RESIDENT CASE STUDIES

Week 4 May 12 - May 16, 2003: Case 2   

Table of Contents | List of Diagnoses | Case 1 | Case 2 | Case 3 | Case 4 

7 month old female with an abdominal mass 

Discussion:
The histologic findings of this case should remind you of the “small round blue cell” tumors which in children include: rhabdomyosarcoma, lymphoma/leukemia, Ewings sarcoma/PNET, medulloblastoma, neuroblastoma, Wilm's tumor, desmoplastic small round blue cell tumor. It is sometimes difficult to differentiate these tumors without the use of immunohistochemistry and/or molecular pathology techniques. All these should feature in the differential diagnosis.

The diagnosis for the above case is Neuroblastoma. Neuroblastoma is the 3^rd most common malignant tumor and the most common extracranial solid tumor in children. Most cases are diagnosed by the age of 4 years, and the median age at diagnosis is 21 months. It is extremely rare in adults. The tumor commonly develops in relationship with the sympathetic nervous system and most often appears as an abdominal mass. Neuroblastoma is twice as likely to occur in the adrenal gland compared to extra-adrenal primary sites (head and neck region, posterior mediastinum or pelvic area). About 80 to 90% of neuroblastomas have elevated catecholamines (norepinephrine, epinephrine) and their metabolites [homovallinic acid (HVA), vanillymandelic acid (VMA) and 3-methoxy-4-hydroxyphenylglycol (MHPG)] in the urine. Measurements of these catecholamines and their metabolites can be used to monitor the course of the disease during therapy. High VMA/HVA ratios have been associated with good prognosis (ratios 1.5 or more). 

On microscopic examinations, neuroblastomas are composed of sheets of small round blue cells (small cells with collections of hyperchromatic nuclei and scant cytoplasm). There may be vague lobulation due to thin fibrovascular septa between groups of tumor cells. A finely fibrillar eosinophilic matrix (schwannian / neuropil) is found between the tumor cells, which at ultrastructural level, corresponds to masses of unmyelinated axons. Schwannian /neuropil stroma, when present, differentiates neuroblastoma from other small round blue cell tumors, even without special stains or molecular pathology. No other non-CNS small round blue cell tumor, has schwannian stroma (Dr. K Atkins, verbal). The schwannian stroma in itself is of no prognostic significance, but it can help differentiate the tumors into “stroma rich” and “stroma poor”. Homer Wright pseudorosettes  (one or two layers of neuroblasts arranged around a central space that is filled with tangles of neuritic processes) are found in about 30% of the cases. Immunohistochemically, neuron specific enolase is present in virtually all cases of neuroblastoma, but this can be present in non neuroblastic tumors. S100 protein is strongly expressed in the ganglioneuromatous portions of these tumors and may correspond to the degree of differentiation. CD99 is usually negative. 

The degree of differentiation should be assessed on microscopic evaluation of the neuroblastoma. Differentiation is evidenced by the development of nuclear enlargement and  more abundant eosinophilic cytoplasm. Differentiation between the following is very important histologically: undifferentiated / poorly differentiated tumor (0 to 5% differentiation), differentiating tumor (>5% but less than 50% differentiation), ganglioneuroblastoma (>50% mature). In addition to differentiation, presence or absence of distinct nodules should be noted. Mitotic Karyorrhexis Index (MKI), which is a count of cells undergoing mitosis or karyorrhexis, based on 5000 cells. A count of greater than 200 mitotic and karyorrhectic cells per 5000 cells is considered high MKI. A count of less than 100 is considered low MKI. A of 100 to 200 is considered intermediate MKI. Low MKI is a favorable histologic finding, but in of itself is not a prognostic factor. 

N-MYC oncogene is present in about a fourth of the cases and is associated with poor prognosis. Increased TRK-A (tyrosine kinase receptor A) expression, on the on the other hand, is associated with good prognosis. 

Staging of the tumor is of utmost prognostic importance.

• I  confined to the organ of origin and completely excised.

• II  extends beyond the organ of origin, but does not cross the midline. Ipsilateral lymph nodes may or may not be positive. Completely/incompletely excised.

• III  Extends beyond midline and unresectable; + or – bilateral lymph node involvement

• IV  Metastasis 

• IV-S Localized primary tumor (I or II) with dissemination to skin, liver or bone. This applies only to infants less than 1 year old. The prognosis for this is good. 

Favorable prognostic factors include:

• Age < I year

• Low stage (I, II, IVS)

• No / low N-MYC amplification

• Hyperdiploidy

• High TRK-A expression

• Presence of CD44

• High urinary VMA/HVA  

Associations: The tumor may be found in association with the Beckwith-Wiedemann syndrome, von Recklinghausen disease, Hirshsprung’s disease, opsoclonus/myoclonus, heterochromia iridis, watery diarrhea or Cushing syndrome.  

References:

1. Verbal communication – Dr Kristen A. Atkins

2. Diagnostic surgical pathology / editor, Stephen S. Stenberg – 3^rd edition.

3. Weiss, Sharon W. Enzinger and Weiss’s soft tissue tuimors / Sharon W. Weiss, John R. Goldblum – 4^th edition.