Aggressive Pituitary Macroadenoma Treated With Capecitabine and Temozolomide Chemotherapy Combination in a Patient With Nelson's Syndrome: A Case Report.

Nelson's syndrome is considered a severe side effect that can occur after a total bilateral adrenalectomy in patients with Cushing's disease. It usually presents with clinical manifestations of an enlarging pituitary tumor including visual and cranial nerve alterations, and if not treated, can cause death through local brain compression or invasion. The first therapeutic option is surgery but in extreme cases of inaccessible or resistant aggressive pituitary tumors; the off-label use of chemotherapy with capecitabine and temozolomide can be considered. However, the use of this treatment is controversial due to adverse events, lack of complete response, and inability to predict results. We present the case of a 48-year-old man diagnosed with Nelson's syndrome with prolonged partial response and significant clinical benefit to treatment with capecitabine and temozolomide.

Stereotactic radiosurgery before bilateral adrenalectomy is associated with lowered risk of Nelson's syndrome in refractory Cushing's disease patients.

BACKGROUND: Nelson's syndrome is a rare but challenging sequelae of Cushing's disease (CD) after bilateral adrenalectomy (BLA). We sought to determine if stereotactic radiosurgery (SRS) of residual pituitary adenoma performed before BLA can decrease the risk of Nelson's syndrome. METHODS: Consecutive patients with CD who underwent BLA after non-curative resection of ACTH secreting pituitary adenoma and had at least one follow-up visit after BLA were studied. Nelson's syndrome was diagnosed based on the combination of rising ACTH levels, increasing volume of the pituitary adenoma and/or hyperpigmentation. RESULTS: Fifty patients underwent BLA for refractory CD, and 43 patients (7 men and 36 women) had at least one follow-up visit after BAL. Median endocrine, imaging, and clinical follow-up were 66 months, 69 months, and 80 months, respectively. Nine patients (22%) were diagnosed with the Nelson's syndrome at median time after BLA at 24 months (range: 0.6-119.4 months). SRS before BLA was associated with reduced risk of the Nelson's syndrome (HR = 0.126; 95%CI [0.022-0.714], p=0.019), while elevated ACTH level within 6 months after BLA was associated with increased risk for the Nelson's syndrome (HR = 9.053; 95%CI [2.076-39.472], p=0.003). CONCLUSIONS: SRS before BLA can reduce the risk for the Nelson's syndrome in refractory CD patients requiring BLA and should be considered before proceeding to BLA. Elevated ACTH concentration within 6 months after BLA is associated with greater risk of the Nelsons' syndrome. When no prior SRS is administered, those with a high ACTH level shortly after BLA may benefit from early SRS.

A 52-year-old male with visual changes.

A 52 year-old male with a history of Cushing's Disease at age 18 and bilateral adrenalectomy at age 23 presented with visual changes. An MRI scan showed a pituitary macroadenoma (Nelson's syndrome). Other than the development of diabetes mellitus at age 32, his disease was stable until presentation. Serum studies show markedly elevated ACTH levels, but he had no hyperpigmentation. The tumor was removed by endoscopic surgery. Microscopic examination showed a pituitary adenoma with strong immunostaining for ACTH. In addition, the tumor cells showed Crooke's hyaline change and stained strongly for cytokeratin (Crooke's Cell Adenoma). Normal pituitary was not present. Crooke's cell adenomas are extremely rare and have not been previously reported in Nelson's Syndrome.

Possible role of a radiation-induced p53 mutation in a Nelson's syndrome patient with a fatal outcome.

Nelson's syndrome (NS) is characterized by the appearance and/or progression of ACTH-secreting pituitary macroadenomas in patients who had previously undergone bilateral adrenalectomy for the treatment of Cushing's disease. Such corticotroph macroadenomas respond poorly to currently available therapeutic options which include surgery, radiotherapy and chemotherapy. P53 protein accumulation may be detected by immunohistochemistry in pituitary corticotroph adenomas and it has been suggested that it might be causally related to tumor development. Wild type P53 protein plays an important role in the cellular response to ionizing radiation and other DNA damaging agents and is mutated in many human tumors. In this study we report an adult male patient with NS who underwent both transsphenoidal and transcranial pituitary surgeries, conventional and stereotaxic radiotherapy and brachytherapy. Despite of the efforts to control tumor mass and growth, this macroadenoma displayed relentless growth and aggressive behavior. DNA extracted from the first two surgical samples, as well as DNA from peripheral blood leukocytes disclosed normal p53 sequence. DNA extracted from tumor samples obtained at surgeries performed after pituitary irradiation carried a somatic heterozygous mutation, consisting of a deletion of four cytosines between nucleotides 12,144-12,149 in exon 4 of the p53 gene. This frameshift mutation creates a stop codon in exon 4 excluding the expression of a functional protein from the defective allele. These data demonstrate a possible association between the P53 protein loss of function induced by radiotherapy and the aggressive course of the disease in this patient.

Síndrome de Nelson: una causa infrecuente de hiperpigmentación cutánea generalizada / Nelson syndrome: a rare cause of generalized hyperpigmentation of the skin

El síndrome de Nelson (SN) supone una causa infrecuente de hiperpigmentación mucocutánea generalizada, cuyas manifestaciones clínicas se derivan de la secreción excesiva de corticotropina por un adenoma hipofisario secundario a la realización de una suprarrenalectomía bilateral terapéutica. Debido a que esta intervención quirúrgica ha caído en desuso en la actualidad, su presentación es hoy sumamente rara y poco reconocible. Presentamos un caso muy grave de hiperpigmentación generalizada por SN en una paciente de 37 años (AU)

Nelson syndrome is a rare cause of generalized mucocutaneous hyperpigmentation. Its clinical manifestations are due to excessive secretion of adrenocorticotropic hormone from a pituitary adenoma, which develops after bilateral therapeutic adrenal ectomy. As this operation has fallen into disuse, Nelson syndrome is now extremely rare and difficult to recognize. We present a very severe case of generalized hyperpigmentation due to Nelson syndrome in a 37-year-old woman (AU)

Easy endotracheal intubation of a patient suffering from both Cushing's and Nelson's syndromes predicted by the upper lip bite test despite a Mallampati Class 4 airway.

A 31-yr-old woman with concurrent Cushing's and Nelson's syndromes was scheduled for transsphenoidal hypophysectomy. The patient had generalized edema, morbid obesity, and a history of sleep apnea. Her Mallampati assessment was Class 4, suggesting very difficult intubation, but the upper lip bite test predicted easy intubation. After rapid sequence induction, there was a Class 1 view on laryngoscopy, and intubation was accomplished easily.

Immunocytochemical accumulation of p53 in corticotroph adenomas: relationship with heat shock proteins and apoptosis.

The pathogenesis of corticotroph adenomas is unknown. In a recent study accumulation of p53 protein was detected by immunohistochemistry in a substantial proportion of pituitary corticotroph adenomas, and it has been suggested that it may be causally related to their development. However, other immunohistochemical studies have not confirmed the high incidence of p53 accumulation in this tumor type. Therefore, in the present study, p53 protein accumulation was re-examined in a series of 31 cases of corticotroph adenomas, using different sets of well validated anti-p53 antibodies. Furthermore, in view of the known association of p53 protein with apoptosis, and the known property of p53 to form complexes with heat shock proteins (HSPs), the relationship of p53 accumulation in corticotroph adenomas with apoptosis and HSP-70 was also investigated. Tumor samples from 31 patients with Cushing's disease or Nelson's syndrome were studied. Accumulation of p53 protein was tested by the standard ABC method using two different sets of clone Pab1801 and DO-7 monoclonal antibodies, applied after incubation of sections in a microwave oven. Using the DO-7 antibody, nuclear accumulation of p53 protein was detected in a total of 15 cases, with cytoplasmic staining observed in only 3 tumors. In contrast, using the Pab1801 antibody nuclear staining was observed in only 5 adenomas, with 11 adenomas demonstrating focal cytoplasmic immunoreactivity. Parallel sections of all corticotroph tumors demonstrating cytoplasmic accumulation of p53 protein were tested for the immunohistochemical presence of heat shock protein HSP-70. A striking similar distribution pattern of these two proteins was observed. Apoptosis, identified by the in situ end labeling technique, was detected in a total of 15 out of 28 corticotroph adenomas tested. Calculation of the apoptotic labeling index (ALI) by image analysis showed a significantly lower ALI in those corticotroph adenomas demonstrating nuclear p53 accumulation compared to those with no nuclear p53 immunostaining (p < 0.05). There was no significant difference in the ALI between cytoplasmic p53 positive and negative tumors. It is concluded that depending on the antibody used there is a significant variation of p53 protein detection in corticotroph adenomas. Overall, a significant proportion of corticotroph adenomas studied expressed the p53 protein, which depending on the antibody used, was located either in the nucleus and/or the cytoplasm of tumorous corticotroph cells. Cytoplasmic accumulation of p53, as shown by our colocalization studies with HSP-70, may be due to p53/HSP-70 complex formation. Although such a complex-mediated cytoplasmic exclusion of p53 has no significant effect on apoptosis, nuclear accumulation of p53 protein is associated with a significantly lower apoptotic index indicating a failure of p53 protein to exert its apoptotic action in at least a subset of this tumor type.

Paratesticular tumours in a patient with Nelson's syndrome.

An extremely rare case of a 39-year-old man with Nelson's syndrome and paratesticular tumours is presented. The patient had undergone bilateral adrenalectomy at the age 23 years for Cushing's syndrome. Later he developed skin and mucosal hyperpigmentation. Nelson's syndrome was diagnosed, and he underwent transfrontal hypophysectomy. At age 29, the presence of paratesticular tumours was noted which were excised together with the left testis. The preoperative levels of testosterone, produced by the paratesticular tumours, were extremely high; they fell after surgery.

Síndrome de nelson: de uma consegüencia par uma convergência com a doença de cushing / Nelson syndrome: a consequence for a convergence with a cushing disease

Em 1958, a descriçao original da síndrome de nelson, incluia a presença de um tumor hipofisário secretor de ACTH, após o tratamento da doença de Cushing pela adrenalectomia bilaterial. Entretanto, hoje, reconhece-se que uma adenoma hipofisário está presente em cerca de 90 por cento dos casos de doença de Cushing, antes de qualquer tratamento. O objetivo desta revisao foi atualizar o conceito e os critérios diagnósticos da síndorme de Nelson. A etiopatogenia dos tumores corticotróficos e a resistência aumentada à retroalimentaçao negativa dos glicoforticóides nao estao totalmente esclarecidas. Embora os tumores da síndrome de Nelson sejam mais agressivos, aparentemente nao existem diferenças de natureza genética ou de processamento dos peptídeos derivados da POMC, entre os adenomas oriundos da doença de Cushing ou da síndrome de Nelson. Os limites biológicos se superpoem. Porém, é de interêsse prático o estabelecimento dos limites e critérios diagnóticos entre a doença de Cushing pós-adrenaloctomia e a síndrome de Nelson, principalmente para determinar a ocasiao da reexploraçao cirúrgica da hipófise. A primeira tem tumores geralmente nao visualizados, menores que 5mm e níveis plasmáticos de ACTH geralmente menores que 1000pg/ml. Na segunda, so níveis de ACTH sao iguais ou maiores que 1000 pg/ml, aos 12 meses pós-adrenalectomia, aumentando rapidamente para 2000 pg/ml ou mais, após o 2§ ano e apresentando-se, através do CT, como tumores em crescimento e iguais ou maiores que 8 mm. A evoluçao científico-tecnológica levou a uma convergência dos conceitos e dos limites diagnósticos entre a síndrome de Nelson e a doença de Cushing. (Arq Bras Endocrinol Metab 1994; 38/1:47-51).

[Nelson's syndrome concomitant with Cushing's syndrome]. / Síndrome de Nelson concomitante con síndrome de Cushing.

A case is presented of Nelson's Syndrome concomitant with Cushing's Syndrome in a female patient who underwent five years earlier bilateral adrenalectomy due to Cushing's Disease. Together with hyperpigmentation, very elevated ACTH, and intrasellar mass in CT scan, plasma cortisol levels without rythm and not suppressible were observed as well as increased cortisol in urine. The macroadenoma was resected though the sphenoid and later hypophysis radiotherapy was given, with a clinical remission and biochemical improvement of the syndrome. At the present time, slightly elevated ACTH levels persist, with panhypopituitarism and empty sella turcica. The clinical picture is described and a literature search is carried out.

[A fatal course of Nelson syndrome]. / Fataler Verlauf eines Nelson-Syndroms.

An unusually therapy-resistant form of Nelson's syndrome developed in a 23-year-old woman two years after treatment of a pituitary-dependent Cushing's syndrome by bilateral adrenalectomy (1977). Removal of a corticotrophic adenoma by a first transsphenoidal pituitary operation (1979) brought only temporary relief. Two years later, regrowth and apoplexy of the pituitary adenoma led to oculomotor paralysis and had to be treated by a second transsphenoidal operation (1981). A second relapse became manifest two years later. Treatment with bromocriptine relieved the headaches but did not diminish the tumor size. A third pituitary operation (1984) became necessary when neurological signs revealed penetration of the cavernous sinus. The tumor was only partly removed by transsphenoidal surgery. Postoperative deterioration of the patient required emergency craniotomy to check a subarachnoidal hemorrhage and for removal of the remaining tumor. The patient died three days later of pneumococcal meningitis which had developed after the third pituitary operation.

Virilizing paraovarian tumors: a consequence of Nelson's syndrome?

In a patient with Nelson's syndrome, elevated peripheral concentrations of androgens usually associated with neoplasm prompted ovarian vein catheterization. Androgen excess was limited to the right ovary. However, laparotomy revealed bilateral multiple paraovarian nodules with histologic appearance of adrenocortical tissue. The occurrence of virilization from ectopic adrenal tissue with markedly elevated ACTH concentrations is exceedingly rare.

Nelson's syndrome and behavioural changes reversed by selective adenomectomy.

A man with Nelson's syndrome developed severe associated behavioural and psychiatric problems, which completely resolved following selective resection of his pituitary tumour. It is postulated that ACTH, beta-endorphin, or related peptides may have caused these problems.

Pituitary pro-opiomelanocortin-cell carcinoma occurring in conjunction with a glioblastoma in a patient with Cushing's disease and subsequent Nelson's syndrome.

Pituitary carcinoma is defined as a malignant pituitary tumour associated with blood- or lymph-borne metastases. Cushing's disease is frequently present in patients with this condition. After adrenalectomy for Cushing's disease, a 37-year-old man developed Nelson's syndrome resulting from a pituitary carcinoma with metastases to the spinal cord, cauda equina, heart, liver, and pancreas. The primary tumour and its metastases showed immunocytochemical staining for ACTH, beta-lipotrophin, and variably for beta-endorphin and alpha-melanocyte stimulating hormone (alpha-MSH). A coincidental glioblastoma was also present. Nine cases of Cushing's disease associated with pituitary carcinoma, including the present patient, are documented in the literature. The case reported is only the second in which immunohistochemical staining of the primary pituitary tumour and its metastases was performed, and the first in which ACTH-related peptides, in addition to ACTH itself, were demonstrated in the carcinoma cells.

Adrenocorticotropin-dependent virilizing paraovarian tumors in Nelson's syndrome.

A 35-yr-old woman with Nelson's syndrome presented with amenorrhea and virilization. Serum testosterone (T) concentration was 605 ng/dl and fell to 33 ng/dl when dexamethasone was administered. The MCR of T fell from 1383 to 991 liters/day and the T production rate decreased by 96%. With administration of synthetic ACTH, T concentration rose to 338 ng/dl. Plasma ACTH concentration paralleled T during repeated suppression testing, suggesting that T secretion was dependent on ACTH hypersecretion. Preoperative and intraoperative ovarian vein catheterization suggested that the predominant source of androgen production was from the right ovarian vein. Laporatomy revealed multiple paraovarian tumors in the right mesosalpinyx and mesovarium. Incubation of tumor slices and ovarian tissue with [3H]pregnenolone and [14C]17-hydroxyprogesterone demonstrated conversion of both precursors to T by the tumor and confirmed that the tumors were the source of androgen excess. The microscopic appearance of the tumors closely resembled the morphology of testicular and paratesticular tumors of men with congenital adrenal hyperplasia and Nelson's syndrome. The analogous dependency of the tumors on ACTH hypersecretion in men with paratesticular tumors and in this woman with paraovarian tumors suggests that the tumors may arise in both males and females from a common steroid-secreting cell of adrenogenital origin.