Case 4 - Crooke's Cell Pituitary Adenoma

Anthony T. Yachnis
University of Florida College of Medicine
Gainesville , FL

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Clinical Summary
This 39-year-old man had been well until three years prior to admission when he developed hypertension that was difficult to control. Also during this time he experienced fatigue, muscle weakness, thinning of the skin, redness and swelling of the face, and difficulty sleeping. More recently, the patient came to clinical attention because of pain in both feet. On physical examination, he was noted to have a plethoric "moon" face, abdominal striae, and marked central adiposity. Radiographic studies revealed generalized osteopenia and several fractures of the feet. A 24-hour urine study showed a free cortisol level of 352 micrograms (mcg) (normal range: 20-50 mcg/24 hrs). The early morning serum cortisol was 26.8 mcg/dl (NL range: 7-22 mcg/dl) with a corresponding ACTH of 115 (NL range: 9-52 pg/ml). There was modest overnight dexamethasone (8mg) suppression of cortisol to 17.5 mcg/dl with a corresponding ACTH of 77 pg/ml.

An initial head MRI showed no apparent abnormality. However, abdominal MRI revealed enlargement of the left adrenal gland with a suggestion of a focal nodularity. CT scan of the chest showed no evidence of a lung tumor but there was mediastinal lipomatosis and multiple healing rib fractures. Three months after the first head MRI, a second study revealed a 5 mm circumscribed mass in the right side of the pituitary gland. Transsphenoidal biopsy and resection of this lesion were performed using a CT-guided stereotactic approach, which provided diagnostic material.

Case 4 - Figure 1 - Crooke's cell pituitary adenoma. H&E-stained section showing a cellular neoplasm composed of pleomorphic, non-uniform tumor cells. Original magnification: 250X.

Case 4 - Figure 2 - Crooke's cell pituitary adenoma. H&E-stained section showing more striking pleomorphism and a prominent population of large eosinophilic cells. Original magnification: 250X.

Case 4 - Figure 3 - Crooke's cell pituitary adenoma. H&E-stained section showing a large multinucleated tumor cell amongst cells with variable amounts of eosinophilic cytoplasm. Original magnification: 1000X.

Case 4 - Figure 4 - Crooke's cell pituitary adenoma. H&E-stained section showing a group of neoplastic cells with homogeneous eosinophilic cytoplasm consistent with Crooke's hyaline change. Original magnification: 1000X.

Case 4 - Figure 5 - Crooke's cell pituitary adenoma. H&E-stained section showing a group of tumor cells with peripherally located basophilic granules near the subplasmalemmal region. Original magnification: 1000X.

Case 4 - Figure 6 - Crooke's cell pituitary adenoma. Reticulin stain (VVG) showing lobular expansion and loss of normal pituitary gland architecture consistent with adenoma. Original magnification: 1000X.

Case 4 - Figure 7 - Crooke's cell pituitary adenoma. Cytokeratin (AE1/3) immunostained tumor showing strong cytoplasmic reactivity in a perinuclear ring-like pattern. Original magnification: 1000X.

Case 4 - Figure 8 - Crooke's cell pituitary adenoma. ACTH immunostained tumor showing positive reactivity that is concentrated near the subplasmalemmal region. Original magnification: 1000X.

I. Crooke's Cell Pituitary Adenoma
A. Cushing's Disease

In a landmark 1912 publication [1], Harvey W. Cushing described the syndrome of obesity, diabetes, hirsutism and adrenal hyperplasia, to which his name was later eponymously linked. Sir William Osler was probably the first to describe a patient with Cushing's syndrome in 1898, but he attributed the signs and symptoms to myxedema, an error that some medical historians believe could have been prevented if an autopsy had been performed [2]. It is now well recognized that the clinical manifestations are due to chronic glucocorticoid excess of diverse causes, including primary lesions of the adrenal cortex, extrapituitary ACTH-producing tumors, and chronic corticosteroid therapy. It was not until 20 years after his initial description of the symptom complex that Cushing reported the association of basophilic pituitary adenomas with the clinical manifestations of the disorder (i.e., Cushing's disease) [3].

Before considering Crooke's cell pituitary adenoma, a few aspects of normal corticotroph biology deserve mention. Embryologically, corticotrophs are the first adenohypophysial cells to differentiate, with characteristic ultrastructural features being present at 6 weeks of gestation and detectable ACTH-immunoreactivity appearing by 7 weeks [4, 5]. In the adult, ACTH-producing corticotrophs account for 15-20% of cells in the adenohypophysis [6]. These cells tend to cluster in the central "mucoid wedge" of the anterior pituitary and are the predominant cell type in the intermediate lobe. Corticotrophs may extend away from the pars intermedia into the neurohypophysis. This "basophil invasion" is considered to be a normal phenomenon seen with increasing age and occurring more commonly in males. Histologically, corticotrophs show varying degrees of cytoplasmic basophilia on H&E stain and are PAS-positive due to the presence of carbohydrate moieties of ACTH precursor proteins. The presence of a large unstained perinuclear vacuole (the "enigmatic body") is also characteristic. It should be noted that corticotrophs normally contain small amounts of perinuclear cytokeratin [7]. Stimulation of corticotrophs by hypothalamic corticotrophin releasing hormone (CRH) results in ACTH production and secretion, which stimulates glucocorticoid production by the adrenal cortex. Increasing serum levels of cortisol normally provide feedback inhibition of ACTH and CRH.

Crooke's hyaline change is a type of metaplasia that occurs in corticotrophs of the adenohypohysis under conditions of sustained glucocorticoid excess [6, 8]. The latter may result from endogenous pathologic production of ACTH (most often due to an ACTH-secreting pituitary adenoma), CRH, or by primary adrenal steroid secretion (adrenal cortical neoplasm). Exogenous therapeutic glucocorticoid administration may have the same effect. Regardless of its source, such steroid excess produces a striking hyalinized eosinophilic appearance of the perinuclear cytoplasm on routine H&E stain. The ultrastructural and immunohistochemical studies of Neumann et al. [9] confirmed that the hyaline material was low molecular weight cytokeratin. Residual ACTH immunoreactivity and PAS staining is characteristically displaced to the periphery of the cytoplasm and may be found in the juxtanuclear Golgi region.

In Cushing's disease, Crooke's hyaline change typically affects the native, non-adenomatous corticotrophs, which are believed to undergo functional suppression. The ACTH-producing adenomatous cells do not usually develop Crooke's hyalinization and are functionally resistant to steroid inhibition. The mechanism of steroid resistance by corticotrophinomas is not clear at present. Glucocorticoid receptors have been identified in multiple adenohypophysial cell types and in several subtypes of adenomas including corticotroph adenomas [10]. Somatic mutations of the glucocorticoid receptor gene are rare and do not account for hormone resistance [11, 12]. Loss of heterozygosity and polymorphisms of this gene have been reported in ACTH adenomas but the relationship of such findings to corticosteroid resistance remains unclear [11].

The Crooke's cell pituitary adenoma (CCA) is a biologically aggressive variant of corticotroph adenoma in which the neoplastic cells develop Crooke's hyaline change [13, 14, 15, 16, 17, 18, 19]. The largest clinicopathologic study of Crooke's cell adenomas was published by George et al. and included cases from the Mayo Clinic (Rochester, MN) and St. Michaels Hospital (Toronto, Ontario) [13]. This study reported thirty-one cases of CCA, which were defined as having more than 50% of adenoma cells showing Crooke's hyaline change. Such cases represented 4.4% (10 of 229) of all corticotroph adenomas undergoing surgery at the Mayo Clinic between 1985 and 2000. There was a wide age range of affected patients (range 18-81; mean 46 years) and 75% were women. About two-thirds of patients had functional adenomas with clinical manifestations of Cushing's disease at presentation while the rest were asymptomatic. Of the patients with apparently "silent" corticotroph adenomas, 7 individuals had symptoms that suggested Cushing's disease in retrospect while 2 patients developed symptoms at recurrence.

The majority of cases reported by George et al. [13] were macroadenomas (81%), and 72% of cases showed radiographic or intraoperative evidence of invasion of adjacent structures. Suprasellar extension was present in 62% of cases.

By H&E histology, Crooke's cell pituitary adenomas show perinuclear, eosinophilic hyalinization, which displaces the residual ACTH-containing (PAS-positive) cytoplasm to the periphery. While such tumors may show the uniform, monomorphous appearance of more common pituitary adenomas, a striking feature of the present case was marked nuclear and cellular pleomorphism with variable degrees of cytoplasmic hyalinization. This histologic appearance could suggest a metastasis as discussed further below. However, mitoses were not observed in the case presented and are only occasionally observed in the Crooke's cell adenoma.

Immunohistochemistry shows strong cytokeratin reactivity of hyalinized areas of the cytoplasm, sometimes in a perinuclear ring-like distribution, especially when the antibody cocktail includes low molecular weight specificity (such as CAM5.2). The case presented here was positive using anti-cytokeratin AE1/AE3. ACTH immunoreactivity may be weak and limited to the periphery of the cell. One case of bihormonal (ACTH and FSH) expression of an invasive Crooke's cell adenoma has been published [17]. Ki67 (MIB-1) labeling indices are generally low (about 1%) but may be higher in recurrent tumors [13, 19]. A range of p53 immunoreactivities has been observed, with a tendency for strong diffuse staining to be associated with recurrent neoplasms [13].

Ultrastructural studies confirm extensive intermediate filament accumulation with a peripheral distribution of spherical, electron dense secretory granules [6, 13, 14, 15, 19].

The pathologic differential diagnosis will be influenced heavily by clinical and radiologic features. However, the striking cytologic atypia and pleomorphism displayed by some Crooke's cell adenomas could suggest a metastatic neoplasm or even an unusual sellar tumor such as a ganglioglioma [6]. Strong cytokeratin immunoreactivity of the neoplastic cells could be misleading to the pathologist if a metastasis is being considered. Another factor that could obscure the diagnosis is the existence of corticotroph cell pituitary adenomas in patients without clinical Cushing's symptomatology [20, 21]. As noted above, such "silent" adenomas accounted for 35% of Crooke's cell tumors in the Mayo Clinic series [13]. Awareness of this tumor type and positive immunoreactivity for ACTH will be useful in making the correct diagnosis.

Clinical Outcome
It is important to recognize the Crooke's cell pituitary adenoma because such tumors may be biologically aggressive [13, 17, 19]. In the Mayo Clinic/St. Michael's Hospital study, 15 of 25 patients who were followed for at least a year (mean 6.7 years) developed recurrent tumor and 6 patients had multiple recurrences. Three patients died of disease: one with multiple local recurrences and two with pituitary carcinoma. Surgery remains the primary diagnostic and therapeutic procedure for all types of pituitary adenomas [22] while various forms of radiation are reserved for invasive or progressive disease. The efficacy of chemotherapeutic options for corticotroph adenomas is not well established but novel strategies are on the horizon [23].


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