7. Gugger M, Kappeler A, Vonlanthen S et al. Alterations of cell

cycle regulators are less frequent in advanced non-small cell lung

cancer than in resectable tumours. Lung Cancer 2001; 33; 229–

239.

8. Keum JS, Kong G, Yang SC et al. Cyclin D1 overexpression is an

indicator of poor prognosis in resectable non-small cell lung

cancer. Br. J. Cancer 1999; 81; 127–132.

9. Folkman J. What is the evidence that tumours are angiogenesis

dependent? J. Natl Cancer Inst. 1990; 82; 4–6.

10. Blood CH, Zetter B et al. Tumor interactions with the vasculature:

angiogenesis and tumor metastases. Biochem. Byophys. Acta

1990; 1032; 89–118.

Psammoma bodies in medulloblastoma

DOI: 10.1111/j.1365-2559.2007.02624.x

Sir: Medulloblastomas (MBs) are malignant embryonaltumours of the cerebellum which predominantly affectchildren.1 Histopathologically, classic MB is composedof densely packed cells with round-to-carrot-shaped,highly hyperchromatic nuclei, surrounded by scantycytoplasm. In addition to the well-known variants ofmedullomyoblastoma and melanotic MB, five histo-logical patterns have been identified: undifferentiatedMB; MB with neuroblastic or neuronal differentiation;desmoplastic MB; MB with glial differentiation; and MBwith epithelial differentiation. Furthermore, large-cellMB has recently been recognized as a distinct variantwith highly aggressive behaviour.1 Psammoma bodies(PBs) are round calcific concretions exhibiting concen-tric lamination that are frequently observed in papil-lary carcinomas of the thyroid gland, serous papillaryadenocarcinomas of the ovary, adenocarcinomas of theendometrium and meningiomas.2 Adenocarcinomasof the lung and mesotheliomas infrequently containPBs, while papillary adenocarcinomas of the endocervixand colon as well as insulinomas rarely contain PBs.2 Inaddition, PBs can also be seen in melanotic schwan-nomas, whose identification is especially importantbecause it may be a component of the Carney complex.3

In this study we report a case of MB with PBs; to the bestof our knowledge, this is the first reported case.

A 9-year-old male presented with headache, lethargyand vomiting of 2 weeks’ duration. Magnetic reson-ance imaging revealed a midline cerebellar mass. Allthe laboratory tests were within normal limits. Totalremoval of the tumour was successfully accomplished.Computed tomography scan of the abdomen and chest,in addition to other examinations, revealed no abnor-malities in any other extracranial organs. Postopera-tively, the patient received chemotherapy as well asradiotherapy and clinical follow-up for the last6 months has revealed no recurrence on neuroimagingor neurological examination.

Histologically, the tumour was composed of diminu-tive, round-to-ovoid cells closely arrayed in packedsheets. The nuclei were densely hyperchromatic,rounded or angulated, and invested with little or nodefinable cytoplasm and seemed prone to deformationor ‘moulding’ by their neighbours. A tendency toswirling or a fascicular architecture and fusiformcellular profiles was encountered, as many nuclei weredisposed in perivascular pseudorosettes. Homer–Wrightrosettes were also seen. The mitotic index was 9 ⁄ 10high-power fields1 . Individual cell death as well assmall areas of coagulative necrosis were noticed.Stromal elements were typically scanty and consistedof scattered small blood vessels. Multiple round purpleconcretions exhibiting concentric lamination and sur-rounded by tumour cells representing PBs were seen(Figure 1). PBs were seen in several foci of the tumourbut not in the vicinity of coagulative necrosis. Apop-totic tumour cells were discernible in the vicinity of PBs(Figure 1).

The tumour cells were phenotyped immunohisto-chemically by the streptavidin–biotin method usingantibodies (Dako, Glostrup, Denmark) diluted to 1 : 50.The neural elements were uniformly neurone-specificenolase- (data not shown) and synaptophysin (data notshown)-positive, while immunoreactivity to neurofila-ment (Figure 2) and chromogranin (data not shown)was seen in a few foci of tumour cells. Glial fibrillaryacidic protein was also discernible in a few tumour cells(data not shown). In addition, vimentin was diffuselypositive in all tumour cells (data not shown). Thetumour cells showed no immunoreactivity to epithelialmembrane antigen, cytokeratin, desmin, smooth mus-cle actin, HMB-45, CD99, S100 or CD45 (data notshown).

Figure 1. Medulloblastoma with a psammoma body surrounded by

tumour cells (H&E), ·1000.

Correspondence 527

� 2007 The Authors. Journal compilation � 2007 Blackwell Publishing Ltd, Histopathology, 50, 511–530.

MB is recognized as one of the most commontumours of the posterior cranial fossa. MB with PBformation has not been previously reported.

PB, a term derived from the Greek word psammosmeaning ‘sand’, is a microscopic round collection ofcalcium with a laminar appearance.2 Its origin iscontroversial, but it has been suggested that the nidusfor its formation is a single necrotic tumour cell, uponwhich successive layers of calcium salt deposits areadded.2

Particular attention has been paid to PBs associatedwith papillary thyroid carcinoma, since these havebeen found to represent the end stages of two differentbiological events. The first event which occurs in thevascular stalk of the neoplastic papillae starts with athickening of the basal lamina followed by vascularthrombosis, calcification and tumour cell necrosis.In the second event, intralymphatic tumour thrombiin the thyroid lobe adjacent to the main tumours or inthe opposite thyroid lobe become necrotic and calcified.In some instances, destruction of lymph vessels leads tofibrin exudation and perilymphatic fibrosis.4

In ovarian serous adenocarcinomas, it has beensuggested that PBs arise as products of neoplastic andhistiocytic cellular degeneration; there is also evidencethat nanobacteria may be involved in their patho-genesis.5

Apoptosis has also been implicated in the develop-ment of psammoma bodies since apoptotic bodies (ABs)can concentrate calcium in a crystallized form.6 ABblebs have similarities with matrix vesicles, which arecellular products responsible for the initiation ofcalcification in cartilage and bone.6 Concomitantincreases in calcium and phosphate in blebs formed byapoptotic cells are apparently the primary mechanism

of calcification.6 The work of Kim5 implicates apoptosisin the process of calcification. In addition, membranouscellular degradation products and organelles extrudedfrom the dead cells, mainly resulting from apoptosis,provide the substrates for calcium binding in thedevelopment of PBs.6

PB formation starts at the submicroscopic level.Initially, microcrystals of oxyapatites are deposited onaccumulations of protein substances in cytoplasmiccisterns and on mitochondrial cristae. With furtheraccumulation of these crystals relatively large intra-cytoplasmic inclusions of oxyapatites are formedwhich, after confluence, fill the cell and result in itsdeath. In this way a small PB becomes free-lying.7

Recently, osteopontin protein produced by macro-phages has been reported to play a significant role inthe development of calcifying foci in both psammo-matous and non-psammomatous human neoplasms.In addition, it has been proposed that bone morpho-genetic protein-2 is involved in the calcification oftumour cells and recent electron microscopic studieshave demonstrated the presence of type IV collagenin PBs.8

We believe that PBs in the present tumour may haveoriginated from apoptotic tumour cells, since apoptotictumour cells were seen in the vicinity of PBs, uponwhich successive layers of calcium salts were depositedand became trapped in the fibrous stroma adjacent tothe viable neoplastic cells.

A C K N O W L E D G E M E N T S

The authors would like to acknowledge Professor G.Buzzell and Associate Professor E. Mensah-Brown inthe Anatomy Department, in the Faculty of Medicineand Health Sciences, United Arab Emirates University,AlAin, UAE, for their support during this work.

S Al-SalamM Al Ashari1

Department of Pathology,

Faculty of Medicine and Health Sciences,

UAEU and 1Department of Pathology,

Tawam Hospital, AlAin, UAE

1. Son EI, Kim IM, Kim DW et al. Immunohistochemical analysis for

histopathological subtypes in pediatric medulloblastomas. Pathol.

Int. 2003; 53; 67–73.

2. Nakayama H, Okumichi T, Nakashima S et al. Papillary adeno-

carcinoma of the sigmoid colon associated with psammoma bodies

and hyaline globules: report of a case. Jpn J. Clin. Oncol. 1997; 27;

193–196.

Figure 2. Neurofilament immunostaining in medulloblastoma

(immunoperoxidase), ·400.

528 Correspondence

� 2007 The Authors. Journal compilation � 2007 Blackwell Publishing Ltd, Histopathology, 50, 511–530.

3. Carney JA. Psammomatous melanotic schwannoma. A distinctive,

heritable tumour with special associations, including cardiac

myxoma and the Cushing syndrome. Am. J. Surg. Pathol. 1990;

14; 206–222.

4. Johannessen JV, Sobrinho-Simoes M. The origin and significance

of thyroid psammoma bodies. Lab. Invest. 1980; 43; 287–296.

5. Hudelist G, Singer CF, Kubista E et al. Presence of nanobacteria in

psammoma bodies of ovarian cancer: evidence for pathogenetic

role in intratumoral biomineralization. Histopathology 2004; 45;

633–637.

6. Kim KM. Apoptosis and calcification. Scanning Microsc. 1995; 9;

1137–1178.

7. Kozlovskii OM, Iagubov AS, Kiparisov LN et al. Mechanism of

formation of the psammoma bodies in serous adenocarcinomas of

the ovaries. Arkh. Patol. 1978; 40; 25–32.

8. Kiyozuka Y, Nakagawa H, Senzaki H et al. Bone morphogenetic

protein-2 and type IV collagen expression in psammoma body

forming ovarian cancer. Anticancer Res. 2001; 21; 1723–1730.

The continued value of centralhistopathological review of testiculartumours

DOI: 10.1111/j.1365-2559.2007.02625.x

Sir: We read with great interest the paper of Delaneyet al.1 regarding the continued value of central histo-pathological review of testicular tumours and agreetotally with their opinion.

Patients with testicular tumours in Birmingham &Black Country are referred to University HospitalBirmingham NHS Foundation Trust (UHB) for treat-ment; hence all testicular cancers in the region arereviewed by two histopathologists in the departmentwith a special interest in urological pathology.

The criteria mentioned in the minimum dataset haveimportant implications for management of germ cellneoplasms of the testis. The histopathology report alsoprovides prognostic criteria with a significant impacton patient outcome. Stage 1 seminoma is managedwith carboplatin-based chemotherapy in our institute,although therapeutic options include prophylacticradiotherapy and surveillance, while advanced stageseminoma is treated with either radiotherapy orchemotherapy.2 It is recommended that Stage 1 non-seminomatous germ cell tumour (NSGCT) is treatedwith orchidectomy alone, with further therapy forthose cases only that show relapse on close monitoring.The ‘surveillance only’ approach is not indicated in thepresence of high-risk factors and is hence replaced bytwo courses of combination chemotherapy in NSGCTexhibiting blood vessel invasion.2 In stage 1 NSGCThistological parameters which may be associated withoccult metastasis in retroperitoneal lymph nodes or

relapse include predominance of embryonal carcinomaand absence of yolk sac tumour.3 Advanced stageNSGCT is treated by three or four courses of combina-tion chemotherapy.2

In a recent audit, we reviewed all testicular cancersreported in our department between January 2004 andSeptember 2005. A total of 63 cases were included inthe study, which consisted of nine cases from UHB and54 referred cases.

The original report was compared with the finalreport from UHB for criteria mentioned in the mini-mum dataset and discrepancies were noted.

The majority of criteria mentioned in the minimumdataset were included in both the original and reviewreports with the exception of pathological stage andpercentage of individual components of NSGCT. Thepathological stage was mentioned in only 60% of initialreports compared with 100% of review reports. Thepercentage of components of NSGCT was mentioned ina minority of the original reports; however, this wasreported in 95% of the reports on review.

There were discrepancies in the reporting of tumourtype in four cases (7%). In one case, the diagnosis waschanged from combined seminoma and embryonalcarcinoma to classic seminoma. In this instance a tinyfocus of tumour cells with a trabecular and glandularpattern was misinterpreted as embryonal carcinomaby the initial pathologist. The focus in question wasmorphologically similar in appearance to the semin-oma and placental alkaline phosphatase (PLAP) posit-ive. This changed the treatment from surveillance onlyto a single dose of carboplatin.

The second case initially assessed as NSGCT withadenocarcinoma was classified as NSGCT with areas ofyolk sac tumour on review, which was confirmed withimmunohistochemistry for broad-spectrum cytokeratinand a-fetoprotein.

In two cases, the original diagnosis was NSGCT, buton review of the slides small groups and cords ofneoplastic cells were observed infiltrating between theseminiferous tubules, which were PLAP+ and CD117+.This was interpreted as microinvasive seminoma atleast and the diagnosis was changed to a combinedgerm cell tumour.

Failure to recognize or misinterpretation of one ormore components of NSGCT was observed in 48% ofthe cases referred for review. Yolk sac tumour wasmost commonly missed or misinterpreted due to itsvariable histological pattern. Staging parameters suchas lymphovascular and cord invasion were wronglyinterpreted or missed in five (9.2%) cases. Four of thesewere upstaged on review and therefore treated bycombined chemotherapy. One case was downstaged,

Correspondence 529

� 2007 The Authors. Journal compilation � 2007 Blackwell Publishing Ltd, Histopathology, 50, 511–530.