Obtaining Expert Opinions in Diagnostically.12

7/26/2019 Obtaining Expert Opinions in Diagnostically.12

1/20Copyright Royal College of pathologists of Australasia Unauthorized reproduction of this article is prohibited

Obtaining expert opinions in diagnosticallydifficult cases

Sir,Klebe et al.1 describe their experience with expert review ofdifficult mesothelial proliferations. They found only 57%complete concordance between the expert and referring path-ologists diagnosis, with some 9.5% of cases having signifi-cant disagreement (benign versus malignant, or mesotheliomaversus another tumour type). Whilst disturbing, this will comeas no surprise to those of us with subspecialty interests in otherrare tumour types such as sarcoma or GIST, and no doubt inother organ systems as well.

These figures are in line with similar studies performedoverseas; for example, intheir review of 349 soft tissue speci-mens, Thway and Fisher2 reported minor diagnostic discre-

pancy in 15.7% and major discrepancy in 10.9%, including adifference of benign versus malignant in 5%. Similarly, in areview of 266 referred soft tissue lesions for which a primarydiagnosis had been offered by the referring pathologist, therewere major discrepancies (e.g., benign versus malignant, non-mesenchymal tumour) in 25% of cases, and minor discre-pancies in 7%.3 Numerous other such studies from a variety ofcountries support the value of timely expert review of rare anddifficult cancers,4 7 with diagnostic discrepancies reportedly ashigh as 45% or more in some series.6,7

This is more than simply an intellectual exercise: delayed orincorrect diagnosis can lead to profound impacts on the patientwho undergoes inappropriate or unnecessary surgery, chemo-or radiotherapy, or who is denied potentially life-savingtherapy. A review of 1996 musculoskeletal tumours in onespecialist unit8 found a diagnostic error in 87 cases, 54 ofwhich (2.7%) resulted in a significant change to the patientsmanagement. In the case of aggressive cancers, even relativelyshortdelays in accurate diagnosis can impact on patient survi-val.9 Even if the correct diagnosis is reached, errors in gradingor risk stratification can also impact on clinical decision-mak-ing, e.g., neoadjuvant radiotherapy versus up-front surgery invarious types of soft tissue sarcoma; adjuvant imatinib versusobservation in GIST; wait and see versus treatment, or choiceof treatment modality, in gastroenteropancreatic neuroendo-crine 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, formany pathologists working in non-specialist centres, there aredifficulties in obtaining such review. Not only does the refer-ring laboratory incur a cost in terms of packaging and sendingthe slides (and hopefully a paraffin block or two!) to theexpert, but the receiving laboratory incurs a significant costin terms of handling the incoming material, making the diag-nosis and issuing an opinion (which is often complex). Thisbrings its own rewards in that the cases are often interesting,and expertise is only accrued through exposure to difficult andunusual cases, but the cost must be borne somewhere. Many ofus choose not to charge a fee for this work, but this is onlysustainable if the number of referrals is relatively small (andwith the indulgence of our heads of department), and someinstitutions insist on a fee of perhaps several hundred dollars a cost which most referring laboratories cannot meet. This

means that the fee is most often passed on to the patient, anadded stress at the very time that they are facing a potentiallydevastating diagnosis. Surely our patients access to accurate

diagnosis and grading, and subsequent management, should beindependent of their personal wealth?There is clearly a need for timely and appropriate referrals of

difficult cases for expert review, and this should be funded in anequitable fashion. The relatively small cost of these referralswould be more than compensated by avoiding unnecessary andinappropriate treatment based on an incorrect diagnosis ortumour grade; for example, only one incorrect diagnosis ofhigh risk GIST will cost in excess of AU$45 000 per annum10 indrug costs alone, for adjuvant imatinib which will not benefitthe patient. Therefore, funding of expert opinion referralswould not only be good medicine, but would be cost effective.The Royal College of Pathologists of Australasia (RCPA) hasprepared two applications to the Medical Services Advisory

Committee (MSAC) to fund retrieval of tissues and such expertopinions, which would help the situation at least in Australia,and this initiative should be strongly supported by pathologistsand clinicians alike.

Patients with rare cancers deserve the same expert diagnosisand management that is afforded to those with commontumours, and that can only be achieved through timely referralfor expert advice when it is needed.

Chris Hemmings

ACT Pathology, Canberra, Australian National University, and

Australasian Sarcoma Study Group, Canberra, ACT, Australia

Contact Dr C. Hemmings.E-mail: [email protected]

1. Klebe S, Greiggs K, Ely M, Henderson D. Is there a need for expert

opinion for biopsy diagnosis of difficult cases of malignant mesothelioma?Pathology 2012; 44: 5623.

2. Thway K, Fisher C. Histopathological diagnostic discrepancies in softtissue tumours referredto a specialistcentre. Sarcoma 2009; May 27: (Epubahead of publication).

3. Arbiser Z, Folpe A, Weiss S. Consultative (expert) second opinions in softtissue pathology: analysis of problem-prone diagnostic situations. Am JClin Pathol 2001; 116: 4736.

4. Lehnhardt M, Daigeler A, Hauser J, et al. The value of expert second

opinion in diagnosis of soft tissue sarcomas. J Surg Oncol 2007; 97:

403.

5. Amant F, Moerman P, Cadron I, e t a l. The diagnostic problem ofendometrial stromal sarcoma: report on six cases. Gynecol Oncol 2003;90: 3743.

6. Lurkin A, Ducimetiere F, Vince D, et al. Epidemiological evaluation ofconcordance between initial diagnosis and central pathology review in acomprehensive and prospective series of sarcoma patients in the Rhone-Alpes region. BMC Cancer2010; 10: 150.

7. Sharif M, Hamdani S. Second opinion and discrepancy in the diagnosis ofsoft tissue lesions at surgicalpathology.Indian J Pathol Microbiol 2010; 53:46670.

8. Grimer R, Carter S, Spooner D, Sneath R. Diagnosing musculoskeletal

tumours. Sarcoma 2001; 5: 8994.

9. Kim M, Lee S, Cho W, et al. Prognostic effects of doctor-associateddiagnostic delays in osteosarcoma. Arch Orthop Trauma Surg 2009;129: 14215.

10. Australian Government, Department of Health and Ageing. Australian

Pharmaceutical Benefits Scheme. Cited Oct 2012. www.pbs.gov.au.

DOI: 10.1097/PAT.0b013e32835baec7

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Rapidly fatal post-allogeneic stem celltransplant lymphoproliferative disorderpresenting with skin and bonemarrow involvement

Sir,Post-transplant lymphoproliferative disorders (PTLD) are anuncommon complication of both solid organ and allogeneicblood or bone marrow transplants (BMT). Early PTLD almostinvariably results from uncontrolled proliferation of EpsteinBarr virus (EBV) infected donor derived B cells in theseimmunosuppressed patients who are unable to mount anEBV specific cytotoxic T-cell response. The main risk factorsfor developing PTLD are the duration and intensity of immu-nosuppression and recipient EBV seronegativity at the time oftransplant. Additional risk factors in recipients of allogeneicBMT include degree of mismatch between the donor andrecipient and T-cell depletion of thegraft.1,2 The 2008 World

Health Organization Classification3 charts the heterogeneousspectrum of PTLD disorders ranging from infectious mono-nucleosis-type polyclonal proliferations, which generallyresolve with reduction in immunosuppression, to monomorphicPTLD which may present as an aggressive lymphoma andrequire chemotherapy. Patients who have received lung, smallbowel or multiple organ transplants are reported to be a t thehighest risk of PTLD, with rates of approximately 5%.2 Bycontrast, the rate of PTLD following allogeneic BMT isreported to be lower, with an overall risk of approximately1%.1

This report describes a patient who developed a highlyaggressive PTLD within 2 months of a second allogeneicBMT for relapsed acute myeloid leukaemia (AML). Clinicalprogression was rapid and the patient died one week afterpresentation. Such a fulminant presentation is extremely rarewith only three similar reported cases.46

A 45-year-old EBV IgG positive Caucasian male with abackground of Crohns disease was diagnosed with AML inAugust 2007. Despite an adverse cytogenetic profile (monos-omy 5, del7q and multiple additional anomalies) a completemorphological and cytogenetic remission was documentedfollowing induction chemotherapy with high dose cytarabineand idarubicin. After two cycles of consolidation chemotherapyhe underwent a matched sibling peripheral blood stem celltransplant in January 2008 with cyclophosphamide and totalbody irradiation conditioning. A bone marrow biopsy on day60 showed evidence of a cytogenetic relapse which was

successfully managed with withdrawal of immunosuppression.Three years post-transplant a routine bone marrow demon-

strated a cytogenetic relapse (1/40 metaphases demonstratingthe complex karyotype notedat diagnosis), and 1 month later hewas in a morphological relapse with 30% bone marrow mye-loblasts. Following two cycles of salvage chemotherapymorphological and cytogenetic remission was again documen-ted. The patient then underwent a fully matched (HLA-A, -B,-C, and -DRB1 by molecular typing) unrelated donor BMTwith fludarabine, busulphan and thymogloblulin conditioning(total dose thymoglobulin 4.5 mg/kg). The EBV status of thedonor was unknown. Post-transplant immunosuppression waswith methotrexate and cyclosporin. The patient engrafted onday 14 and simultaneously developed a rash and derangedliver function tests. A skin biopsy was consistent with graftversus host disease and he was successfully treated with topical

hydrocortisone and 40 mg oral prednisone. A rising cytome-galovirus polymerase chain reaction (PCR) titre on day 35was effectively treated with oral valganciclovir.

The patient was readmitted on day 71 with a 1 week historyof progressive nausea, vomiting and diarrhoea with associatedfever with rigors. Multiple blood cultures were negative

although stool Clostridium difficile toxin PCR and norovirusenzyme immunoassay were both positive. His IgG level waslow at 3.32 g/L and treatment with metronidazole and intrave-nous immunoglobulin was commenced. His clinical conditiondeteriorated with the development of abdominal pain, oliguriaand severe lactic acidosis with a lactate of 7.7 mmol/L. Acomputed tomography (CT) scan showed wall thickening ofthe descending colon along with intra-abdominal lymph nodesmeasuring up to 3 cm. An exploratory laparotomy and colono-scopy, performed due to concern of possible ischaemic bowel,showed only mild inflammation of the colon. Cytologicalanalysis of peritoneal fluid demonstrated a small number ofatypical cells. On day 76 a skin rash developed and wasbiopsied. Simultaneously the patient developed pancytopenia

with Hb 103g/L, WCC 2.7 109/L and platelets 22 109/Land a bone marrow biopsy was performed. The patient diedfrom progressive multiorgan failure on day 78 before theresults of these investigations were available.

The skin biopsy demonstrated an abnormal perivascularinfiltrate of large, morphologically abnormal lymphoid cellswith polymorphic nuclei and prominent nucleoli (Fig. 1A). Theabnormal cells were positive for CD20/CD79a/EBER/MUM-1/PAX-5 and Bcl-2 but negative for CD10/CD30/CD138 andBcl-6 (Fig. 1B). Occasional plasmacytoid lymphoma cells werenoted in the peripheral blood. The bone marrow biopsy washypocellular with an abnormal infiltrate of similar lymphoidcells (Fig. 2A). Flow cytometry of the bone marrow showed anabnormal population of large CD19 and lambda positive cells.Immunohistochemistry of the trephine showed small clusters oflarge cells with strong immunoreactivity for EBER (Fig. 2B)and relative lambda light chain restriction. Cytogenetic analysiswas normal. Whilst the lymphoma cells showed significantpleomorphism, the clinical picture and immunostains wereconsistent with monomorphic PTLD, most likely a non-germ-inal centre diffuse large B-cell lymphoma.

Only one previous case has been reported of simultaneousmultifocal skin and bone marrow involvement in a patient withPTLD. This developed in a 14-month-old EBV seronegativerecipient of a combined smallbowel and liver transplant froman EBV seropositive donor.4 The patient presented withcutaneous PTLD associated with circulating lymphoma cells

5 months post-transplant and died rapidly from multiorganfailure.

Two other cases of similarly fulminant PTLD have beenreported. The first occurred in an EBV seronegative recipient ofa renal transplant from an EBV seropositive donor.5 The seconddeveloped in an EBV seropositive recipient of a non-myelo-blative allogeneic BMT for relapsed anaplastic large celllymphoma.6 The donor had a positive IgM titre for EBV viralcapsid antigen (VCA) in the pre-transplant specimen, consist-ent with recent infection. ln each of these previous cases theaggressive presentation of the disease was attributed either tothe recipient being EBV seronegative or to recent EBV infec-tion in the donor. In our case the recipient was EBV seropo-sitive and we presume the development of PTLD was insteadrelated to the intensive immunosuppression as a result of hisprevious treatments. Although only a relatively low dose of

CORRESPONDENCE 81



thymoglobulin was used in his conditioning regimen, theT-cell depletion associated with thistherapy is a known riskfactorfor thedevelopment of PTLD.3 It is also possible that thehistory of Crohns disease is relevant, although his inflamma-tory bowel disease had been inactive with no specific therapysince his initial diagnosis of AML. Patients with inflammatorybowel disease who are treated with thiopurines are known tohave an increased risk of lymphoma which is often EBVpositive.7

PTLD is a rare complication of allogeneic stem cell trans-plant.1 The disease is often extranodal at presentation which

may result in a delay in diagnosis.8

Historically the prognosisfor patients with PTLD has been poor with survival rates ofaround 30%.9 The cornerstone of treatment for PTLD post-solid organ transplant is withdrawal of immunosuppressivetherapy. However, this is rarely useful post-BMT becausethe defect is delayed EBV-memory cytotoxic T cell recovery,not suppression of their function.10 Treatment with monoclonalantibodies such as rituximab, chemotherapy or ex vivo gener-ated EBV cytotoxic T cells are resulting in improved out-comes.11 Some groups have advocated serial monitoring ofEBV viralload in high risk patients to aid early detection andtreatment.12 This case demonstrates the unique clinical andpathological features of an early onset highly aggressive dis-seminated variant of PTLD post-BMT, highlighting the needfor early and ongoing vigilance in high risk patients. Furtherresearch into the pathogenesis of this devastating complication

may allow improved risk stratification and hence individuali-sation of patient immunosuppressive regimens.

Conflicts of interest andsourcesof funding:The authors statethat there are no conflicts of interest to disclose.

Robin Gasiorowski*

John Gibson{Geoff Watson

Judith Trotman{Stephen Larsen{

ANZAC Research Institute, and{Department of Haematology,

Concord Repatriation General Hospital, Concord, zInstitute ofHaematology, Department of Anatomical Pathology, Royal

Price Alfred Hospital, Camperdown, NSW, Australia

Contact Dr R. Gasiorowski.E-mail: [email protected]

1. Curtis RE, Travis LB, Rowlings PA, et al. Risk of lymphoproliferativedisorders after bone marrow transplantation: a multi-institutional study.Blood1999; 94: 220816.

2. Dharnidharka VR, Tejani AH, Ho PL, Harmon WE. Post-transplant lym-

phoproliferative disorderin the United States: young Caucasian males are athighest risk. Am J Transplant2002; 2: 9938.

3. Swerdlow SH, Campo E, Harris NL,et al.WHO Classification of Tumoursof Haematopoietic and Lymphoid Tissues. 4th ed. Lyon: IARC Press, 2008.

4. Apichai S, Rogalska A, Tzvetanov I, Asma Z, Benedetti E, Gaitonde S.

Multifocal cutaneous and systemic plasmablastic lymphoma in an infantwith combined living donor small bowel and liver transplant. PediatrTransplant2009; 13: 62831.

A

B

Fig. 1 Skin biopsy. (A) Medium power view showing dermal perivascularinfiltrate of lymphoma cells (H&E). (B) EBER staining is strongly positive.

A

B

Fig. 2 (A) High power view of two lymphoma cells seen in the bone marrowaspirate with deep blue markedly vacuolated cytoplasm (MGG). (B) Immuno-histochemistry of the bone marrow trephine shows a hypocellular marrow withan abnormal infiltrate of strongly EBER positive lymphoma cells.

82 CORRESPONDENCE Pathology (2013), 45(1), January
mailto:[email protected]:[email protected]



5. Mathur RV, Kudesia G, Suvarna K, McKane W. Fulminant post-transplantlymphoproliferative disorder presenting with lactic acidosis and acute liverfailure.Nephrol Dial Transplant2004; 19: 191820.

6. Zamkoff KW, Bergman S, Beaty MW, Buss DH, Pettenati MJ, Hurd DD.

Fatal EBV-related post-transplant lymphoproliferative disorder (LPD) aftermatched related donor nonmyeloablative peripheral blood progenitor celltransplant.Bone Marrow Transplant2003; 31: 21922.

7. Beaugerie L, Brousse N, Bouvier AM,et al. Lymphoproliferative disorders

in patients receiving thiopurines for inflammatory bowel disease: a pro-spective observational cohort study. Lancet2009; 374: 161725.

8. Nalesnik MA, Jaffe R, Starzl TE, et al. The pathology of posttransplantlymphoproliferative disorders occurring in the setting of cyclosporine

A-prednisone immunosuppression.Am J Pathol 1988; 133: 17392.

9. Savage P, Waxman J. Post-transplantation lymphoproliferative disease.QJM1997; 90: 497503.

10. Gross TG, Steinbuch M, DeFor T, et al. B cell lymphoproliferativedisorders following hematopoietic stem cell transplantation: risk factors,

treatment and outcome. Bone Marrow Transplant1999; 23: 2518.

11. HeslopHE. HowI treat EBVlymphoproliferation.Blood2009; 114: 4002 8.

12. Stevens SJ, Verschuuren EA, Pronk I, et al. Frequent monitoring of Epstein-Barr virus DNA load in unfractionated whole blood is essential for earlydetection of post transplant lymphoproliferative disease in high-riskpatients.Blood2001; 97: 116571.

DOI: 10.1097/PAT.0b013e32835b5de4

Familial haemophagocyticlymphohistiocytosis in twin infants

Sir,Haemophagocytic lymphohistiocytosis (HLH) is an uncommonentity comprising a constellation of symptoms and laboratoryfindings that together form the clinical inflammatory syn-drome. HLH encompasses two separate conditions: a primaryhereditary form (familial haemophagocytic lymphohistiocyto-sis, 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 malig-nant diseases, notably T-cell lymphomas. FHL is generallyinherited in an autosomal recessive or x-linked manner, pre-sents during infancy or early childhood, and is uniformly fatal ifleft untreated. Here we present an interesting case of FHLpresenting in a pair of identical twins in the immediate post-natal period.

The patients were diamnionic-dichorionic identical twinsborn at 35 weeks gestation. Twin 1 was born via normalspontaneous vaginal delivery, while twin 2 was born viaemergent caesarean section due to placental abruption. The

initial post-natal clinical course was uncomplicated, and thepatients were discharged home without complication. At2 months of age both twins were hospitalised for fever withneutropenia, and severe thrombocytopenia. Liver ultrasoundshowed hepatomegaly. Laboratory studies (Table 1) showedmany abnormalities, including low fibrinogen, elevatedD-dimers, and prolonged coagulation times, indicating likelydisseminated intravascular coagulation. Blood cultures at thistime were negative in both twins. Simultaneous bone marrowaspirates were obtained on both twins. While the bone marrowaspirate from twin 2 showed non-specific findings due tomarkedly haemodilute aspirate smears (i.e., predominantlymature lymphocytes similar to peripheral blood), the bonemarrow aspirate from twin 1 showed significantly increasedhaemophagocytic histiocytes on the smear (Fig. 1) in additionto erythroid hyperplasia and relative decrease in myeloid cells.

Megakaryocytes were unremarkable. Additional laboratorystudies (Table 2) showed elevated alanine aminotransferase(ALT), elevated aspartate aminotransferase (AST), increasedtriglycerides and increased soluble interleukin-2 receptor(CD25) in both twins. Studies for NK-cell functional activitywere non-contributory due to technical reasons in twin 1 and

not decreased significantly in twin 2.Twin 1 met the following criteria for the diagnosis ofhaemophagocytic lymphohistiocytosis: (1) fever, (2) fibrino-gen level less than 1.5g/L, (3) increased haemophagocyticlymphohistiocytosis on bone marrow aspirate smear, (4) ferritinlevel more than 500 ng/mL, and (5) elevated soluble interleu-kin-2 receptor (soluble CD25) level of more than 2400 U/mL.Twin 2 met the following diagnostic criteria for the diagnosis ofhaemophagocytic lymphohistiocytosis: (1) fever, (2) cytope-nias (haemoglobin less than 9 g/dL and platelet count less than100k/mL), (3) fibrinogen level less than 1.5 mg%, (4) ferritinlevel more than 500ng/mL, and (5) soluble interleukin-2receptor (soluble CD25) level more than 2400 U/mL. A diag-nosis of haemophagocytic lymophohistiocytosis was made on

both the twins, based on these findings (see Table 3).2 Due tothe fact that these were identical twins, FHL was consideredand subsequent perforin-1 (PRF1) gene mutation analysisshowed identical mutations, i.e., homozygous for 50delT(L17fsX50), confirming the diagnosis of FHL type 2 in boththe twins. Both patients were started on chemotherapy con-sisting of dexamethasone, etoposide, and cyclosporine accord-ing to the HLH-2004 protocol. Twin 2 progressivelydeteriorated, developing respiratory and hepatic failure, fun-gaemia, and worsening coagulopathy, with death occurring 8days after the start of chemotherapy. Twin 1 did well onchemotherapy and was eventually discharged 4 monthsafter admission.

FHL is a rare condition, most often presenting in infancy,with a peak age of presentation between 1 and 6 months.1 Thereported incidence ranges from 0.12 per 100 000 cases instudies conducted in Sweden3 to 7.5 per 10000 amonghospitalised patients in Turkish studies.4 The high rate ofFHL in the Turkish population may be due to the high rateof consanguineous marriage, fitting with the autosomal reces-sive inheritance patterns seen in most genetically elucidatedtypes of FHL. In addition, as the incidence of FHL variesamongst people of different ethnic backgrounds, so too do thegenetic defects that give rise to the HLH phenotype.

The mechanism of immune impairment leading to the syn-drome is unclear; however, it is clear that the mechanisminvolves the release of inflammatory cytokines, T-cell and

histiocyte activation, and NK-cell impairment. This leads tothe defining clinical and laboratory findings, including fever,splenomegaly, multiple cytopenias, hypertriglyceridaemia

Table 1 Results of laboratory studies on both twins

Test (normal range) Twin 1 Twin 2

Haemoglobin (1015 g/dL) 9.2 8.9WBC (514k/mL) 5.2 4.2Absolute neutrophil count (2 7 k/mL) 1.2 1.1Platelet count (150400 k/mL) 100 34D-dimer (



and/or hypofibrinogenaemia, haemophagocytosis in the bonemarrow, spleen, or lymph nodes, low/absent NK-cell activity,hyperferritinaemia, and increased soluble IL-2 receptor(soluble CD25), in the absence of malignancy (Table 3). Fiveof the eight criteria are necessary for a diagnosis of HLH,though a diagnosis may still be made if there is molecularevidence consistent with HLH.2 Diagnostic work-up includescomplete blood count and blood smear analysis, liver functiontests, blood chemistry, triglyceride and cholesterol levels,ferritin, and coagulation tests. Bone marrow biopsy and aspiratemay be initially negative, and should be repeated over time tosee if evidence of haemophagocytosis appears; biopsies fromother organs can help demonstrate haemophagocytic histocytesor evidence of chronic persistent hepatitis in more uncommoninstances.2

Microscopic features are identical in the familial andacquired forms. The main histological feature is diffuse infil-tration by T-lymphocytes and histiocytes. The organs mostfrequently examined are the bone marrow, spleen, liver, andcentral nervous system, and so are the most frequentlydescribed; however, almost no organ is spared, and the charac-teristic findings may be seen in almost any organ. Perhaps most

frustrating is the fact that the characteristic haemophagocytichistiocytes (showing phagocytosis of nucleated cells as well as

red blood cells) may be absent in some organs, or infrequent atbest, thus necessitating repeated biopsies for histologicalconfirmation. Histological findings in the liver, which maybe the second most common organ biopsied after the bonemarrow, shows a pattern of sinusoidal dilatation, congestionand hyperplasia of Kupffer cells. Haemophagocytic histiocytesare not seen in the portal inflammatory infiltrate, but charac-teristically in the dilated sinusoids.5 The immunophenotype ofthe phagocytic histiocytes are also unique. They express com-mon macrophage-associated antigens, S100 protein and alsomay express CD1a (which are more commonly seen inLangerhans cells or interdigitating dendritic cells).6

Five distinct genetic subtypes of FHL have been identified todate. FHL type 1 has been mapped to chromosome 9 ( 9p21),although the exact protein and gene remain unknown.7 Thismutation is believed to account for 10% of all FHL. FHL type 2has been mappedto the perforin gene located on chromosome10 (10q2122).8 Perforin gene mutations cause either a non-functional form or markedly reduced/absent form of the per-forin protein (PRF1), resulting in decreased granzyme mediatedtoxicity by NK cells and cytotoxic T-cells. Missense mutationsof PRF1 result in a non-functional form of the protein through

conformational changes that inhibit proteolytic processing ofthe protein precursors; nonsense mutations result in absent

Table 2 Results of additional laboratory studies on both twins

Test (normal range) Twin 1 Twin 2

Triglycerides (3385 mg/dL) 125 140Ferritin (322 468 ng/mL) 11460 11057ALT (230 IU/L) 437 435AST (1643 IU/L) 384 1704Soluble interleukin-2 receptor; CD25 (6500 >6500NK-cell activity; NK-cell functional assay (8170 LU30) Non-contributory 15Perforin-1 gene mutation analysis Homozygous for 50 del T(L17fsX50) mutation Homozygous for 50 del T(L17fsX50) mutation

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Fig. 1 May-Grunwald Giemsa; multiple haemophagocytic histocytes.




protein production.9,10 Further, the type of mutation affects theclinical presentation with missense mutations having a later ageof onset than nonsense mutations.11 Mutations in PRF1 accountfor 2040% of FHL. While there have been over 50 differentPRF1 mutations identified, a subset of mutations have beenfound to be more prevalent in certain ethnicities. The1122G!A (W374X) mutation appears to be more prevalentin Turkish cohorts, while the 272C!T (A91 V) mutationappears to dominate in Italian populations.11 The 50delTmutation, also seen in our described patients, is interestinglythe single mutation seen in African/African American individ-uals. FHL type 3 is traced to the hMunc134 gene, encodingthe Munc134 protein, which is involved in vesiclepriming.12 The granules containing perforin and granzymes

A and B are normal, however priming prior to release isabnormal, resulting in the abnormal FHL phenotype. FHL type4 results from abnormalities in the Syntaxin 11 (STX11)gene,13 found only in patients of a Turkish/Kurdish backgroundthus far. Syntaxin 11 is also involved in vesicle priming. FHLtype 5 has been mapped to chromosome 19p, which encodes theSTXBP2 gene encoding Munc182 protein (syntaxin bindingprotein 2).14 This protein is involved in intracellular traffickingand granule exocytosis. Regardless of the mutated protein, orspecific type of mutation, patients with FHL tend to have aclinically similar disease.

Prior to the use of cytotoxic chemotherapy FHL wasuniformly fatal, with patients succumbing to infection andmulti-organ failure. With the use of chemotherapeutic agents,including etoposide, anti-thymocyte globulin, and CSA, as wellas steroids, the majority of patients were able to show

symptomatic improvement; however, a true cure was notobtained without haematopoietic stem cell transplantation.The regimen currently in use, as produced by the 2004 revisionof the Histiocyte Society consensus study protocol (HLH-2004), uses etoposide, dexamethasone, cyclosporine, andintrathecal methotrexate.4

In conclusion, haemophagocytic lymphohistiocytosisis a rare disease that may present in a phenotypicallyindistinguishable acquired or familial form. The familialform is a genetically heterogeneous and phenotypically homo-geneous disease, of which five genetically distinct subtypeshave been described. Diagnosis rests on a combination ofclinical and histological features, and chemotherapy along withhaematopoietic stem cell transplant is the mainstay of therapy.

Conflicts of interest andsourcesof funding:The authors statethat there are no conflicts of interest to disclose.

Bryce Higa

Milind Velankar

Department of Pathology, Loyola University Medical Center,

Maywood, IL, USA

Contact Dr B. Higa.E-mail: [email protected]

1. Henter JI, Samuelsson-Horne AC, Arico M, et al. Treatment of hemopha-gocytic lymphohistiocytosis with HLH-94 immunotherapy and bone mar-row transplantation. Blood2002; 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 PaediatrScand1991; 80: 42835.

4. Gurgey A, Gogus S, Ozyurek E, Aslan E, et al. Primary hemophagocyticlymphohistiocytosis in Turkish children.Pediatr Hematol Oncol2003; 20:36771.

5. de Kerguenec C, Hillaire S, Molinie V, Gardin C, et al. Hepatic manifesta-tions 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 ClinPathol1987; 40: 14137.

7. Ohadi M, Lalloz M, Sham P, et al. Localization of a gene for familialhemophagocytic lymphohistiocytosis at chromosome 9p21.322 by homo-zygosity mapping. Am J Hum Genet1999; 64: 16571.

8. Stepp S, Dufourcq-Lagelouse R, Le Deist F, et al. Perforin gene defects infamilial hemophagocytic lymphohistiocytosis.Science1999; 286: 19579.

9. Risma KA, Frayer RW, Filipovich AH, Sumegi J. Aberrant maturation of

mutant perforin underlies the clinical diversity of hemophagocytic lym-phohistiocytosis.J Clin Invest2006; 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 Genet2004; 41: 13744.

11. Trizzino A, Stadt U, Ueda I, Risma K, et al. Genotype-phenotype study offamilial hemophagocytic lymphohistiocytosis due to perforin mutations.J Med Genet2008; 45: 1521.

12. Feldmann J, Callebaut I, Raposo G, et al. Munc13-4 is essential forcytolytic granules fusion and is mutated in a form of familial hemopha-gocytic lymphohistiocytosis (FHL3). Cell 2003; 115: 46173.

13. Glolam C, Grigoriadou S, Gilmour KC, Gaspar HB. Familial hemopha-gocyt5ic lymphohistiocytosis: advances in the genetic basis, diagnosis andmanagement.Clin Exp Immunol 2011; 163: 27183.

14. Cote M, Menager MM, Burgess A, et al. Munc18-2 deficiency causesfamilial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic

granule exocytosis in patient NK cells.J Clin Invest2009; 119: 376573.

DOI: 10.1097/PAT.0b013e32835b5db2

Table 3 Reviseddiagnostic criteria for haemophagocyticlymphohistiocytosis2

The diagnosis of HLH can be established if either 1 or 2 below is fulfilled:1. A molecular diagnosis consistent with HLH2. Diagnostic criteria for HLH fulfilled (5/8 criteria below)

Initial diagnostic criteria:1. Fever

2. Splenomegaly3. Cytopenias (affecting 2 or more of 3 lineages in the peripheral blood)

a. Haemoglobin



A novel oncocytoid papillary renal cellcarcinoma, type 2, with aberrantcytogenetic abnormalities

Sir,Renal cell carcinoma is classified by the World Health Organ-ization (2004)1 on the basis of histological patterns correlatedwith cytogenetic, genetic and both familial and sporadic cases.Papillary renal cell carcinoma (PRCC) is usually multifocal,comprises 1015% of renal cell carcinomas, and is postulatedto arise from the intercalated cells of the distal tubule.1 4

Benign oncocytoma accounts for 515% of surgically resectedrenal tumours and is believed to arise from the intercalated cellsof collecting ducts. There are case reports of hybrid tumoursoncocytoma/chromophobe RCC,2,4,5 but only four cases ofcombination or hybrid tumour oncocytoma/PRCC have beenreported,2,46 of which three cases are



negative for CD117. The electron microscopy showed mito-chondria admixed with other cell organelles and microvesicles.The one component of the renal tumour showed all the immu-nohistological features of a PRCC, type 2.

Oncocytomas are benign well-circumscribed neoplasmswhich may have a central, stellate scar of hyalinised connective

tissue and are mahogany brown. Haemorrhage and cysticdegeneration may be present, but tumour necrosis is not afeature. They are arranged in nests, tubules, cords or microcystsand the tumour cells have dense eosinophilic cytoplasm, roundnuclei and small nucleolus. Onocytomas are positive forCD117, variable positivity for CD10, and are negative forCK7 and vimentin. Electron microscopy showed a mitochon-dria rich cytoplasm and scanty other organelles. The secondcomponent of the renal tumour in our case supported thefeatures of an oncocytoma.

The papillary carcinoma component in the four casesreported as hybrid tumour were small in size and in two werereported to be a small focus6 and numeroussmall nests2 andin the other two were reported to be 1.5 mm4 and 7 mm.5 Theoncocytoma component of these tumours ranged in size from15mm to 36mm.

As three of the four reported cases were



Conflictsof interest andsources of funding: The authors statethat there are no conflicts of interest to disclose.

Rajalingam Sinniah*

Angeline Teo*

Ashleigh Murch{

*Department of Anatomical Pathology, PathWest Laboratory

Medicine, Royal Perth Hospital, Wellington Street, Perth, and,

and {Cytogenetics Department, Path West Laboratory

Medicine, King Edward Memorial Hospital, Subiaco, WA,

Australia

Contact Professor R. Sinniah.E-mail:[email protected]

1. Eble JN, Sauter G, Epstein JI, Sesterhenn IA, editors. World HealthOrganisation Classification of Tumours. Pathology and Genetics of

Tumours of the Urinary System and Male Genital Organs. Lyon: IARCPress, 2004.

2. Al-Saleem T, Balsara BR, Liu Z, et al. Renal oncocytoma with loss ofchromosomes Y and 1 evolving to papillary carcinoma in connection with

gain of chromosome 7. Coincidence or progression? Cancer Genet Cyto-genet2005; 163: 815.

3. Murphy WM, Girgnon DJ, Perlman EJ. Atlas of Tumour Pathology.Tumours of the Kidney, Bladder, and Related Urinary Structures.4th series,fascicle 1. Washington DC: AFIP, 2004; 16474.

4. Floyd MS Jr, Javed S, Pradeep KE, De Bolla AR. Composite

oncocytoma and papillary renal cell carcinoma of the kidney treated bypartial nephrectomy: a case report. Scientific World Journal 2011; 11:11737.

5. Rowsell C, Fleshner N, Marrano P, Squire J, Evans A. Papillaryrenal cell carcinoma within a renal oncocytoma: case report of anincidental finding of a tumour within a tumour. J Clin Pathol 2007;60: 4268.

6. Vasuri F, Fellegara G. Collision renal tumours.Int J Surg Pathol2009; 17:

3389.

7. Erlandon RA, Shek TW, Reuter VE. Diagnostic significance of mitochon-

dria in four types of renal epithelial neoplasms: an ultrastructural study of60 tumours. Ultrastruct Pathol 1997; 21: 40917.

8. Linehan WM, Walther MM, Zbar B. The genetic basis of cancer of the

kidney.J Urol 2003; 170: 216372.

9. Yang XJ, Tan MH, Kim HL, et al. A molecular classification of papillaryrenal cell carcinoma. Cancer Res 2005; 65: 562837.

10. Tickoo SK, Reuter VE, Amin MB,et al. Renal oncocytosis, a morphologicstudy of fourteen cases. Am J Surg Pathol 1999; 23: 1094101.

DOI: 10.1097/PAT.0b013e32835b682e

Choroid plexus papilloma arising in a mature

cystic teratoma of a 32-year-old female

Sir,Herein, to the best of our knowledge, we report the thirdpublished case of a choroid plexus papilloma arising in amature cystic teratoma. The female patient, aged 32 years,presented with a 6 month history of left loin pain post-partum.She underwent investigation with pelvic ultrasound and com-puted tomography (CT) of the abdomen revealing a 10 cmcomplex mass arising from the left ovary with a large cysticcomponent and elements of fat, all consistent with a dermoidcyst. The affected ovary was removed and submitted forpathological examination.

Macroscopically the specimen consisted of an openedcyst, 80 30 mm when laid flat, with smooth external and

internal surfaces, the latter with adherent aggregates ofhair. No solid or papillary areas were seen. Microscopicexamination showed a multilocular cyst with constituent tis-sues from the three embryonic layers including adipose tissue,skeletal muscle, bone, cartilage with keratinising squamousepithelium and associated skin adnexal structures, pseudos-

tratified ciliated respiratory type epithelium and ciliated epen-dymal cells with associated choroid plexus lining the cysticspaces. Focally the choroid plexus tissue formed a well demar-cated, non-invasive papillary tumour characterised by com-plex branching fibrovascular structures lined by mildlycrowded, elongated and focally stratified columnar ependymalcells without nuclear atypia or mitotic activity. The featureswere diagnostic of a choroid plexus papilloma (WHO Grade I)(Fig. 1).

The basic components of the choroid plexus are glomer-ular vascular tufts derived from the vascular leptomeningesthat are covered by a cobblestoned secretory ependymalepithelium.1 Small nests of meningothelial cells are nativeconstituents of the choroid plexus and can give origin to

psammoma bodies.1 Choroid plexus papillomata are rareprimary central nervous system tumours that grossly appearas a circumscribed, cauliflower-like mass within ventri-cles.2,3 Microscopically, columnar non-ciliated cells thatshow nuclear crowding and stratification are arranged inan orderly fashion around delicate well formed fibrovascular

A

B

Fig. 1 Choroid plexus papilloma in a mature cystic teratoma. (A) Low powerviewof a circumscribedpapillary lesion with delicate, well formedfibrovascular

stalks projecting into a cystic space. (B) A high power view shows thefibrovascular stalks are lined by non-ciliated columnar cells that show nuclearcrowding and stratification.




stalks.2,3 Calcified bodies are often seen in the stroma ofpapillomas.3 An atypical papilloma is defined by the pre-sence of mitoses >2 per 10 high power fields (HPF) and twoor more of increased cellularity, nuclear pleomorphism, solidgrowth and areas of necrosis.3

There are only two other reports of choroid plexus papillo-

mata arising in mature cystic teratomas in the literature. In onereport a choroid plexus papilloma developedin the wall of anovarian dermoid in a 14-year-old female.4 In the other, anatypical choroid plexus papilloma with cytologic atypia, focalnecrosis and mitoses up to 3/10 HPF, was described arising inthe wall of a dermoid in a 26-year-old female.5 Follow-up islimited in both cases.

Usual WHO grade I choroid plexus papillomata arising in thecentral nervous system are considered benign and completeexcision in these cases is considered curative. By extrapolation,the oophrectomies performed to remove the teratoma in thecurrent case and the other reported cases are consideredcurative.

Importantly, choroid plexus papillomata can be confused

with other ovarian papillary epithelial neoplasms that maymimic primary or metastatic tumours including serous, clearcell or endometroid tumours, especially if associated withpsammomatous calcifications.6 8 Metastasis from lung adeno-carcinoma, papillary thyroid carcinoma, urothelial carcinomaand malignant mesothelioma would also enter the differentialdiagnosis.9

In conclusion, we describe another example of the rarephenomenon of a choroid plexus papilloma arising in a maturecystic teratoma of the ovary. Pathologists need to be aware ofthis entity so as not to confuse this with other well differentiatedovarian papillary epithelial neoplasms that may be primaryor metastatic.


Benjamin F. Dessauvagie*{

Sukeerat Ruba*{

Peter D. Robbins{

*Histopathology Department, PathWest, King Edward

Memorial Hospital, Subiaco, and {Division of Tissue

Pathology, PathWest, QEII Medical Centre, Nedlands, WA,

Australia

Contact Dr B. Dessauvagie.

E-mail:[email protected]

1. Sternberg S.Histopathology for Pathologists.2nd ed. Philadelphia: Lippin-cott Raven, 1997; 2713.

2. Tena-Suck T, Salinas-Lara C, Rembao-Bojorquez D, Castillejos M.Clinicopathologic and immunohistochemical study of choroid plexus

tumours: single-institution experience in Mexican population.J Neurooncol

2010; 98: 53765.

3. Nelsen J, Mena H, Parisi J, Schochet S. Principles and Practiceof Neuropathology. 2nd ed. Oxford: Oxford University Press, 2003;3324.

4. von Gunten M, Burger H, Vajtai I. Choroid plexus papilloma developing in adermoid cyst of ovary. Histopathology 2006; 49: 2045.

5. Quadri A, Ganesan R, Hock Y, Karim S, Hirschowitz L. Malignanttransformation in mature cystic teratoma of the ovary: three casesmimicking primary ovarian epithelial tumors. Int J Surg Pathol 2011;

19: 71823.6. Terada T. Immature teratoma of ovary composed largely of choroid plexus.

Int J Gynecol Cancer2010; 20: 11012.

7. Robboy S, Mutter G, Prat J, Bentley R, Russell P, Anderson M. RobboysPathology of the Female Reproductive Tract. 2nd ed. London: ChurchillLivingstone, 2009; 74954.

8. Crum C, Nucci M, Lee K.Diagnostic Gynecologic and Obstetric Pathology.

2nd ed. Philadelphia: Elsevier Saunders, 2011; 9057.9. Ikota H, Tanaka Y, Yokoo H, Nakazato Y. Clinicopathological and

immunohistochemical study of 20 choroid plexus tumours: theirhistological diversity and the expression of markers useful for differ-

entiation from metastatic cancer. Brain Tumor Pathol 2011; 28:21521.

DOI: 10.1097/PAT.0b013e32835b6855

Metastatic papillary thyroid carcinoma to thekidney: report of two cases mimickingprimary renal cell carcinoma and review ofthe literature

Sir,Papillary carcinoma of the thyroid is the most common subtype,accounting for up to 86% of thyroid cancers. Mean age atdiagnosis ranges from 31 to 49 years, with a female to maleratio between 2:1 and 3:1. The main pattern of spread is tocervical lymph nodes, with distant metastases occurringuncommonly and having an adverse impact on survival. Distantmetastases from papillary carcinoma of the thyroid can occur atany time during the course of the disease: initial presentation ofmetastatic disease has been reported in 1 12% of differentiatedthyroid tumours, being less frequent in papillary (2%) than infollicular (10%) thyroid carcinoma, whereas cumulativeincidence, including metastatic disease following initial treat-ment, varies between 10 and 35%, depending upon thehistology, again being least in well-differentiated papillarythyroid carcinoma.1 Increasing age and primary size, malesex, extrathyroidal extension, and histological subtypes, includ-ing tall-cell, columnar-cell, diffuse sclerosing and solid vari-ants, have been associated with adverse prognosis.2 Whenhaematogenous spread occurs, it is usually to bone, brain,lungs and soft tissue. Metastasis to the kidney is found in2.8 3.8% and 6 20% of thyroid papillary and follicular cancercases, respectively, but clinically detectable differentiatedthyroid cancer metastatic to the kidney is exceedingly rare.3

Herein we report two cases of papillary thyroid carcinomametastatic to the kidney. The literature on metastatic thyroidtumours to the kidney is also reviewed and differential diag-

noses are discussed.Case 1 was a 63-year-old man who presented in February

1995 with gastrointestinal symptoms, 10 lb weight loss anddizziness. He had a history of papillary thyroid carcinomastatus post-thyroidectomy (1980), radical neck dissection andbilateral lung metastases (1982), iodine-131 treatment (1986),as well as chemotherapy (1991) and radiation therapy (1992).On admission, abdominal computed tomography (CT) scanshowed a partially cystic mass in the right abdomen. The patientunderwent angio-infarction and subsequent (5 months later)resection of a large right kidney mass eroding into the duode-num and forming a pyelo-duodenal fistula.

Grossly, most of the kidney was involved by a partially solid,cystic and extensively necrotic neoplastic process, 13 cm inlargest dimension. Microscopically, the lesion showed a papil-lary architecture and characteristic nuclear changes (Fig. 1).

CORRESPONDENCE 89



Papillae showed a central fibrovascular stalk lined by neoplas-tic epithelium. The better developed papillae were long with acomplex arborising pattern. Some were straight and slender,arranged in a parallel, regimented fashion; others were shortand stubby. The papillary stalk was mainly composed by looseconnective tissue and variously sized thin-walled vessels; insome cases, it was swollen by oedematous fluid or occupied byan abundant acellular hyaline material. Occasionally, it wasinfiltrated by lymphocytes or clusters of foamy or haemosi-derin-laden macrophages. The neoplastic cells lining the papil-lae often showed tall cell features; they were at least twice aslong (tall) as wide, with large eosinophilic cytoplasm and roundto slightly oval nuclei. Nuclear contour appeared smooth onsuperficial examination, although closer inspection revealedsubtle irregularities in the form of indentations, folds, andgrooves. Another peculiar feature of neoplastic nuclei was theempty appearance of the nucleoplasm, which seemed almosttotally 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 psammomabodies or otherconcretionswere noted. Immunohistochemically,neoplastic epithelial cells showed positive staining for cytoker-atin (CK)19, CK7, CD57, thyroglobulin, and thyroid transcrip-tion factor-1 (TTF-1) (Fig. 2AD). Cells did not react withCK20, racemase, HMWCK, p63, CD10, and RCC marker.

The histological and immunohistochemical findings sup-ported 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 Decem-ber 2008 with haematuria and left flank pain due to an enlargingleft lower pole renal mass. Her past medical history includedmetastatic papillary carcinoma of the thyroid, follicular variantto the brain (resected), thyroidectomy, resection of livermetastasis, and metastatic disease to the left arm treated

by external beam radiation therapy. At ultrasound, a7.9 7.6 6.0 cm heterogeneous mass was identified at theinferior pole of the left kidney.

Needle biopsy of the renal mass showed variably-sizedneoplastic follicles generally filled with homogeneous eosino-philic colloid. Follicles were lined by cuboidal epithelial cellswith overlapping irregular nuclei that focally harboured charac-teristic changes of papillary thyroid carcinoma, such as groovesand intranuclear pseudoinclusions. No psammoma bodies ortrue papillations were identified. By immunoperoxidase stain-ing, performed to further evaluate the lesion, the tumour cellsshowed positive reactivity for CK7, thyroglobulin, TTF-1,and CD57.

In view of the previous diagnoses the findings were con-sidered consistent with metastatic papillary thyroid carcinoma,follicular variant. The patient underwent microsphere emboli-sation of the renal mass and died of disease, 7 years after herfirst diagnosis.

Metastatic disease to the kidney is observed frequently atautopsy, but is rarely found clinically in living patients.3

Although there are no modern autopsy series devoted tokidney metastases, studies performed in the past havereported that renal metastases outnumber primary renaltumours by 4:1, and that up to 12.6% of cancer patientshad metastatic disease to the kidney, with frequencies ofbilaterality and multiplicity being as high as 7181%. Bycontrast, primary renal cell carcinomas are rarely bilateral.Renal metastasis should be suspected whenever there is aknown primary, even in cases of unilateral solitary renalmasses. Although, theoretically, all solid tumours may giverise to renal metastasis, secondary lesions to the kidney occurmore commonly in patients with lung and breast cancer,melanoma, gastric carcinoma and lymphoma. Reports in theliterature suggest rates of epithelial (non-lymphoma) renal

A B

C D

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 ofloose 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 abundanteosinophylic 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 thecharacteristic abnormalities of papillary thyroid carcinoma: optical clearing (arrows), indentations, folds and grooves (arrowhead).




metastases of 1.5 1.8% of the general population.4 Imagingfeatures are rarely pathognomonic.

Metastasis to the kidney of differentiated thyroid cancer is anuncommon event; in an autopsy series of 161 fatal primarymalignant thyroid tumours, only four (6%) differentiated thyr-oid tumours metastasised to the kidney, whereas 35 (54%) and40 (61%) metastasised to the lungs and bones, respectively.5 Inanother autopsy study, Silliphant et al. found that six of 44(14%) differentiated papillary and follicular thyroid cancersmetastasised to kidney, compared to 22 (50%) and 17 ( 26%)cases metastasising to the lungs and bones, respectively.6 Onthe other hand, thyroid cancer represents only 1.02.5% ofprimary tumours metastasising to the kidneys.3

Detection of thyroid carcinoma with clinically apparentkidney metastases is very rare, with less than 30 cases reportedin the literature so far (21 of them referenced in Malhotraet al.).712 Clinical and pathological features were only acces-sible in a subset of cases (n 28) (Table 1). Of the 28 cases ofrenal metastases associated with differentiated thyroid carci-noma, 13 were from papillary carcinoma (7 of which were

follicular-variant papillary carcinomas), and 15 were fromfollicular carcinoma. In five cases there was bilateral involve-ment. In three patients the disease was discovered incidentallyduring intravenous pyelography or ultrasound. In the vastmajority of cases, patients had known thyroid tumours at thetime the renal metastases were identified. However, in someinstances, metastases to the kidney preceded the knowledge ofthe primary thyroid neoplasm and were treated surgically asprimary renal tumours. Ruggiero et al. reported a case of a25-year-old woman who underwent radical nephrectomy for aright renal mass.7 The tumour was diagnosed as papillarythyroid carcinoma, follicular variant. The patient had noprevious history of thyroid disease. During subsequent evalu-ation, metastatic disease was also identified in the patientslungs. More recently, Gupta et al.10 reported a case of meta-static papillary thyroid carcinoma that presented with flank

pain and haematuria and was treated by radical nephrectomy asa primary renal malignancy. The patient had neither history norsigns and symptoms of thyroid disease. Later work-up of thepatient for thyroid disease revealed a nodule of 0.6 cm in theright lobe of the thyroid, which was confirmed as a papillarythyroid carcinoma by ultrasound-guided fine needle aspiration.No other metastatic sites were identified.

Herein we describe two cases of thyroid papillary carcinoma,a tall-cell variant and a follicular variant, metastatic to thekidney. The former (Case 1) to our knowledge is the first case oftall-cell variant papillary thyroid carcinoma metastatic to thekidney described to date. Although both patients initiallypresented with disseminated disease, the renal metastasis pre-sented as a unilateral, large heterogeneous mass located at thelower pole of the kidney.

The differential diagnoses for tall-cell variant papillarythyroid carcinoma metastatic to the kidney include primarypapillary renal cell carcinoma, particularly type 2, micropapil-lary urothelial carcinoma of the upper urinary tract, and metas-tasis of papillary carcinomas from other organs. Papillary renal

cell carcinoma comprises approximately 10% of renal cellcarcinomas. The male to female ratio ranges between 1.8:1and 3.8:1. Papillary renal cell carcinoma frequently containsareas of haemorrhage, necrosis and cystic degeneration. Apseudo-capsule may be identified. Bilateral and multifocaltumours are common. Neoplastic cells typically form varyingproportions of papillae and tubules. Papillae contain a delicatefibrovascular core and aggregates of foamy macrophages;cholesterol crystals may be present. Calcified concretions arecommon in papillary cores and adjacent desmoplastic stroma.Papillary renal cell carcinoma has been subclassified into twomorphological variants, types 1 and 2. Papillary renal cellcarcinoma type 2 is composed of tall cell with eosinophiliccytoplasm and less frequently shows microcalcifications.Neoplastic cells exhibit large and spherical nuclei, prominentnucleoli, and varying degrees of nuclear pseudostratification,

CK7

Thyroglobulin

A

C D

BCD57

TTF-1

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.

CORRESPONDENCE 91



although typical nuclear changes of papillary thyroid carci-noma are not present. Papillary renal cell carcinomas typicallyexpress CK7, CK8, CK18, CK19, CAM 5.2, RCC marker,CD10, and racemase (Table 2). Micropapillary urothelial car-cinoma of the upper urinary tract is a rare variant of urothelialcarcinoma. 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 consistsof slender, delicate fine papillary and filiform processes, withcentral fibrovascular cores. Papillae are lined by high nucleargrade cells with eosinophilic cytoplasm. Psammoma bodies areinfrequent. Micropapillary carcinomas are immunoreactive forCK7, EMA, CK20, Leu M1, and CEA.

The main differential diagnosis for the follicular variant ofpapillary thyroid carcinoma metastatic to the kidney is a

recently described entity called primary thyroid-like follicularcarcinoma of the kidney. Other primary renal cell tumours,including oncocytoma, papillary renal cell carcinoma withtubular architecture, and metanephric adenoma should alsobe considered, although the presence of inspissated colloid-like material and/or follicular architecture is rare and patchy inthese tumours.

First reported in 2004, thyroid-like follicular carcinoma ofthe kidney is an extremely rare variant of renal cell carcinomawith only eight accepted cases described in the literature. Thistumour shows a slight female predominance (M:F 1:2).Histologically, these tumours are well circumscribed with adistinct fibrous capsule, a striking follicular architecture withmicro- and macro-follicles filled with inspissated colloid-likematerial. The cells lining the follicles have moderate to scant

amphophilic to eosinophilic cytoplasm. Nuclei are round tooval, with uniform chromatin and inconspicuous nucleoli.Although these tumours are usually incidentally detected, havea relatively small size, and a predominantly indolent behaviour,a distinct malignant potential is supported by reported meta-static disease in two patients. Thyroid-like follicular carci-nomas of the kidney lack key histological features ofpapillary carcinoma of thyroid, such as papillary architectureand classic nuclear changes. Immunohistochemically, tumourcells are negative for classical markers of thyroid neoplasmssuch as thyroglobulin, TTF-1 and CD57. Pax2, RCC marker,CD10, WT1, Ksp-cadherin, racemase, vimentin, and CD56have been reported to be negative. In a case recently diagnosedat the authors institution, thyroid-like follicular carcinoma ofthe kidney showed strong nuclear staining for PAX8 (unpub-lished data, personal communication).

Table 1 Clinical and pathological features of renal metastases from differentiated thyroid carcinoma

Reference Sex/Age Tumour type Presentation Years after detection Site

Takayasu et al., 19687 F/44 Follicular Abdominal mass 3 BilateralDavis et al., 19797 F/49 Follicular Incidental finding (IVP) 18 BilateralJohnson et al., 19827 F/66 Follicular Gross haematuria 37 Left kidney

Marino et al., 19917

F/ Follicular Neck nodule 23 Right kidneySardi et al., 199212 M/53 Papillary Haematuria 7 Right kidneyTuret al., 19947 F/72 PTC-FV No complaints; liver mass 3 Right kidneyRo et al., 19957 F/47 Follicular Haematuria 7 Right kidneyGraham et al., 19957 M/75 PTC-FV Gross haematuria No previous history* Left kidneyLamet al., 199611 F/91 Follicular Incidental autopsy finding No previous history Left kidneyBenchekroun et al., 19997 M/56 Papillary Low back pain 3 Left kidneyGarcia-Sanchis et al., 19997 F/65 Follicular Neck and sternal mass No previous history Left kidneyGamboa-Domingu ez et al., 19999 F/50 PTC-FV Haematuria and flank pain No previous history* Left kidneyMuller et al., 20007 F/58 Follicular Dyspnoea 11 BilateralSmallridgeet al., 20017 F/53 PTC-FV Back pain No previous history Right kidneySmallridgeet al., 20017 F/61 PTC-FV Upper back mass No previous history Left kidneyAbeet al., 20027 M/37 Papillary Incidental finding (US) No previous history* Left kidneyFerrer Garcia et al., 20027 F/58 Follicular Lumbalgia 5 Left kidneyMoudouni et al., 20027 M/62 Follicular Left upper abdominal discomfort 9 Left kidneyInsabato et al., 20037 F/64 Follicular Incidental finding (US) 35 Right kidneyMatei et al., 20037 F/78 Follicular Microscopic haematuria and flank pain 10 Right kidneyIwai et al., 20057 F/76 Follicular Haematuria and flank pain 13 Right kidneyLiouet al., 20057 F/50 PTC-FV Low back pain No previous history Right kidneyRuggiero et al., 20057 F/25 PTC-FV Abdominal/flank pain No previous history* Right kidneyKumar et al., 20057 F/66 Follicular Scalp mass No previous history Left kidneyvon Falcket al., 20077 F/64 Follicular Constant increase in serum thyroglobulin levels 20 Left kidneyGuptaet al., 200810 M/50 Papillary Flank pain and haematuria No previous history* Right kidneyMalhotra et al., 20107 M/30 Papillary Low backache radiating to the lower limbs 20 BilateralBordeet al., 20118 M/56 Pap illa ry Po st radioiodine-131 treatmen t sc anning No prev io us history BilateralPresent cases:

Case 1 M/63 Papillary Nausea, vomiting, easy satiety 15 Right kidneyCase 2 F/56 PTC-FV Haematuria and flank pain 6 Left kidney

* Treated surgically as primary renal cell tumour.IVP, intravenous pyelogram; PTC-FV, papillary thyroid carcinoma - follicular variant; US, ultrasound.

Table 2 Immunohistochemical comparison between papillary thyroid

carcinoma and papillary renal cell carcinoma

PTC PRCC

TTF-1 Thyroglobulin CK17 CD57 Racemase / CD117 /RCC marker CD15 / CK7 CK19 EMA

PRCC, papillary renal cell carcinoma; PTC, papillary thyroid carcinoma.




In conclusion, thyroid carcinoma should be considered in thedifferential diagnosis of a renal mass, particularly in patientswith a high serum thyroglobulin level, even if the mass issolitary and unilateral, or no history of thyroid cancer is present.The overlapping profile between papillary renal cell carcinomaand metastatic papillary thyroid carcinoma highlights the

importance of clinicopathological correlation, and demon-strates the importance of using a panel of antibodies in differ-entiating these tumours.


Sara M. Falzarano*{Deborah J. Chute*

Cristina Magi-Galluzzi*{

*Pathology and Laboratory Medicine Institute, and{Glickman

Urological and Kidney Institute, Cleveland Clinic, Cleveland,

OH, United States; zDepartment of Pathology and Human

Oncology, University of Siena, Siena, Italy

Contact Dr C. Magi-Galluzzi.E-mail:[email protected]

1. Mihailovic J, Stefanovic L, Malesevic M. Differentiated thyroid carcinomawith distant metastases: probability of survival and its predicting factors.Cancer Biother Radiopharm 2007; 22: 2505.

2. Clark JR, Lai P, Hall F, et al. Variables predicting distant metastases inthyroid cancer. Laryngoscope 2005; 115: 6617.

3. Patel U, Ramachandran N, Halls J, et al. Synchronous renal masses inpatients with a nonrenal malignancy: incidence of metastasis to the kidneyversus primary renal neoplasia and differentiating features on CT. Am JRoentgenol2011; 197: W6806.

4. Pascal RR. Renal manifestations of extrarenal neoplasms. Hum Pathol

1980; 11: 717.5. Heitz P, Moser H, Staub JJ. Thyroid cancer: a study of 573 thyroid tumors

and 161 autopsy cases observed over a thirty-year period.Cancer1976; 37:

232937.

6. Silliphant WM, Klinck GH, Levitin MS. Thyroid carcinoma and death. Aclinicopathological study of 193 autopsies. Cancer1964; 17: 51325.

7. Malhotra G, Upadhye TS, Sridhar E, et al. Unusual case of adrenal andrenal metastases from papillary carcinoma of thyroid. Clin Nucl Med2010;

35: 7316.

8. Borde C, Basu S, Kand P, et al. Bilateral renal metastases from papillarythyroid carcinoma on post 131I treatment scan: flip-flop sign, radioiodineSPET, 18F-FDG PET, CECT and histopathological correlation.Hell J NuclMed2011; 14: 723.

9. Gamboa-Dominguez A, Tenorio-Villalvazo A. Metastatic follicular variant

of papillary thyroid carcinoma manifested as a primary renal neoplasm.Endocr Pathol 1999; 10: 25668.

10. Gupta R, Viswanathan S, DCruzA, et al. Metastatic papillarycarcinoma ofthyroid masquerading as a renal tumour. J Clin Pathol 2008; 61: 143.

11. Lam KY, Ng WK. Follicular carcinoma of the thyroid appearing as asolitary renal mass. Nephron 1996; 73: 3234.

12. Sardi A, AgnoneCM, PellegriniA. Renal metastases from papillarythyroidcarcinoma. J La State Med Soc 1992; 144: 41620.

DOI: 10.1097/PAT.0b013e32835b5dcc

Somatostatin receptor expression in prostatecarcinoma: the urological pathologists role inthe era of personalised medicine

Sir,Somatostatin (SST) is known to inhibit the secretion of awide range of hormones, exocrine glands, and gastrointestinal

motility. Among other actions, SST has revealed an antipro-liferative potential, reversing the impact of mitogenic signalsdelivered by substances such as epidermal growth factor. Theactions of SST are mediated by membrane-associated receptorsthat comprise five distinct subtypes (termed SSTR1 to 5).Frequently multiple subtypes coexist in the same cell.

After binding their ligand, SSTR-ligand complexes undergocellular internalisation with intracytoplasmic and intranucleartranslocation. Reubi et al.1 showed that the degree of internal-isation, i.e., the ratio of internalised SSTR2 to membranousSSTR2, varied greatly from one patient to the other. Althoughgenerallyfound in endosome-like structures, internalised SSTR2were also identified to a small extent in lysosomes, as seenin co-localisation experiments.Very recently Waser etal.2 showed thatphosphorylated SSTR2 was present in most gastrointestinalneuroendocrine tumours from patients treated with octreotidebut that a striking variability existed in the subcellular distri-bution of phosphorylated receptors among such tumours.

Cloning of the five SSTRs has led to the development ofsubtype-selective ligands.3 In the era of personalised medicine

and targeted therapies, SSTR profiling is an important pre-requisite for successful in vivo somatostatin receptor targetingfor imaging or therapeutic purposes in an individual patient.Therefore, localisation and expression of the five SSTRs in atumour must be determined to decide whether the patient iseligible for these applications. Several methods have been usedto determine the expression of SSRTs.

Tissue somatostatin receptors can be measured directlyin vivo by performing a OctreoScan or 68 Ga-DOTATOCpositron emission tomography/computed tomography scan.Molecular techniques such asin situhybridisation histochem-istry and autoradiography have been used in a limited numberof studies.4 The former basically investigates SSTR mRNAexpression in cryostat sections. The latter also utilises cryostatsections and is based on radioligands, i.e., 125I-labelled somato-statin ligands, such as octreotide. Previous studies have dealtwith only some of the subtypes, therefore information islimited. The type of information obtained using these twotechniques is not always comparable to that obtained withimmunohistochemical analysis in formalin fixed, paraffinembedded (FFPE) tissue, in which the architecture and thecytology in the background are well preserved. In addition, theimmunohistochemical technique is widely available, and faster,easier and cheaper to apply than in situ hybridisation histo-chemistry and autoradiography. It can be used even retrospec-tively on archival material.

Weread with great interest the recent publication by Korner

et al.5

This study was performed on neuroendocrine tumoursfrom various gastrointestinal and extragastrointestinal sites andin a small group of non-neuroendocrine tumours. The aim of theinvestigation was to correlate FFPE-based immunohistochem-istry using the monoclonal anti-somatostatin receptor subtype2A antibody UMB-1 (Biotrend Chemikalien, Germany; orEpitomics, USA), with the gold standard in vitro methodquantifying somatostatin receptor levels in tumour tissues.The results obtained by comparing the UMB-1 immunohisto-chemistry with tumoural in vitro 125I-[Tyr3]-octreotide bind-ing site levels allowed recommendations for the use of SSTRimmunohistochemistry in daily diagnostics for optimally tai-lored patient management.

Data on the immunohistochemical patterns of the five SSTRsin prostate cancer (PCa), its precursor high-grade prostaticintraepithelial neoplasia (HGPIN) and normal prostatic

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epitheliumwere obtained by our group in FFPE archival tissuematerial.6 9 Data were collected separately for the luminal/secretory and basal epithelial cells, for the latter when present,as well as for the smooth muscle cells of the stroma and for theendothelial cells (Fig. 1).

For the secretory or luminal cells, differences were found

between normal, HGPIN and PCa (Fig. 2A), and betweenincidentally-detected and clinically-detected acinar PCa, there-fore between insignificant or indolent and significant or aggres-sive cancers.9 Typical patterns in terms of localisation andexpression of the five SSTRs in PCa with neuroendocrinedifferentiation,8 PCa following complete androgen ablation(CAA)6 and hormone refractory PCa7 were identified, withdifferences among these three groups and from untreated acinaradenocarcinoma9 (Fig. 2B).

For the basal cells in normal prostate and HGPIN,immunoreactivity was primarily detected in the cytoplasmin all the five subtypes. In subtypes 1 and 3 the mean pro-portions of positive cells were higher than in the other threesubtypes. The proportions were higher in normal prostate

compared with HGPIN. Immunoreactivity for the five SSTRsin the groups of cases with neuroendocrine tumours was

similar in terms of expression and localisation to that seenin the group of untreated HGPIN. The values in the patientsunder complete androgen ablation were lower than in theuntreated patients.

For the smooth muscle and endothelial cells, there were nocases with a distinct positivity in the cell membrane. Subtype

1 showed a strong immunoreactivity in the cytoplasm in themajority of the smooth muscle cells and the endothelial cells.Nuclear staining was seen only with subtypes 4 and 5.Neuroendocrine differentiation in PCa well as CAA andhormone refractory PCa did not affect SSTR expressionand localisation in the in the endothelial and smooth musclecells.

The limitation of our study was that the immunohistochem-ical results were not compared with data obtained with amolecular technique or with a gold standard in vitro methodquantifying somatostatin receptor levels in tissues, as was in thecase of the Korner paper.5 However, specificity of the anti-bodies used in our studies (Rabbit polyclonal anti-SSTR sub-type antibodies from Chemicon International, USA) was

assessed. Western blot experiments on a prostate tissue extractwere performed. Western blot analysis of prostate tissue

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 inprostate cancer with neuroendocrine differentiation, (E) SSTR4 in complete androgen ablated prostate cancer, and (F) for SSTR4 in hormone refractory prostate cancer.




performed with the panel of five polyclonal anti-SSTR anti-bodiesyielded single bands as previously described by Helboeet 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 cytoplasmicand nuclear localisation, i.e., cellular internalisation, of theSSTRs can be seen intriguing and controversial. For instance,the immunohistochemical expression at the cell level of the fiveSSTRs in normal and pathological prostate tissue was alsoinvestigated by Dizeyiet al.11 There were differences betweenour investigation and that by Dizeyiet al., probably due to thetypes of antibodies used (in Dizeyis investigation the anti-bodies were from a private source and not commerciallyavailable).

In conclusion, our data showed that SSTR profiling in anindividual patient with HGPIN and the multifaceted PCa isfeasible. Even though there is no clinical application for asomatostatin-based diagnostic test for prostate pathology atpresent, as opposed to neuroendocrine tumour, this shouldbe of relevance to better tailor somatostatin analogue-based

diagnostic or therapeutic procedures in neoplasms otherthan neuroendocrine tumours.12 This is particularly import-ant in the era of personalised medicine and targetedtherapies.

Rodolfo Montironi*

Marina Scarpelli*

Liang Cheng{Antonio Lopez-Beltran

Francesco Montorsi{Ziya Kirkalijj

*Section of Pathological Anatomy, Polytechnic University of

the Marche Region, School of Medicine, United Hospitals,

Ancona, and {Department of Urology, University Vita-

Salute, Scientific Institute H San Raffaele, Milan, Italy;

zDepartment of Pathology and Laboratory Medicine,Indiana University School of Medicine, Indianapolis, IN,

USA; Department of Surgery, Cordoba University Medical

School, Cordoba, Spain;jjDepartments of Urology, School of

SSTR1

0

5

10

15%

SSRT2 SSRT3 SSTR4 SSTR5

Nep

PCa

HGPIN

GS 6 PCa

0

10

20

30

40

50

60

70

80

90

100%

GS 8 PCa PCa NE CAA PCa HR PCa

Membrane

Cytoplasm

Nucleus

A

B

Fig. 2 (A) Mean percentages of intensely immunostained luminal (secretory) cells in the cytoplasm for the five SSTR subtypes in normal epithelium (Nep), high-gradeprostatic 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 cellsof 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 beingsignificant. (GS 6, Gleason score 336; GS 8, Gleason score 448; NE, NE differentiation; CAA, PCa following complete androgen ablation; HR, hormonerefractory PCa.)

CORRESPONDENCE 95



Medicine, Dokuz Eylul University, Izmir, Turkey; these

authors contributed equally to this work

Contact Professor R. Montironi.E-mail:[email protected]

1. Reubi JC, Waser B, Cescato R, et al. Internalized somatostatin receptorsubtype 2 in neuroendocrine tumors of octreotide-treated patients. J ClinEndocrinol Metab 2010; 95: 234350.

2. Waser B, Cescato R, Liu Q, et al. Phosphorylation of sst2 receptors inneuroendocrine tumors after octreotide treatment of patients. Am J Pathol

2012; 180: 19429.

3. Hofland LJ, van der Hoek J, Feelders R, et al. Pre-clinical and clinicalexperiences with novel somatostatin ligands: advantages, disadvantagesand new prospects. J Endocrinol Invest2005; 28: 3642.

4. Montironi R, Cheng L, Mazzucchelli R, e t a l. Immunohistochemicaldetection and localization of somatostatin receptor subtypes in prostatetissue from patients with bladder outlet obstruction. Cell Oncol 2008; 30:47382.

5. Korner M, Waser B, Schonbrunn A,et al. Somatostatin receptor subtype 2A

immunohistochemistry using a new monoclonal antibody selects tumorssuitable for in vivo somatostatin receptor targeting.Am J Surg Pathol2012;36: 24252.

6. Mazzucchelli R, Morichetti D, Santinelli A, et al. Immunohistochemical

expression and localization of somatostatin receptor subtypes in androgenablated prostate cancer. Cell Oncol (Dordr) 2011; 34: 23543.

7. Mazzucchelli R, Morichetti D, Scarpelli M, et al. Somatostatin receptorsubtypes in hormone-refractory (castration-resistant) prostatic carcinoma.Asian J Androl2011; 13: 2427.

8. Morichetti D, Mazzucchelli R, Santinelli A, et al. Immunohistochemicalexpression and localization of somatostatin receptor subtypes in prostate

cancer with neuroendocrine differentiation.Int J Immunopathol Pharmacol

2010; 23: 51122.

9. Morichetti D, Mazzucchelli R, Stramazzotti D, et al. Immunohistochemicalexpression of somatostatin receptor subtypes in prostate tissue fromcystoprostatectomies with incidental prostate cancer. BJU Int2010; 106:107280.

10. Helboe L, Mller M, Nrregaard L, et al. Development of selectiveantibodies against the human somatostatin receptor subtypes sst1-sst5.Brain Res Mol Brain Res 1997; 49: 828.

11. DizeyiN, Konrad L, Bjartell A, et al. Localization and mRNA expression of

somatostatin receptor subtypes in human prostatic tissue and prostatecancer cell lines. Urol Oncol 2002; 7: 918.12. Mazzucchelli R, Scarpelli M, Lopez-Beltran A, et al. Immunohistochem-

ical expression and localization of somatostatin receptors in normal pros-tate, high grade prostatic intraepithelial neoplasia and prostate cancer andits many faces. J Biol Regul Homeost Agents 2012; 26: 18192.

DOI: 10.1097/PAT.0b013e32835bae76

Reticular and microcystic schwannoma of theparotid gland

Sir,Reticular and microcystic schwannoma is a recently described,rare, distinctive variant of schwannoma with a predilection forvisceral organs, particularly the gastrointestinal tract.1,2 Fewerthan 20 cases have been described in the literature and involve-ment of the head and neck has not been reported.16 Herein wereport a case of reticular and microcystic variant of schwan-noma in the parotid gland and discuss its unique histomorpho-logical features and the relevant differential diagnoses in thislocation. Microcystic/reticular variant of schwannoma demon-strates similar biological behaviour to usual schwannoma andmust be distinguished from other parotid gland tumours thatmay recur aggressively if incompletely excised.

A 59-year-old woman presented with a small pre-auricularswelling. She did not have any stigmata of neurofibromatosis

(NF) type I or II. Fine needle aspiration smears showed looselycohesive aggregates of cytologically bland spindle shaped cellsadmixed with myxoid stroma (Fig. 1A). The cellular aggregatesshowed swirling patterns (Fig. 1B) and occasional cells showedintracytoplasmic vacuoles (Fig. 1C). The cytological featureswere of a benign lesion and a diagnosis of pleomorphic

adenoma was made on cytology. At surgery, the tumour wasfound closely associated with facial nerve and was resectedwith nerve preservation.

The surgical specimen comprised a portion of the parotidgland with a macroscopically well circumscribed nodulemeasuring 28 20 16mm. On cut section, the tumourappeared pale grey, firm and had a gelatinous texture(Fig. 2A). Histologically, the tumour was well demarcated,but unencapsulated with entrapped ductal structures at theperiphery (Fig. 2B). Occasional lymphoid aggregates were alsoseen at the periphery (Fig. 2C). The tumour was composed ofslender spindle shaped cells arranged in an anastomosinglattice-like pattern amidst myxoid stroma. Microcystic andreticular formations were seen (Fig. 2D). The cells showed

cytoplasmic vacuolation and uniform slender spindle shaped toovoid nuclei (Fig. 2E). Foci of extravasated red blood cellswere seen. Focally, the extravasated red blood cells overlyingcytoplasmic vacuoles appeared reminiscent of intracytoplasmiclumina with red blood cells (Fig. 2F).

The lesion displayed relatively uniform cellularity and hypo-and hypercellular areas, or areas with nuclear palisading werenot seen. Hyalinised, thick walled blood vessels were absent.Degenerative changes, cyst formation, haemorrhage, or foamymacrophages were not seen. Epithelial elements, other than theperipheral entrapped ducts, were not identified within thetumour. Cytological atypia, mitoses or necrosis were notpresent. Special stains with periodic acid-Schiff reagent, withand without diastase digestion, and mucicarmine did not showany intracytoplasmic glycogen or mucin.

Immunohistochemical staining of the tumour showed diffuseand strong nuclear and cytoplasmic immunoreactivity withS100 (Fig. 3A). The tumour also showed immunoreactivityfor GFAP (Fig. 3B) and CD34. The tumour lacked immuno-reactivity with multiple epithelial markers including Pan CK,AE1/AE3, EMA, Cam5.2, mCEA, and CK7. The tumour alsolacked immunoreactivity with myoepithelial markers such assmooth muscle actin (SMA), p63, calponin, smooth musclemyosin heavy chain (SMMHC) and vascular markers such asCD31, D240 and factor VIII. The tumour did not demonstrateimmunoreactivity with desmin and myogenin.

Electron microscopy performed on formalin fixed, paraffin

embedded tissue showed scattered elongated spindle cells in anamorphous matrix with thin cellular processes, scant cyto-plasmic organelles and focal basal lamina-like material(Fig. 3C). Epithelial, myoid or endothelial differentiationwas lacking.

Schwannomas are generally benign, non-recurring tumoursthat can show a plethora of histological appearances and severalvariants are well described in the literature. Liegl et al. haverecently described reticular and microcystic variant of schwan-noma in visceral organs.1 As observed in the current case, thesetumours show a predilection for women in the seventh decadeand tend to be relatively small in size.2 The tumours aretypically well circumscribed and show spindle shaped cellsembedded in myxoid matrix as seen in this case.1,2 The currentcase also showed extensive lattice-like patterns with cribriformmicrocystic areas as described in the literature.1,2 Areas with




extravasated red blood cells were also present. An unusualfeature observed in the current case and not described pre-viously in literature was the presence of intracytoplasmicvacuoles within most of the spindle shaped cells. Thesevacuoles could also be observed in the fine needle aspirationmaterial.

A high index of suspicion and awareness of the histologicalfeatures of this variant are essential for accurate diagnosis as thetumour lacks several typical features seen in a usual schwan-noma. Visceral examples of microcystic and reticular variant ofschwannomas lack encapsulation and may show entrapmentofnormal structures at the periphery as seen in the current case.1 A

peripheral cuff of lymphoid aggregates, as seen in the currentcase, may be helpful when present; however, Liegl et al.observed this feature in only about 10% of their cases.1 Thetumours also generally lack the classic organisation into AntoniA and Antoni B areas, and thick walled hyalinised vessels maybe rare.1,2,4 Immunohistochemistry is of diagnostic utility asmicrocystic and reticular variant of schwannoma demonstratesimmunoreactivity for S100, GFAP and occasionally for CD34,as is the usual case in schwannomas. As expected, the tumourslack immunoreactivity for all epithelial, myoepithelial, muscleand vascular markers such as a broad panel of cytokeratins, p63,calponin, SMA, desmin, CD31, D240 and factor VIII.

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 aanastomosing 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).

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The histopathological appearance of these tumours raises awide spectrum of differential diagnoses, particularly in thesalivary gland where extratemporal schwannomas arising fromthe

Obtaining Expert Opinions in Diagnostically.12

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