REVIEW REVIEW
Crooke’s Cell Tumors of the Pituitary Antonio Di Ieva, MD, PhD*‡
Crooke’s cell adenomas are a rare type of pituitary neoplasm. They produce adrenocorticotropic hormone causing Cushing’s disease or may be endocrinologically silent. These tumors are usually invasive, may exhibit aggressive clinical behavior, and often recur with a low success of cure after reoperation and/or radiotherapy. Due to their rarity, they present great difficulties in assessing prognosis, treatment, and clinical management. Neurosurgeons and physicians dealing with pituitary adenomas diagnosed as Crooke’s cell adenomas have to be aware of their potential clinical aggressiveness to plan strict follow-up of patients and eventual multimodality treatment. We review here the published cases of Crooke’s cell tumors, as well as the clinical and histopathological characteristics of these unusual neoplasms.
Jennilee M. Davidson, BScH*‡ Luis V. Syro, MD§ Fabio Rotondo, BScH¶ Julian F. Montoya, MDk Eva Horvath, PhD¶ Michael D. Cusimano, MD, PhD‡ Kalman Kovacs, MD, PhD¶ ‡Division of Neurosurgery, Department of Surgery, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; §Department of Neurosurgery, Hospital Pablo Tobon Uribe and Clinica Medellin, Medellin, Colombia; ¶Division of Pathology, Department of Laboratory Medicine, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; kDivision of Endocrinology, Hospital Pablo Tobon Uribe and Universidad de Antioquia, Medellin, Colombia *These authors contributed equally. Correspondence: Antonio Di Ieva, MD, PhD, Division of Neurosurgery, Department of Surgery, St. Michael’s Hospital, 30 Bond Street, M5B 1W8 Toronto, Ontario, Canada. E-mail: [email protected] Received, May 25, 2014. Accepted, December 3, 2014. Published Online, January 29, 2015. Copyright © 2015 by the Congress of Neurological Surgeons.
KEY WORDS: Adrenocorticotropic hormone producing pituitary tumor, Aggressive pituitary adenoma, Crooke’s cell, Hyalinization, Pituitary adenoma, Pituitary carcinoma Neurosurgery 76:616–622, 2015
DOI: 10.1227/NEU.0000000000000657
A
rthur Carleton Crooke (1905-1990) was the first to describe the accumulation of hyaline material in the adenohypophysis of patients with Cushing syndrome in 1935.1 This change corresponded to the disappearance of secretory granules and hyalinization of cytoplasm in adenohypophysial basophil cells in patients with primary hypercortisolism, including those with adrenocorticotropic hormone (ACTH)–producing tumors.1,2 Subsequent investigators described histological and ultrastructural findings to aid in identifying these cells.3,4 Crooke’s cells were then considered corticotrophs that, in the presence of glucocorticoid excess, undergo massive accumulation of perinuclear cytokeratin (CK) filaments, giving their cytoplasm a distinct hyalinized appearance on hematoxylin and eosin staining. This material, with a perinuclear and ringlike distribution, is periodic acid–Schiff (PAS) negative and lacks ACTH immunoreactivity. In some clinically aggressive and often recurring pituitary adenomas, authors found massive hyaline changes in the majority of the cells, which were the same as the Crooke’s cells seen in the adenohypophysis of patients with glucocorticoid
ABBREVIATIONS: ACTH, adrenocorticotropic hormone; CCA, Crooke’s cell adenoma; CK, cytokeratin; PAS, periodic acid–Schiff; TMZ, temozolomide
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excess described earlier.5,6 Tumors that contained this Crooke’s hyaline material in the cytoplasm of more than 50% of the cells were then classified as Crooke’s cell adenoma (CCA). CCAs are very rare, accounting for less than 1% of pituitary adenomas,7 and they have not been studied extensively. Currently, recognition of these tumors is becoming more evident, but there is no consistent classification system to identify a CCA based on the percentage of Crooke’s cells present or its aggressive clinical behavior. The identification and mechanism of CCAs, in terms of progression and rate of recurrence, are still poorly understood.7 Due to their rarity, they present great difficulties for prognosis, treatment, and clinical management. CCAs tend to have a low success at reoperation (0%-25%) and are often resistant to radiotherapy,8 hence the need for further studies of larger scale. Here, we review the published cases of CCAs, as well as the histopathological and clinical characteristics of these uncommon tumors.
METHODS Literature Review PubMed (1935 to October 2014), MEDLINE (1946 to October 2014), Web of Science, Scopus, Embase, and Google Scholar were searched using key words including Crooke’s cell adenomas, Crooke’s cell, adrenocorticotropic hormone–producing pituitary tumors, recurrent
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pituitary tumors, aggressive, invasive pituitary adenomas, pituitary carcinomas, and hyalinization. Articles published in English were included. The diagnostic criterion was the presence of Crooke’s hyaline material in the substantial majority of adenoma cells. Hematoxylin and eosin staining, PAS staining, and immunostaining for ACTH and low molecular weight keratin (Cam 5.2) were used to identify the presence of Crooke’s hyaline material. Some authors also made use of electron microscopy.
RESULTS To date, 80 cases of CCAs have been published (Table 1).5,6,8-25 Although excessive amounts of microfilaments in ACTH-producing adenomas have been mentioned before by Landolt9 and Robert et al.,10 Felix et al5 in 1981 described the first 3 cases of ACTH producing pituitary adenomas with massive cytoplasmic deposition of Crooke’s hyaline material. After those, some other cases were described, and finally in 2003, George et al8 published the first series of 36 cases, which, after more than 10 years, is still the largest published cases series. The authors described their clinical presentation, pathological findings, and evolution, suggesting their aggressive clinical behavior. Clinical details were available in most of them (Table 2): 74.6% were female (47/63), with an age range of 16 to 81 years (mean, 42.4), usually macroadenomas (44/57, 77.2%) with invasion to the cavernous or sphenoid sinuses (79.2%, 38/48). Cushing disease was present in 75.6% (59/78), and 24.4% were silent ACTH adenomas. In 6 patients, the tumor gave rise to metastases (6/80, 7.5%).8
CLINICAL FEATURES CCAs usually present as invasive macroadenomas causing Cushing disease or as nonfunctional pituitary macroadenomas. In the majority of the cases, invasion to the cavernous sinuses can be seen on magnetic resonance imaging. Based on the previous reports, CCAs could be suspected in middle-aged women (mean, 42.4 years) with Cushing disease and magnetic resonance imaging findings of pituitary macroadenoma (77.2%) with invasion to the cavernous sinuses (79.2%). Some cases (24.4%) are silent ACTH adenomas and present as nonfunctional pituitary tumors. One case, initially presenting as silent ACTH adenoma, changed to a functional tumor with hypercortisolism and transformed to a pituitary carcinoma.26 Although there are some clinical and radiological findings that suggest the diagnosis of CCA, the final diagnosis is made based only on histopathological findings (summarized in Table 2). Macroadenomas causing Cushing disease are characterized by different biochemical features, invasion to cavernous sinus, initial remission after surgery and recurrence rates compared with microadenomas.27-30 The clinical behavior of CCAs tends to be quite similar to that of corticotroph macroadenomas, but, in comparison, they seem to have a higher rate of cavernous sinus invasion (Table 3). Specific clinical features have been shown to increase the risk of recurrence: young age, severity of Cushing disease, presence of depression, pretreatment and posttreatment
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urinary cortisol levels, and posttreatment ACTH levels.8 A 60% recurrence rate was reported at more than 1 year follow-up in one of the largest series published on CCAs to date, with 24% exhibiting multiple recurrences.8 Taking into account all of the reports of CCAs, a 66% recurrence rate can be inferred, which is higher than in macroadenomas causing Cushing disease,27-30 although the difference is not statistically significant (Tables 1 and 3). In the published cases, 6 cases (7.5%) gave rise to metastases (Table 1).8,21,24,26 Rare cases of Crooke’s cell carcinomas have also been reported by various investigators.26,31-35 These tumors cause cerebrospinal and/or systemic metastases22,36,37 and have been documented to exhibit Crooke’s hyaline change as well.11 Holthouse et al26 followed a 17-year-old patient through several recurrences. The patient’s primary tumor lacked atypical histological features, whereas the first recurrence revealed extensive hyaline change in the neoplastic cells and slightly more prominent nuclear pleomorphism.5,26
HISTOLOGICAL, IMMUNOHISTOCHEMICAL, AND ULTRASTRUCTURAL FINDINGS FOR DIAGNOSIS In a CCA, there is a massive hyaline change in the majority of the cells, same as the Crooke’s cells seen in the adenohypophysis of patients with glucocorticoid excess. Crooke’s cells exhibit a homogeneous pink and glassy cytoplasm, which can be identified with routine hematoxylin and eosin staining. Crooke’s cells can be recognized on PAS-stained sections. The PAS positivity in the cytoplasm is replaced by PAS-negative hyalinous material (Figure, A) and the pattern corresponding to the peripheral cytoplasmic secretory granule localization is demonstrated by ACTH immunoreactivity11 (Figure, B). According to George et al,8 the diagnosis of CCA is made if more than 50% of adenoma cells exhibit Crooke’s hyaline change, and currently this is still the accepted percentage for diagnosis. With regard to the indices of proliferation, George et al8 found that the mean Ki-67/MIB-1 labeling index value was 0.7%, and no statistical difference in such value was found between invasive and noninvasive tumors, although a remarkable increase in the value was reported in 2 recurrent cases. Immunopositivity for p53 (a tumor suppressor) on staining was found in 83% of the cases, with a general tendency for strong and diffuse immunopositivity of such with multiple recurrences. A detailed immunohistochemical analysis of a single case of a CCA revealed that tumor cells with increased Ki-67/MIB-1 nuclear labeling were accompanied by surprisingly low p53 expression as well as 80% immunoreactivity for p27, which is a cell-cycle suppressor.6 In this case, strong and diffuse immunopositivity for topoisomerase2a and vascular endothelial growth factor were also evident.6 Crooke’s hyaline material has been shown to correspond to CK accumulation. It was found immunopositive for 55 to 57 kD CK but negative for 68 kD CK, vimentin, desmin, neurofilament,
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TABLE 1. Crooke’s Cell Adenomas: Review of the Literaturea Reference
No. of Cases
9
Landolt (1975) Robert et al10 (1978) Felix et al5 (1981)
Horvath et al11 (1983) Robert and Hardy12 (1986) Kamijo et al13 (1991) Ikeda et al14 (1997) Kovacs et al15 (1999) Holthouse et al21 (2001) Roncaroli et al16 (2002)
George et al8 (2003) Lopez et al17 (2004) Kovacs et al18 (2005) Sahli et al19 (2006) Pusalkar et al20 (2008) Mohamed et al21 (2009) Takeshita et al22 (2009)
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Atkinson et al23 (2012) Rotondo et al6 (2012) Kovacs et al24 (2013) Sathiyabama et al25 (2014) a
Sex
Age, y
Cushing
Size
F F F F
66 17 25 56
Micro Micro Micro Macro
F
51
Yes Yes Yes Yes Yes Yes Yes No No Yes No No Yes 65%, 22/34
NA NA 1 1 1 1 10 1 1 1 1 1 1 1 6 36
F M F F M
63 37 17 49 52
27 F; 9 M
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
F F F M F M F F M F F F M M F F F
18-81; mean, 41 48 43 66 34 43 60 52 41 37 44 57 58 46 52 49 16 58
No Yes No No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes and Nelson’s Yes Yes Yes
Macro Macro
Invasion
Recurrence
Metastases
Yes
Yes
Yes, ·2
TMZ
Yes Yes
Micro Macro Macro
Yes
81% Macro (26/32)
72% invasive (21/29)
15/25, 60% Multiple in 24%
Macro Macro Macro Macro Micro Macro Macro Macro Macro Macro Micro Micro Macro Macro Macro Macro
Yes Yes No Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Yes
Yes, ·2 Yes, ·2
Yes Yes
Yes Yes Yes
Yes Yes
NA, not available; TMZ, temozolomide; Micro, microadenomas; Macro, macroadenomas.
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Yes
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TABLE 2. Clinical, MRI, and Morphological Features of Crooke’s Cell Adenomas5,7,8,13-15,17,19-25a Sex, % Female Male Age, y, range (mean) Clinical presentation, % Cushing disease Silent ACTH adenoma Size, % Macroadenomas Microadenomas Invasion to the cavernous or sphenoid sinuses (MRI), % Invasive Noninvasive Morphology
74.6 23.6 16-81 (42.4)
of secretory granules can follow different patterns,3 secretory granules, mitochondria, and other cytoplasmic organelles appear in a peripheral subplasmalemmal ring in a dense perinuclear cluster.4,6,26,41
TREATMENT
75.6 24.4 77.2 22.8
79.2 20.8 Chromophobic or acidophilic cells; Crooke’s hyaline change in .50% of cells; ACTH positive at the cell periphery; LMWK, Cam 5.2 with intense ringlike pattern; dense perinuclear keratin at EM
a
MRI, magnetic resonance imaging; ACTH, adrenocorticotropic hormone; LMWK, low molecular weight keratin; EM, electron microscopy.
and glial fibrillary acidic protein.38 The accumulation of CK filaments can be easily distinguished by means of low molecular weight keratin staining (Figure, C). Ultrastructurally, a CCA consists of large, spherical4 or ovoid6 cells with spherical nuclei containing macronucleoli and delicate heterochromatin6 (Figure, D). In these strongly CK-immunoreactive cells, characterized by acidophilic, densely eosinophilic, hyaline cytoplasm,8 both rough endoplasmic reticulum and Golgi complexes are obscured.6,8 There is loss of the normal acinar pattern and reticulin network, a characteristic feature of pituitary tumors,6,8,26 and the vacuoles are large lysosomes that take up the secretory granules.39,40 Although the distribution
Due to the nature of these tumors, surgery is the first treatment option when they present as Cushing disease or as nonfunctional pituitary macroadenomas. Patients with a CCA often require additional surgeries and are often unresponsive to the actual surgical, medical, and/or radiotherapy treatment protocols.8,42 Adrenal corticosteroid inhibitors, such as ketoconazole and metyrapone, act to decrease cortisol production by enzymatic inhibition43 and may be used for rapid control of severe hypercortisolism. However, this treatment has limited efficacy.43 These drugs have the disadvantage to be unable to prevent increases in ACTH levels.44 The value of treatment with dopamine agonists, the somatostatin analog pasireotide, and retinoic acid analogs requires further studies.45,46 Recent evidence suggests that temozolomide (TMZ), an orally active alkylating agent used primarily in the management of glioblastoma, may also be effective in controlling aggressive/ invasive pituitary adenomas/carcinomas.47 A low expression level of O-6-methylguanine-DNA methyltransferase, a DNA-repair enzyme, appears to be common in invasive macroadenomas of Cushing disease,48,49 including CCAs,47 and has been noted to predict TMZ responsiveness in the majority of aggressive pituitary adenomas/carcinomas reported. It is promising that this drug appears to reduce both tumor size and circulating ACTH levels substantially.22 In a series of 12 CCAs, 9 patients (75%) exhibited O-6-methylguanine-DNA methyltransferase immunoreactivity of less than 50%.44 According to the published literature, TMZ has been used in 4 cases of CCA (Table 1).21,22,24 Takeshita et al22 reported a 52-year-old woman with Crooke’s cell carcinoma and Cushing disease that were initially refractory to conventional therapeutic modalities but responded to TMZ with clinical and biochemical improvement as well as tumor shrinkage.
TABLE 3. Comparison of Macroadenomas Causing Cushing Disease With Crooke’s Cell Adenomasa
Reference 27
Blevins et al (1998) Cannavo et al28 (2003) Woo et al28 (2005) Kakade et al30 (2014) This review (2014)
No. of Cases
Female, %
21 26 16 40 80
90 65.3 77.83 60 74
Age, y
CS Invasion, n/N (%)b
Initial Remission, n/N (%)
Recurrence,c n/N (%)
Long-Term Remission, n/N (%)
Mean, 37 42.5 6 12.7 47.3 6 13.4 26.7 6 9.3 Mean 41
6/21 (28) 8/26 (30.7) 7/18 (39) 25/40 (62.5) 38/48 (79.2)
14/21 (67) 8/26 (30.7) 2/16 (12.5) 16/40 (40) NA
5/14 (36) 1/8 (12.5) NA 4/16 (25) 20/30 (66)
9/21 (42.8) 9/26 (34.6) 5/14 (35.7) 27/40 (67.5) NA
a
CS, cavernous sinus; NA, not available. Difference statistically significant (P = .0001) (2-tailed Fisher exact test). c Difference not statistically significant (P = .26) (2-tailed Fisher exact test). b
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FIGURE. A, periodic acid–Schiff (PAS) staining. Crooke’s cells can be recognized on PAS stained sections. The PAS positivity in the cytoplasm is replaced by PAS negativity to hyaline material. B, adrenocorticotropic hormone (ACTH) immunostaining. The Crooke’s hyaline material is immunonegative for ACTH. C, Low molecular weight keratin staining. The adenomatous (bottom right) and nontumorous (upper left) corticotrophs are conclusively immunopositive in their cytoplasm for low molecular weight keratin (A-C, original magnification ·250). D, electron microscopy. The Crooke’s hyaline material consists of microfilaments occupying large areas of the cytoplasm (original magnification ·5000).
In a separate study of 3 patients, in the first 2 with a CCA, TMZ was administered for 12 cycles, followed by radiological, endocrinological, and clinical follow-up at monthly intervals. Clinical and radiological improvement was noted with normalization of pituitary hormones and reduction of the residual tumor.21 Further studies are necessary to substantiate the efficacy of this medication for patients with CCAs who are refractory to standard therapies.22 TMZ is then one of the most promising drugs to be used in pituitary carcinomas as well as aggressive pituitary adenomas, including CCAs.50
DISCUSSION The cytoskeleton provides the cell’s shape, internal organization, and functional properties. The cytoskeleton of epithelial cells is a network of 3 major classes of filamentous biopolymers: microfilaments, microtubules, and intermediate filaments, which were first described by Ishikawa et al51 in 1968. Among the cytoplasmic intermediate filament proteins, CKs make up the largest subgroup of intermediate filaments,52 which are expressed preferentially in epithelial cells. The anterior pituitary is derived from stomodeal ectoderm via the Rathke’s diverticulum and therefore the intermediate filaments in adenohypophysial cells belong to the CK class.4
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The cytoskeletal alteration seen in Crooke’s cells is common in Cushing disease in nonneoplastic corticotrophs. It also happens in patients with hypercortisolism such as ectopic ACTH syndrome, cortisol-producing adrenocortical tumors, and exogenous glucocorticoids. Thus, Crooke’s hyaline change represents a response of corticotrophs to increased glucocorticoid excess and is thought to functionally suppress these cells. Different patterns of CK expression have been found in different epithelial tissues, conferring some degree of tissue or cell type specificity.53 Within a specific tissue, CK composition may vary with cellular growth environment, stage of differentiation, or period of embryonic development.54,55 The expression of specific CKs may also be influenced by hormones and changes in the extracellular matrix. Intermediate filaments form part of the cytoskeletal system and may play a role in secretory granule exocytosis. Corticotrophs of the anterior pituitary normally contain small numbers of perinuclear CK filament bundles and in Crooke’s cells the accumulation of filaments may indicate a disruption of the secretory process. Persistently increased blood cortisol levels result in accumulation of these CK filaments with reduction and displacement of both cytoplasmic organelles and secretory granules. Further studies analyzed the CK using more restricted specificity and found Crooke’s hyaline to be positive for CK8
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(52.5 kD) and 18 (45 kD), but negative for CK1 (68 kD), CK5 (58 kD), CK10 (56.5 kD) CK11 (56 kD), CK3 (64 kD), CK13 (51 kD), CK19 (40 kD), and CK7 (54 kD).56 More recently, CK20 has been shown as a major CK subtype found in corticotroph cells in response to either endogenous or exogenous sources of glucocorticoids and/or increased ACTH levels.41 CK20 now serves as a marker for the subtle cytoskeletal changes that occur before their development into classic Crooke’s cells.41 CK filaments associated with desmosomes and hemidesmosomes connect cells with extracellular matrix, giving strength to the cells and tissues. In addition to providing structural support, there is increasing evidence that the CK filaments participate in signaltransduction pathways.57,58 CKs are considered as dynamic scaffolds in different settings, contributing to cell size, proliferation, translation control, malignant transformation, and stress responses with highly complex patterns of phosphorylation and molecular associations. Without this delicate system, tissues would lack all order and all possibility of function or division. Although the term cytoskeleton suggests a static structure, it is actually a dynamic framework responding to signal transduction pathways and providing cells with order to undertake their functions. Because Crooke’s cells have been found in the pituitary gland of patients with Cushing disease but not after adrenalectomy (Nelson syndrome), inhibition by high steroid levels due to ACTH overproduction by adenoma cells has been suggested as being responsible for the appearance of these cells.51,59 The reason why the cells of CCA produce ACTH and at the same time display Crooke’s hyaline changes in response to increased glucocorticoid excess is not well understood. A plausible explanation for this hypersensitivity of neoplastic Crooke’s cells to physiological cortisol plasma levels may be due to receptor overexpression or lack of receptor downregulation.16 However, some CCAs are not associated with hypercortisolism15,16 and the fact the hyalinization may occur in these nonfunctional ACTH tumors suggests that CK deposition is not always related to hypercortisolism and can be related to other mechanisms. These cells might be hypersensitive to glucocorticoids, being suppressed at physiological levels of cortisol. On the other hand, the adenomatous corticotrophs may have a loss of glucocorticoid receptors and do not present with the usual hyaline changes. In cases of CCA, another mechanism may exist that could explain why the accumulation of CK does not follow the suppression of glucocorticoid production in the tumor cells. Cell proliferation markers are often used to assess tumor aggressiveness despite difficulty in drawing definitive conclusions and comparing results due to the lack of standardization of methods, the uneven cell distribution, as well as the issue of sampling bias. In the largest case series of CCAs, the Ki-67/MIB-1 value was found well lower than the 3% value, which is the actual accepted cutoff for defining a pituitary adenoma as “atypical” according to the latest WHO classification system,60 further proving the controversial standards used to define pituitary adenomas as “atypical,” “invasive,” or “aggressive.”50 Ki-67/MIB-1 and p53 immunostaining
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has been shown to be controversial in CCAs and should be further investigated in such tumors as well as in aggressive pituitary adenomas in general.
CONCLUSION Due to the rarity of CCAs, no clear indications exist yet for the management of patients affected by these tumors. However, ultrastructural and histological findings have made identification of these tumors more conceivable. These findings aid pathologists in the correct identification of the tumor, and physicians and neurosurgeons should be aware of the potential clinical aggressiveness of such pituitary adenomas subtypes. Despite advances being made in recognition of CCAs, little is known about their underlying mechanisms. As in other aggressive pituitary adenomas, patients should undergo a strict clinical, radiological, and biochemical follow-up over time, as well as undergoing a potential multimodality treatment.50 It can be speculated that CCAs have a different clinical behavior compared with the macroadenomas causing Cushing disease, but larger studies are required to substantiate current literature and elucidate the mechanisms by which Crooke’s cells act. Not many neurosurgeons and endocrinologists are aware of the existence of CCAs. Although it is difficult to draw final conclusions about such a rare and understudied type of tumor, our review aims to raise CCA awareness among neurosurgeons, as it is imperative to stimulate further research and to plan strict follow-up and eventual multimodality treatment of patients who have received a diagnosis of such a disease. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.
REFERENCES 1. Crooke A. A change in the basophil cells of the pituitary gland common to conditions which exhibit the syndrome attributed to basophil adenoma. J Pathol Bacteriol. 1935;41(2):339-349. 2. DeCicco FA, Dekker A, Yunis EJ. Fine structure of Crooke’s hyaline change in the human pituitary gland. Arch Pathol. 1972;94(1):65-70. 3. Wågermark J, Wersäll J. Ultrastructural features of Crooke’s changes in pituitary basophil cells. Acta Pathol Microbiol Scand. 1968;72(3):367-375. 4. Neumann PE, Horoupian DS, Goldman JE, Hess MA. Cytoplasmic filaments of Crooke’s hyaline change belong to the cytokeratin class. An immunocytochemical and ultrastructural study. Am J Pathol. 1984;116(2):214-222. 5. Felix IA, Horvath E, Kovacs K. Massive Crooke’s hyalinization in corticotroph cell adenomas of the human pituitary. A histological, immunocytological, and electron microscopic study of three cases. Acta Neurochir (Wien). 1981;58(3-4):235-243. 6. Rotondo F, Cusimano M, Scheithauer BW, Coire C, Horvath E, Kovacs K. Atypical, invasive, recurring Crooke cell adenoma of the pituitary. Hormones (Athens). 2012;11(1):94-100. 7. Saeger W, Ludecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ, Petersenn S. Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. Eur J Endocrinol. 2007;156(2):203-216. 8. George DH, Scheithauer BW, Kovacs K, et al. Crooke’s cell adenoma of the pituitary: an aggressive variant of corticotroph adenoma. Am J Surg Pathol. 2003; 27(10):1330-1336. 9. Landolt AM. Ultrastructure of human sella tumors. Correlations of clinical findings and morphology. Acta Neurochir (Wien). 1975;suppl 22:1-167.
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10. Robert F, Pelletier G, Hardy J. Pituitary adenomas in Cushing’s disease. A histologic, ultrastructural, and immunocytochemical study. Arch Pathol Lab Med. 1978;102(9):448-455. 11. Horvath E, Kovacs K, Josse R. Pituitary corticotroph cell adenoma with marked abundance of microfilaments. Ultrastruct Pathol. 1983;5(2-3):249-255. 12. Robert F, Hardy J. Human corticotroph cell adenomas. Semin Diagn Pathol. 1986; 3(1):34-41. 13. Kamijo K, Sato M, Saito T, et al. An ACTH and FSH producing invasive pituitary adenoma with Crooke’s hyalinization. Pathol Res Pract. 1991;187(5):637-641. 14. Ikeda H, Yoshimoto T, Ogawa Y, Mizoi K, Murakami O. Clinico-pathological study of Cushing’s disease with large pituitary adenoma. Clin Endocrinol (Oxf). 1997;46(6):669-679. 15. Kovacs K, Horvath E, Stenaneanu L, et al. Two cases of pituitary Crooke’s cell adenoma without Cushing’s disease: a histologic, immunocytochemical, electron microscopic and in situ hybridization study. Endocr Pathol. 1999;10(1):65-72. 16. Roncaroli F, Faustini-Fustini M, Mauri F, Asioli S, Frank G. Crooke’s hyalinization in silent corticotroph adenoma: report of two cases. Endocr Pathol. 2002;13(3):245-249. 17. Lopez JA, Kleinschmidt-Demasters Bk Bk, Sze CI, Woodmansee WW, Lillehei KO. Silent corticotroph adenomas: further clinical and pathological observations. Hum Pathol. 2004;35(9):1137-1147. 18. Kovacs K, Diep CC, Horvath E, et al. Prognostic indicators in an aggressive pituitary Crooke’s cell adenoma. Can J Neurol Sci. 2005;32(4):540-545. 19. Sahli R, Christ ER, Seiler R, Kappeler A, Vajtai I. Clinicopathologic correlations of silent corticotroph adenomas of the pituitary: report of four cases and literature review. Pathol Res Pract. 2006;202(6):457-464. 20. Pusalkar P, Zachariah S, Nasruddin A, Russell-Jones D, Roncaroli F. A case of silent ACTH/GH adenoma. Endocr Abstr. 2008;15:216. 21. Mohammed S, Kovacs K, Mason W, Smyth H, Cusimano MD. Use of temozolomide in aggressive pituitary tumors: case report. Neurosurgery. 2009;64 (4):E773-E774; discussion E774. 22. Takeshita A, Inoshita N, Taguchi M, et al. High incidence of low O(6)methylguanine DNA methyltransferase expression in invasive macroadenomas of Cushing’s disease. Eur J Endocrinol. 2009;161(4):553-559. 23. Atkinson DM, Hamilton RL. A 52-year-old male with visual changes. Brain Pathol. 2012;22(4):575-578. 24. Kovacs GL, Goth M, Rotondo F, et al. ACTH-secreting Crooke cell carcinoma of the pituitary. Eur J Clin Invest. 2013;43(1):20-26. 25. Sathiyabama D, Asha U, Shwetha SD, Thakkar R, Dil JS, Santosh V. Crooke’s cell adenoma of the pituitary: a histological, immunocytochemical, and electron microscopic study of a rare case. Neurol India. 2014;62(2):216-217. 26. Holthouse DJ, Robbins PD, Kahler R, Knuckey N, Pullan P. Corticotroph pituitary carcinoma: case report and literature review. Endocr Pathol. 2001;12(3):329-341. 27. Blevins LS Jr, Christy JH, Khajavi M, Tindall GT. Outcomes of therapy for Cushing’s disease due to adrenocorticotropin-secreting pituitary macroadenomas. J Clin Endocrinol Metab. 1998;83(1):63-67. 28. Cannavo S, Almoto B, Dall’Asta C, et al. Long-term results of treatment in patients with ACTH-secreting pituitary macroadenomas. Eur J Endocrinol. 2003;149(3):195-200. 29. Woo YS, Isidori AM, Wat WZ, et al. Clinical and biochemical characteristics of adrenocorticotropin-secreting macroadenomas. J Clin Endocrinol Metab. 2005;90 (8):4963-4969. 30. Kakade HR, Kasaliwal R, Khadilkar KS, et al. Clinical, biochemical and imaging characteristics of Cushing’s macroadenomas and their long-term treatment outcome. Clin Endocrinol (Oxf). 2014;81(3):336-342. 31. Pernicone PJ, Scheithauer BW, Sebo TJ, et al. Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer. 1997;79(4):804-812. 32. Zafar MS, Mellinger RC, Chason JL. Cushing’s disease due to pituitary carcinoma. Henry Ford Hosp Med J. 1984;32(1):61-66. 33. Scheithauer BW, Kovacs KT, Laws ER Jr, Randall RV. Pathology of invasive pituitary tumors with special reference to functional classification. J Neurosurg. 1986;65(6):733-744. 34. Gaffey TA, Scheithauer BW, Lloyd RV, et al. Corticotroph carcinoma of the pituitary: a clinicopathological study. Report of four cases. J Neurosurg. 2002;96(2):352-360. 35. Scheithauer BW, Gaffey TA, Lloyd RV, et al. Pathobiology of pituitary adenomas and carcinomas. Neurosurgery. 2006;59(2):341-353; discussion 341-353. 36. Kaltsas GA, Nomikos P, Kontogeorgos G, Buchfelder M, Grossman AB. Clinical review: diagnosis and management of pituitary carcinomas. J Clin Endocrinol Metab. 2005;90(5):3089-3099.
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37. Scheithauer BW, Kurtkaya-Yapicier O, Kovacs KT, Young WF Jr, Lloyd RV. Pituitary carcinoma: a clinicopathological review. Neurosurgery. 2005;56(5):10661074; discussion 1066-1074. 38. Uei Y. Immunohistological study of Crooke’s cells. Pathol Res Pract. 1988;183(5): 636-637. 39. Saeger W. Ultrastructure of hyperplastic and adenomatous corticotrophic cells in Cushing’s syndrome of hypothalamic-hypophyseal origin (author’s translation) [article in German]. Virchows Arch A Pathol Anat Histol. 1974;362(1):73-88. 40. Saeger W, Ludecke DK, Geislet F. The anterior lobe in Cushing’s disease/ syndrome. In: Ludecke DK, Chrousos C, Tolis G, eds. Cushing’s Syndrome, and Other Hypercortisolemic States. Progress on Endocrine Research and Surgery. 5th ed. New York, NY: Raven Press; 1990:147-156. 41. Eschbacher JM, Coons SW. Cytokeratin CK20 is a sensitive marker for Crooke’s cells and the early cytoskeletal changes associated with hypercortisolism within pituitary corticotrophs. Endocr Pathol. 2006;17(4):365-376. 42. Kaltsas GA, Grossman AB. Malignant pituitary tumours. Pituitary. 1998;1(1):69-81. 43. Patil CG, Hayden M, Katznelson L, Chang SD. Non-surgical management of hormone-secreting pituitary tumors. J Clin Neurosci. 2009;16(8):985-993. 44. Salehi F, Scheithauer BW, Kovacs K, et al. O-6-methylguanine-DNA methyltransferase (MGMT) immunohistochemical expression in pituitary corticotroph adenomas. Neurosurgery. 2012;70(2):491-496; discussion 496. 45. Colao A, Filippella M, Pivonello R, Di Somma C, Faggiano A, Lombardi G. Combined therapy of somatostatin analogues and dopamine agonists in the treatment of pituitary tumours. Eur J Endocrinol. 2007;156(suppl 1):S57-S63. 46. Alexandraki KI, Grossman AB. Pituitary-targeted medical therapy of Cushing’s disease. Expert Opin Investig Drugs. 2008;17(5):669-677. 47. Annamalai AK, Dean AF, Kandasamy N, et al. Temozolomide responsiveness in aggressive corticotroph tumours: a case report and review of the literature. Pituitary. 2012;15(3):276-287. 48. McCormack AI, McDonald KL, Gill AJ, et al. Low O6-methylguanine-DNA methyltransferase (MGMT) expression and response to temozolomide in aggressive pituitary tumours. Clin Endocrinol (Oxf). 2009;71(2):226-233. 49. Widhalm G, Wolfsberger S, Preusser M, et al. O(6)-methylguanine DNA methyltransferase immunoexpression in nonfunctioning pituitary adenomas: are progressive tumors potential candidates for temozolomide treatment? Cancer. 2009;115(5):1070-1080. 50. Di Ieva A, Rotondo F, Syro LV, Cusimano MD, Kovacs K. Aggressive pituitary adenomas—diagnosis and emerging treatments. Nat Rev Endocrinol. 2014;10(7):423-435. 51. Ishikawa H, Bischoff R, Holtzer H. Mitosis and intermediate-sized filaments in developing skeletal muscle. J Cell Biol. 1968;38(3):538-555. 52. Schweizer J, Bowden PE, Coulombe PA, et al. New consensus nomenclature for mammalian keratins. J Cell Biol. 2006;174(2):169-174. 53. Franke WW, Schiller DL, Moll R, et al. Diversity of cytokeratins. Differentiation specific expression of cytokeratin polypeptides in epithelial cells and tissues. J Mol Biol. 1981;153(4):933-959. 54. Tseng SC, Jarvinen MJ, Nelson WG, Huang JW, Woodcock-Mitchell J, Sun TT. Correlation of specific keratins with different types of epithelial differentiation: monoclonal antibody studies. Cell. 1982;30(2):361-372. 55. Moll R, Divo M, Langbein L. The human keratins: biology and pathology. Histochem Cell Biol. 2008;129(6):705-733. 56. Uei Y, Kanzaki M, Yabana T. Further immunohistochemical study of Crooke’s hyalin. Pathol Res Pract. 1991;187(5):539-540. 57. Magin TM, Vijayaraj P, Leube RE. Structural and regulatory functions of keratins. Exp Cell Res. 2007;313(10):2021-2032. 58. Busch T, Armacki M, Eiseler T, et al. Keratin 8 phosphorylation regulates keratin reorganization and migration of epithelial tumor cells. J Cell Sci. 2012;125(pt 9): 2148-2159. 59. Laquer GL. Cytological changes in human hypophyses after cortisone and ACTH treatment. Science. 1950;112:429-430. 60. DeLellis RA, Lloyd RV, Heitz PU, Eng C, eds. World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of Endocrine Organs. Lyon, France: IARC Press; 2004.
Acknowledgment The authors are grateful to the Jarislowsky and Lloyd Carr-Harris Foundations for their generous support.
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Crooke’s Cell Tumors of the Pituitary Antonio Di Ieva, MD, PhD*‡
Crooke’s cell adenomas are a rare type of pituitary neoplasm. They produce adrenocorticotropic hormone causing Cushing’s disease or may be endocrinologically silent. These tumors are usually invasive, may exhibit aggressive clinical behavior, and often recur with a low success of cure after reoperation and/or radiotherapy. Due to their rarity, they present great difficulties in assessing prognosis, treatment, and clinical management. Neurosurgeons and physicians dealing with pituitary adenomas diagnosed as Crooke’s cell adenomas have to be aware of their potential clinical aggressiveness to plan strict follow-up of patients and eventual multimodality treatment. We review here the published cases of Crooke’s cell tumors, as well as the clinical and histopathological characteristics of these unusual neoplasms.
Jennilee M. Davidson, BScH*‡ Luis V. Syro, MD§ Fabio Rotondo, BScH¶ Julian F. Montoya, MDk Eva Horvath, PhD¶ Michael D. Cusimano, MD, PhD‡ Kalman Kovacs, MD, PhD¶ ‡Division of Neurosurgery, Department of Surgery, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; §Department of Neurosurgery, Hospital Pablo Tobon Uribe and Clinica Medellin, Medellin, Colombia; ¶Division of Pathology, Department of Laboratory Medicine, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; kDivision of Endocrinology, Hospital Pablo Tobon Uribe and Universidad de Antioquia, Medellin, Colombia *These authors contributed equally. Correspondence: Antonio Di Ieva, MD, PhD, Division of Neurosurgery, Department of Surgery, St. Michael’s Hospital, 30 Bond Street, M5B 1W8 Toronto, Ontario, Canada. E-mail: [email protected] Received, May 25, 2014. Accepted, December 3, 2014. Published Online, January 29, 2015. Copyright © 2015 by the Congress of Neurological Surgeons.
KEY WORDS: Adrenocorticotropic hormone producing pituitary tumor, Aggressive pituitary adenoma, Crooke’s cell, Hyalinization, Pituitary adenoma, Pituitary carcinoma Neurosurgery 76:616–622, 2015
DOI: 10.1227/NEU.0000000000000657
A
rthur Carleton Crooke (1905-1990) was the first to describe the accumulation of hyaline material in the adenohypophysis of patients with Cushing syndrome in 1935.1 This change corresponded to the disappearance of secretory granules and hyalinization of cytoplasm in adenohypophysial basophil cells in patients with primary hypercortisolism, including those with adrenocorticotropic hormone (ACTH)–producing tumors.1,2 Subsequent investigators described histological and ultrastructural findings to aid in identifying these cells.3,4 Crooke’s cells were then considered corticotrophs that, in the presence of glucocorticoid excess, undergo massive accumulation of perinuclear cytokeratin (CK) filaments, giving their cytoplasm a distinct hyalinized appearance on hematoxylin and eosin staining. This material, with a perinuclear and ringlike distribution, is periodic acid–Schiff (PAS) negative and lacks ACTH immunoreactivity. In some clinically aggressive and often recurring pituitary adenomas, authors found massive hyaline changes in the majority of the cells, which were the same as the Crooke’s cells seen in the adenohypophysis of patients with glucocorticoid
ABBREVIATIONS: ACTH, adrenocorticotropic hormone; CCA, Crooke’s cell adenoma; CK, cytokeratin; PAS, periodic acid–Schiff; TMZ, temozolomide
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excess described earlier.5,6 Tumors that contained this Crooke’s hyaline material in the cytoplasm of more than 50% of the cells were then classified as Crooke’s cell adenoma (CCA). CCAs are very rare, accounting for less than 1% of pituitary adenomas,7 and they have not been studied extensively. Currently, recognition of these tumors is becoming more evident, but there is no consistent classification system to identify a CCA based on the percentage of Crooke’s cells present or its aggressive clinical behavior. The identification and mechanism of CCAs, in terms of progression and rate of recurrence, are still poorly understood.7 Due to their rarity, they present great difficulties for prognosis, treatment, and clinical management. CCAs tend to have a low success at reoperation (0%-25%) and are often resistant to radiotherapy,8 hence the need for further studies of larger scale. Here, we review the published cases of CCAs, as well as the histopathological and clinical characteristics of these uncommon tumors.
METHODS Literature Review PubMed (1935 to October 2014), MEDLINE (1946 to October 2014), Web of Science, Scopus, Embase, and Google Scholar were searched using key words including Crooke’s cell adenomas, Crooke’s cell, adrenocorticotropic hormone–producing pituitary tumors, recurrent
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CROOKE’S TUMORS
pituitary tumors, aggressive, invasive pituitary adenomas, pituitary carcinomas, and hyalinization. Articles published in English were included. The diagnostic criterion was the presence of Crooke’s hyaline material in the substantial majority of adenoma cells. Hematoxylin and eosin staining, PAS staining, and immunostaining for ACTH and low molecular weight keratin (Cam 5.2) were used to identify the presence of Crooke’s hyaline material. Some authors also made use of electron microscopy.
RESULTS To date, 80 cases of CCAs have been published (Table 1).5,6,8-25 Although excessive amounts of microfilaments in ACTH-producing adenomas have been mentioned before by Landolt9 and Robert et al.,10 Felix et al5 in 1981 described the first 3 cases of ACTH producing pituitary adenomas with massive cytoplasmic deposition of Crooke’s hyaline material. After those, some other cases were described, and finally in 2003, George et al8 published the first series of 36 cases, which, after more than 10 years, is still the largest published cases series. The authors described their clinical presentation, pathological findings, and evolution, suggesting their aggressive clinical behavior. Clinical details were available in most of them (Table 2): 74.6% were female (47/63), with an age range of 16 to 81 years (mean, 42.4), usually macroadenomas (44/57, 77.2%) with invasion to the cavernous or sphenoid sinuses (79.2%, 38/48). Cushing disease was present in 75.6% (59/78), and 24.4% were silent ACTH adenomas. In 6 patients, the tumor gave rise to metastases (6/80, 7.5%).8
CLINICAL FEATURES CCAs usually present as invasive macroadenomas causing Cushing disease or as nonfunctional pituitary macroadenomas. In the majority of the cases, invasion to the cavernous sinuses can be seen on magnetic resonance imaging. Based on the previous reports, CCAs could be suspected in middle-aged women (mean, 42.4 years) with Cushing disease and magnetic resonance imaging findings of pituitary macroadenoma (77.2%) with invasion to the cavernous sinuses (79.2%). Some cases (24.4%) are silent ACTH adenomas and present as nonfunctional pituitary tumors. One case, initially presenting as silent ACTH adenoma, changed to a functional tumor with hypercortisolism and transformed to a pituitary carcinoma.26 Although there are some clinical and radiological findings that suggest the diagnosis of CCA, the final diagnosis is made based only on histopathological findings (summarized in Table 2). Macroadenomas causing Cushing disease are characterized by different biochemical features, invasion to cavernous sinus, initial remission after surgery and recurrence rates compared with microadenomas.27-30 The clinical behavior of CCAs tends to be quite similar to that of corticotroph macroadenomas, but, in comparison, they seem to have a higher rate of cavernous sinus invasion (Table 3). Specific clinical features have been shown to increase the risk of recurrence: young age, severity of Cushing disease, presence of depression, pretreatment and posttreatment
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urinary cortisol levels, and posttreatment ACTH levels.8 A 60% recurrence rate was reported at more than 1 year follow-up in one of the largest series published on CCAs to date, with 24% exhibiting multiple recurrences.8 Taking into account all of the reports of CCAs, a 66% recurrence rate can be inferred, which is higher than in macroadenomas causing Cushing disease,27-30 although the difference is not statistically significant (Tables 1 and 3). In the published cases, 6 cases (7.5%) gave rise to metastases (Table 1).8,21,24,26 Rare cases of Crooke’s cell carcinomas have also been reported by various investigators.26,31-35 These tumors cause cerebrospinal and/or systemic metastases22,36,37 and have been documented to exhibit Crooke’s hyaline change as well.11 Holthouse et al26 followed a 17-year-old patient through several recurrences. The patient’s primary tumor lacked atypical histological features, whereas the first recurrence revealed extensive hyaline change in the neoplastic cells and slightly more prominent nuclear pleomorphism.5,26
HISTOLOGICAL, IMMUNOHISTOCHEMICAL, AND ULTRASTRUCTURAL FINDINGS FOR DIAGNOSIS In a CCA, there is a massive hyaline change in the majority of the cells, same as the Crooke’s cells seen in the adenohypophysis of patients with glucocorticoid excess. Crooke’s cells exhibit a homogeneous pink and glassy cytoplasm, which can be identified with routine hematoxylin and eosin staining. Crooke’s cells can be recognized on PAS-stained sections. The PAS positivity in the cytoplasm is replaced by PAS-negative hyalinous material (Figure, A) and the pattern corresponding to the peripheral cytoplasmic secretory granule localization is demonstrated by ACTH immunoreactivity11 (Figure, B). According to George et al,8 the diagnosis of CCA is made if more than 50% of adenoma cells exhibit Crooke’s hyaline change, and currently this is still the accepted percentage for diagnosis. With regard to the indices of proliferation, George et al8 found that the mean Ki-67/MIB-1 labeling index value was 0.7%, and no statistical difference in such value was found between invasive and noninvasive tumors, although a remarkable increase in the value was reported in 2 recurrent cases. Immunopositivity for p53 (a tumor suppressor) on staining was found in 83% of the cases, with a general tendency for strong and diffuse immunopositivity of such with multiple recurrences. A detailed immunohistochemical analysis of a single case of a CCA revealed that tumor cells with increased Ki-67/MIB-1 nuclear labeling were accompanied by surprisingly low p53 expression as well as 80% immunoreactivity for p27, which is a cell-cycle suppressor.6 In this case, strong and diffuse immunopositivity for topoisomerase2a and vascular endothelial growth factor were also evident.6 Crooke’s hyaline material has been shown to correspond to CK accumulation. It was found immunopositive for 55 to 57 kD CK but negative for 68 kD CK, vimentin, desmin, neurofilament,
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TABLE 1. Crooke’s Cell Adenomas: Review of the Literaturea Reference
No. of Cases
9
Landolt (1975) Robert et al10 (1978) Felix et al5 (1981)
Horvath et al11 (1983) Robert and Hardy12 (1986) Kamijo et al13 (1991) Ikeda et al14 (1997) Kovacs et al15 (1999) Holthouse et al21 (2001) Roncaroli et al16 (2002)
George et al8 (2003) Lopez et al17 (2004) Kovacs et al18 (2005) Sahli et al19 (2006) Pusalkar et al20 (2008) Mohamed et al21 (2009) Takeshita et al22 (2009)
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Atkinson et al23 (2012) Rotondo et al6 (2012) Kovacs et al24 (2013) Sathiyabama et al25 (2014) a
Sex
Age, y
Cushing
Size
F F F F
66 17 25 56
Micro Micro Micro Macro
F
51
Yes Yes Yes Yes Yes Yes Yes No No Yes No No Yes 65%, 22/34
NA NA 1 1 1 1 10 1 1 1 1 1 1 1 6 36
F M F F M
63 37 17 49 52
27 F; 9 M
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
F F F M F M F F M F F F M M F F F
18-81; mean, 41 48 43 66 34 43 60 52 41 37 44 57 58 46 52 49 16 58
No Yes No No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes and Nelson’s Yes Yes Yes
Macro Macro
Invasion
Recurrence
Metastases
Yes
Yes
Yes, ·2
TMZ
Yes Yes
Micro Macro Macro
Yes
81% Macro (26/32)
72% invasive (21/29)
15/25, 60% Multiple in 24%
Macro Macro Macro Macro Micro Macro Macro Macro Macro Macro Micro Micro Macro Macro Macro Macro
Yes Yes No Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Yes
Yes, ·2 Yes, ·2
Yes Yes
Yes Yes Yes
Yes Yes
NA, not available; TMZ, temozolomide; Micro, microadenomas; Macro, macroadenomas.
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Yes
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TABLE 2. Clinical, MRI, and Morphological Features of Crooke’s Cell Adenomas5,7,8,13-15,17,19-25a Sex, % Female Male Age, y, range (mean) Clinical presentation, % Cushing disease Silent ACTH adenoma Size, % Macroadenomas Microadenomas Invasion to the cavernous or sphenoid sinuses (MRI), % Invasive Noninvasive Morphology
74.6 23.6 16-81 (42.4)
of secretory granules can follow different patterns,3 secretory granules, mitochondria, and other cytoplasmic organelles appear in a peripheral subplasmalemmal ring in a dense perinuclear cluster.4,6,26,41
TREATMENT
75.6 24.4 77.2 22.8
79.2 20.8 Chromophobic or acidophilic cells; Crooke’s hyaline change in .50% of cells; ACTH positive at the cell periphery; LMWK, Cam 5.2 with intense ringlike pattern; dense perinuclear keratin at EM
a
MRI, magnetic resonance imaging; ACTH, adrenocorticotropic hormone; LMWK, low molecular weight keratin; EM, electron microscopy.
and glial fibrillary acidic protein.38 The accumulation of CK filaments can be easily distinguished by means of low molecular weight keratin staining (Figure, C). Ultrastructurally, a CCA consists of large, spherical4 or ovoid6 cells with spherical nuclei containing macronucleoli and delicate heterochromatin6 (Figure, D). In these strongly CK-immunoreactive cells, characterized by acidophilic, densely eosinophilic, hyaline cytoplasm,8 both rough endoplasmic reticulum and Golgi complexes are obscured.6,8 There is loss of the normal acinar pattern and reticulin network, a characteristic feature of pituitary tumors,6,8,26 and the vacuoles are large lysosomes that take up the secretory granules.39,40 Although the distribution
Due to the nature of these tumors, surgery is the first treatment option when they present as Cushing disease or as nonfunctional pituitary macroadenomas. Patients with a CCA often require additional surgeries and are often unresponsive to the actual surgical, medical, and/or radiotherapy treatment protocols.8,42 Adrenal corticosteroid inhibitors, such as ketoconazole and metyrapone, act to decrease cortisol production by enzymatic inhibition43 and may be used for rapid control of severe hypercortisolism. However, this treatment has limited efficacy.43 These drugs have the disadvantage to be unable to prevent increases in ACTH levels.44 The value of treatment with dopamine agonists, the somatostatin analog pasireotide, and retinoic acid analogs requires further studies.45,46 Recent evidence suggests that temozolomide (TMZ), an orally active alkylating agent used primarily in the management of glioblastoma, may also be effective in controlling aggressive/ invasive pituitary adenomas/carcinomas.47 A low expression level of O-6-methylguanine-DNA methyltransferase, a DNA-repair enzyme, appears to be common in invasive macroadenomas of Cushing disease,48,49 including CCAs,47 and has been noted to predict TMZ responsiveness in the majority of aggressive pituitary adenomas/carcinomas reported. It is promising that this drug appears to reduce both tumor size and circulating ACTH levels substantially.22 In a series of 12 CCAs, 9 patients (75%) exhibited O-6-methylguanine-DNA methyltransferase immunoreactivity of less than 50%.44 According to the published literature, TMZ has been used in 4 cases of CCA (Table 1).21,22,24 Takeshita et al22 reported a 52-year-old woman with Crooke’s cell carcinoma and Cushing disease that were initially refractory to conventional therapeutic modalities but responded to TMZ with clinical and biochemical improvement as well as tumor shrinkage.
TABLE 3. Comparison of Macroadenomas Causing Cushing Disease With Crooke’s Cell Adenomasa
Reference 27
Blevins et al (1998) Cannavo et al28 (2003) Woo et al28 (2005) Kakade et al30 (2014) This review (2014)
No. of Cases
Female, %
21 26 16 40 80
90 65.3 77.83 60 74
Age, y
CS Invasion, n/N (%)b
Initial Remission, n/N (%)
Recurrence,c n/N (%)
Long-Term Remission, n/N (%)
Mean, 37 42.5 6 12.7 47.3 6 13.4 26.7 6 9.3 Mean 41
6/21 (28) 8/26 (30.7) 7/18 (39) 25/40 (62.5) 38/48 (79.2)
14/21 (67) 8/26 (30.7) 2/16 (12.5) 16/40 (40) NA
5/14 (36) 1/8 (12.5) NA 4/16 (25) 20/30 (66)
9/21 (42.8) 9/26 (34.6) 5/14 (35.7) 27/40 (67.5) NA
a
CS, cavernous sinus; NA, not available. Difference statistically significant (P = .0001) (2-tailed Fisher exact test). c Difference not statistically significant (P = .26) (2-tailed Fisher exact test). b
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FIGURE. A, periodic acid–Schiff (PAS) staining. Crooke’s cells can be recognized on PAS stained sections. The PAS positivity in the cytoplasm is replaced by PAS negativity to hyaline material. B, adrenocorticotropic hormone (ACTH) immunostaining. The Crooke’s hyaline material is immunonegative for ACTH. C, Low molecular weight keratin staining. The adenomatous (bottom right) and nontumorous (upper left) corticotrophs are conclusively immunopositive in their cytoplasm for low molecular weight keratin (A-C, original magnification ·250). D, electron microscopy. The Crooke’s hyaline material consists of microfilaments occupying large areas of the cytoplasm (original magnification ·5000).
In a separate study of 3 patients, in the first 2 with a CCA, TMZ was administered for 12 cycles, followed by radiological, endocrinological, and clinical follow-up at monthly intervals. Clinical and radiological improvement was noted with normalization of pituitary hormones and reduction of the residual tumor.21 Further studies are necessary to substantiate the efficacy of this medication for patients with CCAs who are refractory to standard therapies.22 TMZ is then one of the most promising drugs to be used in pituitary carcinomas as well as aggressive pituitary adenomas, including CCAs.50
DISCUSSION The cytoskeleton provides the cell’s shape, internal organization, and functional properties. The cytoskeleton of epithelial cells is a network of 3 major classes of filamentous biopolymers: microfilaments, microtubules, and intermediate filaments, which were first described by Ishikawa et al51 in 1968. Among the cytoplasmic intermediate filament proteins, CKs make up the largest subgroup of intermediate filaments,52 which are expressed preferentially in epithelial cells. The anterior pituitary is derived from stomodeal ectoderm via the Rathke’s diverticulum and therefore the intermediate filaments in adenohypophysial cells belong to the CK class.4
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The cytoskeletal alteration seen in Crooke’s cells is common in Cushing disease in nonneoplastic corticotrophs. It also happens in patients with hypercortisolism such as ectopic ACTH syndrome, cortisol-producing adrenocortical tumors, and exogenous glucocorticoids. Thus, Crooke’s hyaline change represents a response of corticotrophs to increased glucocorticoid excess and is thought to functionally suppress these cells. Different patterns of CK expression have been found in different epithelial tissues, conferring some degree of tissue or cell type specificity.53 Within a specific tissue, CK composition may vary with cellular growth environment, stage of differentiation, or period of embryonic development.54,55 The expression of specific CKs may also be influenced by hormones and changes in the extracellular matrix. Intermediate filaments form part of the cytoskeletal system and may play a role in secretory granule exocytosis. Corticotrophs of the anterior pituitary normally contain small numbers of perinuclear CK filament bundles and in Crooke’s cells the accumulation of filaments may indicate a disruption of the secretory process. Persistently increased blood cortisol levels result in accumulation of these CK filaments with reduction and displacement of both cytoplasmic organelles and secretory granules. Further studies analyzed the CK using more restricted specificity and found Crooke’s hyaline to be positive for CK8
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CROOKE’S TUMORS
(52.5 kD) and 18 (45 kD), but negative for CK1 (68 kD), CK5 (58 kD), CK10 (56.5 kD) CK11 (56 kD), CK3 (64 kD), CK13 (51 kD), CK19 (40 kD), and CK7 (54 kD).56 More recently, CK20 has been shown as a major CK subtype found in corticotroph cells in response to either endogenous or exogenous sources of glucocorticoids and/or increased ACTH levels.41 CK20 now serves as a marker for the subtle cytoskeletal changes that occur before their development into classic Crooke’s cells.41 CK filaments associated with desmosomes and hemidesmosomes connect cells with extracellular matrix, giving strength to the cells and tissues. In addition to providing structural support, there is increasing evidence that the CK filaments participate in signaltransduction pathways.57,58 CKs are considered as dynamic scaffolds in different settings, contributing to cell size, proliferation, translation control, malignant transformation, and stress responses with highly complex patterns of phosphorylation and molecular associations. Without this delicate system, tissues would lack all order and all possibility of function or division. Although the term cytoskeleton suggests a static structure, it is actually a dynamic framework responding to signal transduction pathways and providing cells with order to undertake their functions. Because Crooke’s cells have been found in the pituitary gland of patients with Cushing disease but not after adrenalectomy (Nelson syndrome), inhibition by high steroid levels due to ACTH overproduction by adenoma cells has been suggested as being responsible for the appearance of these cells.51,59 The reason why the cells of CCA produce ACTH and at the same time display Crooke’s hyaline changes in response to increased glucocorticoid excess is not well understood. A plausible explanation for this hypersensitivity of neoplastic Crooke’s cells to physiological cortisol plasma levels may be due to receptor overexpression or lack of receptor downregulation.16 However, some CCAs are not associated with hypercortisolism15,16 and the fact the hyalinization may occur in these nonfunctional ACTH tumors suggests that CK deposition is not always related to hypercortisolism and can be related to other mechanisms. These cells might be hypersensitive to glucocorticoids, being suppressed at physiological levels of cortisol. On the other hand, the adenomatous corticotrophs may have a loss of glucocorticoid receptors and do not present with the usual hyaline changes. In cases of CCA, another mechanism may exist that could explain why the accumulation of CK does not follow the suppression of glucocorticoid production in the tumor cells. Cell proliferation markers are often used to assess tumor aggressiveness despite difficulty in drawing definitive conclusions and comparing results due to the lack of standardization of methods, the uneven cell distribution, as well as the issue of sampling bias. In the largest case series of CCAs, the Ki-67/MIB-1 value was found well lower than the 3% value, which is the actual accepted cutoff for defining a pituitary adenoma as “atypical” according to the latest WHO classification system,60 further proving the controversial standards used to define pituitary adenomas as “atypical,” “invasive,” or “aggressive.”50 Ki-67/MIB-1 and p53 immunostaining
NEUROSURGERY
has been shown to be controversial in CCAs and should be further investigated in such tumors as well as in aggressive pituitary adenomas in general.
CONCLUSION Due to the rarity of CCAs, no clear indications exist yet for the management of patients affected by these tumors. However, ultrastructural and histological findings have made identification of these tumors more conceivable. These findings aid pathologists in the correct identification of the tumor, and physicians and neurosurgeons should be aware of the potential clinical aggressiveness of such pituitary adenomas subtypes. Despite advances being made in recognition of CCAs, little is known about their underlying mechanisms. As in other aggressive pituitary adenomas, patients should undergo a strict clinical, radiological, and biochemical follow-up over time, as well as undergoing a potential multimodality treatment.50 It can be speculated that CCAs have a different clinical behavior compared with the macroadenomas causing Cushing disease, but larger studies are required to substantiate current literature and elucidate the mechanisms by which Crooke’s cells act. Not many neurosurgeons and endocrinologists are aware of the existence of CCAs. Although it is difficult to draw final conclusions about such a rare and understudied type of tumor, our review aims to raise CCA awareness among neurosurgeons, as it is imperative to stimulate further research and to plan strict follow-up and eventual multimodality treatment of patients who have received a diagnosis of such a disease. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.
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DI IEVA ET AL
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Acknowledgment The authors are grateful to the Jarislowsky and Lloyd Carr-Harris Foundations for their generous support.
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