Amelanotic melanoma of the lung and brain with fenestrated intrinsic tumor capillaries

Amelanotic Melanoma of the Lung and Brain with Fenestrated Intrinsic Tumor Capillaries Richard F. Wagner, Jr., M.D.,* Gary Gerard, M.D.,t and James J. Sciubba, D.M.D., Ph.D.S:

Tissue from an amelanotic melanoma which involved the lung and brain was studied by electron microscopy. Endothelial fenestrae were found in the intrinsic tumor capillaries at both locations, a finding which does not appear to have been previously reported for amelanotic melanoma. Pitfalls in the diagnosis of this rare tumor are discussed.

monia at the age of 15 and the use of oral contraceptives for 10 years. She had two children, aged 5 and 8. She denied having had any lesions removed from her skin. She was a nonsmoker. Family history was noncontributory. The general physical examination was normal. There were no skin lesions or palpable lymph nodes. On neurological examination, the optic fundi showed bilateral papilledema without hemorrhages, exudates, or any other Malignant melanoma is often thought of as a black tumor, abnormalities. There was nystagmus on right lateral gaze, although it is well recognized that coal-black primary tu- wide-based ataxic gait, and right-sided dysmetria. No other mors can give rise to nonpigmented secondary metastases, abnormal neurological signs were elicited. and vice versa [24]. The widespread expectation that maNormal diagnostic studies included roentgenographic lignant melanomas are pigmented is exemplified by Cade films of the skull and spine and scans of the liver, spleen, [2], who described this tumor as the "pigmented foe" which and bone. Roentgenograms of the chest revealed a solitary 3 cm density in the lower lobe of the left lung. A computed resulted in a "black death." Amelanotic melanoma (a variant of pigmented ma- tomographic (CT) scan of the chest showed that no callignant melanoma) has been defined at the electron cium, hilar abnormalities, or other lesions in the lungs were microscopic, light microscopic, and macroscopic levels. present. Clark's definition of amelanotic melanoma required that no A C T scan of the brain showed a solitary lesion in the pigment be seen at a magnification of x400 [4]; this is right cerebellar hemisphere. A vertebral angiogram demthe definition that we have employed. The incidence of onstrated that the tumor was vascular, was supplied by the amelanotic melanoma is estimated to range between 2 and anterior inferior cerebellar artery, and was drained by large, 8% of all cutaneous malignant melanomas [4, 14]. The ex- irregular veins. A right suboccipital craniectomy was perpectation that all malignant melanomas are pigmented may formed and revealed a hemorrhagic 2 x 3 cm tumor prelead to misdiagnosis, especially when the tumor arises in an senting on the cerebeUar surface, which was removed in its unusual primary site or first presents as a solitary metastasis. entirety. Routine microscopic examination showed large A case of amelanotic melanoma, possibly primary in either tumor cells with large nuclei, large nucleoli, numerous the lung or brain, is reported. mitotic figures, and foamy cytoplasm. There was no definite organoid pattern (Fig. 1). Staining for lipid and mucin was negative. Sections of dura mater revealed tumor cells firmly Case Report A 31-year-old white woman was hospitalized at Long Island adherent to one surface. There was no evidence of inJewish-Hillside Medical Center in September, 1978, after tracellular or extracellular pigment. Electron microscopy a 4-week history of occipital headaches, dizziness, un- demonstrated the presence of premelanosomes (Fig. 2) and steadiness of gait, and falling to the right. melanosomes in the cytoplasm of the tumor cells as well as The past history was negative except for bronchopneu- numerous fenestrated endothelial cells in the intrinsic tumor capillaries (Figs. 3, 4). A lower lobectomy of the left lung revealed a mass in the *Currentlyat the New YorkMedical College/WestchesterCounty Medical Center, Departmentof Medicine, Valhalla, NY 10595. posterior basal segment. The hilum and bronchial stumps From the Departments of tNeurology and ~:Pathology. Long Island were grossly free of tumor. There was no lymphadenopathy Jewish-Hillside MedicalCenter, New Hyde Park, NY 11040. present. Routine microscopic examination showed large Key words: amelanoticmelanoma;brain; fenestrae;lung; premelanosome; polyhedral cells with abundant cytoplasm arranged in an melanosome. alveolar pattern with little stroma and occasional lympho/

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0090-3019/81/050384-05501.25 O 1980 by Little, Brown and Company (Inc.)

Wagner et al: Amelanotic Melanoma

Fig. 1. Photomicr¢~graphshowing thin-walled vascular spaces surn,unded by tum~r cells u,ith feu,er numbers of lymphocytes scattered irregularly thr~ugh,~ut. In areas, a vague suggesti,m of clustering of tumor cells may be noted. (H&E; x 150 before 25% reduction.)

Fig. 2. Electron micrograph in which a premelanosome can be seen with a typical internal lamelkLr peri~dicity within a p~orly differentiated melan~,ma cell. ( ×70,000 bef,~re 25% reducti~m. )

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Fig. 3. In this elecmm micrograph an area ~f the melan~ma is seen that omtains a small bl~,d vessel within u,hich are noted a feu, erythr,cytes (asterisk) and granular serum protein. The arrow indicates an area of fenvstrati~n , f the endothelial cell cytoplasm. ( ×7,000 before 25 % reduction. )

Fig. 4. This elecmm micr~graph shows distinct fenestrae (arrow) separating the vascular lumen (L) and endmhelial basal lamina. Thickening and duplicati¢m ~f the basal lamina are evident. ( ×34,000 before 25 % reducti¢,n. )

Wagner eta!: Ame!anotic .'v'e:anoma 3£7

cytes. The nuclear chromatin showed an open pattern with condensation on the nuclear membrane. No pigment was found. The small hilar nodes showed no evidence of tumor. Electron microscopy demonstrated the presence of premelanosomes and melanosomes, along with fenestrated endothelial cells in the intrinsic tumor capillaries. The patient made a rapid recovery, was discharged from the hospital in October, 1978, and was treated with radiation therapy (5,000 rads to the posterior fossa), (dimethyltriazenyl)imidazolecarboxamide (DTIC), and melanoma antigen. In March, 1979, the patient was readmitted after three weeks of frontal headache, generalized seizures, left hemiparesis, and urinary incontinence. A C T scan of the brain revealed a solitary lesion in the right frontal lobe; a CT scan of the abdomen showed hepatosplenomegaly with multiple fi)cal hypovascular defects. Examination of the cerebrospinal fluid was negative for melanin and abnormal cells. The following laboratory values were abnormal: calcium, 7.9 mg/dl; albumin, 2.3 gm/dl; cholesterol, 141 mg/dl; serum glutamic oxaloacetic transaminase, 54 units/L; serum glutamic pyruvic transaminase, 62 units/L; and lactic dehydrogenase, 273 units/L. A right frontal craniotomy was performed and the neoplasm was removed. Histologically, the tumor was composed of sheets of cells with hyperchromatic, pleomorphic nuclei, and abundant cytoplasm. Multinucleated tumor giant cells were diffusely scattered and necrosis was evident. Along the tumor margins, hemosiderin was present. No melanin pigment was identified. In November, 1979, the patient was readmitted with a 2-month history of paresthesias in the left arm. A C T scan of the brain demonstrated a solitary right parietal lesion. Roentgenographic examination of the chest showed multiple bilateral 3 to 4 mm lesions. A right craniotomy was performed, and the tumor was excised. Histologically, the neoplasm was similar to that encountered previously. Again no melanin was evident. In January, 1980, the patient was readmitted with aphasia, impaired memory, personality changes, ataxia, and right-sided fi~cal lesions in the left parietal, right temporal, and left occipital regions. She was treated with anticonvulsants and steroids, but died shortly thereafter. No postmortem examination was performed. Discussion This case may be an example of primary malignant melanoma of either the brain or lung in the absence of any other clinically demonstrable primary tumor during the 16-month illness. Primary malignant melanoma of the central nervous system is a relatively rare tumor that has been well described in the literature. As early as 1859, Mohinke and Valentin independently described the presence of melanocytes in human leptomeninges [7]. Later,

Roca de Vinals and his associates fimnd that melanocytes were present in 85% of normal human meninges,; [ 15]. It is now widely accepted that primary malignant melanomas of the central nervous system originate from the melanocytes that are normally present in this location. Primary malignant melanoma of the lower respiratory tract is a very rare tumor. Although melanocytes have never been demonstrated in the normal lower respiratory tract, this anatomical region is embryologically derived from a tubular downgrowth of the primitive foregut, a region in which melanocytes are normally fi)und [201. Therefi~re, it is possible that the lower respiratory tract also contains melanocytes that give origin to malignant melanoma in this location. The difficulty of diagnosing amelanotic melanoma in atypical primary locations is well illustrated by this case. Although primary .malignant melanoma of the central nervous system is usually pigmented, cases have been reported in which pigmented and nonpigmented regions were present in the same tumor [10, 18, 21]. Foot and Zeek [9] described a case of malignant melanoma of both the lung and brain in which there was no macroscopic evidence of pigment, but melanin granules were seen by light microscopy. In the present case, there was no evidence of pigment at either the macroscopic or light microscopic levels. Not until the demonstration of both premelanosomes and melanosomes by electron microscopy did the diagnosis of malignant melanoma become apparent. As seen in our patient, lack of pigmentation is not a reliable criterion by which to rule out the diagnosis of malignant melanoma. Amelanotic melanoma should be included in the differential diagnosis of sarcoma, carcinoma, lymphoma, neuroblastoma, meningioma, perithelioma, endothelioma, and hepatoma [1, 5, 6, 8, 13, 19, 23, 24]. Unequivocal diagnosis of malignant melanoma cannot be made on the basis of either chemical studies or histochemi. cal determinations of tyrosinase, an enzyme found in melanocytes [3]. Silver staining may help to reveal melanin within the neoplastic cells by light microscopy. Premelanosomes and melanosomes may be revealed through the use of electron microscopy [ 16]. The great variations in the histological pattern of amelanotic melanoma necessitates a high index of suspicion on the part of the clinician and the pathologist in order to successfully diagnose this tumor. Recent attention has been directed to the types of capillaries found in tumors. Capillaries in the lung characteristically have a continuous endothelium and those in the brain are similar, with the exception that they may be fenestrated in a few locations [17]. Fenestrated endothelial cells in the central nervous system have also been described in many pathological conditions including a variety of tumors (i.e., malignant melanoma, meningioma, schwannoma, pituitary adenoma, hemangioma, and glioma), delayed radiation he-

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crosis, and experimental conditions (e.g., lead pellet implantation in rat brains and the chronic stages of experimental allergic encephalomyelitis in guinea pigs) [11]. Blood vessels found in the granulation tissue of subdural hematomas also demonstrate fenestrated endothelium [22]. Hirano and Zimmerman [12] reported a case of primary renal cell carcinoma in which metastases to the brain from the primary tumor were shown to have fenestrated endothelial cells lining the intrinsic tumor capillaries. Since the kidney normally contains fenestrated endothelial cells in its capillaries, it was postulated that renal parenchymal cells metastatic to the brain induced the formation of capillaries which were specific for normal kidney parenchyma. In our patient, amelanotic melanoma of both the brain and lung showed similar endothelial fenestrations. As in the case of renal cell carcinoma, it is possible that melanoma cells are responsible for the induction of capillary endothelial cell fenestration. This explanation differs from that Offered by Ward and his associates [25], who described a pigmented primary malignant melanoma of the central nervous system that demonstrated numerous endothelial fenestrae in the intrinsic tumor capillaries. They postulated that the fenestrated endothelial cells were consistent with a well-differentiated tumor; the tumor was considered to be well differentiated by virtue of its mature state of melanin formation. However, in our case similar fenestrated endothelial cells were found in n o n p i g m e n t e d malignant melanomas of the brain and lung. Therefore, fenestrated endothelial cells in the intrinsic tumor capillaries of malign a n t melanoma appear to be independent of the degree of pigmentation found in the tumor.

We wish to thank Karen Dineen Wag~er, Ph.D., for her help in the preparation of this manuscript.

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