Meningeal Mycosis Fungoides: Clinical and Cellular Characteristics THOMAS W. HAUCH, M.D., JOHN D. SHELBOURNE, M.D., Ph.D., HARVEY J. COHEN, M.D., DAVID MASON, M.D., and WILLIAM B. KREMER, M.D., Durham, North Carolina
A patient with mycosis fungoides developed meningeal disease while his skin disease was in remission with systemic chemotherapy. His central nervous system involvement with mycosis fungoides was controlled with intrathecal methotrexate for 7 months. The proliferating cells recovered from the spinal fluid showed similarities to the Sezary cell by light and electron microscopy. Surface receptor studies suggested that these cells were lymphoid cells of thymic derivation. Although mycosis fungoides has been shown to spread to the central nervous system in autopsied cases, reports of clinical neurologic disease are rare, and in only one earlier report have malignant cells been found in the spinal fluid. Thus, as in other lymphoproliferative disorders, prompt consideration of meningeal involvement in a patient exhibiting neurologic symptoms while in peripheral remission may allow earlier treatment of this complication.
MYCOSIS FUNGOIDES is defined as "an uncommon neo-
plastic disease of the lymphoreticular system first manifested in the skin" ( 1 ) . Although the disease was first described in 1835, only very recent autopsy reports have documented visceral spread in the terminal phase of the illness, including a small number of cases that demonstrated central nervous system involvement (2, 3 ) . Surprisingly, there are few reports of clinically symptomatic central nervous system involvement in patients with mycosis fungoides, nor have abnormal cells in the spinal fluid been well documented or described even in patients with evidence at autopsy of central nervous system disease. As a result, little has been reported on the treatment of this invasive form of mycosis fungoides. The circulating Sezary cell associated with erythroderma has been seen in the cutaneous lesions of mycosis fungoides (4). The Sezary cell has been well characterized histochemically, ultrastructurally, and immunologically (5-9). In this report we present a case of a patient with mycosis fungoides in whom abnormal cells were found in the premorbid spinal fluid. The presence of these cells allowed us to study their cytological characteristics without concern for peripheral blood contamination and to compare • From the Departments of Medicine and Pathology, Veterans Administration Hospital and Duke University Medical Center, Durham, North Carolina. Annals of Internal Medicine 82:499-505, 1975
Downloaded from https://annals.org by Karolinska Institute user on 01/18/2019
these cells with the well-described peripheral blood Sezary cell. Case Report
A 45-year-old white real estate agent with a history of ichthyosis since 1965 and well-controlled diabetes mellitus since 1970 noted the appearance of multiple, red, pruritic plaques in January 1973. The skin disease was diagnosed as pityriasis rosea and he was treated without relief with topical steroids and ultraviolet light. In May 1973 tumorous masses appeared on the left forehead and right elbow. He was referred to Duke University Medical Center on 28 June 1973. Physical examination showed an obese man weighing 121.5 kg [268 pounds] with a blood pressure of 140/90 mm Hg and temperature of 37.0 °C [98.6 °F]. There were numerous, elevated, infiltrated plaques from 1 to 3 cm in diameter scattered over the trunk and extremities, and there was a 7 cm X 6.5 cm tumor over the left forehead and a 9.5 cm X 5.5 cm tumor over the right antecubital fossa (Figure \A). The oropharynx was clear and the lymph nodes were not enlarged. A soft systolic murmur was present without other cardiac abnormalities and the liver and spleen were not palpable. His hemoglobin was 16.1 g/100 ml, hematocrit 44.5%, platelet count 140 000/mm3, and leukocyte count 7000/mm3 with no circulating abnormal cells, lymphocytosis, or eosinophilia seen in the peripheral blood film. The urinalysis was normal. The serum lactic acid dehydrogenase was 245 U/ml (normally less than 200 U/ml), but the remaining chemistries were normal. The electrocardiogram was normal; however, the chest X ray showed minimal cardiomegaly. A bone marrow aspirate showed a mild increase in cellularity with normal maturation of all elements, normal lymphocyte content, no foreign cells, and the presence of stainable iron. Skin biopsies of two plaques, one from his back and another from the right arm, showed dense diffuse infiltrates of lymphocytes, histiocytes, and atypical mononuclear cells within the dermis and epidermis in a pattern consistent with mycosis fungoides (Figure 2A, B). Chemotherapy was initiated on 2 July 1973 with the intravenous administration of 1000 mg cyclophosphamide and 2 mg vincristine plus oral methotrexate, 25 mg, every day for 3 days. Within 2 days there was a measurable reduction in the size of the forehead lesion. Subsequently, he received two further courses 2 weeks apart. By 21 August his skin was completely clear (Figure IB). In early October the patient first noted an echoing quality to all noises and he was readmitted on 19 October because of severe confusion, headaches, and progressive lethargy. On examination he was intermittently aware of his surroundings, very agitated, and unable to walk alone. His temperature was 38.9 °C [102 °F]. He complained of pain on motion of his neck and legs, and there was generalized hyporeflexia with downward plantar responses. Papilledema and abnormal eye findings were not present. The skin was clear with the exception of persistent ichthyosis, no lymph nodes were enlarged, and the liver and spleen were not palpable. The peripheral 499
While he was an outpatient the cerebral symptoms continued to improve, but by 29 November 1973 enlarged axillary and inguinal nodes were present. The lumbar puncture was normal with an opening pressure of 2 8 0 # m m H g and a leukocyte count of 2 cells/mm 3 . The protein was 79 mg/100 ml. Systemic chemotherapy was reinitiated and continued every 2 weeks with intravenous cyclophosphamide, 1000 mg, and vincristine, 2 mg, plus prednisone, 100 mg per day for 5 days. Intrathecal methotrexate, 25 mg, was given every 3 to 4 weeks. During the next month there was definite regression in the size of his lymph nodes. For the next 3 months the patient had several relapses of his neurologic symptoms, with malignant cells found in great numbers in the cerebrospinal fluid. He responded again to intrathecal methotrexate, but required therapy every 2 weeks for control. Although the disease originally responded to chemotherapy, the nodes and skin would relapse just before his scheduled treatment. Subsequently, the skin, lymph node, and meningeal disease became refractory to therapy, and after a brief course complicated by Candida enophthalmitis and hepatic failure, the patient died on 11 May 1974. At autopsy a dense infiltrate consistent with that of mycosis fungoides containing large, malignant cells with bizarre, hyperchromatic nuclei was present in the meninges and Virchow-Robin spaces. Only a few malignant cells were seen in the surrounding cerebral parenchyma. The skin, liver, stomach, and lymph nodes contained similar dense malignant infiltrates. Methods LIGHT MICROSCOPY
A pellet of centrifuged spinal fluid was resuspended in normal serum. The suspension was spread thinly on cover slips and stained with either Wright's stain or the PAS stain, the latter using alcoholic formalin as a fixative (10). ELECTRON MICROSCOPY
Figure 1A. (Upper and lower left). There is a large, elevated tumor on the left forehead. An ulcerated, crusted, elevated tumor appears on the right arm. Taken on 3 July 1973. B. (Upper and lower right). Resolution of the same lesions. Taken on 21 August 1973.
blood was normal with a leukocyte count of 6800/mm 3 and a differential of 60 segmented cells, 25 band cells, 1 eosinophil, 2 basophils, 8 lymphocytes, and 4 monocytes. Lumbar puncture showed an opening pressure greater than 460 mm Hg, 1800 mononuclear cells/mm 3 , a protein of 507 mg/100 ml, and a glucose of 34 mg/100 ml with peripheral blood glucose of 134 mg/100 ml. Cerebrospinal fluid cultures were negative. The atypical cells comprised greater than 95% of the cells present; the remainder were normal-appearing lymphocytes (Figure 3A). The periodic acid Schiff (PAS) stain of these abnormal cells was positive (Figure 3B). Treatment was initiated with 1500 R of cranial irradiation during 5 days and 25 mg intrathecal methotrexate. The brain scan was normal, the skull X rays suggested a 3-mm shift of the pineal body to the right, and the electroencephalogram suggested cortical and subcortical involvement on the right. An aspirate and biopsy of the bone marrow showed a normal marrow with no abnormal cells. By 21 October the patient had developed a severe hyperventilation syndrome and nystagmus in the horizontal and vertical directions, and he could not be aroused. A lumbar puncture on 23 October showed only 40/mm 3 atypical mononuclear cells and a protein of 197 mg/100 ml. Methotrexate was again continued by the intrathecal route as follows: 15 mg on 23 October, 10 mg on 26 October, and 15 mg on 9 November. On 24 October, systemic chemotherapy was continued with cyclophosphamide and vincristine. His neurologic status gradually improved, he resumed his ambulatory status, and he was discharged on 10 November with mild dizziness and acoustic reverberation. 500
April 1975 • Annals of Internal Medicine • Volume 82 • Number 4
Downloaded from https://annals.org by Karolinska Institute user on 01/18/2019
A pellet of centrifuged cerebrospinal fluid was fixed in 4% cacodylate-buffered glutaraldehyde for 1.5 hours and washed in cacodylate buffer overnight. Postfixation in 1% cacodylatebuffered tetroxide for 1 hour was followed by dehydration in ethanol and embedding in Epon*. Sections were examined with a Hitachi HS-8 (Hitachi Ltd., Tokyo, Japan) and with a Jeolco 100B electron microscope (Japan Electron Optics Laboratory, USA, Inc., Medford, Massachusetts) at 50 and 60 kV, respectively. These were stained with lead citrate (11) and uranyl acetate (12), with lead citrate alone, and with uranyl acetate alone; some were unstained. SURFACE RECEPTORS
The cell button obtained by centrifuging the cerebrospinal fluid at 200 g was washed three times in Medium 199t with 0.1 % gelatin and resuspended in the same medium. Heparinized blood was sedimented at room temperature with the addition of 20% volume for volume plasmagel. The leukocyte-rich supernatant was incubated with carbonyl iron, placed on a Ficollt-Hypaque§ gradient and centrifuged at 800 g for 30 minutes. The interface band was recovered and contained less than 1% polymorphocytes. N o abnormal cells could be seen in any of the peripheral blood preparations. The cell population was examined for rosette formation with sheep erythrocytes and complement-coated erythrocytes, and for surface immunoglobulins as follows: [1] 0.4 ml of sheep erythrocytes, 1 X 108 cells/ml, were mixed with 0.4 ml of leukocytes at 2 X lOVml, centrifuged at 200 g for 5 minutes and incubated for 60 minutes at room temperature. The cells were gently resuspended, placed on a hemocytometer, and the percentage of leukocytes with three or more sheep erythrocytes attached counted. [2] C3-coated human erythrocytes were prepared by incubating human group O erythrocytes, human se* Fisher Scientific Co., Fairlawn, New Jersey. t Difco Laboratories, Detroit, Michigan. t Pharmacia Laboratories, Piscataway, New Jersey. § Winthrop Laboratories, New York, New York.
Figure 2A. At low-power magnification, the moderately dense diffuse subepidermal perilymphatic and perivascular infiltrate is noted. Slight hyperkeratosis and thinning of the epidermis are present. (Magnification, x 100.) B. A higher power view of the blurred border (double arrows) between the epidermis (E) above and the dermis (D) below. Atypical cells (single arrows) are noted invading the epidermis. (Magnification, x 400.)
mm as a complement source, and IgM cold agglutinin antibody under conditions resulting in erythrocytes containing only complement components on their surfaces as previously described (13). We incubated 0.4 ml of 1 X 108 of C3-coated human erythrocytes/ml with 0.4 ml of 2 X 106 leukocytes/ml for 30 minutes at 37 °C with gentle agitation and rosettes determined as above. [3] Fluorescein-labeled antiserum against Ig (polyvalent anti-G, A, M, K, X—Meloy Laboratory, Springfield, Virginia), 0.05 ml, was mixed with 2 X 106 cells in 0.05 ml, incubated in ice for 45 minutes, washed three times with Medium 199 with 0.1% gelatin, resuspended in minimal volume, and observed as a suspension under a Leitz Ortholux II with Ploem illumination and FITC exciter filters (E. Leitz, Inc., Rockleigh, New Jersey). The percentage of cells containing surface immunoglobulin was then determined by counting 200 cells. Results LIGHT MICROSCOPY
The cells were large with diameters approaching 20 microns (Figure 3A). The nuclear-cytoplasmic ratio was very high. There were multiple nuclear projections, and the nuclear border was irregular. Periodic acid Schiff (PAS) positive vacuoles lined the peripheral cytoplasm (Figure 3B).
ELECTRON MICROSCOPY
By electron microscopy, the abnormal cells exhibited bizarre, convoluted nuclei with thin, ribbon-like regions (Figures 4, 5 ) . Nuclear pores were present and did not appear decreased. Within the cytoplasm, multiple areas of glycogen were noted that were not membrane-limited. In sections stained with uranyl acetate alone or unstained, the glycogen-containing regions were electron-lucent. Sections stained with lead citrate alone or with lead citrate and uranyl acetate showed the characteristic morphology of glycogen particles. Numerous mitochondria and a moderate amount of flattened cisternae of rough endoplasmic reticulum were also present in the cytoplasm. A few aggregates of fine fibrillar material were noted in the cytoplasm. Prominent thin cytoplasmic processes were noted on the cell surface. SURFACE RECEPTORS
The results of the immunologic studies are seen in Table 1. The cerebrospinal cells predominantly formed rosettes with sheep erythrocytes, exhibited virtually no reaction with complement-coated erythrocytes, and had no
Figure 3A. The cerebrospinal fluid cells viewed by light microscopy are large (the largest is 20 microns) in diameter. The nuclei have fingerlike projections. Clear vacuoles are present. (Magnification, x 1600.) B. The vacuoles of the same cells stain densely with the periodic acid Schiff reagent. (Magnification, x 1100.) Hauch et al. • Meningeal Mycosis Fungoides
Downloaded from https://annals.org by Karolinska Institute user on 01/18/2019
501
Figure 4. Electron micrograph of a typical cell of the cerebrospinal fluid exhibiting a bizarre, convoluted nucleus (N), which in some areas is drawn out into narrow ribbons of chromatin between nuclear envelopes (highlighted arrow). Note also the prominent nucleolus (Nu), the large areas of glycogen (G) that are not membrane-bound, and the aggregate of fine fibrillar material (arrow). Mitochondria (M), rough endoplasmic reticulum (RER), Golgi apparatus (Go), and microvilli (MV) are also present. (Magnification, x 19 570.)
502
April 1975 • Annals of Internal Medicine • Volume 82 • Number 4
Downloaded from https://annals.org by Karolinska Institute user on 01/18/2019
Figure 5. A slightly higher power of another cerebrospinal fluid cell exhibiting prominent nuclear pores sectioned longitudinally {highlighted arrows) and viewed en face (arrows). Large amounts of glycogen (G) are present. N = nucleus, MV = microvilli. (Magnification, x 22 170.)
surface immunoglobulin. In the peripheral blood where no abnormal cells were seen, the distribution was essentially normal although the sheep erythrocyte-reacting cell number was in the low normal range. Discussion
The diagnosis of mycosis fungoides in this case seems certain. An inflammatory skin disorder progressed and culminated in several pruritic, erythematous plaques and two large tumors. The biopsies showed diffuse dermal and epidermal infiltration with atypical cells possessing highly convoluted nuclei. Finally, at the time of the initial diagnosis, there was no other measurable lymphoreticular disease at sites other than the skin. Pautrier's abscesses were not present, but these are not a prerequisite for the diagnosis ( 1 ) . Because, on careful scrutiny, abnormal circulating cells were not present at any time during the clinical course, the Sezary syndrome with erythroderma and Sezary cell leukemia was not, strictly speaking, present ( 5 ) . However, the initial response to chemotherapy in
this patient was dramatic and the appearance of this syndrome may have been dampened. At autopsy, mycosis fungoides has been found to involve the central nervous system. In the largest series, 8 of 86 autopsied cases had meningeal infiltration ( 3 ) . In a smaller earlier series, which included several of the same cases, 1 of 17 autopsied cases had central nervous system involvement, although the precise anatomical location was not specified ( 2 ) . A literature review of 19 individually described cases that showed mycosis fungoides of the central nervous system at autopsy (14-26) yielded 13 with meningeal involvement (14-23). Other forms of central nervous system spread included direct parenchymal extension from the perivascular spaces (14-18) and frank tumor nodules (16, 17, 22, 26). Thus, among autopsied cases, meningeal disease is the most common form of mycosis fungoides in the central nervous system. The clinical expression of the neurologic disease is protean, and both pressure and focal signs are described (1417, 24, 2 5 ) . Abnormal brain scans have not been reported, Hauch et al. • Meningeal Mycosis Fungoides
Downloaded from https://annals.org by Karolinska Institute user on 01/18/2019
503
Table 1. Surface Receptor Properties* Cells
Sheep Erythrocyte Rosettes
ComplementReacting Cells
Cells Containing Surface Immunoglobulin
°7 /o Spinal fluid Peripheral blood Normal peripheral blood
2t
701 39
10
21
40-70
5-25
5-25
IX
* Cells were isolated and studied as described in Methods. t Some small lymphocytes were seen that did not bind sheep erythrocytes. In addition, many of the large cells not counted as rosette-forming cells had 1 or 2 sheep erythrocytes attached. t All complement-reacting cells and cells containing immunoglobulin were morphologically small lymphocytes.
but electroencephalographic changes have been (14). In only two of the above patients was a lumbar puncture done. In one, seven apparently normal leukocytes per cubic millimetre were present (14). In a poorly documented case reported in 1933, abnormal cells were recovered from the cerebrospinal fluid, but their number and microscopic description were not given (22). Thus, clinical neurologic involvement is rare, the incidence falling far behind the other visceral manifestations. The clinical course of this patient is reminiscent of meningeal leukemia, which may occur when patients with acute myeloblasts or lymphoblastic leukemia are in bone marrow remission (27). Central nervous system involvement with malignant cells has been well described for acute lymphoblastic leukemia (28). Blast cells progressively accumulate along the veins and pia mater, ultimately filling the subarachnoid space. Eventually, they will fill the pial-neuroglial space and extend into the parenchyma. The leukemic cells find sanctuary in the central nervous system where the concentrations of cytotoxic drugs are low. Leptomeningitis occurs clinically in patients with lymphoma and, as in mycosis fungoides, the incidence is estimated to be low. In a recent study of 22 such cases, several features were noteworthy: the disease occurred only when the bone marrow was involved; circulating abnormal cells were often found; and the histological pattern in 15 of 21 of the cases was that of histiocytic lymphoma (29). Because this patient did not initially have widespread disease, his clinical central nervous system disease was more similar to that encountered with leukemia than lymphoma. Leukemic meningitis may be effectively treated with either craniospinal irradiation or intrathecal methotrexate. The former produced slightly higher remission rates (92% compared with 7 8 % ) , but the latter produced longer remissions (30). The central nervous system response in our patient was dramatic to both modalities, and as has been demonstrated with acute lymphoblastic leukemia, recurrences were again successfully treated with methotrexate (31). The aberrant cell with a highly serpentine nucleus that circulates in the peripheral blood of patients with the Sezary syndrome has been seen in the cutaneous lesions of mycosis fungoides and occasionally in benign dermatoses 504
April 1975 • Annals of Internal Medicine • Volume 82 • Number 4
Downloaded from https://annals.org by Karolinska Institute user on 01/18/2019
(32). However, many of the cells in the lesions of mycosis fungoides have nuclei that are less convoluted and serpentine than nuclei of the circulating Sezary cells (4, 32). In our patient, the cerebrospinal fluid cells with highly serpentine nuclei were not prominent by light microscopy, although the electron micrographs clearly showed that the nucleus possessed ribbon-like connections and an irregular contour. The cells recovered from our patient were morphologically comparable to those described and sketched by Sezary. They possessed a large nucleus characterized by an irregular border with a "sprouting appearance" formed by numerous "finger-like pointed extensions" (5). Cytoplasmic PAS-positive, glycogen-containing vacuoles and cytoplasmic fibrils, features previously described in Sezary cells, were also present in our patient's cells (9, 33). Thus, the cells described herein are morphologically similar to both the classical Sezary cell and the tissue-bound cells associated with mycosis fungoides. Previous studies have indicated that the Sezary cell is of lymphoid origin, rather than monocytic or histiocytic. It is neither adherent nor phagocytic (9) and is capable of transforming in vitro in the presence of phytohemagglutinin (34); histochemical stains have suggested major similarities to lymphocytes (33, 35). Lymphocytes that form rosettes with sheep erythrocytes are felt to be thymic derived (T cells), and those containing surface immunoglobulins and complement receptors are thought to be bone marrow derived ( 3 6 ) . Although the validity for classifying lymphoproliferative diseases by this system is by no means established, T-cell characteristics have been described in Sternberg's sarcoma (37), acute lymphoblastic leukemia (38), infectious mononucleosis (39), and recently the Sezary syndrome (7, 8 ) . In the latter, circulating cells and cells recovered from cutaneous lesions and involved lymph nodes have reacted as T cells ( 4 0 ) . The uniform population of cells from our patient's spinal fluid reacted as T cells and, within the limits of the methods used, this supports the concept that the cell associated with mycosis fungoides, even when it appears outside the circulation, is a T-cell variant. In summary, meningeal mycosis fungoides may be detected clinically. The condition has an ominous prognosis but responds to modalities of therapy used for leukemic and lymphomatous meningeal disease. The abnormal cells found proliferating in the central nervous system in this patient were morphologically similar to the Sezary cell and the cells found in the cutaneous lesions and lymph nodes of many patients with mycosis fungoides. Although the malignant nature of the Sezary cell is in question because similar cells have been seen in the cutaneous lesions of some patients with benign dermatoses (32), the finding of chromosomal abnormalities and hypertetraploid DNA content in Sezary cells suggests that they are malignant (34, 41). The finding of morphologically and functionally similar cells proliferating in the central nervous system and comprising the extensive tumor invasion at postmortem in our patient supports this conclusion. A C K N O W L E D G M E N T S : The authors thank the many house officers who have compassionately cared for the patient and D r . H a r o l d Silberman for providing the clinical photographs.
G r a n t support: Veterans Administration Research P r o g r a m (4980-01), Veterans Administration Electron Microscopy Laboratory, and Public Health Service Research G r a n t CA-05634 from the National Cancer Institute. Received 28 June 1974; revision accepted 6 December 1974. • Requests for reprints should b e addressed to William B. Kremer, M.D., Chief, Section of Hematology, V A Hospital, D u r h a m , N C 27705.
19. T O M M A S I : Micosifungoide a tumori d'emblee Haut-u viscerali e spinali ( a b s t r a c t ) . Zentralbl Grenzgeb 5:236-237, 1922 20.
21. 22.
References 1. V A N SCOTT E J , H A Y N E S H A : Cutaneous lymphomas, in Dermatology in General Medicine, edited by FITZPATRICK T B , et al. New York, McGraw-Hill Book Co., 1971, pp. 556-573 2.
BLOCK
JB,
EDGCOMB
J,
EISEN
A,
et
al:
Mycosis
4.
EH
JR, LEVIN
DL,
CROFT
JD
J R , et
al:
response to therapy, 51:61-72, 1972
LUTZNER
Ultrastructure
HOBBS JW,
HORVATH
P:
of
BROUET
JC,
FLANDRIN
G,
SELIGMANN
M:
Indications
of
26.
ab-
normal cells in Sezary syndrome, mycosis fungoides, and parapsoriasis en plaque. Arch Dermatol 103:375-386, 1971 5. SEZARY A : Une nouvelle reticulose cutanee: la reticulose maligne leucemique a histio-monocytes monstrueux et a forme d'erythrodermie oedemateuse et pigmentee. Ann Dermatol Syphiligr (Paris) 9:5-22, 1949 6. LUTZNER M A , JORDAN H W : T h e ultrastructure of a n abnormal cell in Sezary's syndrome. Blood 31:719-726, 1968 7.
25.
Mycosis
fungoides. Survival, prognostic features, and autopsy findings. Medicine {Baltimore) MA,
24.
fungoides.
Natural history and aspects of its relationship to other malignant lymphomas. Am J Med 34:228-235, 1963 3. E P S T E I N
23.
the
27.
29.
10.
11. 12. 13.
14.
15. 16.
17. 18.
D,
MELTON
JW,
QUAGLIATA
F:
Ultra-
structural, immunologic, and functional studies o n Sezary cells: A neoplastic variant of the thymus-derived ( T ) lymphocytes. Proc Natl Acad Sci USA 71:1877-1881, 1974 W I L L I A M S W J : P A S staining, in Hematology, edited by W I L L I A M S WJ, et al. N e w York, McGraw-Hill Book Co., 1972, p p . 13581359 VENABLE J H , COGGESHALL R : A simplified lead citrate stain for use in electron microscopy. J Cell Biol 25:407-408, 1965 W A T S O N M L : Staining of tissue sections for electron microscopy with heavy metals. / Biophys Biochem Cytol 4:475-478, 1958 C O H E N H J : Lymphocyte surface immunoglobulin a n d C 3 r e ceptors in advanced, early a n d controlled chronic lymphocytic leukemia ( C L L ) ( a b s t r a c t ) . Clin Res2\:51, 1973 ROSAI J, SPIRO J M : Central nervous system involvement by mycosis fungoides. Acta Derm Venereol (Stockh) 48:482-488, 1968 TREBBIN H , G U T J A H R L : Mycosis fungoides mit Beteiligung des Gehirns. Acta Neuropathol (Berl) 13:282-288, 1969 M O N C O R P S C, BORGER G : Mycosis fungoides mit mykosiden Virchows Veranderungen im Gehirn u n d in den gehirnnerven. Arch (Pathol Anat) 286:157-166, 1932 BRAND WEINER A : Zur Kenntnis der Mykosis fungoides. Monatsh Prakt Derm 41:415-439, 1905 PAUTRIER L M , H O E R N E R G, W O R I N G E R F : Resultats fournis p a r
l'autopsie d u e cas de mycosis fungoi'de avec tumeurs, present^ a la seance de m a r s dernier. Bull Soc Fr Dermatol Syphiligr 47:8-14, 1940
CURTIS
AC,
LEACH
JE:
IS mycosis
fungoides
DAWSON
DM,
ROSENTHAL
DS,
MOLONEY
WC:
Neurological
G R I F F I N J W , T H O M P S O N R W , M I T C H I N S O N M J , et a l :
Lympho-
30.
SULLIVAN
MP,
VIETTI
TJ,
FERNBACH
DJ,
et
al:
Clinical
in-
vestigations in t h e treatment of meningeal leukemia: radiation therapy regimens vs. conventional intrathecal methotrexate. Blood 34:301-319, 1969 31. RIESELBACH R E , M O R S E E E , R A L L D P , et a l : I n t r a t h e c a l a m i n o p -
terin therapy of meningeal leukemia. Arch 630, 1963 32.
FLAXMAN
BA, Z E L A Z N Y
G,
V A N SCOTT
Intern EJ:
Med 111:620-
Nonspecificity
of
characteristic cells in mycosis fungoides. Arch Dermatol 104: 141-147, 1971 33. TASWELL H F , W I N K L E M A N R K : Sezary syndrome—a malignant reticulemic erythroderma. JAMA 177:465-472, 1961 34.
C R O S S E N P E , M E L L O R J E L , F I N L E Y A G , et a l : T h e Sezary syn-
d r o m e : cytogenic studies and identification of the Sezary cell as an abnormal lymphocyte. Am J Med 50:24-34, 1971 35. FLANDRIN G, BROUET J C : T h e Sezary cell: Cytologic, cytochemical a n d immunologic studies. Mayo Clin Proc 49:575-583, 1974 36. JONDAL M , WIGZELL H , A I U T I F : H u m a n lymphocyte subpopulations: Classification according t o surface markers a n d / o r functional characteristics. Transplant Rev 16:163-195, 1973 37.
SMITH
JL, CLEIN
GP,
BARKER
CR,
et a l :
Characterisation
of
malignant mediastinal lymphoid neoplasm (Sternberg sarcoma) as thymic in origin. Lancet 1:14-11, 1973 38.
K E R S E Y J H , SABAD A, GAJL-PECZALSKA K, et a l : A c u t e l y m p h o -
blastic leukemia cells with T (thymus-derived) markers. Science 182:1355-1356, 1973 39.
SHELDON
PJ,
HEMSTED
EH,
PAPAMICHAIL
M,
et
origin of atypical lymphoid cells in infectious Lancet 1:1153-1155, 1973 40.
EDELSON
RL,
LUTZNER
MA,
KIRKPATRICK
CH,
lymphocyte al:
Thymic
mononucleosis. et
al:
Mor-
phological and functional properties of the atypical T lymphocytes of the Sezary syndrome. Mayo Clin Proc 49:558-566, 1974 41. PRUNIERAS M : D N A content and cytogenetics of the Sezary cell. Mayo Clin Proc 49:548-552, 1974
Hauch et a/. • Meningeal Mycosis Fungoides
Downloaded from https://annals.org by Karolinska Institute user on 01/18/2019
a
matous leptomeningitis. Am J Med 51:200-208, 1971
8. B R O O M E J D , Z U C K E R - F R A N K L I N D , W E I N E R M S , et a l : Leukemic
9. Z U C K E R - F R A N K L I N
EP,
reticuloendothelial neoplastic entity? Arch Dermatol Syphilol 64:255-272, 1951 RIECKE E : Zwei-Falle von Mycosis fungoides. Arch Dermatol Syph 67:193-226, 1903 BUSCHKE, S I M M O N S , A N D E R S : Mycosis fungoides mit Beteilung des Zentralnervensystems ( a b s t r a c t ) . Zentralbl Haut-u Geschlechtskr Grenzgeb 43:723-724, 1933 B E N N E K J : Mycosis Fungoides inneren organ. Zentralbl Haut-u Geschlechtskr Grenzgeb 60:1-21, 1938 H E I T E H J , SOCHA P : Haufigkeitsanalytische untersuchungen zur Symptomatologie der Mycosis fungoides. Arch Dermatol Syph 193:118-142, 1951 PALTAUF R, SCHERBER G : E i n Fall of Mycosis fungoides mit E r k r a n k u n g von Nerven u n d mit Lokalisation in der inneren Organen. Virchows Arch [Pathol Anat] 222:9-27, 1916 H E M M I N G S O N H : Ein Fall von Mycosis fungoides mit M e tastasierung als polymorphzelliges Sarkom. Acta Radiol (Stockh) 22:606-619, 1941
complications of acute leukemia in adults: changing rate. Ann Intern Med 79:541-544, 1973 28. PRICE R A , J O H N S O N W W : T h e central nervous system in childhood leukemia. I. The arachnoid. Cancer 31:520-533, 1973
thymus-derived nature of the proliferating cells in six patients with Sezary's syndrome. N Engl J Med 289:341-344, 1973 cells with m e m b r a n e properties of thymus-derived ( T ) lymphocytes in a case of Sezary's syndrome: Morphologic and immunologic studies. Clin Immunol Immunopathol 1:319-329, 1973
CAWLEY
con metastasi Geschlechtskr
505
A patient with mycosis fungoides developed meningeal disease while his skin disease was in remission with systemic chemotherapy. His central nervous system involvement with mycosis fungoides was controlled with intrathecal methotrexate for 7 months. The proliferating cells recovered from the spinal fluid showed similarities to the Sezary cell by light and electron microscopy. Surface receptor studies suggested that these cells were lymphoid cells of thymic derivation. Although mycosis fungoides has been shown to spread to the central nervous system in autopsied cases, reports of clinical neurologic disease are rare, and in only one earlier report have malignant cells been found in the spinal fluid. Thus, as in other lymphoproliferative disorders, prompt consideration of meningeal involvement in a patient exhibiting neurologic symptoms while in peripheral remission may allow earlier treatment of this complication.
MYCOSIS FUNGOIDES is defined as "an uncommon neo-
plastic disease of the lymphoreticular system first manifested in the skin" ( 1 ) . Although the disease was first described in 1835, only very recent autopsy reports have documented visceral spread in the terminal phase of the illness, including a small number of cases that demonstrated central nervous system involvement (2, 3 ) . Surprisingly, there are few reports of clinically symptomatic central nervous system involvement in patients with mycosis fungoides, nor have abnormal cells in the spinal fluid been well documented or described even in patients with evidence at autopsy of central nervous system disease. As a result, little has been reported on the treatment of this invasive form of mycosis fungoides. The circulating Sezary cell associated with erythroderma has been seen in the cutaneous lesions of mycosis fungoides (4). The Sezary cell has been well characterized histochemically, ultrastructurally, and immunologically (5-9). In this report we present a case of a patient with mycosis fungoides in whom abnormal cells were found in the premorbid spinal fluid. The presence of these cells allowed us to study their cytological characteristics without concern for peripheral blood contamination and to compare • From the Departments of Medicine and Pathology, Veterans Administration Hospital and Duke University Medical Center, Durham, North Carolina. Annals of Internal Medicine 82:499-505, 1975
Downloaded from https://annals.org by Karolinska Institute user on 01/18/2019
these cells with the well-described peripheral blood Sezary cell. Case Report
A 45-year-old white real estate agent with a history of ichthyosis since 1965 and well-controlled diabetes mellitus since 1970 noted the appearance of multiple, red, pruritic plaques in January 1973. The skin disease was diagnosed as pityriasis rosea and he was treated without relief with topical steroids and ultraviolet light. In May 1973 tumorous masses appeared on the left forehead and right elbow. He was referred to Duke University Medical Center on 28 June 1973. Physical examination showed an obese man weighing 121.5 kg [268 pounds] with a blood pressure of 140/90 mm Hg and temperature of 37.0 °C [98.6 °F]. There were numerous, elevated, infiltrated plaques from 1 to 3 cm in diameter scattered over the trunk and extremities, and there was a 7 cm X 6.5 cm tumor over the left forehead and a 9.5 cm X 5.5 cm tumor over the right antecubital fossa (Figure \A). The oropharynx was clear and the lymph nodes were not enlarged. A soft systolic murmur was present without other cardiac abnormalities and the liver and spleen were not palpable. His hemoglobin was 16.1 g/100 ml, hematocrit 44.5%, platelet count 140 000/mm3, and leukocyte count 7000/mm3 with no circulating abnormal cells, lymphocytosis, or eosinophilia seen in the peripheral blood film. The urinalysis was normal. The serum lactic acid dehydrogenase was 245 U/ml (normally less than 200 U/ml), but the remaining chemistries were normal. The electrocardiogram was normal; however, the chest X ray showed minimal cardiomegaly. A bone marrow aspirate showed a mild increase in cellularity with normal maturation of all elements, normal lymphocyte content, no foreign cells, and the presence of stainable iron. Skin biopsies of two plaques, one from his back and another from the right arm, showed dense diffuse infiltrates of lymphocytes, histiocytes, and atypical mononuclear cells within the dermis and epidermis in a pattern consistent with mycosis fungoides (Figure 2A, B). Chemotherapy was initiated on 2 July 1973 with the intravenous administration of 1000 mg cyclophosphamide and 2 mg vincristine plus oral methotrexate, 25 mg, every day for 3 days. Within 2 days there was a measurable reduction in the size of the forehead lesion. Subsequently, he received two further courses 2 weeks apart. By 21 August his skin was completely clear (Figure IB). In early October the patient first noted an echoing quality to all noises and he was readmitted on 19 October because of severe confusion, headaches, and progressive lethargy. On examination he was intermittently aware of his surroundings, very agitated, and unable to walk alone. His temperature was 38.9 °C [102 °F]. He complained of pain on motion of his neck and legs, and there was generalized hyporeflexia with downward plantar responses. Papilledema and abnormal eye findings were not present. The skin was clear with the exception of persistent ichthyosis, no lymph nodes were enlarged, and the liver and spleen were not palpable. The peripheral 499
While he was an outpatient the cerebral symptoms continued to improve, but by 29 November 1973 enlarged axillary and inguinal nodes were present. The lumbar puncture was normal with an opening pressure of 2 8 0 # m m H g and a leukocyte count of 2 cells/mm 3 . The protein was 79 mg/100 ml. Systemic chemotherapy was reinitiated and continued every 2 weeks with intravenous cyclophosphamide, 1000 mg, and vincristine, 2 mg, plus prednisone, 100 mg per day for 5 days. Intrathecal methotrexate, 25 mg, was given every 3 to 4 weeks. During the next month there was definite regression in the size of his lymph nodes. For the next 3 months the patient had several relapses of his neurologic symptoms, with malignant cells found in great numbers in the cerebrospinal fluid. He responded again to intrathecal methotrexate, but required therapy every 2 weeks for control. Although the disease originally responded to chemotherapy, the nodes and skin would relapse just before his scheduled treatment. Subsequently, the skin, lymph node, and meningeal disease became refractory to therapy, and after a brief course complicated by Candida enophthalmitis and hepatic failure, the patient died on 11 May 1974. At autopsy a dense infiltrate consistent with that of mycosis fungoides containing large, malignant cells with bizarre, hyperchromatic nuclei was present in the meninges and Virchow-Robin spaces. Only a few malignant cells were seen in the surrounding cerebral parenchyma. The skin, liver, stomach, and lymph nodes contained similar dense malignant infiltrates. Methods LIGHT MICROSCOPY
A pellet of centrifuged spinal fluid was resuspended in normal serum. The suspension was spread thinly on cover slips and stained with either Wright's stain or the PAS stain, the latter using alcoholic formalin as a fixative (10). ELECTRON MICROSCOPY
Figure 1A. (Upper and lower left). There is a large, elevated tumor on the left forehead. An ulcerated, crusted, elevated tumor appears on the right arm. Taken on 3 July 1973. B. (Upper and lower right). Resolution of the same lesions. Taken on 21 August 1973.
blood was normal with a leukocyte count of 6800/mm 3 and a differential of 60 segmented cells, 25 band cells, 1 eosinophil, 2 basophils, 8 lymphocytes, and 4 monocytes. Lumbar puncture showed an opening pressure greater than 460 mm Hg, 1800 mononuclear cells/mm 3 , a protein of 507 mg/100 ml, and a glucose of 34 mg/100 ml with peripheral blood glucose of 134 mg/100 ml. Cerebrospinal fluid cultures were negative. The atypical cells comprised greater than 95% of the cells present; the remainder were normal-appearing lymphocytes (Figure 3A). The periodic acid Schiff (PAS) stain of these abnormal cells was positive (Figure 3B). Treatment was initiated with 1500 R of cranial irradiation during 5 days and 25 mg intrathecal methotrexate. The brain scan was normal, the skull X rays suggested a 3-mm shift of the pineal body to the right, and the electroencephalogram suggested cortical and subcortical involvement on the right. An aspirate and biopsy of the bone marrow showed a normal marrow with no abnormal cells. By 21 October the patient had developed a severe hyperventilation syndrome and nystagmus in the horizontal and vertical directions, and he could not be aroused. A lumbar puncture on 23 October showed only 40/mm 3 atypical mononuclear cells and a protein of 197 mg/100 ml. Methotrexate was again continued by the intrathecal route as follows: 15 mg on 23 October, 10 mg on 26 October, and 15 mg on 9 November. On 24 October, systemic chemotherapy was continued with cyclophosphamide and vincristine. His neurologic status gradually improved, he resumed his ambulatory status, and he was discharged on 10 November with mild dizziness and acoustic reverberation. 500
April 1975 • Annals of Internal Medicine • Volume 82 • Number 4
Downloaded from https://annals.org by Karolinska Institute user on 01/18/2019
A pellet of centrifuged cerebrospinal fluid was fixed in 4% cacodylate-buffered glutaraldehyde for 1.5 hours and washed in cacodylate buffer overnight. Postfixation in 1% cacodylatebuffered tetroxide for 1 hour was followed by dehydration in ethanol and embedding in Epon*. Sections were examined with a Hitachi HS-8 (Hitachi Ltd., Tokyo, Japan) and with a Jeolco 100B electron microscope (Japan Electron Optics Laboratory, USA, Inc., Medford, Massachusetts) at 50 and 60 kV, respectively. These were stained with lead citrate (11) and uranyl acetate (12), with lead citrate alone, and with uranyl acetate alone; some were unstained. SURFACE RECEPTORS
The cell button obtained by centrifuging the cerebrospinal fluid at 200 g was washed three times in Medium 199t with 0.1 % gelatin and resuspended in the same medium. Heparinized blood was sedimented at room temperature with the addition of 20% volume for volume plasmagel. The leukocyte-rich supernatant was incubated with carbonyl iron, placed on a Ficollt-Hypaque§ gradient and centrifuged at 800 g for 30 minutes. The interface band was recovered and contained less than 1% polymorphocytes. N o abnormal cells could be seen in any of the peripheral blood preparations. The cell population was examined for rosette formation with sheep erythrocytes and complement-coated erythrocytes, and for surface immunoglobulins as follows: [1] 0.4 ml of sheep erythrocytes, 1 X 108 cells/ml, were mixed with 0.4 ml of leukocytes at 2 X lOVml, centrifuged at 200 g for 5 minutes and incubated for 60 minutes at room temperature. The cells were gently resuspended, placed on a hemocytometer, and the percentage of leukocytes with three or more sheep erythrocytes attached counted. [2] C3-coated human erythrocytes were prepared by incubating human group O erythrocytes, human se* Fisher Scientific Co., Fairlawn, New Jersey. t Difco Laboratories, Detroit, Michigan. t Pharmacia Laboratories, Piscataway, New Jersey. § Winthrop Laboratories, New York, New York.
Figure 2A. At low-power magnification, the moderately dense diffuse subepidermal perilymphatic and perivascular infiltrate is noted. Slight hyperkeratosis and thinning of the epidermis are present. (Magnification, x 100.) B. A higher power view of the blurred border (double arrows) between the epidermis (E) above and the dermis (D) below. Atypical cells (single arrows) are noted invading the epidermis. (Magnification, x 400.)
mm as a complement source, and IgM cold agglutinin antibody under conditions resulting in erythrocytes containing only complement components on their surfaces as previously described (13). We incubated 0.4 ml of 1 X 108 of C3-coated human erythrocytes/ml with 0.4 ml of 2 X 106 leukocytes/ml for 30 minutes at 37 °C with gentle agitation and rosettes determined as above. [3] Fluorescein-labeled antiserum against Ig (polyvalent anti-G, A, M, K, X—Meloy Laboratory, Springfield, Virginia), 0.05 ml, was mixed with 2 X 106 cells in 0.05 ml, incubated in ice for 45 minutes, washed three times with Medium 199 with 0.1% gelatin, resuspended in minimal volume, and observed as a suspension under a Leitz Ortholux II with Ploem illumination and FITC exciter filters (E. Leitz, Inc., Rockleigh, New Jersey). The percentage of cells containing surface immunoglobulin was then determined by counting 200 cells. Results LIGHT MICROSCOPY
The cells were large with diameters approaching 20 microns (Figure 3A). The nuclear-cytoplasmic ratio was very high. There were multiple nuclear projections, and the nuclear border was irregular. Periodic acid Schiff (PAS) positive vacuoles lined the peripheral cytoplasm (Figure 3B).
ELECTRON MICROSCOPY
By electron microscopy, the abnormal cells exhibited bizarre, convoluted nuclei with thin, ribbon-like regions (Figures 4, 5 ) . Nuclear pores were present and did not appear decreased. Within the cytoplasm, multiple areas of glycogen were noted that were not membrane-limited. In sections stained with uranyl acetate alone or unstained, the glycogen-containing regions were electron-lucent. Sections stained with lead citrate alone or with lead citrate and uranyl acetate showed the characteristic morphology of glycogen particles. Numerous mitochondria and a moderate amount of flattened cisternae of rough endoplasmic reticulum were also present in the cytoplasm. A few aggregates of fine fibrillar material were noted in the cytoplasm. Prominent thin cytoplasmic processes were noted on the cell surface. SURFACE RECEPTORS
The results of the immunologic studies are seen in Table 1. The cerebrospinal cells predominantly formed rosettes with sheep erythrocytes, exhibited virtually no reaction with complement-coated erythrocytes, and had no
Figure 3A. The cerebrospinal fluid cells viewed by light microscopy are large (the largest is 20 microns) in diameter. The nuclei have fingerlike projections. Clear vacuoles are present. (Magnification, x 1600.) B. The vacuoles of the same cells stain densely with the periodic acid Schiff reagent. (Magnification, x 1100.) Hauch et al. • Meningeal Mycosis Fungoides
Downloaded from https://annals.org by Karolinska Institute user on 01/18/2019
501
Figure 4. Electron micrograph of a typical cell of the cerebrospinal fluid exhibiting a bizarre, convoluted nucleus (N), which in some areas is drawn out into narrow ribbons of chromatin between nuclear envelopes (highlighted arrow). Note also the prominent nucleolus (Nu), the large areas of glycogen (G) that are not membrane-bound, and the aggregate of fine fibrillar material (arrow). Mitochondria (M), rough endoplasmic reticulum (RER), Golgi apparatus (Go), and microvilli (MV) are also present. (Magnification, x 19 570.)
502
April 1975 • Annals of Internal Medicine • Volume 82 • Number 4
Downloaded from https://annals.org by Karolinska Institute user on 01/18/2019
Figure 5. A slightly higher power of another cerebrospinal fluid cell exhibiting prominent nuclear pores sectioned longitudinally {highlighted arrows) and viewed en face (arrows). Large amounts of glycogen (G) are present. N = nucleus, MV = microvilli. (Magnification, x 22 170.)
surface immunoglobulin. In the peripheral blood where no abnormal cells were seen, the distribution was essentially normal although the sheep erythrocyte-reacting cell number was in the low normal range. Discussion
The diagnosis of mycosis fungoides in this case seems certain. An inflammatory skin disorder progressed and culminated in several pruritic, erythematous plaques and two large tumors. The biopsies showed diffuse dermal and epidermal infiltration with atypical cells possessing highly convoluted nuclei. Finally, at the time of the initial diagnosis, there was no other measurable lymphoreticular disease at sites other than the skin. Pautrier's abscesses were not present, but these are not a prerequisite for the diagnosis ( 1 ) . Because, on careful scrutiny, abnormal circulating cells were not present at any time during the clinical course, the Sezary syndrome with erythroderma and Sezary cell leukemia was not, strictly speaking, present ( 5 ) . However, the initial response to chemotherapy in
this patient was dramatic and the appearance of this syndrome may have been dampened. At autopsy, mycosis fungoides has been found to involve the central nervous system. In the largest series, 8 of 86 autopsied cases had meningeal infiltration ( 3 ) . In a smaller earlier series, which included several of the same cases, 1 of 17 autopsied cases had central nervous system involvement, although the precise anatomical location was not specified ( 2 ) . A literature review of 19 individually described cases that showed mycosis fungoides of the central nervous system at autopsy (14-26) yielded 13 with meningeal involvement (14-23). Other forms of central nervous system spread included direct parenchymal extension from the perivascular spaces (14-18) and frank tumor nodules (16, 17, 22, 26). Thus, among autopsied cases, meningeal disease is the most common form of mycosis fungoides in the central nervous system. The clinical expression of the neurologic disease is protean, and both pressure and focal signs are described (1417, 24, 2 5 ) . Abnormal brain scans have not been reported, Hauch et al. • Meningeal Mycosis Fungoides
Downloaded from https://annals.org by Karolinska Institute user on 01/18/2019
503
Table 1. Surface Receptor Properties* Cells
Sheep Erythrocyte Rosettes
ComplementReacting Cells
Cells Containing Surface Immunoglobulin
°7 /o Spinal fluid Peripheral blood Normal peripheral blood
2t
701 39
10
21
40-70
5-25
5-25
IX
* Cells were isolated and studied as described in Methods. t Some small lymphocytes were seen that did not bind sheep erythrocytes. In addition, many of the large cells not counted as rosette-forming cells had 1 or 2 sheep erythrocytes attached. t All complement-reacting cells and cells containing immunoglobulin were morphologically small lymphocytes.
but electroencephalographic changes have been (14). In only two of the above patients was a lumbar puncture done. In one, seven apparently normal leukocytes per cubic millimetre were present (14). In a poorly documented case reported in 1933, abnormal cells were recovered from the cerebrospinal fluid, but their number and microscopic description were not given (22). Thus, clinical neurologic involvement is rare, the incidence falling far behind the other visceral manifestations. The clinical course of this patient is reminiscent of meningeal leukemia, which may occur when patients with acute myeloblasts or lymphoblastic leukemia are in bone marrow remission (27). Central nervous system involvement with malignant cells has been well described for acute lymphoblastic leukemia (28). Blast cells progressively accumulate along the veins and pia mater, ultimately filling the subarachnoid space. Eventually, they will fill the pial-neuroglial space and extend into the parenchyma. The leukemic cells find sanctuary in the central nervous system where the concentrations of cytotoxic drugs are low. Leptomeningitis occurs clinically in patients with lymphoma and, as in mycosis fungoides, the incidence is estimated to be low. In a recent study of 22 such cases, several features were noteworthy: the disease occurred only when the bone marrow was involved; circulating abnormal cells were often found; and the histological pattern in 15 of 21 of the cases was that of histiocytic lymphoma (29). Because this patient did not initially have widespread disease, his clinical central nervous system disease was more similar to that encountered with leukemia than lymphoma. Leukemic meningitis may be effectively treated with either craniospinal irradiation or intrathecal methotrexate. The former produced slightly higher remission rates (92% compared with 7 8 % ) , but the latter produced longer remissions (30). The central nervous system response in our patient was dramatic to both modalities, and as has been demonstrated with acute lymphoblastic leukemia, recurrences were again successfully treated with methotrexate (31). The aberrant cell with a highly serpentine nucleus that circulates in the peripheral blood of patients with the Sezary syndrome has been seen in the cutaneous lesions of mycosis fungoides and occasionally in benign dermatoses 504
April 1975 • Annals of Internal Medicine • Volume 82 • Number 4
Downloaded from https://annals.org by Karolinska Institute user on 01/18/2019
(32). However, many of the cells in the lesions of mycosis fungoides have nuclei that are less convoluted and serpentine than nuclei of the circulating Sezary cells (4, 32). In our patient, the cerebrospinal fluid cells with highly serpentine nuclei were not prominent by light microscopy, although the electron micrographs clearly showed that the nucleus possessed ribbon-like connections and an irregular contour. The cells recovered from our patient were morphologically comparable to those described and sketched by Sezary. They possessed a large nucleus characterized by an irregular border with a "sprouting appearance" formed by numerous "finger-like pointed extensions" (5). Cytoplasmic PAS-positive, glycogen-containing vacuoles and cytoplasmic fibrils, features previously described in Sezary cells, were also present in our patient's cells (9, 33). Thus, the cells described herein are morphologically similar to both the classical Sezary cell and the tissue-bound cells associated with mycosis fungoides. Previous studies have indicated that the Sezary cell is of lymphoid origin, rather than monocytic or histiocytic. It is neither adherent nor phagocytic (9) and is capable of transforming in vitro in the presence of phytohemagglutinin (34); histochemical stains have suggested major similarities to lymphocytes (33, 35). Lymphocytes that form rosettes with sheep erythrocytes are felt to be thymic derived (T cells), and those containing surface immunoglobulins and complement receptors are thought to be bone marrow derived ( 3 6 ) . Although the validity for classifying lymphoproliferative diseases by this system is by no means established, T-cell characteristics have been described in Sternberg's sarcoma (37), acute lymphoblastic leukemia (38), infectious mononucleosis (39), and recently the Sezary syndrome (7, 8 ) . In the latter, circulating cells and cells recovered from cutaneous lesions and involved lymph nodes have reacted as T cells ( 4 0 ) . The uniform population of cells from our patient's spinal fluid reacted as T cells and, within the limits of the methods used, this supports the concept that the cell associated with mycosis fungoides, even when it appears outside the circulation, is a T-cell variant. In summary, meningeal mycosis fungoides may be detected clinically. The condition has an ominous prognosis but responds to modalities of therapy used for leukemic and lymphomatous meningeal disease. The abnormal cells found proliferating in the central nervous system in this patient were morphologically similar to the Sezary cell and the cells found in the cutaneous lesions and lymph nodes of many patients with mycosis fungoides. Although the malignant nature of the Sezary cell is in question because similar cells have been seen in the cutaneous lesions of some patients with benign dermatoses (32), the finding of chromosomal abnormalities and hypertetraploid DNA content in Sezary cells suggests that they are malignant (34, 41). The finding of morphologically and functionally similar cells proliferating in the central nervous system and comprising the extensive tumor invasion at postmortem in our patient supports this conclusion. A C K N O W L E D G M E N T S : The authors thank the many house officers who have compassionately cared for the patient and D r . H a r o l d Silberman for providing the clinical photographs.
G r a n t support: Veterans Administration Research P r o g r a m (4980-01), Veterans Administration Electron Microscopy Laboratory, and Public Health Service Research G r a n t CA-05634 from the National Cancer Institute. Received 28 June 1974; revision accepted 6 December 1974. • Requests for reprints should b e addressed to William B. Kremer, M.D., Chief, Section of Hematology, V A Hospital, D u r h a m , N C 27705.
19. T O M M A S I : Micosifungoide a tumori d'emblee Haut-u viscerali e spinali ( a b s t r a c t ) . Zentralbl Grenzgeb 5:236-237, 1922 20.
21. 22.
References 1. V A N SCOTT E J , H A Y N E S H A : Cutaneous lymphomas, in Dermatology in General Medicine, edited by FITZPATRICK T B , et al. New York, McGraw-Hill Book Co., 1971, pp. 556-573 2.
BLOCK
JB,
EDGCOMB
J,
EISEN
A,
et
al:
Mycosis
4.
EH
JR, LEVIN
DL,
CROFT
JD
J R , et
al:
response to therapy, 51:61-72, 1972
LUTZNER
Ultrastructure
HOBBS JW,
HORVATH
P:
of
BROUET
JC,
FLANDRIN
G,
SELIGMANN
M:
Indications
of
26.
ab-
normal cells in Sezary syndrome, mycosis fungoides, and parapsoriasis en plaque. Arch Dermatol 103:375-386, 1971 5. SEZARY A : Une nouvelle reticulose cutanee: la reticulose maligne leucemique a histio-monocytes monstrueux et a forme d'erythrodermie oedemateuse et pigmentee. Ann Dermatol Syphiligr (Paris) 9:5-22, 1949 6. LUTZNER M A , JORDAN H W : T h e ultrastructure of a n abnormal cell in Sezary's syndrome. Blood 31:719-726, 1968 7.
25.
Mycosis
fungoides. Survival, prognostic features, and autopsy findings. Medicine {Baltimore) MA,
24.
fungoides.
Natural history and aspects of its relationship to other malignant lymphomas. Am J Med 34:228-235, 1963 3. E P S T E I N
23.
the
27.
29.
10.
11. 12. 13.
14.
15. 16.
17. 18.
D,
MELTON
JW,
QUAGLIATA
F:
Ultra-
structural, immunologic, and functional studies o n Sezary cells: A neoplastic variant of the thymus-derived ( T ) lymphocytes. Proc Natl Acad Sci USA 71:1877-1881, 1974 W I L L I A M S W J : P A S staining, in Hematology, edited by W I L L I A M S WJ, et al. N e w York, McGraw-Hill Book Co., 1972, p p . 13581359 VENABLE J H , COGGESHALL R : A simplified lead citrate stain for use in electron microscopy. J Cell Biol 25:407-408, 1965 W A T S O N M L : Staining of tissue sections for electron microscopy with heavy metals. / Biophys Biochem Cytol 4:475-478, 1958 C O H E N H J : Lymphocyte surface immunoglobulin a n d C 3 r e ceptors in advanced, early a n d controlled chronic lymphocytic leukemia ( C L L ) ( a b s t r a c t ) . Clin Res2\:51, 1973 ROSAI J, SPIRO J M : Central nervous system involvement by mycosis fungoides. Acta Derm Venereol (Stockh) 48:482-488, 1968 TREBBIN H , G U T J A H R L : Mycosis fungoides mit Beteiligung des Gehirns. Acta Neuropathol (Berl) 13:282-288, 1969 M O N C O R P S C, BORGER G : Mycosis fungoides mit mykosiden Virchows Veranderungen im Gehirn u n d in den gehirnnerven. Arch (Pathol Anat) 286:157-166, 1932 BRAND WEINER A : Zur Kenntnis der Mykosis fungoides. Monatsh Prakt Derm 41:415-439, 1905 PAUTRIER L M , H O E R N E R G, W O R I N G E R F : Resultats fournis p a r
l'autopsie d u e cas de mycosis fungoi'de avec tumeurs, present^ a la seance de m a r s dernier. Bull Soc Fr Dermatol Syphiligr 47:8-14, 1940
CURTIS
AC,
LEACH
JE:
IS mycosis
fungoides
DAWSON
DM,
ROSENTHAL
DS,
MOLONEY
WC:
Neurological
G R I F F I N J W , T H O M P S O N R W , M I T C H I N S O N M J , et a l :
Lympho-
30.
SULLIVAN
MP,
VIETTI
TJ,
FERNBACH
DJ,
et
al:
Clinical
in-
vestigations in t h e treatment of meningeal leukemia: radiation therapy regimens vs. conventional intrathecal methotrexate. Blood 34:301-319, 1969 31. RIESELBACH R E , M O R S E E E , R A L L D P , et a l : I n t r a t h e c a l a m i n o p -
terin therapy of meningeal leukemia. Arch 630, 1963 32.
FLAXMAN
BA, Z E L A Z N Y
G,
V A N SCOTT
Intern EJ:
Med 111:620-
Nonspecificity
of
characteristic cells in mycosis fungoides. Arch Dermatol 104: 141-147, 1971 33. TASWELL H F , W I N K L E M A N R K : Sezary syndrome—a malignant reticulemic erythroderma. JAMA 177:465-472, 1961 34.
C R O S S E N P E , M E L L O R J E L , F I N L E Y A G , et a l : T h e Sezary syn-
d r o m e : cytogenic studies and identification of the Sezary cell as an abnormal lymphocyte. Am J Med 50:24-34, 1971 35. FLANDRIN G, BROUET J C : T h e Sezary cell: Cytologic, cytochemical a n d immunologic studies. Mayo Clin Proc 49:575-583, 1974 36. JONDAL M , WIGZELL H , A I U T I F : H u m a n lymphocyte subpopulations: Classification according t o surface markers a n d / o r functional characteristics. Transplant Rev 16:163-195, 1973 37.
SMITH
JL, CLEIN
GP,
BARKER
CR,
et a l :
Characterisation
of
malignant mediastinal lymphoid neoplasm (Sternberg sarcoma) as thymic in origin. Lancet 1:14-11, 1973 38.
K E R S E Y J H , SABAD A, GAJL-PECZALSKA K, et a l : A c u t e l y m p h o -
blastic leukemia cells with T (thymus-derived) markers. Science 182:1355-1356, 1973 39.
SHELDON
PJ,
HEMSTED
EH,
PAPAMICHAIL
M,
et
origin of atypical lymphoid cells in infectious Lancet 1:1153-1155, 1973 40.
EDELSON
RL,
LUTZNER
MA,
KIRKPATRICK
CH,
lymphocyte al:
Thymic
mononucleosis. et
al:
Mor-
phological and functional properties of the atypical T lymphocytes of the Sezary syndrome. Mayo Clin Proc 49:558-566, 1974 41. PRUNIERAS M : D N A content and cytogenetics of the Sezary cell. Mayo Clin Proc 49:548-552, 1974
Hauch et a/. • Meningeal Mycosis Fungoides
Downloaded from https://annals.org by Karolinska Institute user on 01/18/2019
a
matous leptomeningitis. Am J Med 51:200-208, 1971
8. B R O O M E J D , Z U C K E R - F R A N K L I N D , W E I N E R M S , et a l : Leukemic
9. Z U C K E R - F R A N K L I N
EP,
reticuloendothelial neoplastic entity? Arch Dermatol Syphilol 64:255-272, 1951 RIECKE E : Zwei-Falle von Mycosis fungoides. Arch Dermatol Syph 67:193-226, 1903 BUSCHKE, S I M M O N S , A N D E R S : Mycosis fungoides mit Beteilung des Zentralnervensystems ( a b s t r a c t ) . Zentralbl Haut-u Geschlechtskr Grenzgeb 43:723-724, 1933 B E N N E K J : Mycosis Fungoides inneren organ. Zentralbl Haut-u Geschlechtskr Grenzgeb 60:1-21, 1938 H E I T E H J , SOCHA P : Haufigkeitsanalytische untersuchungen zur Symptomatologie der Mycosis fungoides. Arch Dermatol Syph 193:118-142, 1951 PALTAUF R, SCHERBER G : E i n Fall of Mycosis fungoides mit E r k r a n k u n g von Nerven u n d mit Lokalisation in der inneren Organen. Virchows Arch [Pathol Anat] 222:9-27, 1916 H E M M I N G S O N H : Ein Fall von Mycosis fungoides mit M e tastasierung als polymorphzelliges Sarkom. Acta Radiol (Stockh) 22:606-619, 1941
complications of acute leukemia in adults: changing rate. Ann Intern Med 79:541-544, 1973 28. PRICE R A , J O H N S O N W W : T h e central nervous system in childhood leukemia. I. The arachnoid. Cancer 31:520-533, 1973
thymus-derived nature of the proliferating cells in six patients with Sezary's syndrome. N Engl J Med 289:341-344, 1973 cells with m e m b r a n e properties of thymus-derived ( T ) lymphocytes in a case of Sezary's syndrome: Morphologic and immunologic studies. Clin Immunol Immunopathol 1:319-329, 1973
CAWLEY
con metastasi Geschlechtskr
505
