Pheochromocytoma / Paraganglioma

 

Epidemiology:

    • 40-60y
      • F >= M
    • Children (10%)
      • Usually familial
      • M >>F
    • High altitudes:
      • Higher incidence of paraganglionic hyperplasia and neoplasia

 

Common sites:

    • extra-adrenal sites (10%) (paraganglioma):
      • branchiomeric (near major arteries and cranial nerves of head and neck, ex. Carotid bodies)
      • intravagal
      • aorticosympathetic
      • urinary bladder

 

Gross features:

    • range in size (must be >1cm by definition in adrenal – otherwise medullary hyperplasia)
      • weight > 300g – suspicious for malignancy
    • well demarcated
    • lobular pattern due to richly vascularized fibrous trabeculae
    • adrenal remnant stretched around the edge often
    • yellow-tan cut surface
      • larger lesions hemorrhagic, necrotic, cystic

 

Histologic features:

    • chromaffin cell differentiation
    • variable
    • nests or alveoli (zellballen) of chromaffin cells or chief cells with sustentacular cells
    • rich vascular network between nests
    • chromaffin cells:
      • polygonal to spindle-shaped
      • abundant cytoplasm with fine catecholamine granules (silver stains bring them out)
      • nuclei round to ovoid
      • stippled “salt and pepper” chromatin
    • sometimes dominant cell type is spindle or small
    • nuclear pleomorphism is not uncommon and is not a criterion for malignancy
    • malignancy criteria:
      • solely based on presence of metastasis
        • lymph nodes
        • liver, lung, bone
      • other features are soft and practically not useful:
        • LVI (can be seen in benign pheo)
        • cellular monotony is paradoxically associated with aggressive behaviour
        • mitosis count (>3/10HPF)
        • confluent tumour necrosis
        • spindle cell morphology
        • absent hyaline globules
    • capsular and vascular invasion may be seen in benign lesions
    • MEN 2:
      • medullary hyperplasia
        • extension of medulla to the tips of the wings
        • extension of medulla into the tail
    • vHL:
      • vaculolated cytoplasm (lipid)
      • stromal degeneration (lipid accumulation)

 

Immunophenotype:

Marker:

Sensitivity:

Specificity:

Chromogranin

 

 

Synaptophysin

 

 

S-100 (sustentacular)

 

 

Tyrosine hydroxylase

 

Excellent

RB (loss associated with malignancy in one study)

 

Molecular features:

    •  CGH:
      • chromosome 11 alterations more frequent in malignant in one study
      • losses on chromosomes 6q and 17p more common in malignant in another study
    • somatic VHL mutations more frequent in malignant
    • TP53 mutations higher frequency in malignant

 

Other features:

    • vanillylmandelic acid (VMA) in urine
    • metanephrines in urine
    • EM – membrane0-bound, electron-dense granules (catecholamines and other peptides)
    • Clinical features:
      • Generally they are functional
        • Head and neck paragangliomas are only rarely functional
      • Hypertension (chronic, sustained)
      • May have abrupt onset of attacks/paroxysms:
        • Hypertension (can be fatal)
        • Tachycardia
        • Palpitations
        • Headache
        • Sweating
        • Tremor
        • Sense of apprehension
        • Chest or abdomen pain
        • Nausea/vomiting
    • Rule of 10’s is WRONG:
      • 50% are familial
        • MEN 2
          1. MEN 2A and MEN 2B
          2. more likely benign
        • NF1
        • vHL
        • Sturge-Weber syndrome
        • Mitochondrial complex II genes:
          1. SDHD genes
          2. SDHB
          3. SDHC
      • 10% are extra-adrenal
      • 10% are bilateral (70% in familial)
      • 10% are malignant
        • 3-13% overall
        • 23-44% 5y survival (97% for benign)
        • intra-abdominal extra-adrenal have highest rate of malignancy
        • intra-adrenal unilateral solitary have lowest rate of malignancy
        • SDHD mutations greater chance of malignancy
      • 10% arise in childhood (usually familial)
    • potassium chromate turns the tumour brown

 

References:

    • Robbins 2005
    • WHO Tumours of Endocrine Organs (2004)