Pulmonary miliary papillary/micropapillary adenocarcinoma manifesting as carcinomatous encephalitis.

The histological pattern and the associated molecular aberrations have an important bearing in the prognosis of pulmonary adenocarcinomas. Papillary and micropapillary growth patterns with mutations in epidermal growth factor receptor and anaplastic large-cell lymphoma kinase rearrangements have an aggressive clinical course. We report one such cancer in a 49-year-old woman, where it assumed a miliary pattern in the lungs, and the patient presented with neurological symptoms related to carcinomatous encephalitis, an infrequent metastatic manifestation.

Introduction

Lung cancers continue to be one of the most frequent causes of cancer incidence and mortality globally. Among the histological subtypes, adenocarcinoma is the most common type, seen in the half of lung cancer cases and has a widely divergent clinical, radiological, and pathological spectrum.[1] Furthermore, the detection of mutations in epidermal growth factor receptor (EGFR) and anaplastic large-cell lymphoma kinase (ALK) rearrangements have an important bearing on the adenocarcinomatous pattern, treatment, and prognosis.[2] This is a report of a middle-aged woman who presented with neurological symptoms due to an uncommon metastatic pattern of carcinomatous encephalitis from miliary lung adenocarcinoma with predominant papillary/micropapillary histology.

Case Report

A 49-year-old postmenopausal female, hypertensive for the past 3 years, had been discharged after the 4-day hospitalization with a clinical diagnosis of an acute conversion reaction. She had presented with holocranial headache and vomiting for 10 days, followed by altered sensorium. Apart from anemia (hemoglobin 10.6 g/dl), all her investigations, including cerebrospinal fluid examination, had been normal. She was re-admitted after 23 days with recurrence of headache and altered behavior. Her vital parameters and routine investigations were within normal limits. A computed tomographic scan of the brain revealed mild generalized cerebral atrophy, mild left parieto-occipital convexity leptomeningeal enhancement, and sub-cortical white matter hypodensity around occipital horns of lateral ventricles. With a clinical diagnosis of meningitis, she was administered antibiotics and intracranial tension-lowering agents. The cerebrospinal fluid examination and adenosine deaminase level were normal. Subsequent magnetic resonance imaging of the brain showed bilateral mild leptomeningeal involvement, the loss of sulcal/gyral pattern in the left occipital region with ill-defined heterogeneous enhancement and multiple small sub-centimetric sized lesions in bilateral parietal and left basifrontal regions. Hence, metastases were considered and an abdominal imaging was planned. However, her condition deteriorated and she expired 3 days after admission.

At autopsy, significant findings were seen in the brain and lungs. The leptomeninges showed focal opacification and appeared shiny due to meningeal carcinomatosis produced by metastatic papillary adenocarcinoma [Figure 1a and b]. In the occipital cortices and over both the cerebellar hemispheres, the surface showed a distinct granularity and a few tiny protrusions [Figure 1c]. The histology in these areas as well as in normal-appearing parenchyma showed papillary adenocarcinoma extensively involving the Virchow–Robin spaces [Figure 1d] - carcinomatous encephalitis. The primary cancer was present in the lungs, represented by multiple well-circumscribed, firm, grayish-white widely separated miliary lesions, 0.1–0.5 cm [Figure 2a]. The miliary lesions were composed of cuboidal to columnar epithelial cells with focal nuclear pleomorphism, multinucleation and mitotic figures, disposed in a lepidic, papillary and micro-papillary patterns [Figure 2b-d]. The cells were very strongly positive for CK7, thyroid transcription factor 1, and EGFR on immunohistochemistry (IHC); ALK-1 IHC was negative [Figure 2e]. No lesions were noted in the tracheo-bronchial tree. Metastases were present in the small-sized hilar and carinal lymph nodes. Papillary adenocarcinoma was seen over the external surfaces of the gall bladder and right ovary; interestingly, the right adrenal revealed a small adenoma in which was present metastatic foci [Figure 2f-h].

Figure 1

(a) Base of the brain showing milky white and shiny appearance of the leptomeninges; (b) metastatic papillary adenocarcinoma infiltrating the sub-arachnoid space (H and E, ×250); (c) A distinct granularity and sub-centimetric protrusions (arrows) are present over the surface of the right occipital lobe; (d) The Virchow–Robin spaces show the vessels surrounded by adenocarcinoma (H and E, ×250)

Figure 2

(a) The cut surface of left lower lobe showing grey-white miliary lesions; the largest lesion was 0.5 cm in diameter (arrow). The miliary lesions (H and E, ×400) showed: (b) Lepidic pattern, (c) papillary pattern with characteristic fibrovascular cores, (d) micro-papillary pattern showing tufts of cells within alveoli; (e) positive immunohistochemical demonstration of epidermal growth factor receptor (×400); (f) deeply yellow adenoma in the right adrenal gland; (g) papillary adenocarcinoma within the adenoma (H and E, ×250); (h) a displaced foamy cell (arrow) within the metastasis (H and E, ×400)

Discussion

Invasive nonmucinous adenocarcinoma of the lung is sub-typed depending on the predominance of the lepidic, acinar, papillary, and solid components; these patterns have prognostic implications.[3] The papillary variant has two architectural configurations: True papillae with fibro-vascular cores and micropapillae devoid of fibro-vascular cores.[3] Both patterns were seen in the index case and were, surprisingly, superimposed on a lepidic pattern, a feature described recently.[4] Our patient was a nonsmoker. Lung cancer in nonsmokers (never smoked or have smoked <100 cigarettes in their lifetime) is emerging as a prominent public health issue. The prevalence of such lung cancers is approximately 25% and they are attributed to exposure to environmental pollutants or even human papilloma virus.[5] Furthermore, many of these patients tended to be Asian women of a younger age with a higher prevalence of EGFR mutations.[5] The adenocarcinoma was multifocal, miliary in both lungs and EGFR positivity was demonstrated by IHC, an association that has been previously documented.[6] Since the histomorphological features of the miliary lesions were dissimilar, we diagnosed them as multiple primary tumors.[7]

The metastatic capability of these aggressive tumors to distant sites, as was noted in our case, is well-known. Apart from meningeal carcinomatosis, the brain metastases also showed an unusual spread confined to the Virchow–Robin spaces, referred to as carcinomatous encephalitis. This spread is seldom associated with intra-parenchymal invasion, undetected in plain skull films and computed tomography, but better demonstrated by magnetic resonance imaging,[8] as noted in our case as well. The condition poses a clinical challenge as symptoms are diverse. Some patients are asymptomatic, whereas others have symptoms that mimic psychiatric, metabolic, or infective disorders.[8] Our patient had a clinical diagnosis of conversion reaction. On literature review, about 24 cases have been reported, with the majority of the metastases originating from papillary/micropapillary pulmonary adenocarcinomas.[89] Although the prognosis remains dismal, targeted therapy along with radiation can be effective treatment options.[89] The right adrenal in this patient showed "tumor-to-tumor" metastasis.[10] Metastasis of existing carcinoma to adrenal adenoma is well-known for nonfunctional adenomas but rare in functional adenomas. It is possible that the hypertension may have been due to the adrenal adenoma (clinically unsuspected Conn's syndrome); aldosterone assay was not performed in this case.

With this case, we have described a multifocal and miliary lung adenocarcinoma with carcinomatous encephalitis and tumor-to-tumor metastasis in an adrenal adenoma. The case also highlights that the histologic type of adenocarcinoma often decides the prognosis.

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Conflicts of interest

There are no conflicts of interest.