Professional Documents
Culture Documents
8099
CORRESPONDENCE
Obtaining expert opinions in diagnostically
difficult cases
Sir,
Klebe et al.1 describe their experience with expert review of
difficult mesothelial proliferations. They found only 57%
complete concordance between the expert and referring pathologists diagnosis, with some 9.5% of cases having significant disagreement (benign versus malignant, or mesothelioma
versus another tumour type). Whilst disturbing, this will come
as no surprise to those of us with subspecialty interests in other
rare tumour types such as sarcoma or GIST, and no doubt in
other organ systems as well.
These figures are in line with similar studies performed
overseas; for example, in their review of 349 soft tissue specimens, Thway and Fisher2 reported minor diagnostic discrepancy in 15.7% and major discrepancy in 10.9%, including a
difference of benign versus malignant in 5%. Similarly, in a
review of 266 referred soft tissue lesions for which a primary
diagnosis had been offered by the referring pathologist, there
were major discrepancies (e.g., benign versus malignant, nonmesenchymal tumour) in 25% of cases, and minor discrepancies in 7%.3 Numerous other such studies from a variety of
countries support the value of timely expert review of rare and
difficult cancers,47 with diagnostic discrepancies reportedly as
high as 45% or more in some series.6,7
This is more than simply an intellectual exercise: delayed or
incorrect diagnosis can lead to profound impacts on the patient
who undergoes inappropriate or unnecessary surgery, chemoor radiotherapy, or who is denied potentially life-saving
therapy. A review of 1996 musculoskeletal tumours in one
specialist unit8 found a diagnostic error in 87 cases, 54 of
which (2.7%) resulted in a significant change to the patients
management. In the case of aggressive cancers, even relatively
short delays in accurate diagnosis can impact on patient survival.9 Even if the correct diagnosis is reached, errors in grading
or risk stratification can also impact on clinical decision-making, e.g., neoadjuvant radiotherapy versus up-front surgery in
various types of soft tissue sarcoma; adjuvant imatinib versus
observation in GIST; wait and see versus treatment, or choice
of treatment modality, in gastroenteropancreatic neuroendocrine tumour (GEP-NET).
It is clear, therefore, that timely expert review of difficult and
rare entities is in the best interests of the patient; however, for
many pathologists working in non-specialist centres, there are
difficulties in obtaining such review. Not only does the referring laboratory incur a cost in terms of packaging and sending
the slides (and hopefully a paraffin block or two!) to the
expert, but the receiving laboratory incurs a significant cost
in terms of handling the incoming material, making the diagnosis and issuing an opinion (which is often complex). This
brings its own rewards in that the cases are often interesting,
and expertise is only accrued through exposure to difficult and
unusual cases, but the cost must be borne somewhere. Many of
us choose not to charge a fee for this work, but this is only
sustainable if the number of referrals is relatively small (and
with the indulgence of our heads of department), and some
institutions insist on a fee of perhaps several hundred dollars
a cost which most referring laboratories cannot meet. This
Print ISSN 0031-3025/Online ISSN 1465-3931
DOI: 10.1097/PAT.0b013e32835baec7
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
CORRESPONDENCE
81
hydrocortisone and 40 mg oral prednisone. A rising cytomegalovirus polymerase chain reaction (PCR) titre on day 35
was effectively treated with oral valganciclovir.
The patient was readmitted on day 71 with a 1 week history
of progressive nausea, vomiting and diarrhoea with associated
fever with rigors. Multiple blood cultures were negative
although stool Clostridium difficile toxin PCR and norovirus
enzyme immunoassay were both positive. His IgG level was
low at 3.32 g/L and treatment with metronidazole and intravenous immunoglobulin was commenced. His clinical condition
deteriorated with the development of abdominal pain, oliguria
and severe lactic acidosis with a lactate of 7.7 mmol/L. A
computed tomography (CT) scan showed wall thickening of
the descending colon along with intra-abdominal lymph nodes
measuring up to 3 cm. An exploratory laparotomy and colonoscopy, performed due to concern of possible ischaemic bowel,
showed only mild inflammation of the colon. Cytological
analysis of peritoneal fluid demonstrated a small number of
atypical cells. On day 76 a skin rash developed and was
biopsied. Simultaneously the patient developed pancytopenia
with Hb 103 g/L, WCC 2.7 109/L and platelets 22 109/L
and a bone marrow biopsy was performed. The patient died
from progressive multiorgan failure on day 78 before the
results of these investigations were available.
The skin biopsy demonstrated an abnormal perivascular
infiltrate of large, morphologically abnormal lymphoid cells
with polymorphic nuclei and prominent nucleoli (Fig. 1A). The
abnormal cells were positive for CD20/CD79a/EBER/MUM-1/
PAX-5 and Bcl-2 but negative for CD10/CD30/CD138 and
Bcl-6 (Fig. 1B). Occasional plasmacytoid lymphoma cells were
noted in the peripheral blood. The bone marrow biopsy was
hypocellular with an abnormal infiltrate of similar lymphoid
cells (Fig. 2A). Flow cytometry of the bone marrow showed an
abnormal population of large CD19 and lambda positive cells.
Immunohistochemistry of the trephine showed small clusters of
large cells with strong immunoreactivity for EBER (Fig. 2B)
and relative lambda light chain restriction. Cytogenetic analysis
was normal. Whilst the lymphoma cells showed significant
pleomorphism, the clinical picture and immunostains were
consistent with monomorphic PTLD, most likely a non-germinal centre diffuse large B-cell lymphoma.
Only one previous case has been reported of simultaneous
multifocal skin and bone marrow involvement in a patient with
PTLD. This developed in a 14-month-old EBV seronegative
recipient of a combined small bowel and liver transplant from
an EBV seropositive donor.4 The patient presented with
cutaneous PTLD associated with circulating lymphoma cells
5 months post-transplant and died rapidly from multiorgan
failure.
Two other cases of similarly fulminant PTLD have been
reported. The first occurred in an EBV seronegative recipient of
a renal transplant from an EBV seropositive donor.5 The second
developed in an EBV seropositive recipient of a non-myeloblative allogeneic BMT for relapsed anaplastic large cell
lymphoma.6 The donor had a positive IgM titre for EBV viral
capsid antigen (VCA) in the pre-transplant specimen, consistent with recent infection. ln each of these previous cases the
aggressive presentation of the disease was attributed either to
the recipient being EBV seronegative or to recent EBV infection in the donor. In our case the recipient was EBV seropositive and we presume the development of PTLD was instead
related to the intensive immunosuppression as a result of his
previous treatments. Although only a relatively low dose of
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
82
CORRESPONDENCE
A
A
B
B
Fig. 1 Skin biopsy. (A) Medium power view showing dermal perivascular
infiltrate of lymphoma cells (H&E). (B) EBER staining is strongly positive.
Fig. 2 (A) High power view of two lymphoma cells seen in the bone marrow
aspirate with deep blue markedly vacuolated cytoplasm (MGG). (B) Immunohistochemistry of the bone marrow trephine shows a hypocellular marrow with
an abnormal infiltrate of strongly EBER positive lymphoma cells.
may allow improved risk stratification and hence individualisation of patient immunosuppressive regimens.
thymoglobulin was used in his conditioning regimen, the
T-cell depletion associated with this therapy is a known risk
factor for the development of PTLD.3 It is also possible that the
history of Crohns disease is relevant, although his inflammatory bowel disease had been inactive with no specific therapy
since his initial diagnosis of AML. Patients with inflammatory
bowel disease who are treated with thiopurines are known to
have an increased risk of lymphoma which is often EBV
positive.7
PTLD is a rare complication of allogeneic stem cell transplant.1 The disease is often extranodal at presentation which
may result in a delay in diagnosis.8 Historically the prognosis
for patients with PTLD has been poor with survival rates of
around 30%.9 The cornerstone of treatment for PTLD postsolid organ transplant is withdrawal of immunosuppressive
therapy. However, this is rarely useful post-BMT because
the defect is delayed EBV-memory cytotoxic T cell recovery,
not suppression of their function.10 Treatment with monoclonal
antibodies such as rituximab, chemotherapy or ex vivo generated EBV cytotoxic T cells are resulting in improved outcomes.11 Some groups have advocated serial monitoring of
EBV viral load in high risk patients to aid early detection and
treatment.12 This case demonstrates the unique clinical and
pathological features of an early onset highly aggressive disseminated variant of PTLD post-BMT, highlighting the need
for early and ongoing vigilance in high risk patients. Further
research into the pathogenesis of this devastating complication
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
CORRESPONDENCE
DOI: 10.1097/PAT.0b013e32835b5de4
Familial haemophagocytic
lymphohistiocytosis in twin infants
Sir,
Haemophagocytic lymphohistiocytosis (HLH) is an uncommon
entity comprising a constellation of symptoms and laboratory
findings that together form the clinical inflammatory syndrome. HLH encompasses two separate conditions: a primary
hereditary form (familial haemophagocytic lymphohistiocytosis, FHL) and a secondary/acquired form (secondary HLH,
sHLH).1 sHLH may follow a variety of stimuli including viral,
bacterial, and fungal infections, as well as a number of malignant diseases, notably T-cell lymphomas. FHL is generally
inherited in an autosomal recessive or x-linked manner, presents during infancy or early childhood, and is uniformly fatal if
left untreated. Here we present an interesting case of FHL
presenting in a pair of identical twins in the immediate postnatal period.
The patients were diamnionic-dichorionic identical twins
born at 35 weeks gestation. Twin 1 was born via normal
spontaneous vaginal delivery, while twin 2 was born via
emergent caesarean section due to placental abruption. The
initial post-natal clinical course was uncomplicated, and the
patients were discharged home without complication. At
2 months of age both twins were hospitalised for fever with
neutropenia, and severe thrombocytopenia. Liver ultrasound
showed hepatomegaly. Laboratory studies (Table 1) showed
many abnormalities, including low fibrinogen, elevated
D-dimers, and prolonged coagulation times, indicating likely
disseminated intravascular coagulation. Blood cultures at this
time were negative in both twins. Simultaneous bone marrow
aspirates were obtained on both twins. While the bone marrow
aspirate from twin 2 showed non-specific findings due to
markedly haemodilute aspirate smears (i.e., predominantly
mature lymphocytes similar to peripheral blood), the bone
marrow aspirate from twin 1 showed significantly increased
haemophagocytic histiocytes on the smear (Fig. 1) in addition
to erythroid hyperplasia and relative decrease in myeloid cells.
83
Twin 1
Twin 2
9.2
5.2
1.2
100
3660.00
<50
140
8.9
4.2
1.1
34
3780.00
<50
30.5
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
84
CORRESPONDENCE
Table 2
Twin 1
Twin 2
125
11460
437
384
>6500
Non-contributory
Homozygous for 50 del T(L17fsX50) mutation
140
11057
435
1704
>6500
15
Homozygous for 50 del T(L17fsX50) mutation
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
CORRESPONDENCE
85
1. Henter JI, Samuelsson-Horne AC, Arico M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunotherapy and bone marrow transplantation. Blood 2002; 100: 236773.
2. Henter J, Horne A, Arico M, et al. HLH-2004: Diagnostic and therapeutic
guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer
2007; 48: 12431.
3. Henter J, Elinder G, Soder O, Ost A. Incidence in Sweden and clinical
features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr
Scand 1991; 80: 42835.
4. Gurgey A, Gogus S, Ozyurek E, Aslan E, et al. Primary hemophagocytic
lymphohistiocytosis in Turkish children. Pediatr Hematol Oncol 2003; 20:
36771.
5. de Kerguenec C, Hillaire S, Molinie V, Gardin C, et al. Hepatic manifestations of hemophagocytic syndrome: a study of 30 cases. Am J Gastroenterol
2001; 96: 8527.
6. Herlin T, Pallesen G, Kristensen T, Clausen N. Unusual immunophenotype
displayed by histiocytes in haemophagocytic lymphohistiocytosis. J Clin
Pathol 1987; 40: 14137.
7. Ohadi M, Lalloz M, Sham P, et al. Localization of a gene for familial
hemophagocytic lymphohistiocytosis at chromosome 9p21.322 by homozygosity mapping. Am J Hum Genet 1999; 64: 16571.
8. Stepp S, Dufourcq-Lagelouse R, Le Deist F, et al. Perforin gene defects in
familial hemophagocytic lymphohistiocytosis. Science 1999; 286: 19579.
9. Risma KA, Frayer RW, Filipovich AH, Sumegi J. Aberrant maturation of
mutant perforin underlies the clinical diversity of hemophagocytic lymphohistiocytosis. J Clin Invest 2006; 116: 18292.
10. Molleran S, Villanueva J, Sumegi J, et al. Characterization of diverse
PRF1 mutations leading to decreased natural killer cell activity in
North American Families with hemophagocytic lymphohistiocytosis.
J Med Genet 2004; 41: 13744.
11. Trizzino A, Stadt U, Ueda I, Risma K, et al. Genotype-phenotype study of
familial hemophagocytic lymphohistiocytosis due to perforin mutations.
J Med Genet 2008; 45: 1521.
12. Feldmann J, Callebaut I, Raposo G, et al. Munc13-4 is essential for
cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 2003; 115: 46173.
13. Glolam C, Grigoriadou S, Gilmour KC, Gaspar HB. Familial hemophagocyt5ic lymphohistiocytosis: advances in the genetic basis, diagnosis and
management. Clin Exp Immunol 2011; 163: 27183.
14. Cote M, Menager MM, Burgess A, et al. Munc18-2 deficiency causes
familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic
granule exocytosis in patient NK cells. J Clin Invest 2009; 119: 376573.
DOI: 10.1097/PAT.0b013e32835b5db2
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
86
CORRESPONDENCE
Sir,
Renal cell carcinoma is classified by the World Health Organization (2004)1 on the basis of histological patterns correlated
with cytogenetic, genetic and both familial and sporadic cases.
Papillary renal cell carcinoma (PRCC) is usually multifocal,
comprises 1015% of renal cell carcinomas, and is postulated
to arise from the intercalated cells of the distal tubule.14
Benign oncocytoma accounts for 515% of surgically resected
renal tumours and is believed to arise from the intercalated cells
of collecting ducts. There are case reports of hybrid tumours
oncocytoma/chromophobe RCC,2,4,5 but only four cases of
combination or hybrid tumour oncocytoma/PRCC have been
reported,2,46 of which three cases are <5 mm and would
qualify as adenomas. The present case is the second case to
qualify as a hybrid tumour oncocytoma/PRCC.
A 64-year-old man, with a known medical history of autoimmune haemolytic anaemia, hypertension and hepatitis B,
presented with an incidental finding of a right lower pole renal
mass during an ultrasound scan performed for his hepatitis. A
subsequent computed tomography (CT) scan demonstrated a
66 63 47 mm complex renal mass and multiple small cysts
scattered in both kidneys. There was no evidence of hydronephrosis or hydroureter. There was no extension of tumour into
veins and no lymphadenopathy was seen.
The patient had no history of hereditary polycystic kidney
disease. A core biopsy of the renal mass showed a PRCC. Due
to other medical conditions, a partial nephrectomy was not
performed until a year later, and the partial nephrectomy
measured 72 50 47 mm and a separate piece of perinephric
fat 65 50 45 mm. Part of two simple cysts were seen at the
resection margin, and measured 30 23 mm and 32 25 mm
each. On sectioning, there was a circumscribed tumour measuring 72 50 46 mm. The tumour was protuberant and had two
distinct areas: one area had a tan/fleshy appearance and was
multicystic at one edge, and the other area was haemorrhagic
and with a red-brown colour and areas of golden-yellow. The
tumour was situated 1 mm from the closest resection margin,
and showed attenuation, but no invasion through the renal
capsule.
Microscopically, the tumour showed two distinct morphological features corresponding to the macroscopic appearance.
The darker brown/haemorrhagic areas showed papillary tubulopapillary and cystic growth pattern with fibrovascular stalks
Fig. 1 (A) The heterogeneous part of the renal tumour shows features of a PRCC with well-formed papillae, interstitial foam cells and plentiful calcified psammoma
bodies (H&E). (B) The fleshy tumour area shows the typical features of oncocytoma with rounded nuclei and plentiful eosinophilic cytoplasm. There are also myxoid
areas (H&E). (C) The renal tumour shows a well demarcated zone between the PRCC (left) and the oncocytoma (right) (H&E).
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
CORRESPONDENCE
CD10
Vimentin
87
C-kit
Fig. 2 Immunohistochemistry. The PRCC (left) shows positive staining for (A) vimentin and (B) CD10. The oncocytoma (right) is negative for these markers.
(C) CD117 stain is positive for the oncocytoma and negative for the PRCC.
negative for CD117. The electron microscopy showed mitochondria admixed with other cell organelles and microvesicles.
The one component of the renal tumour showed all the immunohistological features of a PRCC, type 2.
Oncocytomas are benign well-circumscribed neoplasms
which may have a central, stellate scar of hyalinised connective
tissue and are mahogany brown. Haemorrhage and cystic
degeneration may be present, but tumour necrosis is not a
feature. They are arranged in nests, tubules, cords or microcysts
and the tumour cells have dense eosinophilic cytoplasm, round
nuclei and small nucleolus. Onocytomas are positive for
CD117, variable positivity for CD10, and are negative for
CK7 and vimentin. Electron microscopy showed a mitochondria rich cytoplasm and scanty other organelles. The second
component of the renal tumour in our case supported the
features of an oncocytoma.
A
10 m
B
10 m
Fig. 3 Electron microscopy. (A) The fleshy area of the tumour shows the
features of oncocytoma: a tubular structure with plentiful mitochondria and a
well formed basal lamina (6000). (B) The PRCC shows cells with variably
sized luminal microvilli resting on a basal lamina. The cytoplasm contains
variable numbers of mitochondria and other cell organelles (6000).
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
88
CORRESPONDENCE
DOI: 10.1097/PAT.0b013e32835b682e
B
Fig. 1 Choroid plexus papilloma in a mature cystic teratoma. (A) Low power
view of a circumscribed papillary lesion with delicate, well formed fibrovascular
stalks projecting into a cystic space. (B) A high power view shows the
fibrovascular stalks are lined by non-ciliated columnar cells that show nuclear
crowding and stratification.
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
CORRESPONDENCE
89
DOI: 10.1097/PAT.0b013e32835b6855
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
90
CORRESPONDENCE
Fig. 1 Papillary carcinoma of the thyroid, tall-cell variant, metastatic to the kidney (H&E). (A) Neoplastic papillae are characterised by a central fibrovascular stalk of
loose connective tissue and thin-walled vessels, and (B) in some cases show abundant acellular hyaline material. The papillae are lined by cells that often show abundant
eosinophylic cytoplasm and are at least twice as tall as large. The nuclei (A, C, D) sometimes conform the elongated cells in which they are contained, and show the
characteristic abnormalities of papillary thyroid carcinoma: optical clearing (arrows), indentations, folds and grooves (arrowhead).
Papillae showed a central fibrovascular stalk lined by neoplastic epithelium. The better developed papillae were long with a
complex arborising pattern. Some were straight and slender,
arranged in a parallel, regimented fashion; others were short
and stubby. The papillary stalk was mainly composed by loose
connective tissue and variously sized thin-walled vessels; in
some cases, it was swollen by oedematous fluid or occupied by
an abundant acellular hyaline material. Occasionally, it was
infiltrated by lymphocytes or clusters of foamy or haemosiderin-laden macrophages. The neoplastic cells lining the papillae often showed tall cell features; they were at least twice as
long (tall) as wide, with large eosinophilic cytoplasm and round
to slightly oval nuclei. Nuclear contour appeared smooth on
superficial examination, although closer inspection revealed
subtle irregularities in the form of indentations, folds, and
grooves. Another peculiar feature of neoplastic nuclei was the
empty appearance of the nucleoplasm, which seemed almost
totally devoid of chromatin strands. These nuclei were similar to
the ones previously described as pale, optically clear, watery,
empty, ground glass, or Orphan Annies eyes. No psammoma
bodies or other concretions were noted. Immunohistochemically,
neoplastic epithelial cells showed positive staining for cytokeratin (CK)19, CK7, CD57, thyroglobulin, and thyroid transcription factor-1 (TTF-1) (Fig. 2AD). Cells did not react with
CK20, racemase, HMWCK, p63, CD10, and RCC marker.
The histological and immunohistochemical findings supported the diagnosis of metastatic papillary thyroid carcinoma,
tall-cell variant. The patient was lost to follow-up.
Case 2 was a 56-year-old woman who presented in December 2008 with haematuria and left flank pain due to an enlarging
left lower pole renal mass. Her past medical history included
metastatic papillary carcinoma of the thyroid, follicular variant
to the brain (resected), thyroidectomy, resection of liver
metastasis, and metastatic disease to the left arm treated
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
CORRESPONDENCE
CK7
Thyroglobulin
CD57
TTF-1
91
Fig. 2 Papillary carcinoma of the thyroid metastatic to the kidney (immunohistochemistry). Tumour cells show strong positivity for (A) CK7, (B) CD57,
(C) thyroglobulin and (D) TTF-1.
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
92
CORRESPONDENCE
Table 1
Clinical and pathological features of renal metastases from differentiated thyroid carcinoma
Reference
Sex/Age
Tumour type
Presentation
Site
F/44
F/49
F/66
F/
M/53
F/72
F/47
M/75
F/91
M/56
F/65
F/50
F/58
F/53
F/61
M/37
F/58
M/62
F/64
F/78
F/76
F/50
F/25
F/66
F/64
M/50
M/30
M/56
Follicular
Follicular
Follicular
Follicular
Papillary
PTC-FV
Follicular
PTC-FV
Follicular
Papillary
Follicular
PTC-FV
Follicular
PTC-FV
PTC-FV
Papillary
Follicular
Follicular
Follicular
Follicular
Follicular
PTC-FV
PTC-FV
Follicular
Follicular
Papillary
Papillary
Papillary
Abdominal mass
Incidental finding (IVP)
Gross haematuria
Neck nodule
Haematuria
No complaints; liver mass
Haematuria
Gross haematuria
Incidental autopsy finding
Low back pain
Neck and sternal mass
Haematuria and flank pain
Dyspnoea
Back pain
Upper back mass
Incidental finding (US)
Lumbalgia
Left upper abdominal discomfort
Incidental finding (US)
Microscopic haematuria and flank pain
Haematuria and flank pain
Low back pain
Abdominal/flank pain
Scalp mass
Constant increase in serum thyroglobulin levels
Flank pain and haematuria
Low backache radiating to the lower limbs
Post radioiodine-131 treatment scanning
3
18
37
23
7
3
7
No
No
3
No
No
11
No
No
No
5
9
35
10
13
No
No
No
20
No
20
No
Bilateral
Bilateral
Left kidney
Right kidney
Right kidney
Right kidney
Right kidney
Left kidney
Left kidney
Left kidney
Left kidney
Left kidney
Bilateral
Right kidney
Left kidney
Left kidney
Left kidney
Left kidney
Right kidney
Right kidney
Right kidney
Right kidney
Right kidney
Left kidney
Left kidney
Right kidney
Bilateral
Bilateral
M/63
F/56
Papillary
PTC-FV
15
6
previous history*
previous history
previous history
previous history*
previous history
previous history
previous history*
previous history
previous history*
previous history
previous history*
previous history
Right kidney
Left kidney
although typical nuclear changes of papillary thyroid carcinoma are not present. Papillary renal cell carcinomas typically
express CK7, CK8, CK18, CK19, CAM 5.2, RCC marker,
CD10, and racemase (Table 2). Micropapillary urothelial carcinoma of the upper urinary tract is a rare variant of urothelial
carcinoma. There is a male predominance (M:F 3.2:1).
Almost all the reported cases occur in the urinary bladder,
but it may also involve the renal pelvis and the ureter. It consists
of slender, delicate fine papillary and filiform processes, with
central fibrovascular cores. Papillae are lined by high nuclear
grade cells with eosinophilic cytoplasm. Psammoma bodies are
infrequent. Micropapillary carcinomas are immunoreactive for
CK7, EMA, CK20, Leu M1, and CEA.
The main differential diagnosis for the follicular variant of
papillary thyroid carcinoma metastatic to the kidney is a
Table 2 Immunohistochemical comparison between papillary thyroid
carcinoma and papillary renal cell carcinoma
TTF-1
Thyroglobulin
CK17
CD57
Racemase
CD117
RCC marker
CD15
CK7
CK19
EMA
PTC
PRCC
/
/
/
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
CORRESPONDENCE
DOI: 10.1097/PAT.0b013e32835b5dcc
93
motility. Among other actions, SST has revealed an antiproliferative potential, reversing the impact of mitogenic signals
delivered by substances such as epidermal growth factor. The
actions of SST are mediated by membrane-associated receptors
that comprise five distinct subtypes (termed SSTR1 to 5).
Frequently multiple subtypes coexist in the same cell.
After binding their ligand, SSTR-ligand complexes undergo
cellular internalisation with intracytoplasmic and intranuclear
translocation. Reubi et al.1 showed that the degree of internalisation, i.e., the ratio of internalised SSTR2 to membranous
SSTR2, varied greatly from one patient to the other. Although
generally found in endosome-like structures, internalised SSTR2
were also identified to a small extent in lysosomes, as seen in colocalisation experiments. Very recently Waser et al.2 showed that
phosphorylated SSTR2 was present in most gastrointestinal
neuroendocrine tumours from patients treated with octreotide
but that a striking variability existed in the subcellular distribution of phosphorylated receptors among such tumours.
Cloning of the five SSTRs has led to the development of
subtype-selective ligands.3 In the era of personalised medicine
and targeted therapies, SSTR profiling is an important prerequisite for successful in vivo somatostatin receptor targeting
for imaging or therapeutic purposes in an individual patient.
Therefore, localisation and expression of the five SSTRs in a
tumour must be determined to decide whether the patient is
eligible for these applications. Several methods have been used
to determine the expression of SSRTs.
Tissue somatostatin receptors can be measured directly
in vivo by performing a OctreoScan or 68 Ga-DOTATOC
positron emission tomography/computed tomography scan.
Molecular techniques such as in situ hybridisation histochemistry and autoradiography have been used in a limited number
of studies.4 The former basically investigates SSTR mRNA
expression in cryostat sections. The latter also utilises cryostat
sections and is based on radioligands, i.e., 125I-labelled somatostatin ligands, such as octreotide. Previous studies have dealt
with only some of the subtypes, therefore information is
limited. The type of information obtained using these two
techniques is not always comparable to that obtained with
immunohistochemical analysis in formalin fixed, paraffin
embedded (FFPE) tissue, in which the architecture and the
cytology in the background are well preserved. In addition, the
immunohistochemical technique is widely available, and faster,
easier and cheaper to apply than in situ hybridisation histochemistry and autoradiography. It can be used even retrospectively on archival material.
We read with great interest the recent publication by Korner
et al.5 This study was performed on neuroendocrine tumours
from various gastrointestinal and extragastrointestinal sites and
in a small group of non-neuroendocrine tumours. The aim of the
investigation was to correlate FFPE-based immunohistochemistry using the monoclonal anti-somatostatin receptor subtype
2A antibody UMB-1 (Biotrend Chemikalien, Germany; or
Epitomics, USA), with the gold standard in vitro method
quantifying somatostatin receptor levels in tumour tissues.
The results obtained by comparing the UMB-1 immunohistochemistry with tumoural in vitro 125I-[Tyr3]-octreotide binding site levels allowed recommendations for the use of SSTR
immunohistochemistry in daily diagnostics for optimally tailored patient management.
Data on the immunohistochemical patterns of the five SSTRs
in prostate cancer (PCa), its precursor high-grade prostatic
intraepithelial neoplasia (HGPIN) and normal prostatic
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
94
CORRESPONDENCE
Fig. 1 Immunoreactivity for (A) SSTR4 in the luminal and basal cells in normal prostate, (B) SSTR3 in untreated HGPIN, (C) SSTR4 in untreated PCa, (D) SSTR4 in
prostate cancer with neuroendocrine differentiation, (E) SSTR4 in complete androgen ablated prostate cancer, and (F) for SSTR4 in hormone refractory prostate cancer.
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
CORRESPONDENCE
95
15
10
Nep
HGPIN
PCa
5
0
SSTR1
A
%
SSRT2
SSRT3
SSTR4
SSTR5
100
90
80
70
60
50
Membrane
40
Cytoplasm
30
Nucleus
20
10
0
GS 6 PCa
GS 8 PCa
PCa NE
CAA PCa
HR PCa
Fig. 2 (A) Mean percentages of intensely immunostained luminal (secretory) cells in the cytoplasm for the five SSTR subtypes in normal epithelium (Nep), high-grade
prostatic intraepithelial neoplasia (HGPIN) and prostate cancer (PCa) from untreated patients. (B) Mean percentages of immunostained luminal cells for SSTR4 in PCa,
separately for cell membrane, cytoplasm and nucleus from all groups. The mean values of SSTR expression in the cytoplasm, membrane and nuclei of the epithelial cells
of hormone refractory PCa are lower than in the cancer areas of the PCa of the other two groups. The highest values are seen in the cytoplasm, the difference being
significant. (GS 6, Gleason score 336; GS 8, Gleason score 448; NE, NE differentiation; CAA, PCa following complete androgen ablation; HR, hormone
refractory PCa.)
performed with the panel of five polyclonal anti-SSTR antibodies yielded single bands as previously described by Helboe
et al.10
We agree with Korner et al.5 that the type of antibodies can
have an influence on the result to the point that the cytoplasmic
and nuclear localisation, i.e., cellular internalisation, of the
SSTRs can be seen intriguing and controversial. For instance,
the immunohistochemical expression at the cell level of the five
SSTRs in normal and pathological prostate tissue was also
investigated by Dizeyi et al.11 There were differences between
our investigation and that by Dizeyi et al., probably due to the
types of antibodies used (in Dizeyis investigation the antibodies were from a private source and not commercially
available).
In conclusion, our data showed that SSTR profiling in an
individual patient with HGPIN and the multifaceted PCa is
feasible. Even though there is no clinical application for a
somatostatin-based diagnostic test for prostate pathology at
present, as opposed to neuroendocrine tumour, this should
be of relevance to better tailor somatostatin analogue-based
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
96
CORRESPONDENCE
DOI: 10.1097/PAT.0b013e32835bae76
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
CORRESPONDENCE
97
Figure 1 (A) Fine needle aspiration smears showed loosely cohesive aggregates of cytologically bland spindle shaped cells admixed with myxochondroid matrix
(DiffQuik). (B) Swirling pattern within the cellular aggragates (PAP). (C) Intracytoplasmic vacuoles (PAP).
Figure 2 (A) Parotid gland with a well circumscribed nodule measuring pale grey, firm tumour with a gelatinous texture. (B) Well demarcated, but unencapsulated
tumour with entrapped ductal structures at the periphery (H&E). (C) Lymphoid aggregates at the periphery (H&E). Slender spindle shaped cells arranged in a
anastomosing lattice-like pattern amidst myxoid stroma with formation of microcystic and reticular areas (H&E). Spindle shaped cells with cytoplasmic vacuolation
(H&E). Foci of extravasated red overlying cytoplasmic vacuoles reminiscent of intracytoplasmic lumina with red blood cells (H&E).
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
98
CORRESPONDENCE
Figure 3 (A) Diffuse nuclear and cytoplasmic immunoreactivity with S100. (B) Immunoreactivity with GFAP. (C) Electron micrograph showing schwannian features
such as slender, elongated interdigitating cell processes covered by a thin, continuous layer of basement membrane material and scant cytoplasmic organelles.
DOI: 10.1097/PAT.0b013e32835be3ec
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
CORRESPONDENCE
99
Table 1
MelT
Possible ST*
CC
Sir,
The molecular epidemiology of Enterococcus faecium in an
Australian setting has recently been described for the first
time.1 Johnson et al. described the epidemiology of 85 E.
faecium isolates in blood culture over a 12 year period at a
single institution in Victoria, Australia (Austin Health,
Melbourne).1 This comprised 34 vancomycin resistant E.
faecium (VREfm) and 51 vancomycin susceptible E. faecium
(VSEfm) isolates. They defined 17 different sequence types
(STs) amongst 85 E. faecium isolates using multilocus
sequence typing (MLST) and found three dominant STs
(ST17, ST252 and ST203). Amongst the VREfm isolates, all
but one carried the resistance gene, vanB.1 ST17, the putative
founder of clonal complex 17 (CC17), was stable and predominated in VREfm and VSEfm for the first 10 years of the
12 year study period. From 2007 to 2009, a significant increase
in VREfm bacteraemia was identified.1 The predominant ST
was ST203, accounting for 76% and 81.8% of VREfm bacteraemia isolates in 2007 and 2009, respectively. ST203 is a
double-locus variant of ST17 and both STs belong to CC17.
We have investigated 765 VREfm isolates (39 clinical and
726 screening isolates) from hospitalised patients across 26
hospitals in Queensland, collected from January to November
2010. Van genotyping was performed on all isolates. A total of
758 isolates (99.1%) had a vanB genotype while seven isolates
were positive for vanA. Ninety-one vanB VREfm were selected
to study molecular epidemiology using repetitive polymerase
chain reaction (PCR) (DiversiLab; bioMerieux, France), comprising both clinical (n 39) and screening (n 62) specimens.
Results revealed that the majority of isolates from Queensland
(n 88) were very closely related (>92% similarity).
Fourteen isolates from this major group were further analysed by high resolution melting (HRM) genotyping as
described.2 Four melting types (MelTs) were identified,
MelT11 (n 1), MelT34 (n 1), MelT121 (n 11) and one
novel MelT. MelT11, MelT34 and MelT121 represent STs
which are clustered in CC17. MelT11 and MelT121 include
various STs from each subgroup founded by ST17 and ST203,
respectively. MelT34 incorporated multiple subgroups of CC17
as well as the singleton ST51 (Table 1). MLST was performed
in all 14 isolates as previously described;3 of these, 12 isolates
were ST203. The results from MLST were correlated with
HRM genotyping except the novel MelT that was identified as
ST203 (Table 1).
In conclusion, our results indicate that 88 of 91 isolates
(97%) were closely related. HRM genotyping and MLST of
representative isolates from this cluster revealed that ST203
was predominant. This suggests that ST203 may be responsible
for VREfm in Queensland. These findings correspond with
what was found by Johnson et al. The same ST causing
outbreaks in two geographically non-contiguous states suggests
11
17, 63, 103, 180, 187, 234, 267, 295, 307, 308, 357, 460,
475, 480, 538, 543, 554, 578, 584
49, 51, 177, 232, 341, 547, 548, 556
203, 365, 412, 478, 483, 577
17
34
121
17
17
*
Generated by Enterococcus faecium MLST and MelT key as described by
Tong et al.2 and found at http://menzies.edu.au/node/43174.
Bold type indicates ST identified by MLST.
CC, clonal complex; MelT, melting type; MLST, multilocus sequence
typing; ST, sequence type.
DOI: 10.1097/PAT.0b013e32835b68d2
Copyright Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.