Despite a strong body of literature, the cytological approach for the diagnosis of paediatric tumours is not universally accepted among clinicians and pathologists. However, several studies have shown that in the hands of a well-trained team with good collaboration between paediatrician, radiologist and cytopathologist, fine needle aspiration (FNA) followed by cytological examination is a highly accurate approach for quickly rendering a preliminary or final diagnosis.^1,2 The definitive diagnosis may sometimes necessitate the use of ancillary studies such as immunocytochemistry and molecular genetic testing. In some cases, tissue examination by means of a needle core or an open surgical biopsy may be required.^3,4

Childhood tumours are quite different from those observed in adults: (1) they are rare, corresponding to less than 1% of all malignancies and only one case of cancer is encountered annually among 10 000 children up to 15 years of age; (2) less than 5% are derived from respiratory, gastrointestinal and reproductive organs, whereas 80% of adult cancers are derived from these tissues; (3) most childhood tumours are embryonal and immature neoplasms.

Major contributions of diagnostic and prognostic value are to be gained by a detailed evaluation of the findings on cytology.^5–7 Cytological evaluation may be undertaken to determine the nature of a lesion (benign versus malignant) and attempt to define its histological subtype further. This is the case when the clinician deals with a child with lymphadenopathy or with a lesion which has to be treated by primary chemotherapy as soon as possible. When a diagnosis has been previously established, cytological evaluation may be requested to define the anatomical extent of disease and identify tumour-related prognostic factors. This type of evaluation may provide important information for staging purposes, to help define prognosis and for monitoring response to therapy. Finally, in the follow-up of children with tumours, cytology can confirm the presence of recurrence, metastasis or secondary neoplasms.

Our policy in taking cytological samples from children is the following: (1) in palpable lesions, children are given local anaesthesia in the form of a cream which is applied over the area to be sampled a half to 1 hour prior to the procedure. Only babies are held down in order to ensure that they will not move during the procedure. With older children who recognise the doctor and injections, we ask them for cooperation and they usually do so perfectly. If they are unable to cooperate, the sample is taken under sedation or light general anaesthesia. In both cases the cytopathologist performs the procedure; (2) in non-palpable lesions, the sample is guided by image (usually ultrasound echography) and done either by the cytopathologist or the radiologist. The needles we use are 0.6–0.7 mm in diameter. It is important to emphasise that the presence of the cytopathologist is crucial for checking sample adequacy and ensuring proper handling of the specimen for smearing, fixation and triage for ancillary techniques.

Some of the most frequently suspected diagnoses based on symptoms and locations are summarised in Table 33.1. Common tumour types in foetuses and newborns are listed in Box 33.1 and the distribution by percentage of malignant tumour types in children and adolescents is shown in Table 33.2.

Table 33.1 Presenting symptoms and commonly associated suspected diagnoses

Table 33.2 Distribution (by percentage) of malignant tumour types in children (0–14 years) and adolescents (15–19 years)

In the foetal and neonatal periods (0–3 months of age), tumours are similar to those occurring in older infants. However, they differ in terms of frequency, sites of involvement, distribution, degree of differentiation and prognosis.

Tumours in children (3 months to 14 years of age) and adolescents (15–19 years of age) have distinct characteristics in terms of distribution. As shown above: (1) more than half of malignancies in children are acute leukaemias and central nervous system tumours; (2) Hodgkin disease and germ cell tumours are more frequent in adolescents than in children; (3) neuroblastoma, nephroblastoma and retinoblastoma are exceptional in adolescents. Other variations in incidence are also noted depending on gender and ethnicity.

About 10% of all childhood neoplasms are lymphomas and most of these are of the non-Hodgkin type (Table 33.2).

Diagnosis and classification is based on morphology⁸ and results of ancillary testing such as immunophenotyping by flow cytometry, cytogenetic studies (karyotype, FISH) and molecular genetic testing (PCR). Non-Hodgkin lymphoma (NHL) is rare in children less than 2 years of age and a peak incidence is observed between 5 and 15 years of age. More than 90% of NHL are high-grade lymphomas and include precursor and mature B-cell, T-cell or natural killer-cell neoplasms. High-grade mature B-cell neoplasms are represented by Burkitt and diffuse large B-cell lymphomas, whereas high-grade mature T-cell tumours are most frequently anaplastic large cell lymphomas. The most frequently encountered lymphoma types in childhood are summarised in Table 33.3.

Table 33.3 Most frequent non-Hodgkin lymphomas in children and adolescents

Burkitt and Burkitt-like lymphomas^9,10

Background

Classical Burkitt (BL) and Burkitt-like lymphomas (BLL or atypical BL) (Fig. 33.1A) may present at extranodal sites or as an acute leukaemia. BL is mainly observed in equatorial Africa in its endemic form, with a peak incidence in children aged 4–7 years. The abdomen and jaw are the main sites of involvement in approximately 70% of children less than 5 years of age and in 25% of children over the age of 14 years. The sporadic form of BL is seen throughout the world, mainly arising in the abdomen and the Waldeyer’s ring of children and young adults. A third form of BL is related to immunosuppression and may be the initial manifestation of the acquired immunodeficiency syndrome (AIDS) due to the human immunodeficiency virus (HIV) infection.

Fig. 33.1 (A) Burkitt lymphoma. Medium-sized lymphoid cells with scanty blue cytoplasm showing lipid vacuoles. Note the dense chromatin and the presence of several mitoses and of a macrophage with tingible bodies (MGG). (B) Burkitt lymphoma. FISH on a metaphase with a c-myc «break apart» probe showing a translocation of part of cmyc gene to chromosome 14 (green spots). Part of the gene is still visible on chromosome 8 (red). The second-normal c-myc gene is composed of two overlapping parts on normal chromosome 8.

Cytological findings: Burkitt and Burkitt-like lymphomas

• Relatively uniform population of isolated medium-sized tumour cells

• Rounded nuclei with a high mitotic rate

• Granular or speckled chromatin with multiple small but prominent nucleoli

• Thin rim of dense blue cytoplasm with small lipid vacuoles

• Tingible body macrophages (producing a ‘starry sky’ pattern on histological sections) often prominent, apoptotic bodies in the background

• Variants: BL with plasmacytoid differentiation may show tumour cells with abundant blue cytoplasm and a single eccentric nucleus with central nucleolus. BLL usually exhibits a higher degree of pleomorphism in nuclear size and shape. Both of these variants are rare entities.

Diagnostic pitfalls: BL and BLL

• B-cell lymphoblastic lymphoma

• Diffuse large B-cell lymphoma in BLL (atypical)

• Extramedullary myeloid malignancies (granulocytic or myeloid sarcoma)

• Other small round cell tumours (Box 33.2): CD45 may be absent in BL.

Box 33.2 Main malignant round cell tumours

1. Lymphomas

• Burkitt, lymphoblastic and centroblastic variant of diffuse large B cell (small cells)

• Diffuse large B cell

2. Neuroblastoma (small and/or large cells)

3. Nephroblastoma (small and/or large cells)

4. Rhabdomyosarcoma of the alveolar type (small and/or large cells)

5. Germ cell tumours (large cells)

6. Other soft tissue sarcomas (small and/or large cells)

• Malignant peripheral nerve sheath tumour

• Liposarcoma

• Malignant rhabdoid tumour

• Desmoplastic small round cell tumour

7. Ewing family of tumours or pPNET (small cells)

8. Liver tumours (small or large cells)

Usefulness of ancillary techniques

Immunophenotyping of tumour cells demonstrates: (1) the absence of precursor markers (TdT negativity); (2) the presence of B-cell-associated antigens (CD19, CD20, and CD10); (3) expression of surface IgM with light chain (kappa or lambda) restriction; (4) over 95% of tumour cells express the Ki67 proliferative marker. Molecular genetic testing reveals a translocation of the MYC gene (Fig. 33.1B) at band q24 from chromosome 8 with the Ig heavy chain region on chromosome 14 at band q32 corresponding to t(8;14). Less commonly, translocations involve the MYC gene (8q24) and light chain loci on 2q11 (kappa chain) or on 22q11 (lambda chain) corresponding to t(2;8) and t(8;22), respectively. However, these translocations involving MYC may also be observed in other lymphomas, such as diffuse large B-cell lymphoma.

Precursor T and B lymphoblastic lymphoma (LL)(Fig. 33.2)^11–13

Background

LL may present at nodal sites or as an acute lymphoblastic leukaemia (ALL) with bone marrow (>25%) and blood involvement. Precursor T-LL is the most frequent disease, usually affecting children >6 years and adolescents in a nodal form, and a mediastinal (thymic) mass is frequently present (85%), sometimes also with meningeal involvement. Precursor B-LL affects children <6 years and is more commonly seen in the leukaemic form.

Fig. 33.2 Lymphoblastic lymphoma. Monomorphous population of blasts with irregular or convoluted nuclei and dense finely granular chromatin (bone marrow) (MGG).

Cytological findings: precursor T and B lymphoblastic lymphoma

• Relatively uniform population of isolated medium-sized tumour cells

• Anisonucleosis and convoluted nuclei classically more prominent in T-cell than in B-cell variants

• Finely granular chromatin with inconspicuous nucleoli in the T-cell variant and granular or speckled chromatin with multiple small but prominent nucleoli in the B-cell variant

• Cytoplasm usually fragile and small cytoplasmic vacuoles may be seen.

Diagnostic pitfalls: precursor T and B LL

• BL

• Distinction between T and B forms of lymphoblastic lymphoma

• Extramedullary myeloid malignancies (granulocytic or myeloid sarcoma)

• Other small round cell tumours (Box 33.2): CD45 may be negative in lymphoblastic lymphoma.

Usefulness of ancillary techniques

Immunophenotyping of tumour cells demonstrates: (1) precursor markers (TdT positivity); (2) T-cell markers are identified in 85% of cases (CD3 and CD7 often present; CD4 and CD8 positivity variable and depends on degree of maturation), but aberrant T-cell populations with the loss of one or more pan-T-cell markers (CD2, CD3, CD5, CD7) can also be identified. B-cell markers are detected in 15% of cases (CD19 and CD79a are almost always present; CD34, CD10 and cytoplasmic Ig positivity depends on the degree of maturation); (3) absence of surface Ig. A variety of molecular abnormalities of no currently defined clinical significance can be identified in precursor T-cell lymphoblastic lymphoma. However, some molecular abnormalities are of prognostic importance and are used to modify treatment in precursor B-LL. For example, hyperdiploidy with more than 50 chromosomes, corresponding to a DNA index of 1.16 to 1.60, or the presence of a t(12;21) translocation is associated with an improved prognosis, whereas hypodiploidy or detection of t(1;19), t(9;22) or t(4;11) is associated with a poor outcome.

Anaplastic large cell lymphoma (ALCL)^15–17

Background

ALCL (Fig. 33.3) is a mature T-cell or null cell lymphoma. It usually consists of large lymphoid cells frequently expressing CD30 (Ki-1) and the anaplastic large cell lymphoma kinase (ALK) protein. Most children present with lymphadenopathy and skin involvement may occur.

Fig. 33.3 Anaplastic large cell lymphoma. Large isolated lymphoid cells (intense basophilic cytoplasm) showing pleomorphic and ‘kidney-shaped’ nuclei (MGG).

Cytological findings: anaplastic large cell lymphoma

• Common variant (70%): large lymphoid cells with abundant cytoplasm and pleomorphic, often horseshoe-shaped nuclei (so-called hallmark cells)

• Lymphohistiocytic variant (10%): admixed histiocytes may obscure tumour cells

• Small cell variant (10%): small- to medium-sized plasmacytoid, spindle or tadpole cells, pale basophilic cytoplasm. Usually, diagnostic hallmark cells are admixed.

Diagnostic pitfalls: ALCL

• Classic Hodgkin lymphoma (CD30 positive and ALK negative) in the case of T-cell common variant and the null cell form (CD15 and EBV negative)

• Malignant histiocytosis in the case of lymphohistiocytic variant

• Reactive lymphadenopathy in the case of small cell variant

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