Cutaneous-immuno-neuro-endocrine (CINE) system: A complex enterprise transforming skin into a super organ.

Skin is now emerging as a complex realm of three chief systems viz. immune system, nervous system, and endocrine system. The cells involved in their intricate crosstalk, namely native skin cells, intra-cutaneous immune cells and cutaneous sensory neurons have diverse origin and distinct functions. However, recent studies have explored their role beyond their pre-defined functional boundaries, such that the cells shun their traditional functions and adopt unconventional roles. For example, the native skin cells, apart from providing for basic structural framework of skin, also perform special immune functions and participate in extensive neuro-endocrine circuitry, which were traditionally designated as functions of cutaneous resident immune cells and sensory neurons respectively. At the cellular level, this unique collaboration is brought out by special molecules called neuromediators including neurotransmitters, neuropeptides, neurotrophins, neurohormones and cytokines/chemokines. While this intricate crosstalk is essential for maintaining cutaneous homeostasis, its disruption is seen in various cutaneous diseases. Recent study models have led to a paradigm shift in our understanding of pathophysiology of many such disorders. In this review, we have described in detail the interaction of immune cells with neurons and native skin cells, role of neuromediators, the endocrine aspect in skin and current understanding of cutaneous neuro-immuno-endocrine loop in one of the commonest skin diseases, psoriasis. An accurate knowledge of this unique crosstalk can prove crucial in understanding the pathophysiology of different skin diseases and allow for generation of targeted therapeutic modalities.

Mucormycosis: Cytomorphological Spectrum in Fine-Needle Aspiration Cytology.

Background: Mucormycosis is a fungal infection that can affect multiple organs. The role of fine-needle aspiration cytology (FNAC) in its diagnosis is not well documented. Aim: The objective of this study was to describe the detailed cytomorphologic features of mucormycosis on FNAC samples. Materials and Methods: A retrospective analysis of all cases diagnosed as mucormycosis on FNAC between January 2014 and July 2021 was performed for detailed cytomorphological evaluation and correlation to clinical data and microbiological studies wherever available. FNA was computed tomography-guided (n = 38), ultrasonography-guided (n = 31) or palpation-guided (n = 12), and slides were reviewed in two cases. Results: A total of 83 cases of mucormycosis were evaluated. An immunocompromised setting was observed in 48 cases. The most common site of FNA was the lung (n = 57) followed by liver, soft tissue, palate, mediastinum, orbital/ocular region, and lymph node. Isolated renal involvement, a unique feature, was seen in seven cases. The aspirates were necrotic to pus-like or blood-mixed particulate. Broad, nonseptate, foldable, ribbon-like fungal hyphae showing right-angled branching were seen. The tissue reaction was predominantly necro-inflammatory (n = 36), bland necrotic (n = 22), mixed inflammatory (n = 16), suppurative (n = 5), necrotizing granulomatous (n = 3), and granulomatous (n = 1). Immunocompromised patients showed mixed inflammatory responses more frequently. Fungal culture was positive for Rhizopus species in 2/13 cases and molecular testing in two additional cases corresponding to Rhizopus and Syncephalastrum spp. Conclusion: FNA provides quick and conclusive diagnosis of mucormycosis from varied anatomic sites enabling prompt institution of therapy. The tissue response is variable and to some extent dependent on the immune status of the patient.

Understanding the Constraints and Optimization of Serum Immunofixation Electrophoresis and Serum Free Light Chains for Detecting Monoclonal Proteins: A Single-Center Experience.

Introduction Serum immunofixation electrophoresis (SIFE) and serum free light chain (SFLC) assay are imperative investigations in diagnosis and follow-up of multiple myeloma (MM). SFLC assays are reported to have higher sensitivity than SIFE. However, discrepancies have been reported between them. The current study was aimed at assessing concordance and discordance between SIFE and SFLC results in MM. Methods A total of 450 observations of both SIFE and SFLC were obtained from treatment-naive and follow-up MM patients. Results One hundred and twenty-nine (28.7%) values were observed as discordant, that is, positive SIFE with normal SFLC ratio or negative SIFE with abnormal SFLC ratio ( p -value < 0.00001). Proportion of discordance was higher in SIFE positive-SFLC normal cases than SIFE negative-SFLC abnormal cases. Discordance was more frequent in follow-up cases. Conclusion Negative SFLC alone may not be reliable for MM follow-up. Algorithm may be based on SFLC measurements on each follow-up till attainment of normal SFLC ratio. Once SFLC normalizes, follow-up may be done with SIFE. If SIFE is positive, further follow-up with SIFE may be initiated.

Inflammatory markers in geriatric anemia: A study from North India.

Background: Inflammation has several effects in the geriatrics with reference to iron deficiency anemia (IDA), anemia of chronic disease (ACD), and unexplained anemia (UA). Whether hyperinflammation is part of their pathogenesis or just incidental is unknown. Data are limited regarding inflammatory patterns in IDA, ACD, and UA in anemic geriatrics and inflammation as a component of UA. There is little known about the overlap of inflammation between ACD and UA. Objective: The study was undertaken to find the proportion of anemic geriatric patients, aged ≥60 years with raised serum levels of inflammatory markers and their study within IDA, ACD, and UA. Materials and Methods: Seventy-five anemic geriatric patients were evaluated for raised serum levels of inflammatory markers: high sensitive C-reactive protein (hsCRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8) along with serum ferritin (SF). Results: Raised markers were seen in 94.7% of anemic geriatric patients.IL-8 was raised most frequently followed by TNF-α, IL-6, hsCRP, and SF. No distinct inflammatory profile could be elicited between ACD and UA. The hyperinflammatory profile irrespective of the underlying etiology of geriatric anemia suggests that aging per se is pro-inflammatory state. Conclusion: Geriatric anemia can be thought to develop on background of subclinical low-grade inflammation along with superimposed nutritional deficiencies or chronic diseases.

Effusion cytology of metastatic carcinosarcoma.

Objectives: Carcinosarcomas (CSs) are rare gynecological neoplasms seen in elderly females. These are composed of malignant epithelial and mesenchymal components, which appear as adenocarcinoma and high-grade sarcoma. Effusions are encountered uncommonly in CS. Material and Methods: The study focuses on the cytomorphology of 10 cases of metastatic CS in effusions. In 6 years, there were 10 (0.45%) cases of metastatic CS in effusion samples out of 2240 malignant effusion samples. The samples were processed by SurePath™ and centrifuge technique. Both May-Grünwald-Giemsa and Papanicolaou stained smears were evaluated for cytomorphological features, and the findings were correlated with subsequent histopathology. Results: The cells were predominantly arranged in ball-like clusters and discretely. The cells had abundant vacuolated cytoplasm and enlarged pleomorphic nuclei. Occasional cases showed scattered spindle cells. The cases were diagnosed as metastatic adenocarcinoma (7/10) and positive for malignant cells (3/10). None of the cases was diagnosed as CS. The primary of these cases was in the uterus (7/10) and ovary (3/10). Conclusion: The cytological evaluation of such effusion samples rarely demonstrates the classical biphasic pattern of these tumors. Mostly, the carcinomatous component is evident, and the sarcomatous element is inapparent and readily missed.

Clinico-cytomorphological Spectrum of Calcinosis Cutis.

Introduction: The deposition of calcium in the skin is known as calcinosis cutis. It can affect any part of the body and can mimic soft tissue or bony lesions clinically. Aim: To describe the clinical and cytomorphologic features of calcinosis cutis on fine needle aspiration cytology smears. Materials and Methods: A total of 17 cases reported as calcinosis cutis on fine needle aspiration cytology were reviewed for the available clinical and cytological details. Results: The cohort included both adult and pediatric patients. Clinically, the lesions appeared as painless swellings of variable sizes. The common sites affected were the scrotum, iliac region, scalp, pinna, neck, axilla, elbow, arm, thigh, and gluteal region. Aspirate was chalky white, paste-like in all the cases. The cytologic evaluation revealed amorphous crystalline deposits of calcium along with histiocytes, lymphocytes, and multinucleated giant cells. Conclusions: Calcinosis cutis has a wide spectrum of clinical presentations. Fine needle aspiration cytology is a minimally invasive approach for diagnosing calcinosis cutis, thus eliminating the need for more extensive biopsy procedures.

Cerebrospinal fluid infiltration by chronic myeloid leukaemia: Evaluation of cytomorphological features.

BACKGROUND AND AIM: To describe the cytomorphological findings of all cerebrospinal fluid (CSF) cytology samples showing infiltration by chronic myeloid leukaemia (CML) and their correlation with haematological findings. MATERIALS AND METHODS: A retrospective analysis of all CSF samples reported as showing infiltration by CML on cytology from January 2014 to December 2021 was performed. RESULTS: A total of 10 cases with positive CSF cytology were evaluated. The mean age of the patients was 34.1 years (range 17-70 years). There were more males than females. All cases were pre-diagnosed cases of CML on haematological investigations. On cytology, the smears showed atypical/immature blast-like cells, with a high nucleo-cytoplasmic ratio, opened-up chromatin, 1-2 conspicuous nucleoli and a scant to moderate amount of agranular to fine granular cytoplasm along with occasional granulocytic precursors. The shortest time interval for CSF positivity in a known case of CML was 5 months, and the longest interval was 11 years. CONCLUSION: It is extremely uncommon to encounter CML infiltration in CSF. Timely analysis of CSF cytology samples can allow quick diagnosis and alter the patient management protocol.

Cystic hepatic metastases in treatment naïve neuroendocrine tumor: Cytomorphology clubbed with cell block immunocytochemistry clinches the diagnosis.

Cystic hepatic lesions encompass a vast spectrum of infectious, non-neoplastic, and neoplastic entities. Most hepatic cysts are benign and asymptomatic, requiring no active intervention. However, symptomatic and malignant cysts need proper evaluation and specific treatment. An accurate preoperative diagnosis is pivotal for patient management. At times, these lesions may mimic, especially symptomatology and radiology, leading to a diagnostic ordeal. We herein present a case of a patient with cystic liver lesions in a treatment naïve neuroendocrine tumor that was a diagnostic dilemma on radiology. Low cellularity of cytology smears made the diagnosis challenging, and cell block immunocytochemistry finally clinched the diagnosis. A timely diagnosis provided on cytology fuelled further work-up, the discovery of primary tumor, and initiation of appropriate therapy.

Scalp metastasis of pulmonary blastoma-a rare entity: Cytomorphology with differential diagnoses.

BACKGROUND: Pulmonary blastomas are exceptionally rare tumours. These tumours behave aggressively, with a propensity to metastasise to the brain and mediastinum. A definitive diagnosis of pulmonary blastoma is challenging to obtain on cytomorphology alone. CASE REPORT: We herein describe a case of a 59-year-old female who presented with a scalp lesion. The patient was diagnosed to have pulmonary blastoma on histopathology of left lower lobectomy specimen. Fine needle aspiration cytology was done from this recently developed scalp swelling. Cytomorphology supplemented with immunocytochemistry on cell block confirmed the diagnosis of a metastatic pulmonary blastoma. CONCLUSIONS: In a known case of primary pulmonary blastoma, any newly developing lesion at any anatomical site should be carefully evaluated for metastasis. If metastasis is needled and no previous histology is available, it carries a reasonable risk of erroneous interpretation. It is essential not to overlook often subtle biphasic malignant cells on the smears, which otherwise resemble other poorly differentiated tumours. Immunocytochemistry coupled with morphology is confirmatory.

Breast filariasis masquerading as carcinoma: Cytologic diagnosis in two cases.

Filariasis is a common public health problem in the Indian subcontinent. Microfilariae are usually detected in the peripheral circulation; however, the clinical manifestations are related to the lymphatic system primarily. The breast is an uncommon site for filariasis, and the lesion clinically mimics malignancy. We should consider filariasis in the differential diagnoses of breast lumps, especially in endemic areas. Fine-needle aspiration cytology from the breast lump allows easy detection of filarial infection, and this can be managed by medical treatment, thereby avoiding surgical procedures.

Sequential small cell transformation and T790M mutation in an epidermal growth factor-mutant lung adenocarcinoma: A rare occurrence with significant management implications.

BACKGROUND: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) resistance may be acquired via genotypic and/or phenotypic transformations. Herein, we report an extremely uncommon case with sequential small cell transformation and EGFR T790M mutation, in an elderly female with EGFR exon 21 L858R-mutant lung adenocarcinoma, following treatment with a first-generation EGFR-TKI. CASE: A 67-year-old female never-smoker presented with a cough and dyspnoea of 2 months' duration. Computerised tomography revealed a 39 mm lesion in the upper lobe of the right lung with pleural effusion. Pleural fluid cytology revealed metastatic lung adenocarcinoma, and EGFR testing revealed exon 21 L858R mutation. She was started on gefitinib. After a progression-free survival of 31 months, she presented with disease progression and multiple extra-thoracic metastases. Fine needle aspiration cytology of a chest wall lesion revealed metastatic small cell carcinoma. EGFR testing on this aspirate revealed persistent L858R mutation only. In view of small cell transformation, chemotherapy (etoposide and carboplatin) was administered. After 4 months, ascitic fluid cytology revealed metastatic adenocarcinoma with persistent L858R mutation and an acquired T790M mutation (both detected on liquid biopsy as well) indicating amplification of the adenocarcinoma clone and regression of the small cell carcinoma clone. She was then initiated on osimertinib. CONCLUSIONS: The index case highlights the significance of serial EGFR genotyping along with repeated tissue and/or blood sampling in the prompt detection of genetic and phenotypic resistance mechanisms to EGFR-TKIs. Furthermore, it lends evidence in support of the upfront treatment approaches targeting the heterogeneity of acquired EGFR-TKI resistance mechanisms.

Cytomorphological spectrum of solitary fibrous tumour: revisited.

BACKGROUND: Solitary fibrous tumour (SFT) is a tumour of mesenchymal origin. Its diagnosis on cytology is challenging, owing to variation in cellularity, sparsely distributed cellular and stromal components. Cytomorphological findings for this type of tumour have rarely been described in the literature-only a few case reports and the occasional case series have been presented thus far. We present the cytomorphological features of SFT with special emphasis on immunochemical findings. MATERIALS AND METHODS: We present cytological data from eight cases of histopathologically proven SFTs. The cytomorphological features, immunochemical markers and differential diagnostic entities on fine needle aspiration cytology are discussed. RESULTS: Fine needle aspiration was performed at various anatomical sites. Cytology smears showed variable cellularity, with tumour cells arranged in loose clusters and as singly scattered cells. Interlacing fascicles with palisading of cells was noted. The cells were predominantly spindle to elongated, having moderate cytoplasm with elongated wavy nuclei. These nuclei had fine to coarse chromatin, with inconspicuous to prominent nucleoli. There was prominent, metachromatically staining, amorphous to fibrillary, collagenous to myxoid matrix material associated with the tumour cells. Other findings included intranuclear pseudo-inclusions, multinucleated giant cells and atypical mitoses. Cytological diagnoses offered varied from 'spindle cell neoplasm' to 'spindle cell sarcoma' or 'suggestive of sarcoma'. Immunocytochemistry (ICC) performed on cell block sections showed positivity for STAT6, CD34 and Bcl-2. CONCLUSION: Cytological diagnosis of SFT can be challenging. A careful search for characteristic cytomorphological features is diagnostically helpful. The cytomorphology should be interpreted with caution, with an appropriate ICC panel, including STAT6 and CD34.

Cytopathology of the distant metastasis of papillary carcinoma of thyroid.

AIMS: To describe the cytomorphological features at distant metastatic sites apart from lymph nodes in papillary thyroid carcinoma (PTC). MATERIALS AND METHODS: A total of eight cytology cases from seven patients reported as metastatic papillary carcinoma of thyroid were reviewed including available clinical and radiological details. The details clinical and cytological features were studied. RESULTS: There were a total of five males and two female patients. Two of these patients presented with lung nodules, two patients had bony lesion and lesion in kidney respectively and one patient had both bony and soft tissue lesions. Pleural fluid and bronchoalveolar lavage were received from remaining two patients. Cytology smears revealed papillary clusters and sheets of tumor cells, having round to oval nuclei with pale powdery chromatin, inconspicuous nucleoli and scant to moderate amount of cytoplasm. Nuclear features such as longitudinal nuclear grooves, intranuclear cytoplasmic inclusions were seen in all but one case. Nuclear enlargement and overlapping were variably present. CONCLUSIONS: The diagnosis of metastatic PTC at uncommon locations is difficult. Since many of these locations are amenable to fine needle aspiration or exfoliative cytology evaluation, clinical awareness, and identification of classic cytomorphologic features can offer quick and accurate diagnoses. In cases with occult or unknown PTC presenting with metastases, cytomorphology may help in the prompt suggestion of detecting primary tumor in the thyroid.

Massive swelling of the thyroid in a young patient.

Extraskeletal Ewing sarcoma (EES) in the thyroid is extremely rare. This report describes a rare case of EES in thyroid gland in an 18 year female, diagnosed on fine needle aspiration cytology (FNAC).

Plentiful melanin pigment containing histiocyte-like cells in Coats disease: Awareness avoids diagnostic pitfall.

Coats disease is an exudative retinal vasculopathy characterised by presence of yellow-golden deposits in the retina and retinal detachment. Subretinal fluid drainage performed as a part of therapeutic management makes the fluid amenable to cytological examination. Infection by Toxoplasma may closely simulate the ocular symptoms seen in Coats disease. Awareness of the cytological findings in Coats disease helps to clinch accurate diagnosis. We herein present a case of Coats disease with many histiocyte-like cells with plentiful intracytoplasmic melanin pigment in cytology smears from subretinal fluid, where cytological diagnosis was challenging and a correct diagnosis was made with the aid of ancillary techniques.

Fine needle aspiration cytology of a space-occupying lesion in the lung.

This case discussion describes the fine needle aspiration cytology of a lung lesion with frequent intranuclear inclusions and grooves and outlines how a robust final diagnosis can be made.

Conjunctival Amyloidosis: A Report of Two Cases with Review of Literature - 2000-2020.

Amyloidosis is a complex multisystem disorder characterized by deposition of an aberrant protein in tissues and results in disruption of the normal organ function. Localized amyloidosis is a rare disorder. It commonly affects the head-and-neck region, and only 4% of these lesions are encountered in the orbital region. Hence, conjunctival amyloidosis is a very rare entity. It is thought to be a manifestation of local immunologic disorders. Amyloidosis of conjunctiva is more often localized with no other systemic features. Here, we present two cases of unilateral conjunctival amyloidosis, one with extensive calcification. Conjunctival amyloidosis must be considered in the differential diagnosis of conjunctival neoplasms. Histopathological examination and apple-green birefringence on polarized microscopy with Congo red stain remain the gold standard for diagnosing this entity.

Cytodiagnosis of giant cell tumour presenting at unusual age and site with review of literature.

Giant cell tumour (GCT), also known as osteoclastoma, is an osteolytic tumour. It involves the epiphyseal and metaphyseal regions of long bones in adults. On rare occasions, these may occur in paediatric patients, and may involve uncommon locations such as the sternum, pelvis and, particularly infrequently, rib bones. We present a rare case of GCT in the rib of a child, diagnosed on fine needle aspiration.

Cerebrospinal fluid cytology in a toddler with a posterior fossa space-occupying lesion.

An atypical teratoid rhabdoid tumour (AT/RT) is an extremely rare malignant neoplasm. Cerebrospinal fluid (CSF) involvement at presentation indicates intracranial dissemination and is associated with an aggressive course and worse outcomes. We present the characteristic cytomorphological features of AT/RT in the cerebrospinal fluid from a toddler presenting with a posterior fossa space-occupying lesion.