1. Case Study 56 Kenneth Clark, MD

2. Question 1 This is a 59-year-old Caucasian woman with a history of granulomatous nephritis (diagnosed 7 years prior), myelodysplastic syndrome, and common variable immunodeficiency with progressively worsening dizziness, blurry vision and headache. Workup at an outside hospital revealed a “sellar mass” along with panhypopituitarism, adrenal insufficiency and hypothyroidism. Describe the MRI findings.

3. Axial T1Axial T1 + Contrast Axial T2 Axial T2 FLAIR

4. Answer Symmetric enlargement of pituitary gland and infundibulum with mild homogeneous enhancement. No areas of T2 or T2 FLAIR signal abnormality are evident.

5. Question 2 What is the differential diagnosis of a sellar lesion?

6. Answer Pituitary Adenoma Craniopharyngioma Meningioma Pituitary Carcinoma Pituicytoma Oncocytoma Granular Cell Tumor Lymphocytic Hypophysitis Granulomatous Hypophysitis Metastatic Disease (rare)

7. Question 3 What are the common signs and symptoms of sellar lesions (tumors or inflammatory)?

8. Answer Headaches (non-specific) Double Vision (non-specific) Loss of Peripheral Vision – Bitemporal Hemianopsia (non-specific) Facial Pain and Numbness (non-specific) Symptoms related to hormonal abnormalities –lack of energy –weight loss, nausea, vomiting, constipation –amenorrhea and infertility –dry skin, increased pigmentation of the skin –cold intolerance –mental status changes: sleepiness, psychosis

9. Question 4 The lesion was resected. Describe the findings. Click here to view the slidehere

10. Answer The tissue shows near complete effacement of pituitary architecture by a rich lymphohistiocytic infiltrate. The histiocytes have large irregularly shaped nuclear with prominent nucleoli and finely distributed pale blue chromatin. The cytoplasmic borders are completely indistinct, resulting in a syncytial appearance of groups of histiocytes. Small numbers of small monomorphic lymphocytes are positioned around the periphery of the histiocyte collections. Small randomly isolated nests of polytypic pituitary cells are seen randomly distributed throughout the specimen.

11. Question 5 What is your diagnostic impression?

12. Answer The lesion appears to be inflammatory in nature rich in histiocytes – either infectious or idiopathic in etiology. It does not appear to be neoplastic, although lymphoma cannot be entirely ruled out at this point.

13. Question 6 What immunohistochemical and/or special stains would be helpful in confirming your initial impression of this lesion?

14. Answer Inflammatory Cell Markers –CD3 (T-cells) –CD20 (B-cells) –CD68 (macrophages, histiocytes) GFAP, IDH1 (to rule out an unusual glial process) Synaptophysin (to ascertain the pituitary element) Reticulin (to evaluate residual pituitary structure/architecture) Click to view CD3, CD68, ReticulinCD3CD68Reticulin

15. Question 7 Based on the results of the stains (see below) and H&E slides, what is the general diagnostic category? CD3 - highlights numerous small mature lymphocytes CD20 - very rare positive b-lymphocytes CD68 - strong staining in numerous histiocytes; highlights ill-defined granuloma formation Synaptophysin - positive in sparse scattered small nests of pituitary cells; highlights architectural distortion by histiocytes GFAP - rare positive glial cells near periphery of lesion IDH1 - negative Reticulin – highlights total effacement of nested pituitary architecture

16. Answer Inflammatory/histiocytic process

17. Question 8 What is the differential diagnosis of a non- necrotizing histiocytic / granulomatous process?

18. Answer Neurosarcoidosis Infectious (fungal or mycobacterial) Langerhans cell histiocytosis Erdheim Chester disease Rosai-Dorfman disease

19. Question 9 What additional stains would you order to better characterize the lesion?

20. Answer Acid Fast, Grocott (rule out infectious process) CD1A & S100 –Langerhans cell histiocytosis: histiocytes are CD1a and S100 positive –Erdheim Chester disease: histiocytes are S100 negative (usually) and CD1a negative –Rosai Dorfman disease: histiocytes are S100 positive and CD1a negative –Sarcoidosis has similar staining profile of ECD

21. Question 10 The results of the additional stains are as follows: –S100: shows sparsely scattered background folliculo-stellate cells; negative in histiocytes –CD1a: negative –Grocott: negative –Acid Fast: negative What is your diagnosis?

22. Answer Non-necrotizing granulomatous hypophysitis, favor neurosarcoidosis

23. Question 11 Why favor sarcoidosis when Erdheim Chester disease has a similar histologic appearance and immunohistochemical profile? Explain.

24. Answer ECD, which is far more rare than sarcoidosis (300-400 reported cases worldwide), is also called polyostotic sclerosing histiocytosis because it most often involves long bones. Because this patient had a history of non- necrotizing renal granulomas and no bone lesions it is much more likely that this represents sarcoidosis involving the pituitary than ECD. Furthermore, ECD has a progressive and usually fatal course in cases with extra-osseous involvement and is not responsive to steroid therapy; if this patient had ECD at the time of her renal biopsies her clinical course would likely have been much more aggressive and probably fatal. Histologically, ECD lesions often show Touton-like giant cells and are rich in eosinophils – neither of which are seen in this lesion. Considering the clinical AND histopathologic elements of this case, it seems that sarcoidosis is more likely than ECD.

25. References Veyssier-Belot C, Cacoub P, Caparros-Lefebvre D, Wechsler J, Brun B, Remy M, Wallaert B, Petit H, Grimaldi A, Wechsler B, Godeau P (1996) Erdheim–Chester disease. Clinical and Radiologic Characteristics of 59 Cases. Medicine (Baltimore). 75:157–169. Louis D, Ohgaki H, Wiestler O, Cavanee W. WHO Classification of Tumours of the Central Nervous System. IARC: Lyon 2007. Burns T. Neurosarcoidosis (2003). Arch Neurol. 60:1166-1168. Rosai J. Rosai and Ackerman’s Surgical Pathology. Elsevier 2004.