—  SPECIALTY CONFERENCE  —

Neuropathology

Case 1 - Primary Central Nervous System Lymphoma, B-Cell, Diffuse Large Cell, With Extensive Histiocytic Reaction, Probably Secondary To Partial Remission Induced By Prolonged Steroid Administration

B.K. DeMasters
University of Colorado Health Sciences Center
Denver, CO


Click on each slide thumbnail image for an enlarged view
Clinical Summary
The patient was a 76-year-old female who was brought to the emergency department of an outside medical facility by her sons with complaints of generalized pain and 2-3 days of fever. The family had noted an acute change in her cognition in the several days prior to admission. PMH was significant for CREST syndrome, remote breast cancer (1989) with adjuvant radiation therapy, obstructive sleep apnea, and polyneuropathy. There was no history of alcohol, tobacco, or substance use. Medications on admission did not include any immunosuppressive drugs.

In the emergency department she was alert and oriented to name only, and was unable to follow commands. Head CT scan revealed a left frontal lobe lesion. Chest X-ray was normal. The patient was admitted to hospital. Lumbar puncture done the same day showed a cerebrospinal fluid protein of 24, glucose of 93, and 3 white blood cells (48% polys, 41 lymphs, 1 mono); CSF cultures were negative. CSF cytology was negative for malignancy on two separate occasions.

The patient was empirically placed on antibiotics for presumed meningitis, but medication was discontinued the next day after a consultation was obtained from Neurology. An MRI scan obtained the day after admission showed multiple masses involving the left suprasylvian frontal area measuring 4.4 cm, the left posterior temporal region measuring 3.9 cm, the high frontal region measuring 2.3 cm, and small lesions in the right frontal and left occipital lobes. These were associated with significant edema and were thought to be metastatic lesions or septic emboli/cerebritis. Echocardiogram showed no valvular vegetations. A stereotactic brain biopsy was obtained 10 days after admission, which showed perivascular T cells, but was non-diagnostic.

Under the presumption that the most treatable condition in this elderly patient was vasculitis, she was discharged to a skilled nursing facility for rehabilitation and placed on 80 mg of Prednisone per day for three weeks, and an 8-week taper was planned (60 mg qd x 2 wks, 40 mg qd x 2, 30 mg qd x 2, 20 mg qd x 2 wks). Her condition then worsened, necessitating readmission to the hospital. She was placed on higher steroid doses with 40 mg given per day for a week followed by 30 mg qd, 20 mg, 10 mg, and 5 mg respectively for a 5-week taper. The last few weeks of life she continued to deteriorate and succumbed 3 months after presentation. Permission was granted for a brain-only autopsy.


Case 1 - Figure 1 - Preoperative MRI of brain, showing several enhancing masses, the largest of which are centered around the left Sylvian fissure.
Case 1 - Figure 2 - Coronal section of brain at autopsy, demonstrating the biopsy site, as well as the ill-defined masses in the left inferior frontal gyrus and superior temporal gyrus.
Case 1 - Figure 3 - Photomicrograph of the lesion, taken several microscopic fields away from the biopsy site.



Case 1 - Figure 4 - Immunohistochemistry for CD20.
Case 1 - Figure 5 - Photomicrograph of the dominant component of the lesion seen at autopsy.
Case 1 - Figure 6 - Immunohistochemistry for CD68 in the dominant component of the lesion seen at autopsy.


Diagnosis
Primary central nervous system lymphoma, B-cell, diffuse large cell, with extensive histiocytic reaction, probably secondary to partial remission induced by prolonged steroid administration (B-cell lymphoma CD45+, CD20+, CD79a+, CD30-, Epstein Barr virus - by in situ hybridization probe [EBER]. with profuse CD68 macrophage and CD3 T-cell lymphocyte response)

Discussion
Several questions are worth addressing briefly in this complicated case of an elderly woman with known CREST syndrome who develops PCNSL.

1. How commonly are stereotactic biopsies negative in this situation?
The ideal application of the stereotactic biopsy is in this patient's situation: targeting enhancing, discrete brain masses, particularly if lymphoma is suspected. Resection has no role in the treatment for PCNSL, does not add to survival, and may even increase the patient's deficits [1]. Stereotactic biopsy procedures are also ideally applied for elderly patients or medically ill patients who may be poor surgical candidates for open resection neurosurgical procedures. The diagnostic yield of stereotactic biopsies for enhancing discrete masses is high, but not 100%. The use of multiple, serial sampling techniques (which both targets slightly different points along the trajectory and increases the volume of tissue available for the pathologist) improves yield. Non-enhancing, diffuse processes are less likely to be able to be diagnosed accurately by stereotactic procedures, as shown in the study by Brainard et al. [2].

2. Given the final diagnosis of PCNSL, how commonly is cerebrospinal fluid cytology negative in this situation?
CSF cytology is unfortunately quite often negative in PCNSL, even on multiple sampling (this patient had 2 premortem studies). The yield of CSF cytology for diagnosis of PCNSL is usually cited as 25% or less [3, 4]. This is because the leptomeninges/CSF often contains only the non-neoplastic T-cell lymphocytic accompaniment of the B-cell lymphoma and few, if any, neoplastic B-cells. As is always the case, false-negative CSF cytology in patients with either lymphomatous and carcinomatous meningitis may be caused by inadequate volume being sampled (ie., less than 10.5 mL of CSF), failure to process the CSF specimen immediately, doing only a single sampling, or obtaining CSF from a site (lumbar vs. ventricular) unaffected by disease (as assessed by clinical and neuroimaging studies) [5]. If adequate numbers of cells are present in the CSF, yield can be increased by B-cell gene rearrangement studies [6] or flow cytometry [1]. Elderly patients usually develop B-cell lymphomas which are EBV -, explaining why CSF PCR for EBV cannot be used as a potential test for this disease (as it can be for PCNSLs in immunocompromised individuals).

3. Is the multiplicity of the brain lesions unusual in an immunocompetent patient with PCNSL?
Some older studies emphasized a higher incidence of multiplicity of brain lesions in immunodeficient patients as compared to immunocompetent patients with PCNSL. Several recent reviews of magnetic resonance imaging (MRI) findings have shown that 35-50% of all immunocompetent patients with PCNSLs have multiple brain lesions [1, 7]. Furthermore, in patients who do have multiple lesions, the mean number of cerebral lesions revealed by MRI is 3, and may be as high as 8 [7]. Lesions are almost always enhancing and only rarely necrotic in immunocompetent patients [7]. The most common location for lesions is the cerebral hemispheric cortex and white matter, usually in contact with the subarachnoid space, followed by periventricular areas or basal ganglia [1, 7]. Hence, this patient's MRI features are fairly typical.

4. What is the relationship between this patient's CREST syndrome and her PCNSL?
CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) is often associated with a localized form of scleroderma. CREST has no specific CNS manifestations: there is neither an increased incidence of CNS telangiectasias nor CNS tumors of any kind. Like several other autoimmune/rheumatological diseases, scleroderma has been occasionally associated with lymphomas [8, 9, 10], but these are usually systemic lymphomas, not PCNSLs. The association between autoimmune diseases and lymphoma is more commonly cited with Sjogren's syndrome than with scleroderma [9]. Hence, there is little evidence that this patient's PCNSL was directly related to her CREST syndrome.

A second possibility is that a patient with an autoimmune disease may be on long-term immunosuppressive/immunomodulatory medications which increase their risk for lymphomas. One of the most striking recent examples that we, and others, have reported is the development of PCNSLs in patients with myasthenia gravis and long-term azathioprine usage [11, 12, 13]. These PCNSLs mimic all other PCNSLs in immunosuppressed patients in that they are high grade B-cell lymphomas which are EBV+. The patient being discussed here was not on immunosuppressive medications to our knowledge, and our patient's lymphoma was EBV-. Hence, we do not think her PCNSL was due to immunosuppressive medications.

5. Is her PCNSL due to her advanced age?
This is the most plausible explanation. Ostensibly immunocompetent, elderly men and women are well-known to develop PCNSLs, and the risk for PCNSLs in the elderly seems to be stable since 1994, at approximately 16 per 1 million person-years [14]. As the number of PCNSLs in patients with acquired immunodeficiency syndrome decreases [14], the attention is again focusing on PCNSLs in immunocompetent patients. These tumors show distinct biological differences from lymphomas in the immunocompromised patient [15]. Diffuse, sometimes even extensively diffuse "leukoencephalopathy-like", patterns of brain involvement (known as lymphomatosis cerebri) [16, 17], may be seen in immunocompetent patients.

6. Why is the histiocytic, vaguely granulomatous, reaction present in this patient?
This represents the patient's immune response to her lymphoma, aided and abetted by her steroid therapy. Clearly at the end of her life, her lymphoma started to re-emerge at the edges of the lesions. Our interpretation of this case is that this immune response was largely due to the partial treatment she received with steroids. Steroids have a well-documented lympholytic effect on lymphoma [18, 19, 20, 21, 22, 23]. Steroids should therefore not be administered prior to biopsing a patient with suspected PCNSL [23]. When corticosteroid sensitivity of PCNSL is defined as any reduction of tumor volume on CT; PCNSLs are sensitive to steroids in 20-60% of cases [20]. Hochberg et al. found that 43% of patients achieved complete remissions with their PCNSL with only 10 days of steroid treatment (24 mg dexamethasone daily) [24]. Some have suggested that remission of a mass following steroid administration is virtually diagnostic for PCNSL. Although patients with demyelinating lesions may also have significant amelioration in their neuroimaging abnormalities after steroids, it is usually not a sustained response [25]. The remissions induced with steroids in PCNSLs occasionally last for several years [19, 20]; this has usually been reported in immunocompetent patients. Most patients, however, eventually have re-emergence of their PCNSL, and then the tumor may no longer be steroid-sensitive [20]. The histological findings of macrophage influx, myelin pallor, and T-cell influx are similar to those documented by others in steroid-treated patients with PCNSLs [22, 23]. Although steroid-treated lymphoma lesions that come to biopsy and are devoid of lymphoma cells are often described as "demyelinating" lesions, there are subtle histological differences between these and most other demyelinating lesions prompting biopsy [22, 23].

Another consideration in this patient might be angioimmunoproliferative lesion (AIL; formerly lymphomatoid granulomatosis LG). However, the "granulomatous" response in AIL is usually more focal and perivascular than in the current case, which contains broad sheets of histiocytes and lymphocytes. AIL occurs in a spectrum from grade I (a vasculitic disease with atypical perivascular lymphocytes, vessel wall destruction, and infarcts) to grade II (beginning emergence of rare cytologically atypical EBV+ B-cells, but still with a predominance of non-neoplastic T-cells) to grade III (overt malignant lymphoma which is an EBV+ high grade B-cell lymphoma, often CD30+ with loss of some B-cell markers). Although first described in the lung, CNS is one of the known extranodal affected sites, along with skin and kidneys. The intermediate (grade II) and early stages (grade I) of AIL represent the host response of large numbers of T cells and histiocytes keeping a B-cell lymphoma "in check". Our patient had no systemic manifestations of AIL in life (autopsy was limited to the brain). Given the absence of recent infarcts in our patient and the immunophenotype (CD30-, retention of all B cell markers), and EBV- status, we have no evidence that this patient had LG/AIL.

7. If they had gotten the correct diagnosis and treated her aggressively might she have done well?
Unfortunately elderly patients with PCNSLs poorly tolerated the combination radiation and chemotherapy with which they were treated, and toxicity was significant. New treatment paradigms have been developed, including high dose methotrexate without adjuvant radiotherapy, with dosage adjusted for glomerular filtration rate; these appear to be less toxic [26]. However there is a need for even further improvement in the treatment of elderly patients with brain tumors. Her clinicians knew that PCNSL might be present, and that vasculitis had not been present on the small stereotactic biopsy, but opted for a conservation "middle-ground" treatment approach.

References

  1. Herrlinger U, Schabet M, Bitzer M, Petersen D, Krauseneck P. Primary central nervous system lymphoma: from clinical presentation to diagnosis. J Neuro-oncol. 1999;43(3):219-26.

  2. Brainard JA, Prayson RA, Barnett GH. Frozen section evaluation of stereotactic brain biopsies: diagnostic yield at the stereotactic target position in 188 cases. Arch Pathol Lab Med. 1997;121(5):481-4.

  3. Selch MT , Shimizu KT, De Salles AF, Sutton C, Parker RG. Primary central nervous system lymphoma. Results at the University of California at Los Angeles and review of the literature. Am J Clin Oncol. 1994;17(4):286-93.

  4. Balmaceda C, Gaynor JJ, Sun M, Gluck JT, DeAngelis LM. Leptomeningeal tumor in primary central nervous system lymphoma: recognition, significance, and implications. Ann Neurol 1995;38:202-9.

  5. Glantz MJ, Cole BF, Glantz LK, Cobb J, Mills P, Lekos A, Walters BC, Recht LD. Cerebrospinal fluid cytology in patients with cancer: minimizing false-negative results. Cancer. 1998;82(4):733-9.

  6. Rhodes CH, Glantz MJ, Glantz L, Lekos A, Sorenson GD, Honsinger C, Levy NB. A comparison of polymerase chain reaction examination of cerebrospinal fluid and conventional cytology in the diagnosis of lymphomatous meningitis. Cancer. 1996;77(3):543-8.

  7. Kuker W, Nagele T, Korfel A, Heckl S, Thiel E, Bamberg M, Weller M, Herrlinger U. Primary central nervous system lymphomas (PCNSL): MRI features at presentation in 100 patients. J Neurooncol. 2005;72(2):169-77.

  8. Prochorec-Sobieszek M, Mielnik P, Wagner T, Chwalinska-Sadowska H. Mucosa-associated lymphoid tissue lymphoma (MALT) of salivary glands and scleroderma: a case report. Clin Rheumatol. 2004;23(4):348-50.

  9. Varoczy L, Gergely L, Zeher M, Szegedi G, Illes A. Malignant lymphoma-associated autoimmune diseases--a descriptive epidemiological study. Rheumatol Int. 2002;22(6):233-7.

  10. Rosenthal AK , McLaughlin JK, Linet MS, Persson I. Scleroderma and malignancy: an epidemiological study. Ann Rheum Dis. 1993;52(7):531-3.

  11. Finelli PF. Primary CNS lymphoma in myasthenic on long-term azathioprine. J Neurooncol. 2005;74(1):91-2.

  12. Kleinschmidt-DeMasters BK, Gilden DH. The expanding spectrum of herpesvirus infections of the nervous system. Brain Pathol. 2001;11(4):440-51.

  13. Herrlinger U, Weller M, Dichgans J, Melms A. Association of primary central nervous system lymphoma with long-term azathioprine therapy for myasthenia gravis? Ann Neurol. 2000 47(5):682-3.

  14. Kadan-Lottick NS , Skluzacek MC, Gurney JG. Decreasing incidence rates of primary central nervous system lymphoma. Cancer. 2002;95(1):193-202.

  15. Christov C, Adle-Biassette H, Lechapt E, Poron F, Gray F, Gaulard P, Gherardi RK. Primary brain lymphoma cell turnover differs in patients with and without AIDS: relationships to bcl-2 expression and host cell reaction. J Neuropathol Exp Neurol. 1999;58(10):1069-77.

  16. Rollins KE, Kleinschmidt-DeMasters BK, Corboy JR, Damek DM, Filley CM. Lymphomatosis cerebri as a cause of white matter dementia. Hum Pathol. 2005;36(3):282-90.

  17. Bakshi R, Mazziotta JC, Mischel PS, Jahan R, Seligson DB, Vinters HV. Lymphomatosis cerebri presenting as a rapidly progressive dementia: clinical, neuroimaging and pathologic findings. Dement Geriatr Cogn Disord. 1999;10(2):152-7.

  18. Todd FD, Miller CA, Yates AJ, Mervis LJ. Steroid-induced remission in primary malignant lymphoma of the central nervous system. Surg Neurol. 1986;26:79-84.

  19. van den Bent MJ, Vanneste JA, Ansink BJ. Prolonged remission of primary central nervous system lymphoma after discontinuation of steroid therapy. J Neurooncol. 1992;13(3):257-9.

  20. Herrlinger U, Schabet M, Eichhorn M, Petersen D, Grote EH, Meyermann R, Dichgans J. Prolonged corticosteroid-induced remission in primary central nervous system lymphoma: report of a case and review of the literature. Eur Neurol. 1996;36(4):241-3.

  21. Pirotte B, Levivier M, Goldman S, Brucher JM, Brotchi J, Hildebrand J. Glucocorticoid-induced long-term remission in primary cerebral lymphoma: case report and review of the literature. J Neuro-oncol. 1997;32(1):63-9.

  22. Alderson L, Fetell MR, Sisti M, Hochberg F, Cohen M, Louis DN. Sentinel lesions of primary CNS lymphoma. J Neurol Neurosurg Psychiatry. 1996;60(1):102-5.

  23. Geppert M, Ostertag CB, Seitz G, Kiessling M. Glucocorticoid therapy obscures the diagnosis of cerebral lymphoma. Acta Neuropathol (Berl). 1990;80(6):629-34.

  24. Hochberg FH, Loeffler JS, Prados M. The therapy of primary brain lymphoma. J Neuro-oncol. 1991;10(3):191-201.

  25. DeAngelis LM. Primary central nervous system lymphoma imitates multiple sclerosis. J Neuro-oncol. 1990;9(2):177-81.

  26. Jahnke K, Korfel A, Martus P, Weller M, Herrlinger U, Schmittel A, Fischer L, Thiel E. High-dose methotrexate toxicity in elderly patients with primary central nervous system lymphoma. Ann Oncol 2005;16:445-9.