Letter to the Editor

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Letter to the Editor. Kalman Kovacs & Fabio Rotondo & Eva Horvath ... Published online: 23 October 2014. © Springer Science+Business Media New York 2014.
Endocr Pathol (2015) 26:93–94 DOI 10.1007/s12022-014-9342-7

Letter to the Editor Kalman Kovacs & Fabio Rotondo & Eva Horvath & Luis V. Syro & Antonio Di Ieva & Michael D. Cusimano & David G. Munoz

Published online: 23 October 2014 # Springer Science+Business Media New York 2014

We read Dr. Trouillas’ recent article published in Endocrine Pathology (25: 124–132, 2014), with great interest. Earlier attempts have been made to create a proper classification for pituitary tumors, yet a proper classification is still unresolved. Dr. Trouillas and colleagues’ effort should be applauded. However, we believe the proposed classification is complicated and, unfortunately, not as reliable as it may seem. Implementing it would be extremely time consuming and expensive and not only add extra burden to already strained resources in pathology departments around the world but also be achievable by few. To go to this expense for little gain would not advance the care of patients with pituitary tumors. Several studies indicate that pituitary tumor subtypes are not uniform. Gonadotroph adenomas usually occur in older patients; however, they may be diagnosed in young people as well. Crooke’s cell adenomas are usually aggressive tumors; however, some Crooke’s cell adenomas are slow growing, benign, and not aggressive. Corticotroph adenomas may be associated with overproduction of ACTH, yet some are silent and unassociated with hormone excess. In our view, the proposed classification is a major step forward and Dr. Trouillas should be congratulated. It is, however, not reliable in every case.

K. Kovacs : F. Rotondo (*) : E. Horvath : D. G. Munoz Department of Laboratory Medicine, Division of Pathology, St. Michael’s Hospital, Toronto, ON, Canada e-mail: [email protected] L. V. Syro Department of Neurosurgery, Hospital Pablo Tobon Uribe and Clinica Medellin, Medellin, Colombia A. Di Ieva : M. D. Cusimano Department of Surgery, Division of Neurosurgery, St. Michael’s Hospital, Toronto, ON, Canada

A simplified and standardized classification should be introduced which would not put a strain on the budgetary restraints of the laboratories, increase reliability, and allow more pathologists who do not specialize in pituitary morphology to feel at ease to diagnose pituitary tumor cases within their departments. Several people, including our group, have reported subtypes of adenomas utilizing electron microscopy, in situ hybridization, and molecular/genetic studies, but it is questionable what benefit this information will provide to the patient or to the mode of treatment. At this moment, these expensive tests that are not in the reach of many pathologists internationally should continue to be used in research but not incorporated into a complicated, unreliable classification system that would be inherently imposed on pathologists around the world. Instead, we propose a very simple classification which could be used by every pathologist, even those whose primary interest is not pituitary tumors. The basis of this simple classification system would use the following stains: Hematoxylin and eosin This is the gold standard in (H&E) diagnostic pathology and 90 % of pituitary tumors can be diagnosed properly using only H&E staining. Reticulin stains are useful to determine the loss of acinar architecture, a characteristic feature of pituitary tumors. Routine immunostains GH, PRL, ACTH, TSH, FSH, LH, for adenohypophysial and alpha subunit. One can distinguish between hormones monohormonal, bihormonal, and plurihormonal tumors by simply looking for immunopositive cells in the various stained slides.

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Low molecular weight keratin (LMWK)

Ki-67 nuclear labeling index

Endocr Pathol (2015) 26:93–94

Synaptophysin can be utilized as a marker to confirm whether the tissue is of pituitary origin since both adenohypophysial and tumor cells will contain cytoplasmic immunopositivity. Cam5.2 may be used for GH- and ACTH-producing adenomas. Its pattern is characteristic in sparsely granulated GH adenomas, silent or functional ACTH adenomas, and Crooke’s cell adenomas. Tumor aggressiveness is not possible to assess reliably. In our experience, and that of many biomarkers, the Ki-67 nuclear labeling index using the MIB1 antibody is the most reliable test to assess aggression. In the normal pituitary, there are no immunopositive nuclei. In the slow growing, expansively growing pituitary adenomas, the ratio of Ki-67 immunopositive nuclei are usually 1–3 % of all cells. In carcinomas, the Ki-67 nuclear immunopositivity is >10 %. We and others have seen exceptions to these general principles: low Ki-67 levels may rarely occur in rapidly growing pituitary tumors and high Ki-67 labeling index can very occasionally be seen in slow growing tumors, but in the vast majority, the indices we have indicated above are useful

measures of the growth potential of tumors. To minimize misclassifications with the MIB1 antibody, strict attention to technical details are also important: the type of fixative, proper fixation, proper embedding, and immunostaining technique are critical. Pathologist should be encouraged to replace estimates with accurate counts achievable with programs available free on the web (http://imagej.nih.gov/ij/) In our simplified proposal, if the Ki-67 nuclear labeling index is >10 %, these tumors are called “aggressive” pituitary adenomas. Since they can be problematic to manage, clinical colleagues are notified about aggressive adenomas and advised to carefully follow up these patients with close surveillance imaging and potentially adjuvant treatment. At present, a diagnosis of carcinoma can only be made if distant and/or cerebrospinal metastases can be documented. A standardized vocabulary and mode of reporting is of crucial importance as we are to make advances with the prognosis and treatment of pituitary tumors. Although Dr. Trouillas’ proposal is an important step in the right direction, a widespread consensus on a new classification does not exist. Pathologists need a system that is simple, feasible, economical, and reliable and provides prognostic information to clinicians. What we have proposed would provide this and would be immediately applicable without undue strain on resources immediately. Ultimately, we believe that much more work is needed on this subject. We need to develop consensus and develop a classification that moves us into the next phase of better care for these patients.