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Leptomeningeal Carcinomatosis as the Initial Manifestation of Metastatic Disease diagnosed in Postmortem Examination: A Case Series.

Leptomeningeal carcinomatosis (LMC) is a complication of advanced stage cancer in which malignant cells have metastasized to the pia-arachnoid. Metastases to the meninges is known to occur through several routes, including hematogenous spread, via the endoneural/perineural route, and cerebrospinal fluid (CSF) dissemination (1). The overall incidence of clinically diagnosed LMC in malignant solid tumors is currently at 5%, a value likely increasing due to advancements in neuroimaging, including the visualization of the subarachnoid space by MRI, and increased life expectancy in various malignant cancers (1-3). Despite diagnostic improvements, approximately 20% of cases of LMC remain undiagnosed until autopsy (1). This represents a detriment in prognosis evidenced by a decreased overall survival (1,5,8-10).

Carcinomas of the breast (12-25%) and lung (10-26%) are the solid tumors

most often presenting with LMC (Chart 1) (1,7). However, several other malignancies have been shown to be prone to meningeal metastasis, including head-neck, cervical, ovarian, renal, bladder, relapsed leukemia, non-Hodgkin's lymphoma, and pediatric malignancies such as rhabdomyosarcoma and retinoblastoma (6,11).

Clinical features of LMC often include nonspecific neurologic symptoms such as headache and mental status change, or may mimic an inflammatory process like meningitis (Chart 2)(1,5-10). The lack of specific symptoms makes diagnosis challenging, especially in the scenario of no previous history if neoplastic process. CSF cytology revealing neoplastic cells is the gold standard for LMC diagnosis (1-3,5). However, CNS imaging is often the initial diagnostic tool utilized, due to the vagueness of the patient's symptomatology, with MRI proving to be the imaging modality with most sensitivity in the diagnosis of LMC (1,2).

Nonetheless, gross and histologic examination of the leptomeninges remains the most accurate technique in confirming LMC, making postmortem examination an invaluable tool in establishing this pathology.

We present three patients with leptomeningeal carcinomatosis as the initial manifestation of metastatic disease diagnosed in postmortem examination.
CASE 1

A 52 year old woman with history of breast cancer, diagnosed 4 years
prior, status post chemotherapy and radiotherapy on remission
developed headaches, generalized weakness, and difficulty walking one
month before admission. Lumbar puncture was remarkable for increased
opening pressure. Neurological imaging studies were unremarkable.
Cerebrospinal fluid cytology revealed chronic inflammation. Patient
was admitted under the clinical suspicion of a chronic inflammatory
meningitis without a clear etiology. Postmortem examination showed
metastatic carcinomatosis involving the lungs, and periaortic lymph
nodes. Gross brain examination revealed opaque leptomeninges (Fig 1).
Microscopic examination showed diffuse infiltration of malignant
cells in the leptomeninges (Fig. 2A). Breast cancer etiology
compatible with known primary was confirmed with immunohistochemistry
studies (Fig. 2B and C). There was no evidence of residual breast
disease.

Chart 1: Maximal Distribution of Propensity to LMC by Cancer Type. (1)

LMC: Leptomeningea/ Carcinomatosis

Maximal Distribution of Propensity to
LMC by Cancer Type

Breast             34%
Lung               26%
Melanoma           25%
Gastrointestinal   14%
Unknown primary     7%

Table made from pie chart

CASE 2

A 2 year old boy recently diagnosed with
left ear rhabdomyosarcoma. After 2 weeks of
chemotherapy, he presented with vomiting,
abdominal pain, poor oral intake and
seizures. Head computed tomography (CT)
scan revealed marked edema, ventricular
system dilation and changes suggestive
of anoxic encephalopathy. CSF cytologic
examination was unremarkable. The patient
presented rapid clinical deterioration
followed by brain death. Postmortem
microscopic examination revealed diffuse
meningeal infiltration of malignant cells
consistent with rhabdomyosarcoma
(Fig.3a-b). No evidence of residual disease
was found in the primary's site.

CASE 3

A 59 year old woman with history of chronic tobacco smoking and
alcoholism was just diagnosed with communicating hydrocephalus
of unknown etiology. One week after discharge, she presented with
headaches, vomiting, unsteady gait, and seizures. An abdominal CT
scan revealed a mass effect in the colon. CSF cytology was negative
for infection or malignancy. She developed a rapidly deteriorating
clinical picture with death occurring less than a week after admission.
Autopsy revealed perforated diverticular disease with plastron
Formation involving the sigmoid, cecum and uterus in addition to a
2-cm peripheral lung mass. Metastatic lung adenocarcinoma involving
the mesentery and leptomeninges was confirmed by microscopic analysis
and immunohistochemistry studies (Fig 4c-e).


Discussion

The incidence of Leptomeningeal carcinomatosis has shown to be increasing, likely due to a combination of factors, including improved diagnostic imaging, prolonged life-expectancy in several carcinomas, and limited CNS penetration of most chemotherapeutic agents (1-3). A concurrent increase in undiagnosed cases of LMC, however, shows that this diagnosis requires a high level of clinical suspicion. The usual presentation of vague, nonspecific neurologic symptoms makes diagnosis of LMC challenging, especially in the scenario of unknown malignancy. (1,5-10) Signs and symptoms of LMC are associated to a wide range of diseases, including meningitis, with which many cases of LMC are confused (1,5,7). Our cases were consistent with the already described most common symptomatology for LMC.

Cerebrospinal fluid cytology has proven to be an important tool in the diagnosis of LMC, but is limited by a sensitivity of <50%, often yielding false negative results (13). Several studies have shown that serial testing can greatly improve the diagnostic accuracy of CSF cytology, and should be considered if clinical suspicion exists (1,12,13). Negative CSF cytology was found in our cases.

Almost 90% of cases have abnormalities in the CSF examination; most notably increased opening pressure, elevated leukocytes, elevated protein and decreased glucose (1,12,14,15). Case number 1 exhibited the first two abnormalities.

Post mortem examination is essential to develop an understanding of LMC and in fine-tuning the clinical suspicion necessary to avoid undiagnosed cases, especially considering its detrimental prognosis, 1,8 It is also a necessary means to diagnose and/or confirm meningeal carcinomatosis as part of the multidisciplinary approach aiming towards the improvement of clinical diagnosis (8).

Conclusion

Leptomeningeal carcinomatosis is an unfavorable complication with an increasing incidence. The nonspecific clinical neurologic symptoms that characterize its clinical picture, however, denote a diagnostic challenge. Cerebrospinal fluid cytology has proven a valuable tool to aid in the diagnosis, yet an acceptable level of sensitivity is only achieved when performed in a serial manner. Postmortem examination is an essential tool to rule-out or confirm the diagnosis and improve overall clinical awareness.

References

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(2.) Clarke JL, Perez HR, Jacks LM, Panageas KS, Deangelis LM. Leptomeningeal metastases in the MRI era. Neurology 2010;74:1449-1454.

(3.) Lee DW, Lee KH, Kim JW, Keam B. Molecular Targeted Therapies for the Treatment of Leptomeningeal Carcinomatosis: Current Evidence and Future Directions. Int J Mol Sci 2016;17:7-10.

(4.) Kumar V, Abbas Ak, Fausto N, Aster JC, editors,. Robbins and Cotran Pathologic Basis of Disease, 8th Edition. Saunders Company; 2010, pp 297-301.

(5.) Chuang TY Yu CJ, Shih JY Yang PC, Kuo SH. Cytologically proven meningeal carcinomatosis in patients with lung cancer: Clinical observation of 34 cases. J Formos Med Assoc 2008;107:851-856. Balbuena-Merle et al

(6.) Salunke P, Sura S, Tripathi M, Aggarwal A, Gupta K. Middle ear rhabdomyosarcoma infiltrating the petrous with diffuse leptomeningeal spread in a child. J Pediatr Neurosci 2012;7:103.

(7.) Kaplan JG, DeSouza TG, Farkash A, et al. Leptomeningeal metastases: Comparison of clinical features and laboratory data of solid tumors, lymphomas and leukemias. J Neurooncol 1990;9:225-229.

(8.) Olson M, Chernik N, Posner J. Infiltration of the leptomeninges by systemic cancer: A clinical and pathologic study. Arch Neurol 1974;30:122-137.

(9.) Wasserstrom WR. Leptomeningeal metastases, In: Wiley RG, editor. Neurological Complications of Cancer. New York: Marcel Dekker; 1995.p.45-71.

(10.) Balm M, Hammack J. Leptomeningeal carcinomatosis: Presenting features and prognostic factors. Arch Neurol 1996;53:626-632.

(11.) Pavlidis N. The diagnostic and therapeutic management of leptomeningeal carcinomatosis. Ann Oncol 2004;15(SUPPL. 4):285-291.

(12.) Chamberlain MC. Leptomeningeal metastasis. Curr Opin Oncol 2010;22:627-35.

(13.) Chamberlain MC, Glantz M, Groves MD, et al. Diagnostic tools for neoplastic meningitis: detecting disease, identifying patient risk, and determining benefit of treatment. Semin Oncol 2009;36(Suppl 2):S35- S45.

(14.) Glass JP, Melamed M, Chernik NL, Posner JB. Malignant cells in cerebrospinal fluid (CSF): the meaning of a positive CSF cytology. Neurology 1979;29:1369-75.

(15.) Lee SJ, Lee J-I, Nam D-H, et al. Leptomeningeal Carcinomatosis in Non-Small-Cell Lung Cancer Patients: Impact on Survival and Correlated Prognostic Factors. J Thorac Oncol 2013;8:185-191.

Raisa I. Balbuena-Merle, MD; Maria Sante-Perez, MD; Juan Perez-Berenguer, MD; Roman Velez-Rosario, MD; Maria Correa-Rivas, MD; Alexandra Jimenez, MD

Department of Pathology and Laboratory Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico; Administracion de Servicios Medicos de Puerto Rico, San Juan, Puerto Rico

The author/s has/have no conflict/s of interest to disclose.

Address correspondence to: Raisa I. Balbuena-Merle, MD, 330 Cedar Street, Clinic Building 441, New Haven, CT 06520-8035. Email: raisa.balbuena-merle@yale.edu

Caption: Chart 2: Most Frequent symptoms in LMC. (1)

Caption: Fig. 2 B and C: Lymph node: Tumor cells positive for Mammaglobin and GCDFP-15 (100X)

Caption: Fig. 3. A. Brain; Cerebral cortex (arrow head) and Leptomeninges (black arrow) with a diffuse infiltrate of maligrant cells. (H&E 200x), FIG 3. B. Insert: Rhabdomyoblasts: tumor cells with a spindle cell conformation and eosinophilic cytoplasm with striations (red arrows) (H&E 100X).

Caption: Fig. 4. A. Lung Distended alveoli (arrow head) and peripheral mass with glandular formation and extensive mucin production (box) (H&E 20x) B: Malignant glands composed of tall columnar epithelial cells lining the alveolar septa. (Red arrow) (H&E 100x)

Caption: Fig 4. C and D. Tumor cells positive for CK7 and TTF-1, respectively (200x).
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Title Annotation:CASE REPORT
Author:Balbuena-Merle, Raisa I.; Sante-Perez, Maria; Perez-Berenguer, Juan; Velez-Rosario, Roman; Correa-Ri
Publication:Puerto Rico Health Sciences Journal
Date:Mar 1, 2019
Words:1592
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