DIAGNOSIS: MALIGNANT PSAMMOMATOUS MELANOTIC SCHWANNOMA IN A PATIENT WITHOUT SIGNS OF CARNEY COMPLEX.
Melanotic schwannoma (MS) is a rare melanin-producing nerve sheath tumor with over 70 reported patients affected with one or more tumors (5, 10). MSs are of neural crest origin probably caused by the neoplastic proliferation of a common precursor cell for both Schwann cells and melanocytes (10, 11).
In approximately 40 to 50% of MSs psammoma bodies can be found and such tumors are designated "psammomatous melanotic schwannomas" (PMSs) (1, 5). Nearly 60% of PMSs exhibit adipose-like cells with cytoplasmic vacuoles, large examples of which show appearance of mature adipose tissue (1, 5). Over 53% of MSs involve cranial or spinal nerve roots (10) with a clear predominance of spinal (particularly cervical and thoracic) nerves (46% of cases) (5). Approximately 10% of MSs involve sympathetic chain (10). Rarer examples are located in the alimentary tract, skin, soft tissues, bone, liver, heart, bronchus etc. (5, 10). While most of the MSs of the spinal nerves are of the nonpsammomatous type, PMSs predominate in the alimentary tract tumors (5).
Identification of PMSs is especially important because it may be a component of Carney complex (1, 2). Carney complex is an often familial multiple neoplasia syndrome of autosomal-dominant inheritance featuring a variable frequency of spotty skin pigmentation, myxomas (cardiac, cutaneous, mucosal and breast), multiple endocrine neoplasia (primary pigmented nodular adrenocortical disease, GH- and PRL-producing pituitary adenoma, testicular neoplasms (primarily large-cell calcifying Sertoli cell tumor), thyroid adenoma or carcinoma and ovarian cysts), blue nevi, breast ductal adenoma, osteochondromyxoma and PMS (1, 2, 5, 7, 9, 11). PMSs in Carney complex affect primarily posterior spinal nerve roots, upper alimentary tract, bone and skin (5, 9). Carney complex is a rare disorder of which 338 affected patients are recorded in a recent review (9). It is genetically heterogeneous: approximately half of the known Carney complex kindreds show inactivating mutations of the tumor suppressor gene PRKAR1A at the 17q22-24 locus and most but not all of the remaining kindreds map to a second locus at chromosome 2p16 (9). In total, 41% of all patients with Carney complex (familial and sporadic cases) have mutations in the PRKAR1A gene (7). In about 10% of patients with Carney complex PMSs could be found (9) and in recently published diagnostic criteria for Carney complex (9) histologically confirmed PMS is one criterion in a list of 12 disease manifestations of which 2 are required for diagnosis. On the other hand, more than half (55%) of the patients with PMS have Carney complex and in patients with multiple PMSs - which are seen in 19% of PMSs - Carney complex can even be found in 83% of the cases (1, 5). Therefore, histological diagnosis of a PMS should prompt clinicians to look for Carney complex in this patient. In a patient with Carney complex detection and surgical treatment of cardiac myxomas - which occur in approximately half of the cases (9) - is of critical importance (12). Recently, a nonpsammomatous lumbar MS was reported in a patient with Carney complex (12). But even extremely careful microscopic search does not definitely preclude the presence of psammoma bodies since they may be very rare in individual MS cases.
In our patient, no additional manifestations of Carney complex have been found like in other cases of the literature (case 1 and case 2 in 10). Her hyperthyroidism may arouse suspicion, since thyroid gland abnormalities are indeed common in patients with Carney complex (8). But thyroid carcinoma or multiple, hypoechoic nodules on thyroid ultrasonography as recorded in the list of diagnostic criteria for Carney complex (9) were not reported. Carney complex patients with such thyroid abnormalities usually show normal levels of thyroid hormones (8). Hyperthyroidism in our patient was probably caused by autoimmune thyroiditis. The mean age at diagnosis of patients with PMS and Carney complex is 27 years (5) which is considerably younger than in all patients with MSs where mean age at diagnosis is 38 years (10). No sex predominance (10) or a slight (1.4 to 1) female predominance (5) have been reported in MSs.
It was stressed that the long-term prognosis of MS is not good (10): 25 out of 57 reported cases with known follow-up (43.8%) showed local recurrences or metastases (10 local recurrences/local extension and 15 metastases) and 13 out of these 57 patients (22.8%) died of the disease (10). Among 51 patients with Carney complex who are deceased PMS caused death in 14 % of cases (7 patients: 6 with metastatic PMS, 1 with intracranial PMS) (9). Since tumor recurrences or metastases of MS may occur after more than 5 years (even in cases without overt malignant histological features), appropriate long-term follow-up is required (10).
Approximately 10% of all MSs are malignant (5) and in 33 patients with PMS and Carney complex, the tumor was malignant in 6 patients (18%) (9). However, histologic criteria for malignancy in MSs are not clearly defined but large, vesicular nuclei with scant chromatin and very prominent macronucleoli, increased mitotic activity including abnormal mitoses and broad zones of necroses are features common to clinically malignant tumors and occur in varying combinations (5). In our case, frequent vesicular nuclei with distinct nucleoli, occasional mitoses and apoptoses and increased focal MIB-1 labeling indices prompted us to diagnose a malignant PMS. But altogether, there is no reliable histopathological indicator of malignancy in MSs, since histologically malignant-appearing tumors have followed a benign clinical course and MSs with clinically malignant behavior were histologically indistinguishable from benign tumors (11). Therefore, it may be more appropriate in cases like ours to use the more general designation "PMS with malignant histologic features".
Total surgical excision of MS with tumor-free margins is the treatment of choice (5). Especially in cases with incomplete excision, additional radiotherapy may be considered, although data of its efficiency are not yet available (10).
Histological diagnosis of MS requires careful differential diagnostic considerations. MSs differ from conventional schwannomas by the identification of melanin (which must not be confused with lipofuscin), the frequent presence of epithelioid cells and the additional detection of psammoma bodies and often adipose-like cells in PMSs (5). Unlike conventional schwannomas, MSs lack a distinct capsule, well-formed Verocay bodies and clear-cut Antoni A and B areas, and in PMSs vessels are often rather thin-walled than thickened and hyalinized (5). Distinction from pigmented neurofibroma (PN) (3) may be more difficult (5): PN shows only microscopic pigmentation and lacks both psammoma bodies and adipose-like cells. Its cells have small, often elongate nuclei and only scant cytoplasm, while cells of MS exhibit abundant cytoplasm and often round nuclei with delicate chromatin, a distinct central nucleolus and frequent intranuclear cytoplasmic pseudoinclusions. PN exhibits no uniform S-100 protein-immunoreactivity and electron microscopy reveals heterogeneous cell types (5). Melanocytomas of CNS with typical location in the cranial or spinal meninges differ from MSs by their site usually without connection with a nerve (5, 6), while histologic distinction is difficult and may require ultrastructural examinations where melanocytomas lack both pericellular basement membrane and long-spacing collagen (5). Furthermore, immunoreactivity for collagen type 4 may be less abundant in melanocytomas (5). Psammoma bodies and adipose-like cells of PMS are not seen in melanocytomas (5).
The most important distinction of MS from malignant melanoma may be difficult. Dendritic-appearing cells of MS are rarely seen in malignant melanoma (1, 5). Cytologic features of malignancy as seen in most melanomas allow distinction only from benign-appearing MSs. Ultrastructurally, basement membrane formation is a rare finding in malignant melanoma (5). Malignant melanoma does not show adipose-like cells of PMS but a regular lack of psammoma bodies in malignant melanoma was recently called in question by the description of a cutaneous psammomatous malignant melanoma (4).
The postoperative course of the patient was unremarkable without additional neurologic deficits. One year after operation there is only a residual C6 hypesthesia on the right side without clinical signs of cervical myelopathy. MRI disclosed no tumor recurrence.
Three years and 8 months after the initial resection there was recurrence of the tumor, which was also resected. Histopathologically, the recurrent tumor was identical to the previous material, except that the recurrent material lacked psammoma bodies.
Contributed by Klaus Kuchelmeister MD, Claudia Lotz MD, Robert Schönmayr MD, Walter Schachenmayr MD