Adrenal Gland

A healthy and athletic 15-year-old adolescent is hit by a car while riding her bicycle, sustaining minor injuries. At the local hospital, a computer tomography scan demonstrates a left adrenal gland mass. She undergoes resection of a 15 x 14 x 13 cm well-circumscribed adrenal mass that, upon sectioning, is firm, smooth, and tan. The pathologist samples the mass extensively and submits fresh frozen tissue for possible special studies.

Master List of Diagnoses

  • Ganglioneuroblastoma, intermixed
  • Ganglioneuroblastoma, nodular
  • Ganglioneuroma, mature
  • Ganglioneuroma, maturing
  • Neuroblastoma
  • Neurofibroma
View slide image with DigitalScope

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2018, Case 27, and is a mature ganglioneuroma of the adrenal gland.

Criteria for Diagnosis and Comments

The histologic sections reveal an abundant, variably edematous, and cellular Schwannian stroma composed of organized fascicles of nerve fibers, mature Schwann cells, and fibrous tissue associated with scattered mature ganglion cells arranged in small clusters and as single cells. Adipose tissue and clusters of mature lymphocytes are noted in a few areas, but no mitotic activity, neuroblasts, maturing ganglion cells, necrosis, or hemorrhage are identified. The findings are consistent with a ganglioneuroma (GN), mature subtype.

GN, a Schwannian stroma-dominant tumor, is the most differentiated/mature of the peripheral neuroblastic tumors (PNBTs). GN tends to occur in patients older than 10 years of age. It arises most commonly in the posterior mediastinum and the retroperitoneum. Although most GNs arise de novo, some tumors may result from spontaneous or chemotherapy-induced maturation of preexisting neuroblastomas and ganglioneuroblastomas. In these cases, the maturation process affects the primary and metastatic tumors and may explain the presence of GNs with a “metastatic pattern.” This is a benign tumor with a good prognosis. On rare occasions, residual GNs can undergo malignant transformation.

The majority of GNs are asymptomatic, although symptoms may occur secondary to tumor compression. Some patients, especially those with very large tumors, may present with symptoms associated with tumor synthesis of catecholamines such as hypertension and hypokalemia. GNs can arise in association with Cowden syndrome, juvenile polyposis syndrome, multiple endocrine neoplasia type 2b, tuberous sclerosis, and neurofibromatosis type 1.

Peripheral neuroblastic tumors

Neuroblastoma (NBL), ganglioneuroblastoma (GNB), and GN form a group of neoplasms derived from primordial neural crest cells of the sympathetic nervous system. Although these tumors have different histological characteristics, they share some unique features, including spontaneous or therapy-induced maturation and/or spontaneous tumor regression.

NBL is the most common extracranial solid tumor of childhood, and the most frequently diagnosed tumor of infancy. NBLs are slightly more common in males and less common in African Americans. Close to 90% of NBLs produce catecholamines, and the metabolites can be detected in the patient’s serum and urine. Primary involvement by NBL includes the adrenal medulla (35%), the extra-adrenal retroperitoneum (30% - 35%), and the posterior mediastinum (20%). Germline mutations in the ALK (anaplastic lymphoma kinase) oncogene have been identified as a major cause of familial predisposition to NBL.

Following a modification of the original 1984 Shimada Classification by the International Neuroblastoma Pathology Committee (INPC) in 1999, peripheral neuroblastic tumors were classified into four categories:

  • Neuroblastoma (Schwannian stroma-poor): Grossly, these tumors can be well-circumscribed single nodules or multinodular masses. Cut surfaces may exhibit areas of hemorrhage, necrosis, calcification, and/or cystic change. Microscopically, they are composed of small round to oval cells with scant cytoplasm and nuclei with “salt and pepper” chromatin. The neoplastic cells may be arranged in a lobular pattern with fine fibrovascular septae or as solid sheets. Brisk mitotic activity, karyorrhexis, and pleomorphism may be prominent. The background is variably composed of neuropil, an eosinophilic fibrillary network. Homer Wright rosettes characterized by neoplastic cells arranged around a central neuropil-filled space may be seen.

Some tumors contain neuroblasts differentiating toward ganglion cells; these more mature cells exhibit large, eccentrically located vesicular nuclei with prominent nucleoli and more abundant eosinophilic cytoplasm. NBLs are defined as being “Schwannian stroma-poor.” Schwannian stroma refers to a proliferation of fibroblasts associated with organized fascicles of neuritic processes and mature Schwann cells.

NBLs are further subclassified into “undifferentiated,” “poorly differentiated,” and “differentiating” subtypes. The undifferentiated subtype is characterized by undifferentiated neuroblasts. A diffuse growth pattern is commonly seen. Ancillary studies are needed to establish the diagnosis. The poorly differentiated subtype is the most common pattern. Differentiating neuroblasts comprise less than 5% of these tumors; neuropil, Homer Wright rosettes, and a lobular growth pattern are common findings. In the “differentiating subtype,” ≥5% of the tumor cells are differentiating neuroblasts, and neuropil is a prominent feature.

  • Ganglioneuroblastoma, intermixed (Schwannian stroma-rich): Grossly, these tumors are usually nodular and firm, with a tan-yellow homogeneous cut surface that may exhibit fibrous bands. Microscopically, there are foci of neuroblasts displaying varying stages of differentiation and neuropil. The Schwannian stroma occupies greater than 50% of the tumor. It is not uncommon to identify mature ganglion cells associated with the Schwannian stroma in a pattern similar to GNs.
  • Ganglioneuroblastoma, nodular (Schwannian stroma-dominant/stroma-rich and stroma poor): One or more neuroblastic nodules co-exist with GNB-intermixed or GN. Grossly, the more immature/malignant nodules exhibiting areas of hemorrhage and/or necrosis alternate with homogeneous tan-yellow regions of mature/better-differentiated elements.
  • Ganglioneuroma (Schwannian stroma-dominant): Grossly, these tumors can exhibit features similar to those described in cases of GNB intermixed (Schwannian stroma-rich). They are usually well-circumscribed with a fibrous capsule. The cut surface is firm and may be whorled or trabeculated; the color varies from tan to light yellow. Microscopically, they are defined as being “Schwannian stroma-dominant.”

GNs are further subclassified into “maturing” and “mature” subtypes. In the maturing subtype, there are mature ganglion cells and dispersed individual maturing ganglion cells associated with a prominent Schwannian stroma. In the mature subtype, the minor component consists of mature ganglion cells surrounded by satellite cells associated with a prominent Schwannian stroma; a neuroblastomatous component is absent. GNs are not mitotically active tumors. The neoplastic ganglion cells may have more than one nucleus and may exhibit cytoplasmic brown pigment resembling lipofuscin or neuromelanin.

Evaluation of neuroblastic tumors

Histological evaluation of a NBL includes determination of the mitotic-karyorrhexis index (MKI) of the tumor by counting the number of neoplastic cells undergoing mitosis and karyorrhexis. MKI can be low (<2% or <100 mitotic and karyorrhectic cells per 5,000 neuroblasts), intermediate (2%-4% or 100-200 mitotic and karyorrhectic cells per 5,000 neuroblasts), and high (>4% or >200 mitotic and karyorrhectic cells per 5,000 neuroblasts). Increased MKI correlates with MYCN amplification.

The International Neuroblastoma Pathology Classification distinguishes two pathologic-prognostic groups: favorable histology and unfavorable histology. This classification is age-linked and uses three histological indicators: Schwannian stromal development, neuroblastic differentiation, and MKI. The evaluation should be performed on a resected specimen or biopsy prior to treatment. Metastatic specimens are eligible for evaluation prior to therapy, except for bone marrow biopsies.

Age

Favorable Histology Group

Unfavorable Histology Group

Any

Ganglioneuroma (Schwannian stroma-dominant)

  • Maturing
  • Mature

Ganglioneuroblastoma, intermixed (Schwannian stroma-rich)

Neuroblastoma (Schwannian stroma-poor)

  • Undifferentiated and any MKI

< 1.5 years

Neuroblastoma (Schwannian stroma-poor)

  • Poorly differentiated and low or intermediate MKI
  • Differentiating and low or intermediate MKI

Neuroblastoma (Schwannian stroma-poor)

  • Poorly differentiated and high MKI
  • Differentiating and high MKI

1.5 years up to < 5 years

Neuroblastoma (Schwannian stroma-poor)

  • Differentiating and low MKI

Neuroblastoma (Schwannian stroma-poor)

  • Poorly differentiated and any MKI
  • Differentiating and intermediate or high MKI

Equal to or > 5 years

Ganglioneuroblastoma, nodular (Schwannian stroma-dominant/stroma-rich and stroma poor), favorable subset*

Neuroblastoma (Schwannian stroma-poor)

  • Any subtype and any MKI

Ganglioneuroblastoma, nodular (Schwannian stroma-dominant/stroma-rich and stroma poor), unfavorable subset*

*The revised INCP classification (2003) distinguishes a favorable and unfavorable subset by applying the same age-linked evaluation to the nodular (NBL) components of the tumors in this category.

In NBLs, prognostic (or risk) factors include age, stage, N-myc status, histology, and DNA ploidy. Based on these core prognostic factors, patients are classified as low, intermediate, or high risk.

Histology is an independent prognostic factor. The presence of Schwannian stroma and ganglionic differentiation is considered a favorable prognostic indicator, and its absence is considered unfavorable. Because neuroblastic tumors may demonstrate variable histological features, extensive sampling is recommended. Immunohistochemical stains can also assist in confirming the diagnosis. Neuroblasts are immunopositive for PHOX2B, neuron-specific enolase, PGP9.5, synaptophysin, chromogranin, S100, and tyrosine hydroxylase; the Schwann cells and ganglion cells are immunopositive for S100.

The differential diagnosis of a GN includes GNB (both intermixed and nodular varieties) and neurofibroma (NF). If a resected tumor exhibits prominent Schwannian stroma, extensive sampling should be performed to exclude the presence of malignant neuroblastic elements. To prevent sampling errors, small biopsies should be avoided when possible if the clinical differential diagnosis includes malignant PNBTs.

NFs can be solitary, diffuse, or plexiform. Solitary NFs are the most common and present as well-circumscribed, non-encapsulated polypoid or nodular soft tan skin lesions. Solitary cutaneous neurofibromas have a wide anatomic distribution, affect adults, are not associated with neurofibromatosis, and rarely undergo malignant transformation. Solitary neurofibromas involving peripheral nerves are more often associated with neurofibromatosis type 1 (NF1) and have a small risk of undergoing malignant transformation. Microscopically, the tumors are well-delineated and exhibit a proliferation of axons, Schwann cells, and fibroblasts mixed with mast cells. Schwann cells, with elongated nuclei, serpentine configuration, and pointed ends, are the predominant cell type. Mitotic activity is scant or absent, and the Ki67 index is low. The fibromyxoid stroma associated with the cellular component is variable; prominent myxoid, collagenous, or hyalinized stromal components may be seen.

Diffuse neurofibromas are rare subcutaneous lesions that arise in the trunk, the head and neck area, or the limbs of patients between the ages of 10-30 years. These lesions are ill-defined, plaque-like, and large but only rarely undergo malignant transformation. Microscopically, they resemble solitary NFs, although they may also exhibit other changes including the presence of multinucleated giant cells of unknown origin.

Plexiform NFs are usually seen in the context of NF1. They tend to diffusely involve (mostly large) nerves and are more common in the orbit, neck, back, and inguinal regions. Microscopically, plexiform NFs infiltrate and expand nerves; the cellular component is similar to solitary NFs and is commonly associated with a prominent loose myxoid stroma.

The stroma of GNs and NFs share numerous features, including cellular elements. Therefore, some ancillary tests like immunohistochemical stain for S100 protein are not helpful in differentiating these lesions in the absence of ganglion cells. Small biopsies be challenging, as ganglion cells may not be present.

GNs are usually treated by surgical excision, and local recurrence is rare. If complete resection cannot be achieved (and in the absence of malignant growth or symptomatic compression of an organ), patients can be followed by close observation and serial imaging studies.

  1. Which of the following features is shared by all peripheral neuroblastic tumors??

    1. Loss of function mutations in the homeobox gene PHOX2B
    2. Spontaneous or therapy-induced maturation and/or spontaneous tumor regression
    3. The fact that they are slightly more common in males and less common in African Americans
    4. The presence of germline mutations in the ALK oncogene
    5. The tendency to occur in patients older than 10 years of age
  2. Which of the following is true about ganglioneuromas?

    1. They are rare subcutaneous lesions that arise in the trunk, the head and neck area, or the limbs of patients between the ages of 10-30 years.
    2. They can arise in association with several syndromes, including Cowden syndrome, juvenile polyposis syndrome, and multiple endocrine neoplasia type 2b.
    3. They commonly exhibit the presence of multinucleated giant cells of unknown origin.
    4. They tend to diffusely involve (mostly large) nerves and are more common in the orbit, neck, back, and inguinal regions.
    5. They tend to involve peripheral nerves, are more often associated with neurofibromatosis type 1, and have a small risk of undergoing malignant transformation.
  3. Which of the following is true about the prognosis of a ganglioneuroma?

    1. It depends on the presence of the metabolites of certain catecholamines that can be detected in the patient’s serum and urine.
    2. It is worse if the tumor shows a low mitotic-karyorrhexis index.
    3. It is based on the evaluation of five core prognostic factors: age, stage, MYCN status, histology, and DNA ploidy.
    4. It is good, although residual tumors can rarely undergo malignant transformation.
    5. It is influenced by the age of the patient at the time of diagnosis.

References

  1. Decarolis B, Simon T, Krug B, et al. Treatment and outcome of ganglioneuroma and ganglioneuroblastoma intermixed. BMC Cancer. 2016;16:542.
  2. Fletcher CDM. Ch. 27, Peripheral Neuroectodermal Tumors. In Fletcher CDM, ed. Diagnostic Histopathology of Tumors. Fourth ed. Philadelphia, PA: Mosby Elsevier; 2013:2040-2042.
  3. Hicks MJ, Cipriani N, Pytel P, Shimada H. Ch. 21, The Pineal, Pituitary, Parathyroid, Thyroid, and Adrenal Glands. In: Stocker JT, Dehner LP, Husain AN, eds. Stocker & Dehner’s Pediatric Pathology. Fourth ed. Philadelphia, PA: Wolters Kluwer; 2016:997-1008.
  4. Maitra A. Ch. 10, Diseases of Infancy and Childhood. In: Kumar V, Abbas AK, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. Ninth ed. Philadelphia, PA: Elsevier Saunders; 2015:475-479.
  5. Maris JM. Recent advances in neuroblastoma. N Engl J Med. 2010;362(23):2202-2211.
  6. Oderda M, Cattaneo E, Soria F, et al. Adrenal ganglioneuroma with multifocal retroperitoneal extension: a challenging diagnosis. Scientific World Journal. 2011;11:1548-1553.
  7. Peuchmaur M, d’Amore ESG, Joshi W, et. al. Revision of the International Neuroblastoma Pathology Classification: confirmation of favorable and unfavorable prognostic subsets of ganglioneuroblastoma, nodular. Cancer. 2003;98:2274-2281.
  8. Rosai J. Ch. 16, Adrenal gland and other paraganglia - Lesions of adrenal medulla. In Rosai J, ed. Rosai and Ackerman’s Surgical Pathology. Eleventh ed. Philadelphia, PA: Mosby Elsevier; 2011:1074-1075.
  9. Rosai J. Ch. 25, Soft tissues - Tumors and tumor like conditions of peripheral nerves. In Rosai J, ed. Rosai and Ackerman’s Surgical Pathology. Eleventh ed. Philadelphia, PA: Mosby Elsevier; 2011:2132-2135.
  10. Rozmus J, Langer M, Murphy JJ, Dix D. Multiple persistent ganglioneuromas likely arising from the spontaneous maturation of metastatic neuroblastoma. J Pediatr Hematol Oncol. 2012;34(2):151-153.
  11. Shimada H, Ambros IM, Dehner LP, et al. Terminology and morphologic criteria of neuroblastic tumors: Recommendation by the International Neuroblastoma Pathology Committee. Cancer. 1999;86:349-363.

Author

Nilsa C. Ramirez, MD
Surgical Pathology Committee
Nationwide Children’s Hospital
Columbus, OH


Answer Key

  1. Spontaneous or therapy-induced maturation and/or spontaneous tumor regression (b)
  2. They can arise in association with several syndromes, including Cowden syndrome, juvenile polyposis syndrome, and multiple endocrine neoplasia type 2b. (b)
  3. It is good, although residual tumors can rarely undergo malignant transformation. (d)