressed in our case. For tumours with mesenchymal characteristics which compromise the stomach wall, some of the early diagnoses
Table 1
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that arise are GIST, leiomyosarcoma and sarcomatoid carcinoma. When the immunohistochemical profile of the tumour under study does not support any of the alternatives mentioned above, it is necessary to broaden the diagnostic approach to entities that were initially ruled out because of the location of the tumour. SS has a characteristic immunohistochemical profile, which includes AE1/AE3, CK7 and EMA positivity, as well as CD117, CD34, desmin and S100 protein negativity. One of the most distinctive features of the GIST is its positivity for CD117, although in a small, non-negligible percentage of cases (5%) this positivity is absent. It is precisely in those cases that difficulties in differential diagnosis may arise, especially when the histological pattern and the other stains are not conclusive. Our patient’s tumour was negative for CD117, CD34, Dog-1 and muscle markers, therefore the diagnosis of GIST was highly unlikely. Additional data, such as the absence of mutations in KIT and PDGFR genes, also didn’t support the diagnosis of GIST. Cytokeratin and EMA positivity suggested a monophasic SS. In 12 of the 14 cases reported in scientific journals, the X;18 (SYT-SSX, p11.2-q11.2) translocation was studied, with a positive result in all of them. In our case this translocation was observed as well. The diagnostic performance of this test for SS shows a sensitivity and specificity higher than 95%.8 The implementation of this test, either by polymerase chain reaction (PCR) or FISH techniques, to suspected SS tumours of unusual location is mandatory to establish the diagnosis with certainty. It is known that fusion of SYT and SSX genes results in a chimaeric protein that is linked to the origin and pathophysiology of this entity, since these genes are co-regulators of cellular differentiation processes. The most important variants of the SSX gene involved in synovial sarcomas are 1 and 2.
Clinicopathological features of 14 gastric synovial sarcomas
Source Billings et al. 20005
Akhunji et al. 20076 Makhlouf et al. 20084
Wang et al. 20127 Current case
Case
Age
Sex
Tumour size (cm)
Gastric location
Subtype
Mitosis
Treatment
Metastasis
Follow-up (months)
1
47
M
5.2
Gastro-oesophageal junction Distal stomach
Biphasic
110 HPF
Partial gastrectomy
No evidence
ADF 21 months
2
55
F
16
Monophasic
9–50 10 HPF
Liver
Died 6 months after surgery
11.5
Posterior gastric wall
Biphasic
>10 HPF
Mesenteric
F
0.8
Body antrum junction
Monophasic
No data available
Hemigastrectomy/ retrocolic Billroth II Tumour resection/ chemotherapy Partial gastrectomy
3
42
M
No evidence
Died 24 months after diagnosis ADF 12 months
4
67
5
49
M
2
Body
Monophasic
Omentum
Died 29 months
6 7 8
68 29 54
F M F
2 2.8 3
Monophasic Monophasic Monophasic
No evidence No evidence No evidence
ADF 22 months ADF 224 months Follow-up case
9 10
58 37
F F
3 4
Body Body Antrum, gastroduodenal junction Lesser curvature/body Fundus
Segmental/wedge resection Wedge resection Partial gastrectomy Antrum, gastroduodenal resection Wedge resection Partial gastrectomy
No evidence No evidence
11
50
M
6
Distal fundus
Monophasic
No evidence
12
66
F
15
Fundus
Monophasic
No evidence
13
42
M
8
Great curvature/body
Biphasic
No evidence
Died 25 months
14
38
F
7.5
Body (middle portion)
Monophasic
44
M
15
Lesser curvature
Monophasic
Omentum/ Liver No evidence
Follow-up case
15
Tumour resection, chemotherapy Gastrectomy/partial oesophagectomy Partial gastrectomy, chemotherapy Tumour resection/ chemotherapy Gastrectomy total
ADF 21 months Local recurrence / DOD 48 months Recurrence 6 months Monitoring loss
Monophasic Monophasic
>20 10 HPF 11/10 HPF
Follow-up case ADF
ADF, alive disease-free; DOD, died of other disease.
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Each of them seems to correspond to a histological subtype and a specific biological behaviour. Therefore, SYT/SSX1 rearrangement is more common in the biphasic subtype and entails a higher risk of distant metastases. The specific SYT/SSX2 translocation is related to the monophasic subtype, with a more indolent or benign clinical course.9,10 The treatment offered to patients with gastric SS was surgical. Four of them received post-operative chemotherapy (after showing local recurrence and/or metastases). The reviewed publications document four deaths directly related to this disease, three of which were monophasic cases with metastases and one case belonged to the biphasic subtype. The deaths occurred between 24 and 29 months following diagnosis.4–7 Our patient underwent total gastrectomy without further evidence of residual disease and therefore no additional treatment was introduced, apart from a strict follow-up (18 months disease free). In summary, primary gastric SS is a rare and underdiagnosed neoplasm. Molecular biology techniques are vital for accurate diagnosis. The prognostic factors and the treatment of this tumour are similar to those observed and offered to patients with a usual SS location, although an increase in the number of cases reported will determine whether there are variations of interest in the pathobiological behaviour. This is a unique case, and the number of gastric SS remains small. Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. He´ctor E. Torres Rivas Soledad Ferna´ndez Manuel F. Fresno Department of Pathology, Central University Hospital of Asturias, Oviedo, Spain Contact Dr H. E. Torres Rivas. E-mail: [email protected] 1. Spillane AJ, A’Hern R, Judson IR, et al. Synovial sarcoma: a clinicopathologic, staging, and prognostic assessment. J Clin Oncol 2000; 18: 3794– 803. 2. Siegel HJ, Sessions W, Casillas MA Jr, et al. Synovial sarcoma: clinicopathologic features, treatment, and prognosis. Orthopedics 2007; 30: 1020–5. 3. Alsharief AN, Fageeh M, Alabdulkarim Y. Monophasic synovial sarcoma presenting as a primary ileal mass: a case report and review of the literature. J Med Case Rep 2012; 6: 83. 4. Makhlouf HR, Ahrens W, Agarwal B, et al. Synovial sarcoma of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 10 cases. Am J Surg Pathol 2008; 32: 275–81. 5. Billings SD, Meisner LF, Cummings OW, et al. Synovial sarcoma of the upper digestive tract: a report of two cases with demonstration of the X;18 translocation by fluorescence in situ hybridization. Mod Pathol 2000; 13: 68–76. 6. Akhunji S, Musil I, Baisre de Leon A, et al. Synovial sarcoma arising in the gastric wall: case report and literature review. Case Report. Cancer Ther 2007; 5: 457–62. 7. Wang CC, Wu MC, Lin MT, et al. Primary gastric synovial sarcoma. J Formosan Med Assoc 2012; 111: 516–20. 8. Coindre JM, Pelmus M, Hostein I, et al. Should molecular testing be required for diagnosing synovial sarcoma? A prospective study of 204 cases. Cancer 2003; 98: 2700–7. 9. Ladanyi M, Antonescu CR, Leung DH, et al. Impact of SYT-SSX fusion type on the clinical behavior of synovial sarcoma: a multiinstitutional retrospective study of 243 patients. Cancer Res 2002; 62: 135–40.
10. Inagaki H, Nagasaka T, Otsuka T, et al. Association of SYT-SSX fusion types with proliferative activity and prognosis in synovial sarcoma. Mod Pathol 2000; 13: 482–8.
DOI: 10.1097/PAT.0000000000000078
Urothelial bladder carcinoma metastasising to the scrotum mimicking primary extramammary Paget’s disease Sir, Invasive urothelial carcinoma is an aggressive disease that preferentially metastasises to the pelvic lymph nodes, bones, liver and lung.1 Metastasis to the scrotum or vulva is rare.2 Primary extramammary Paget’s disease of the scrotum is a rare entity of adenocarcinoma originating from malignant transformation of pluripotent intraepidermal cells as they differentiate into apocrine glands3 and dermal invasion and is rare.4 Secondary extrammary Paget’s disease of the scrotum from the bladder has not been recorded. Here, we report a case of metastatic urothelial bladder carcinoma to the scrotum masquerading as primary extramammary Paget’s disease. A 71-year-old male was diagnosed with high grade papillary urothelial carcinoma of the bladder invading the lamina propria (Fig. 1A) on transurethral bladder tumour resection. Clinical and cystoscopic follow-up were unremarkable 4 years later when a 2 cm ulcerated lesion with underlying firmness was noted on the lateral aspect of the right hemiscrotum. A biopsy was performed and was diagnosed as extramammary Paget’s disease (Fig. 1B). A right hemiscrotectomy was subsequently carried out. Pathological analysis revealed a poorly differentiated large cell carcinoma with focal glandular differentiation and inguinal lymph node metastasis. In the overlying epidermis, there were extensive changes mimicking primary extrammary Paget’s disease (Fig. 2A,B). Immunohistochemical staining showed positivity for GCDFP-15, CK7 (Fig. 2C) and CEA-monoclonal (Fig. 2D). Immunohistochemistry for CDX2, CK20, and S100 was negative. Special stain for Alcian Blue 2.5 showed the presence of mucin in the neoplastic cells (Fig. 2E). In view of the clinincal history of urothelial carcinoma, further immunohistochemical testing showed positive immunoreactivity for GATA 3 (Fig. 2F). Lymphovascular invasion was identified and surgical resection margins were free of malignancy. Follow-up CT scan confirmed periaortic adenopathy as well as a small lytic lesion in the right side of T11. The patient was started on palliative chemotherapy and died 6 months later. It is felt that the metastatic urothelial carcinoma was masquerading as primary extramammary Paget’s disease of the scrotum. The mechanism of spread was likely direct spread from inguinal lymph nodes after intralymphatic spread from the primary bladder lesion, and not direct spread of tumour cells to the scrotum from the primary lesion. This case demonstrates the fact that metastatic urothelial carcinoma to the scrotum can mimic primary extramammary Paget’s disease, and therefore must be excluded during pathological analysis.
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A
257
B
Fig. 1 (A) Transurethral resection of bladder tumour showing invasive urothelial carcinoma into the lamina propria (H&E). (B) Biopsy from scrotal resection (H&E).
Fig. 2 Lesion from scrotal resection (A,B, H&E; C, CK7; D, CEA-monoclonal; E, Alcian blue 2.5; F, GATA 3).
Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. Previn Gulavita Kien T. Mai The Ottawa Hospital and University of Ottawa, Pathology and Laboratory Medicine, Ottawa, ON, Canada Contact Dr P. Gulavita. E-mail: [email protected]
1. Jemal A, Siegel R, Ward E, et al. Cancer statistics. CA Cancer J Clin 2009; 59: 225–49. 2. Hoyt BS, Cohen PR. Cutaneous scrotal metastasis: origins and clinical characteristics of visceral malignancies that metastasize to the scrotum. Int J Dermatol 2013; 52: 398–405. 3. Minsky B, Hoffman J, Kelsen D. Cancer of the Anal Region. In: DeVita Jr V, Hellman S, Rosenberg SA, editors. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia: JB Lippincott Co, 2001;1319–42. 4. Lai YL, Yang WG, Tsay PK, et al. Penoscrotal extramammary Paget’s disease: a review of 33 cases in a 20-year experience. Plast Reconstr Surg 2003; 112: 1017–23.
DOI: 10.1097/PAT.0000000000000084
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Multifocal, co-located angiokeratomas and syringomas of the vulva Sir, Syringoma and angiokeratoma are common benign lesions on the vulva.1 Therefore, it would not be surprising to occasionally find them co-located by co-incidence. However, we have recently observed a woman with three co-located vulval lesions. Two showed syringomas and angiokeratomas and the third showed a dilated, budding eccrine gland and an angiokeratoma. Our case is evidence of a relationship between these two benign lesions. The patient was a 66-year-old female (P1, G1) with no relevant medical or surgical history. She presented for investigation of the three palpable lesions, which were otherwise asymptomatic. On examination, the lesions were 1–2 mm in diameter, round, red/ blue, firm, and very well demarcated on the outer right upper and lower and left upper surfaces of the labia majora. No extra-genital lesions were identified. Excisional punch biopsy was performed on all lesions. The right upper and right lower lesions had similar pathological features. Hair bearing skin showed vascular lesions immediately beneath the epidermis and composed of large ectatic capillaries (Fig. 1A). Beneath the vascular lesions, but separated by some normal dermis, were haphazard proliferations of dilated
and small eccrine ducts associated with dense fibrous stroma. No atypia or mitoses were seen. The left upper lesion showed a similar vascular abnormality, but did not contain a proliferation of eccrine ducts. Rather, there was a single dilated eccrine duct with early budding (Fig. 1B). The pathological diagnoses were angiokeratomas associated with syringomas in the first two lesions and angiokeratoma associated with abnormal eccrine duct in the third. Syringomas and angiokeratomas are common benign vulval lesions.1 Syringomas are small benign adnexal neoplasms composed of sweat gland epithelium within densely sclerotic stroma.2 They may be associated with lichen simplex chronicus, in which case they are multiple.1 It is not known whether the syringomas precede or cause the lichen simplex chronicus.1 Angiokeratomas are constellations of superficial ectatic cutaneous blood vessels.3 They are usually asymptomatic and when occurring on the vulva tend to be red/blue in colour. Vulval angiokeratomas may be idiopathic, but are often associated with factors causing venous congestion, particularly previous pelvic surgery.4 We considered a differential diagnosis of multiple eccrine angiomatous hamartomas (EAH) as this rare lesion involves a proliferation of eccrine ducts and blood vessels. EAH is a circumscribed, mid to deep dermal proliferation of mature appearing eccrine ducts intimately associated with a benign vascular proliferation of dilated small capillaries.5 Our case is not EAH because our lesions were close, but entirely separated angiokeratomas and syringomas (or, in the third lesion, an abnormal eccrine gland), with the vascular proliferation superficial in the dermis. Furthermore, the late onset of 66 years, absence of pain and hyperhidrosis and the unusual site were not typical of EAH, which usually presents in childhood, is painful and/or causes hyperhidrosis, and typically occurs on acral areas or, less commonly, the face, neck and trunk.2 We note, however, that one vulval case of EAH has been reported.6 We do not know the mechanism of association of the two types of lesion, but the pathology in our third lesion of an established angiokeratoma and eccrine duct dilatation and budding (but not syringoma) provides a clue to the possible mechanism for these curious tumours, in that the vascular lesions may precede the syringoma. Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. Christina Botfield1 Reidar Agdestein1 Brett Locker2 James Scurry3 1
Faculty of Health Sciences, University of Newcastle, Department of Obstetrics and Gynaecology, John Hunter Hospital, and 3Anatomical Pathology, HAPS, Newcastle, NSW, Australia 2
Contact Associate Professor J. Scurry. E-mail: [email protected]
Fig. 1 (A) Right upper labium majus lesion: angiokeratoma (black arrow) and syringoma (white arrow) (H&E). (B) Left upper labium majus lesion: angiokeratoma comprising superificial and mid-dermal ectatic blood vessels (black arrows) and dilated eccrine duct with early budding (white arrow) (H&E).
1. Lynch PJ. Pigmented disorders. In: Edwards L, Lynch PJ. Genital Dermatology Atlas. 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2010; 228–44. 2. LeBoit PE, Burg G, Weedon D, Sarasin A, editors. Pathology and Genetics: Skin Tumours. Lyon: IARC Press, 2006; 139–48.
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3. Dennerstein G, Scurry J, Brennan J, Allen D, Marin M-G. The Vulva and Vagina Manual. Melbourne: Gynederm Publishing, 2005; 262–81. 4. Requena L, Sangueza OP. Cutaneous vascular anomalies. Part I. Hamartomas, malformations, and dilation of preexisting vessels. J Am Acad Dermatol 1997; 37: 523–49. 5. Calonje E, Brenn T, Lazar A, McKee PH. McKee’s Pathology of the Skin. 4th ed. Philadelphia: Elsevier, 2012; 1508–70. 6. Nowakowski K, Dyduch G. Adult-onset eccrine angiomatous hamartoma on the vulva. Int J Dermatol 2012; 51: 840–1.
DOI: 10.1097/PAT.0000000000000081
Confirmation of tertiary Treponema pallidum infection by polA polymerase chain reaction (PCR) Sir, We report a novel case of tertiary cardiovascular syphilis presenting with aortic regurgitation and low grade fever, diagnosed using different methods including serology and a Treponema pallidum specific polA polymerase chain reaction (PCR). A male patient in his mid-30s was transferred to our institution, Royal Melbourne Hospital (RMH), from another local metropolitan hospital (institution A), with a provisional diagnosis of aortic valve endocarditis. He presented initially to institution A with a 2 day history of fever, left upper quadrant abdominal and lower thoracic back pain. He was previously fit and well, and had no history of rheumatic fever or valvular heart disease. He denied illicit drug use, or symptoms of sexually transmitted infections. He had migrated from South Asia 6 years previously, was married with two young children, and claimed marital monogamy. Clinical examination revealed occasional low grade temperatures and severe aortic regurgitation without signs of heart failure. Investigations revealed a raised C-reactive protein (CRP) of 225 mg/L (normal range
CORRESPONDENCE High concordance rate of HER2 status assessed via silver in situ hybridisation (SISH) between core biopsy and excision specimens: a 4 year retrospective review from a single institution Sir, HER2 amplification occurs in about 15% of breast carcinomas and these tumours have an aggressive behaviour. Currently, there is no consensus as to whether HER2 in situ hybridisation (ISH) is best performed on core biopsy (CBx) or excision specimens. In our department, we prefer to perform testing on excision specimens partly because the initial Roche-funded HER2 testing program was largely limited to excision specimens. We present a 4 year experience of HER2 SISH testing on CBx of invasive breast carcinomas between 2008 and 2012 from the Department of Tissue Pathology and Diagnostic Oncology at Westmead Hospital, Sydney. The overall aim of the study was to assess the suitability of CBx for HER2 ISH testing and to determine the concordance rate between the CBx and the excision specimens. HER2 SISH testing was performed on a total of 194 breast CBx from 185 patients using either Inform HER2 SISH or INFORM HER2 dual SISH stains (Ventana, USA) in accordance with the protocol from Ventana. The reporting was based on the American Society of Clinical Oncology (ASCO) guidelines.1 A tumour was HER2 amplified if the HER2 copy was >6 on the single HER2 SISH probe, or if the HER2:Cep 17 ratio was >2.2. Negative tumours would have HER2 copy of A indicates that this mutation may have triggered the oncocytic phenotype, as a consequence of a feedback compensatory mechanism.2 Moreover, the mitochondrial damage caused by m.4561T>A may have contributed to hampering the tumourigenic potential conferred by the HPV
infection, a hypothesis that is in line with recent findings on the role of mtDNA mutations in tumour progression, but warrants further investigation to recognise whether the mitochondrial genetic hit was subsequent to the viral one. In order to investigate whether the m.4561T>A was a tumour specific event in the two hyperplasias, Sanger sequencing was performed on DNA extracted from the patient’s blood, hair and saliva. Analysis of the unaffected peritumoural tissue was not feasible since the hyperplasia occupied the whole parotid tissue (Fig. 1A,B). The mutation was not initially detected in any of the specimens (Fig. 2A). Nonetheless, due to the multi-copy nature of the mitochondrial genome, mtDNA mutations may be present at a low mutant load that goes undetected with Sanger sequencing. Low heteroplasmy mtDNA mutations have been detected in healthy germ-line tissue of patients with oncocytic tumours, and observed to shift to homoplasmy only in neoplastic cells,10 thus we decided to investigate this aspect in our case. A highly sensitive allele specific locked nucleic acid quantitative realtime PCR (ASLNAqRT-PCR)12 assay was performed, which allows detection of 1/1000 mutant molecules. ASLNAqRTPCR confirmed that the two hyperplasias both carried nearly homoplasmic m.4561T>A (Fig. 2C,D and Supplementary Fig. 4, http://links.lww.com/PAT/A14). Blood and hair DNA results showed wild-type mitochondrial genomes. Interestingly, the saliva specimen harboured the m.4561T>A at a low mutant load (2.6%) (Fig. 2D,E and Supplementary Figure 4, http://links.lww.com/PAT/A14), indicating that the mutation was neither germ-line nor tumour-specific, but likely occurred de novo during embryonic development in the cells from which
14 052
P1 12 052
10 052
P2 8 052
P1,P2
8 052
B
S
4 052
H
2 052
B,H 0 052
A
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
D
S
WT specific primer Ct
B ATP5B
C
NDUFB6
NDUFB8
Copy number
Mutant specific primer Ct
Copy number
Mutant load (%)
P1
16.42
98056
9.08
10534975
99.1
P2
16.08
118581
11.14
3758612
96.9
B
15.73
144208
n.d.
0
0.0
H
23.17
2253
n.d.
0
0.0
S
13.27
570449
22.19
14929
2.6
E
Fig. 2 Genetic and functional analysis of the m.4561T>A mutation. (A) MT-ND2 electropherograms showing m.4561T>A mutation (black arrow) in parotid hyperplasias (P1 and P2), but not in the blood (B), hair (H) or saliva (S) specimens. (B) Phylogenetic alignment showing a conserved region of MT-ND2 affected by m.4561T>A/(V31E). Phylogenetically conserved amino acids are labelled with an asterisk; the numbering corresponds to the H. sapiens amino acid sequence and the black arrow indicates the mutation site. (C) Immunohistochemical analysis of the right parotid hyperplasia showing lack of NDUFB8 staining. (D) Raw data output of the mutant specific LNAqRT-PCR performed on two parotid hyperplasias (P1 and P2), blood (B), hair (H) and saliva (S). Positive signal is observed in the two hyperplasias and in the patient’s saliva (S). (E) Detailed cycle threshold (ct) and copy number data presenting mutant load levels of the m.4561T>A.
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CORRESPONDENCE
the two parotids derived. The saliva specimen was collected 2 months after the last surgical resection, and contamination by hyperplastic cells may be ruled out. Although m.4561T>A was not tumour specific per se, it shifted to homoplasmy exclusively in the two hyperplasias suggesting common aetiopathogenesis of the two lesions, possibly due to an exceptionally premature disease onset, initiated in tissues from which the two parotids developed. This would explain why only the parotid tissue was affected. On the other hand, HPV infection might have been responsible for transmission of the proliferating potential from one parotid to the other, albeit it remains unexplained why such transmission would not be extended to other tissues. Taken together, this case brings attention to the existence of novel molecular markers of MNOH, namely mtDNA mutations and HPV infection. Here, their identification enabled us to clarify the unusual presentation of hyperplasias in two anatomically separate sites. Generally, such analysis may provide insight in aetiopathogenesis of other bilateral parotid lesions, particularly in the context of oncocytic phenotype development. Conflicts of interest and sources of funding: This work was supported by grant IG8810 from the Associazione Italiana Ricerca sul Cancro (AIRC), by grant DISCO TRIP from Fondazione Umberto Veronesi and by grant FIRB ‘Futuro in Ricerca’ TRANSMIT J31J10000040001 to GG; IK is supported by an AIRC triennial fellowship ‘Borromeo’. The authors state that there are no conflicts of interest to disclose. Ivana Kurelac1 Nunzio Cosimo Salfi2 Claudio Ceccarelli3 Federica Alessandrini3 Monica Cricca3 Umberto Caliceti4 Giuseppe Gasparre1 1
U. O. Genetica Medica, Dip. di Scienze Mediche e Chirurgiche, U. O. Anatomia e Istologia Patologica, 3Dipartimento di Medicina Clinica Diagnostica e Sperimentale, and 4U. O. Otorinolaringoiatria, Policlinico Universitario S. OrsolaMalpighi, Universita` di Bologna, Bologna, Italy 2
Contact Dr G. Gasparre. E-mail: [email protected] 1. Gregorie C. Salivary gland tumors: the parotid gland. In: Bagheri S, Bell B, Khan H, editors. Current Therapy In Oral and Maxillofacial Surgery. Missouri, MO: Elsevier Saunders, 2011; 450–460. 2. Gasparre G, Romeo G, Rugolo M, Porcelli AM. Learning from oncocytic tumors: Why choose inefficient mitochondria? Biochim Biophys Acta 2010; 1807: 633–42. 3. Chen S, Paul BC, Myssiorek D. An algorithm approach to diagnosing bilateral parotid enlargement. Otolaryngol Head Neck Surg 2013; 148: 732–9. 4. Ethunandan M, Pratt CA, Morrison A, Anand R, Macpherson DW, Wilson AW. Multiple synchronous and metachronous neoplasms of the parotid gland: the Chichester experience. Br J Oral Maxillofac Surg 2006; 44: 397– 401. 5. Ellis GL, Auclair P. Tumors of the Salivary Glands. Atlas of Tumor Pathology. Series 4. Washington, DC: AFIP and American Registry of Pathology, 2008.
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6. Kirdar S, Basak S, Odobasi O, Doger FK, Erpek G. Human papillomavirus in rare unilateral benign intranasal tumours. Rhinology 2009; 47: 349–53. 7. Vageli D, Sourvinos G, Ioannou M, Koukoulis GK, Spandidos DA. High-risk human papillomavirus (HPV) in parotid lesions. Int J Biol Markers 2007; 22: 239–44. 8. Iommarini L, Calvaruso MA, Kurelac I, Gasparre G, Porcelli AM. Complex I impairment in mitochondrial diseases and cancer: parallel roads leading to different outcomes. Int J Biochem Cell Biol 2012; 45: 47–63. 9. Ugalde C, Hinttala R, Timal S, et al. Mutated ND2 impairs mitochondrial complex I assembly and leads to Leigh syndrome. Mol Genet Metab 2007; 90: 10–4. 10. Gasparre G, Iommarini L, Porcelli AM, et al. An inherited mitochondrial DNA disruptive mutation shifts to homoplasmy in oncocytic tumor cells. Hum Mutat 2009; 30: 391–6. 11. Kurelac I, MacKay A, Lambros MB, et al. Somatic complex I disruptive mitochondrial DNA mutations are modifiers of tumorigenesis that correlate with low genomic instability in pituitary adenomas. Hum Mol Genet 2013; 22: 226–38. 12. Strand H, Ingebretsen OC, Nilssen O. Real-time detection and quantification of mitochondrial mutations with oligonucleotide primers containing locked nucleic acid. Clin Chim Acta 2008; 390: 126–33.
DOI: 10.1097/PAT.0000000000000079
Primary gastric synovial sarcoma Sir, Synovial sarcoma (SS) accounts for 5–10% of soft tissue sarcomas. It mostly occurs in young adults (15–40 years old), with a slight predominance in males. The most common locations are in the limbs, near the joints, which account more than 80% of new cases, the knee being the most affected joint.1,2 However, cases with unusual locations such as head, neck, skin, lungs, abdomen, mediastinum, retroperitoneum, kidneys, oral cavity and digestive tract,3 among others, have been described, representing approximately the remaining 10%. To date, only 14 gastric synovial sarcomas have been reported in the English literature. The site of occurrence of this neoplasm often determines the onset and development of symptoms. Neoplastic growth into the gastric cavity or on adjacent structures can be considerable before it starts causing discomfort, thus delaying the diagnosis.3,4 In its gastrointestinal location, SS presents similar microscopy characteristics to other locations. There are three classically defined microscopic variants: biphasic, monophasic and poorly differentiated.2 The origin of these tumour cells may correspond to a mesenchymal pluripotent cell, which could explain the development thereof in almost any anatomical location. A 44-year-old male, current smoker, with a previous diagnosis of ulcerative colitis, received discontinuous treatment with steroid drugs for 5 years. Symptoms initiated 5 months before admission, characterised by abdominal discomfort which exacerbated with prolonged fasting and post-prandial fullness, dizziness and weight loss of 2 kg in a month. A gastrosendoscopic examination was performed, where an ulcerated polypoid lesion was seen, extending from the subcardial region to the lesser curvature. Serological tumour markers were negative. The patient underwent a total gastrectomy. A polylobulated and solid mass, 15 10 9 cm, was found at the lesser curvature with a cut surface suggestive of fibrous tissue (Fig. 1A,B). Microscopic examination with
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Pathology (2014), 46(3), April
10 high power fields (HPFs). The cells were organised in a solid, non-specific pattern and infiltrated the entire gastric wall (Fig. 1C,D). The immunohistochemical study showed widespread vimentin positivity, and focal cytokeratin AE1/ AE3 (AE1/AE3) and epithelial membrane antigen (EMA) positivity (Fig. 2A). CD34, CD117 (Fig. 2B), common muscle actin (CMA), desmin, S100 and Dog-1 staining were negative. The cell proliferation rate estimated with Ki-67 antibody was approximately 5%. Specific molecular analysis for gastrointestinal stromal tumour (GIST; PDGRF and KIT
Fig. 1 Gross and microscopic features of gastrectomy specimen. (A) Polylobulated yellowish mass, emerging from the lesser curvature. (B) Post-fixation cross-section showing the solid-fibre pattern of the neoplasm. Histological features of gastric SS: (C) spindle cell neoplasm, organised in fascicles, (D) with frequent atypical mitotic figures (H&E).
haematoxylin and eosin (H&E) revealed a lesion almost exclusively composed of spindle cells with elongated nuclei and well-defined cytoplasm with a mitotic rate of 11 per
Fig. 2 Immunohistochemistry and FISH. (A) EMA with focal positivity. (B) Negative CD117 in tumour cells. (C) Positive X;18 translocation confirmed by FISH break-apart probe: one separate red and green signal per nucleus indicating the presence of a (X;18) translocation.
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CORRESPONDENCE
genes) was negative. The characteristic X;18 translocation of SS was detected by fluorescence in situ hybridisation (FISH; Fig. 2C). In 2000 Billings et al.5 first described two SS cases of primary gastric origin. Seven years later, Akhunji et al.6 presented a new case, and the following year Makhlouf et al.4 published the largest series, which included 10 patients. The latest published case belongs to Wang et al. (2012).7 The fact that the number of cases is so small poses limitations to any studies being performed (e.g., diagnostic tests, therapeutic targets), therefore the information provided by each new case of gastric SS is relevant to improve the understanding of the disease and its characteristics. A synopsis of the information available on gastric SS clinical-pathological features has been summarised in Table 1. The gastric body and fundus are the most common locations, with two cases (including ours) placed in the lesser curvature. The location and the large size of the tumour may have conditioned the early onset of symptoms (age below the expected average for an SS of the stomach). Three biphasic gastric SS have been reported.4–6 The rest (including ours) belong to the monophasic subclass, which poses a difficult differential diagnosis in this setting.7,8 The immunohistochemical studies of this neoplasm have been varied, although determination of expression of wide spectrum cytokeratin was a constant, obtaining positive results in all the reported cases. EMA was positive in all the cases as well. Additionally, CD117 and CD34 were negative in all the tumours in which they were carried out. This immunohistochemical profile is similar to that expressed in our case. For tumours with mesenchymal characteristics which compromise the stomach wall, some of the early diagnoses
Table 1
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that arise are GIST, leiomyosarcoma and sarcomatoid carcinoma. When the immunohistochemical profile of the tumour under study does not support any of the alternatives mentioned above, it is necessary to broaden the diagnostic approach to entities that were initially ruled out because of the location of the tumour. SS has a characteristic immunohistochemical profile, which includes AE1/AE3, CK7 and EMA positivity, as well as CD117, CD34, desmin and S100 protein negativity. One of the most distinctive features of the GIST is its positivity for CD117, although in a small, non-negligible percentage of cases (5%) this positivity is absent. It is precisely in those cases that difficulties in differential diagnosis may arise, especially when the histological pattern and the other stains are not conclusive. Our patient’s tumour was negative for CD117, CD34, Dog-1 and muscle markers, therefore the diagnosis of GIST was highly unlikely. Additional data, such as the absence of mutations in KIT and PDGFR genes, also didn’t support the diagnosis of GIST. Cytokeratin and EMA positivity suggested a monophasic SS. In 12 of the 14 cases reported in scientific journals, the X;18 (SYT-SSX, p11.2-q11.2) translocation was studied, with a positive result in all of them. In our case this translocation was observed as well. The diagnostic performance of this test for SS shows a sensitivity and specificity higher than 95%.8 The implementation of this test, either by polymerase chain reaction (PCR) or FISH techniques, to suspected SS tumours of unusual location is mandatory to establish the diagnosis with certainty. It is known that fusion of SYT and SSX genes results in a chimaeric protein that is linked to the origin and pathophysiology of this entity, since these genes are co-regulators of cellular differentiation processes. The most important variants of the SSX gene involved in synovial sarcomas are 1 and 2.
Clinicopathological features of 14 gastric synovial sarcomas
Source Billings et al. 20005
Akhunji et al. 20076 Makhlouf et al. 20084
Wang et al. 20127 Current case
Case
Age
Sex
Tumour size (cm)
Gastric location
Subtype
Mitosis
Treatment
Metastasis
Follow-up (months)
1
47
M
5.2
Gastro-oesophageal junction Distal stomach
Biphasic
110 HPF
Partial gastrectomy
No evidence
ADF 21 months
2
55
F
16
Monophasic
9–50 10 HPF
Liver
Died 6 months after surgery
11.5
Posterior gastric wall
Biphasic
>10 HPF
Mesenteric
F
0.8
Body antrum junction
Monophasic
No data available
Hemigastrectomy/ retrocolic Billroth II Tumour resection/ chemotherapy Partial gastrectomy
3
42
M
No evidence
Died 24 months after diagnosis ADF 12 months
4
67
5
49
M
2
Body
Monophasic
Omentum
Died 29 months
6 7 8
68 29 54
F M F
2 2.8 3
Monophasic Monophasic Monophasic
No evidence No evidence No evidence
ADF 22 months ADF 224 months Follow-up case
9 10
58 37
F F
3 4
Body Body Antrum, gastroduodenal junction Lesser curvature/body Fundus
Segmental/wedge resection Wedge resection Partial gastrectomy Antrum, gastroduodenal resection Wedge resection Partial gastrectomy
No evidence No evidence
11
50
M
6
Distal fundus
Monophasic
No evidence
12
66
F
15
Fundus
Monophasic
No evidence
13
42
M
8
Great curvature/body
Biphasic
No evidence
Died 25 months
14
38
F
7.5
Body (middle portion)
Monophasic
44
M
15
Lesser curvature
Monophasic
Omentum/ Liver No evidence
Follow-up case
15
Tumour resection, chemotherapy Gastrectomy/partial oesophagectomy Partial gastrectomy, chemotherapy Tumour resection/ chemotherapy Gastrectomy total
ADF 21 months Local recurrence / DOD 48 months Recurrence 6 months Monitoring loss
Monophasic Monophasic
>20 10 HPF 11/10 HPF
Follow-up case ADF
ADF, alive disease-free; DOD, died of other disease.
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Each of them seems to correspond to a histological subtype and a specific biological behaviour. Therefore, SYT/SSX1 rearrangement is more common in the biphasic subtype and entails a higher risk of distant metastases. The specific SYT/SSX2 translocation is related to the monophasic subtype, with a more indolent or benign clinical course.9,10 The treatment offered to patients with gastric SS was surgical. Four of them received post-operative chemotherapy (after showing local recurrence and/or metastases). The reviewed publications document four deaths directly related to this disease, three of which were monophasic cases with metastases and one case belonged to the biphasic subtype. The deaths occurred between 24 and 29 months following diagnosis.4–7 Our patient underwent total gastrectomy without further evidence of residual disease and therefore no additional treatment was introduced, apart from a strict follow-up (18 months disease free). In summary, primary gastric SS is a rare and underdiagnosed neoplasm. Molecular biology techniques are vital for accurate diagnosis. The prognostic factors and the treatment of this tumour are similar to those observed and offered to patients with a usual SS location, although an increase in the number of cases reported will determine whether there are variations of interest in the pathobiological behaviour. This is a unique case, and the number of gastric SS remains small. Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. He´ctor E. Torres Rivas Soledad Ferna´ndez Manuel F. Fresno Department of Pathology, Central University Hospital of Asturias, Oviedo, Spain Contact Dr H. E. Torres Rivas. E-mail: [email protected] 1. Spillane AJ, A’Hern R, Judson IR, et al. Synovial sarcoma: a clinicopathologic, staging, and prognostic assessment. J Clin Oncol 2000; 18: 3794– 803. 2. Siegel HJ, Sessions W, Casillas MA Jr, et al. Synovial sarcoma: clinicopathologic features, treatment, and prognosis. Orthopedics 2007; 30: 1020–5. 3. Alsharief AN, Fageeh M, Alabdulkarim Y. Monophasic synovial sarcoma presenting as a primary ileal mass: a case report and review of the literature. J Med Case Rep 2012; 6: 83. 4. Makhlouf HR, Ahrens W, Agarwal B, et al. Synovial sarcoma of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 10 cases. Am J Surg Pathol 2008; 32: 275–81. 5. Billings SD, Meisner LF, Cummings OW, et al. Synovial sarcoma of the upper digestive tract: a report of two cases with demonstration of the X;18 translocation by fluorescence in situ hybridization. Mod Pathol 2000; 13: 68–76. 6. Akhunji S, Musil I, Baisre de Leon A, et al. Synovial sarcoma arising in the gastric wall: case report and literature review. Case Report. Cancer Ther 2007; 5: 457–62. 7. Wang CC, Wu MC, Lin MT, et al. Primary gastric synovial sarcoma. J Formosan Med Assoc 2012; 111: 516–20. 8. Coindre JM, Pelmus M, Hostein I, et al. Should molecular testing be required for diagnosing synovial sarcoma? A prospective study of 204 cases. Cancer 2003; 98: 2700–7. 9. Ladanyi M, Antonescu CR, Leung DH, et al. Impact of SYT-SSX fusion type on the clinical behavior of synovial sarcoma: a multiinstitutional retrospective study of 243 patients. Cancer Res 2002; 62: 135–40.
10. Inagaki H, Nagasaka T, Otsuka T, et al. Association of SYT-SSX fusion types with proliferative activity and prognosis in synovial sarcoma. Mod Pathol 2000; 13: 482–8.
DOI: 10.1097/PAT.0000000000000078
Urothelial bladder carcinoma metastasising to the scrotum mimicking primary extramammary Paget’s disease Sir, Invasive urothelial carcinoma is an aggressive disease that preferentially metastasises to the pelvic lymph nodes, bones, liver and lung.1 Metastasis to the scrotum or vulva is rare.2 Primary extramammary Paget’s disease of the scrotum is a rare entity of adenocarcinoma originating from malignant transformation of pluripotent intraepidermal cells as they differentiate into apocrine glands3 and dermal invasion and is rare.4 Secondary extrammary Paget’s disease of the scrotum from the bladder has not been recorded. Here, we report a case of metastatic urothelial bladder carcinoma to the scrotum masquerading as primary extramammary Paget’s disease. A 71-year-old male was diagnosed with high grade papillary urothelial carcinoma of the bladder invading the lamina propria (Fig. 1A) on transurethral bladder tumour resection. Clinical and cystoscopic follow-up were unremarkable 4 years later when a 2 cm ulcerated lesion with underlying firmness was noted on the lateral aspect of the right hemiscrotum. A biopsy was performed and was diagnosed as extramammary Paget’s disease (Fig. 1B). A right hemiscrotectomy was subsequently carried out. Pathological analysis revealed a poorly differentiated large cell carcinoma with focal glandular differentiation and inguinal lymph node metastasis. In the overlying epidermis, there were extensive changes mimicking primary extrammary Paget’s disease (Fig. 2A,B). Immunohistochemical staining showed positivity for GCDFP-15, CK7 (Fig. 2C) and CEA-monoclonal (Fig. 2D). Immunohistochemistry for CDX2, CK20, and S100 was negative. Special stain for Alcian Blue 2.5 showed the presence of mucin in the neoplastic cells (Fig. 2E). In view of the clinincal history of urothelial carcinoma, further immunohistochemical testing showed positive immunoreactivity for GATA 3 (Fig. 2F). Lymphovascular invasion was identified and surgical resection margins were free of malignancy. Follow-up CT scan confirmed periaortic adenopathy as well as a small lytic lesion in the right side of T11. The patient was started on palliative chemotherapy and died 6 months later. It is felt that the metastatic urothelial carcinoma was masquerading as primary extramammary Paget’s disease of the scrotum. The mechanism of spread was likely direct spread from inguinal lymph nodes after intralymphatic spread from the primary bladder lesion, and not direct spread of tumour cells to the scrotum from the primary lesion. This case demonstrates the fact that metastatic urothelial carcinoma to the scrotum can mimic primary extramammary Paget’s disease, and therefore must be excluded during pathological analysis.
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CORRESPONDENCE
A
257
B
Fig. 1 (A) Transurethral resection of bladder tumour showing invasive urothelial carcinoma into the lamina propria (H&E). (B) Biopsy from scrotal resection (H&E).
Fig. 2 Lesion from scrotal resection (A,B, H&E; C, CK7; D, CEA-monoclonal; E, Alcian blue 2.5; F, GATA 3).
Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. Previn Gulavita Kien T. Mai The Ottawa Hospital and University of Ottawa, Pathology and Laboratory Medicine, Ottawa, ON, Canada Contact Dr P. Gulavita. E-mail: [email protected]
1. Jemal A, Siegel R, Ward E, et al. Cancer statistics. CA Cancer J Clin 2009; 59: 225–49. 2. Hoyt BS, Cohen PR. Cutaneous scrotal metastasis: origins and clinical characteristics of visceral malignancies that metastasize to the scrotum. Int J Dermatol 2013; 52: 398–405. 3. Minsky B, Hoffman J, Kelsen D. Cancer of the Anal Region. In: DeVita Jr V, Hellman S, Rosenberg SA, editors. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia: JB Lippincott Co, 2001;1319–42. 4. Lai YL, Yang WG, Tsay PK, et al. Penoscrotal extramammary Paget’s disease: a review of 33 cases in a 20-year experience. Plast Reconstr Surg 2003; 112: 1017–23.
DOI: 10.1097/PAT.0000000000000084
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Multifocal, co-located angiokeratomas and syringomas of the vulva Sir, Syringoma and angiokeratoma are common benign lesions on the vulva.1 Therefore, it would not be surprising to occasionally find them co-located by co-incidence. However, we have recently observed a woman with three co-located vulval lesions. Two showed syringomas and angiokeratomas and the third showed a dilated, budding eccrine gland and an angiokeratoma. Our case is evidence of a relationship between these two benign lesions. The patient was a 66-year-old female (P1, G1) with no relevant medical or surgical history. She presented for investigation of the three palpable lesions, which were otherwise asymptomatic. On examination, the lesions were 1–2 mm in diameter, round, red/ blue, firm, and very well demarcated on the outer right upper and lower and left upper surfaces of the labia majora. No extra-genital lesions were identified. Excisional punch biopsy was performed on all lesions. The right upper and right lower lesions had similar pathological features. Hair bearing skin showed vascular lesions immediately beneath the epidermis and composed of large ectatic capillaries (Fig. 1A). Beneath the vascular lesions, but separated by some normal dermis, were haphazard proliferations of dilated
and small eccrine ducts associated with dense fibrous stroma. No atypia or mitoses were seen. The left upper lesion showed a similar vascular abnormality, but did not contain a proliferation of eccrine ducts. Rather, there was a single dilated eccrine duct with early budding (Fig. 1B). The pathological diagnoses were angiokeratomas associated with syringomas in the first two lesions and angiokeratoma associated with abnormal eccrine duct in the third. Syringomas and angiokeratomas are common benign vulval lesions.1 Syringomas are small benign adnexal neoplasms composed of sweat gland epithelium within densely sclerotic stroma.2 They may be associated with lichen simplex chronicus, in which case they are multiple.1 It is not known whether the syringomas precede or cause the lichen simplex chronicus.1 Angiokeratomas are constellations of superficial ectatic cutaneous blood vessels.3 They are usually asymptomatic and when occurring on the vulva tend to be red/blue in colour. Vulval angiokeratomas may be idiopathic, but are often associated with factors causing venous congestion, particularly previous pelvic surgery.4 We considered a differential diagnosis of multiple eccrine angiomatous hamartomas (EAH) as this rare lesion involves a proliferation of eccrine ducts and blood vessels. EAH is a circumscribed, mid to deep dermal proliferation of mature appearing eccrine ducts intimately associated with a benign vascular proliferation of dilated small capillaries.5 Our case is not EAH because our lesions were close, but entirely separated angiokeratomas and syringomas (or, in the third lesion, an abnormal eccrine gland), with the vascular proliferation superficial in the dermis. Furthermore, the late onset of 66 years, absence of pain and hyperhidrosis and the unusual site were not typical of EAH, which usually presents in childhood, is painful and/or causes hyperhidrosis, and typically occurs on acral areas or, less commonly, the face, neck and trunk.2 We note, however, that one vulval case of EAH has been reported.6 We do not know the mechanism of association of the two types of lesion, but the pathology in our third lesion of an established angiokeratoma and eccrine duct dilatation and budding (but not syringoma) provides a clue to the possible mechanism for these curious tumours, in that the vascular lesions may precede the syringoma. Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. Christina Botfield1 Reidar Agdestein1 Brett Locker2 James Scurry3 1
Faculty of Health Sciences, University of Newcastle, Department of Obstetrics and Gynaecology, John Hunter Hospital, and 3Anatomical Pathology, HAPS, Newcastle, NSW, Australia 2
Contact Associate Professor J. Scurry. E-mail: [email protected]
Fig. 1 (A) Right upper labium majus lesion: angiokeratoma (black arrow) and syringoma (white arrow) (H&E). (B) Left upper labium majus lesion: angiokeratoma comprising superificial and mid-dermal ectatic blood vessels (black arrows) and dilated eccrine duct with early budding (white arrow) (H&E).
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CORRESPONDENCE
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DOI: 10.1097/PAT.0000000000000081
Confirmation of tertiary Treponema pallidum infection by polA polymerase chain reaction (PCR) Sir, We report a novel case of tertiary cardiovascular syphilis presenting with aortic regurgitation and low grade fever, diagnosed using different methods including serology and a Treponema pallidum specific polA polymerase chain reaction (PCR). A male patient in his mid-30s was transferred to our institution, Royal Melbourne Hospital (RMH), from another local metropolitan hospital (institution A), with a provisional diagnosis of aortic valve endocarditis. He presented initially to institution A with a 2 day history of fever, left upper quadrant abdominal and lower thoracic back pain. He was previously fit and well, and had no history of rheumatic fever or valvular heart disease. He denied illicit drug use, or symptoms of sexually transmitted infections. He had migrated from South Asia 6 years previously, was married with two young children, and claimed marital monogamy. Clinical examination revealed occasional low grade temperatures and severe aortic regurgitation without signs of heart failure. Investigations revealed a raised C-reactive protein (CRP) of 225 mg/L (normal range
