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2012 — February Case of the Month

Posted February 21, 2012

CLINICAL SUMMARY: Soft tissue  

CAP Foundation February 2012 Online Case of the Month

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After reading the summary, try answering the three related multiple-choice questions below.

A 7-year-old boy presented with intermittent abdominal pain and was found to have a large right retroperitoneal mass on imaging. He was taken to the operating room, where a gross total resection was achieved. The tumor measured 15.5 x 8.5 x 7.5 cm and weighed 460 g. The cut surface was firm and yellow-tan with no evidence of distinct nodules. Two lymph nodes were also sampled and showed no evidence of metastatic tumor.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2009, case 7, and is ganglioneuroma.

Criteria for Diagnosis and Comments:
The diagnosis in this case is a maturing ganglioneuroma, a benign form of neuroblastic tumor with abundant Schwannian stroma and ganglion cell differentiation. Neuroblastic tumors are tumors of neural crest origin which arise from the adrenal gland or sympathetic ganglia (paraspinal region of the posterior mediastinum or retroperitoneum), typically in the pediatric age group. While neuroblastomas have a predilection for infants and toddlers, ganglioneuromas are more likely in older children and adolescents. The three basic types of neuroblastic tumors, from least mature to most mature, are neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. These tumor types are classified according to the presence or absence of neuroblasts and the relative amount of Schwannian stroma. Neuroblastoma and nodular ganglioneuroblastoma are further subclassified into prognostic groups based on age of the patient, degree of cytodifferentiation, and the mitosis-karyorrhexis index (MKI). The MKI reflects the number of mitotic figures and karyorrhectic bodies per 5000 cells, and is designated as low (<100 per 5000 cells; <2%), intermediate (100 – 200 per 5000 cells; 2 – 4%), or high (>200 per 5000 cells; >4%). The International Neuroblastoma Pathology Committee (INPC) classification is summarized below, including basic diagnostic criteria and prognostic groups. Generally speaking, favorable prognostic features include presence of abundant Schwannian stroma, differentiating cytomorphology, low MKI, and infant age group (age <1.5 years). Unfavorable histology tumors include any neuroblastoma with undifferentiated morphology, high MKI, or patient age 5 years or greater. Most neuroblastomas diagnosed between age 1.5 and 5 years are also considered “unfavorable histology,” except for one “favorable” subset that shows both differentiating morphology and low MKI. It should be noted that nodular neuroblastomas may be either “favorable” or “unfavorable” histology, depending on the age of the patient and histologic features of the neuroblastic clone giving rise to the dominant nodule.

According to the INPC classification, ganglioneuroma is separated into two morphologic types: maturing and mature. Mature ganglioneuroma consists only of Schwannian stroma and scattered admixed ganglion cells with completely mature cytodifferentiation. In contrast, maturing ganglioneuroma shows both mature ganglion cells and intermediate cells, that is, cells with incomplete maturation toward ganglion cells. Intermediate cells are differentiating neuroblasts that are typically smaller than mature ganglion cells and have less abundant cytoplasm, central nuclei, and/or inconspicuous nucleoli. The distinction between maturing and mature ganglioneuroma has no clinical consequence, as both are “favorable histology” tumors, and are managed by complete surgical excision alone. However, maturing ganglioneuroma has been recognized as a distinct entity in order to distinguish it from intermixed ganglioneuroblastoma, a malignant lesion. While maturing ganglioneuroma contains individually dispersed differentiating neuroblasts and ganglion cells embedded within Schwannian stroma, intermixed ganglioneuroblastoma contains small discrete islands of neuropil and neuroblastic cells randomly interspersed within the Schwannian stroma. These neuroblastic islands typically include an admixture of primitive neuroblasts, abundant differentiating neuroblasts, and mature ganglion cells. Recognition of this low power pattern of randomly distributed islands should prompt further examination for presence of primitive neuroblasts within these islands. Due to the abundance of Schwannian stroma, intermixed ganglioneuroblastoma may be difficult to diagnose at the time of intraoperative consultation if only the Schwannian stroma component is sampled. Definitive diagnosis in this setting is dependent on more thorough sampling of the tumor for permanent sections.

DIAGNOSIS

CRITERIA

Unfavorable Histology (UH)

Favorable Histology (FH)

Neuroblastoma

Neuroblasts
<50% Schwannian stroma

 

 

Undifferentiated

Primitive cells only; no neuropil or cytodifferentiation by light microscopy

All

--

Poorly differentiated

Neuropil, few ganglion-like cells (5% or less)

Age <1.5 y (H)
Age 1.5 – 5 y (any MKI)
Age >5 y (any MKI)

Age <1.5 y (I, L)

Differentiating

Neuropil, many ganglion-like cells (>5%)

Age <1.5 y (H)
Age 1.5 – 5 y (H, I)
Age >5 y (any MKI)

Age <1.5 y (I, L)
Age 1.5 – 5 y (L)

Ganglioneuro-
blastoma

Neuroblasts
>50% Schwannian stroma

 

 

Nodular

 

Gross nodule with
neuroblasts

Similar to NB

Similar to NB

Intermixed

Microscopic nests with neuroblasts and neuropil

--

All

Ganglioneur-
oma

Absent or rare neuroblasts
>50% Schwannian stroma

 

 

Maturing

Individual differentiating neuroblasts, intermediate cells, and mature ganglion cells

--

All

Mature

All mature ganglion cells

--

All

MKI (mitosis-karyorrhexis index), H (high MKI), I (intermediate MKI), L (low MKI), NB (neuroblastoma)

An important biologic characteristic of neuroblastic tumors is the presence or absence of amplification of the MYCN oncogene on the short arm of chromosome 2, defined as greater than 10 copies of MYCN by southern blot analysis or by fluorescence in situ hybridization (FISH). MYCN amplification is used to determine both prognosis and treatment stratification in some patients, and fresh tissue or touch preparation slides should be submitted for FISH analysis on all neuroblastic tumors. In addition to MYCN gene amplification, other unfavorable genetic markers include chromosome 1p deletion, 14q deletion, 11q deletion, and 17q gain. Neuroblastoma is rarely familial and has been associated with germline mutations in PHOX2B. Neuroblastic tumors are reported only rarely in association with the multiple endocrine neoplasia syndromes or neurofibromatosis.

The differential diagnosis of mature and maturing ganglioneuroma includes other tumors with abundant Schwann cells or neural differentiation. Schwannoma is typically easily distinguished by presence of Verocay bodies and absence of ganglion cells. Neurofibroma also has distinctive morphology with admixture of neural cells, fibrocytes, and collagen. More specifically, plexiform neurofibromas are typically arranged in large neural fascicles with a loose myxoid intercellular matrix, unlike the compact sheets of dense Schwannian stroma seen in ganglioneuroma. Ganglion cells are absent in neurofibroma, although they may be seen in normal ganglia adjacent to or entrapped within the tumor.

Supplementary Questions: For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
1. This tumor is most likely to arise from which of the following anatomic sites? A. Adrenal gland
B. Anterior mediastinum
C. Optic nerve
D. Organ of Zuckerkandl
E. Spinal cord
2. Neuroblastic tumors are most often associated with which of the following genetic abnormalities or syndromes? A. Multiple endocrine neoplasia syndrome
B. MYCN gene amplification
C. Neurofibromatosis type I
D. Neurofibromatosis type II
E. RET oncogene mutation
3. Which morphologic feature distinguishes intermixed ganglioneuroblastoma from ganglioneuroma? A. High mitotic-karyorrhectic index (MKI)
B. Nodular gross morphology
C. Presence of islands of neuropil and differentiating cells
D. Presence of mature ganglion cells
E. Schwannian stroma > 50% of tumor area

References

  1. Askin FB, Perlman EJ. Neuroblastoma and peripheral neuroectodermal tumors. Am J Clin Pathol. 1998;109:S23-S30.
  2. Goto S, Umehara S, Gerbing RB, et al. Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors. A report from the Children’s Cancer Group. Cancer. 2001;92:2699-2708.
  3. Peuchmaur M, D’Amore ESG, Josh VV, et al. Revision of the International Neuroblastoma Pathology Classification. Confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular. Cancer. 2003;98:2274-2281.
  4. Qualman SJ, Bowen J, Fitzgibbons PL, et al. Protocol for the examination of specimens from patients with neuroblastoma and neuroblastic tumors. Arch Pathol Lab Med. 2005;129:874-883.
  5. Shimada H, Ambros IM, Dehner LP, et al. Terminology and morphologic criteria of neuroblastic tumors. Recommendations by the International Neuroblastoma Pathology Committee. Cancer. 1999;86:349-363.
  6. Shimada H, Umehara S, Monobe Y, et al. International Neuroblastoma Pathology Classification for prognostic evaluation of patients with peripheral neuroblastic tumors. A report from the Children’s Cancer Group. Cancer. 2001;92:2451-2461.

Author:
2009
Megan K. Dishop, MD FCAP
Surgical Pathology Committee
Texas Children’s Hospital
Houston, TX